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1.
Mol Cell ; 83(16): 2884-2895.e7, 2023 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-37536340

RESUMEN

DNA replication ensures the accurate transmission of genetic information during the cell cycle. Histone variant H2A.Z is crucial for early replication origins licensing and activation in which SUV420H1 preferentially recognizes H2A.Z-nucleosome and deposits H4 lysine 20 dimethylation (H4K20me2) on replication origins. Here, we report the cryo-EM structures of SUV420H1 bound to H2A.Z-nucleosome or H2A-nucleosome and demonstrate that SUV420H1 directly interacts with H4 N-terminal tail, the DNA, and the acidic patch in the nucleosome. The H4 (1-24) forms a lasso-shaped structure that stabilizes the SUV420H1-nucleosome complex and precisely projects the H4K20 residue into the SUV420H1 catalytic center. In vitro and in vivo analyses reveal a crucial role of the SUV420H1 KR loop (residues 214-223), which lies close to the H2A.Z-specific residues D97/S98, in H2A.Z-nucleosome preferential recognition. Together, our findings elucidate how SUV420H1 recognizes nucleosomes to ensure site-specific H4K20me2 modification and provide insights into how SUV420H1 preferentially recognizes H2A.Z nucleosome.


Asunto(s)
Histonas , Nucleosomas , Histonas/metabolismo , Nucleosomas/genética , Metilación , ADN/metabolismo , Replicación del ADN
2.
Genes Dev ; 35(23-24): 1610-1624, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34819355

RESUMEN

Chromosomal duplication requires de novo assembly of nucleosomes from newly synthesized histones, and the process involves a dynamic network of interactions between histones and histone chaperones. sNASP and ASF1 are two major histone H3-H4 chaperones found in distinct and common complexes, yet how sNASP binds H3-H4 in the presence and absence of ASF1 remains unclear. Here we show that, in the presence of ASF1, sNASP principally recognizes a partially unfolded Nα region of histone H3, and in the absence of ASF1, an additional sNASP binding site becomes available in the core domain of the H3-H4 complex. Our study also implicates a critical role of the C-terminal tail of H4 in the transfer of H3-H4 between sNASP and ASF1 and the coiled-coil domain of sNASP in nucleosome assembly. These findings provide mechanistic insights into coordinated histone binding and transfer by histone chaperones.


Asunto(s)
Chaperonas de Histonas , Histonas , Sitios de Unión , Proteínas de Ciclo Celular/metabolismo , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Nucleosomas , Unión Proteica
3.
Nature ; 593(7857): 56-60, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33953409

RESUMEN

Exciting phenomena may emerge in non-centrosymmetric two-dimensional electronic systems when spin-orbit coupling (SOC)1 interplays dynamically with Coulomb interactions2,3, band topology4,5 and external modulating forces6-8. Here we report synergetic effects between SOC and the Stark effect in centrosymmetric few-layer black arsenic, which manifest as particle-hole asymmetric Rashba valley formation and exotic quantum Hall states that are reversibly controlled by electrostatic gating. The unusual findings are rooted in the puckering square lattice of black arsenic, in which heavy 4p orbitals form a Brillouin zone-centred Γ valley with pz symmetry, coexisting with doubly degenerate D valleys of px origin near the time-reversal-invariant momenta of the X points. When a perpendicular electric field breaks the structure inversion symmetry, strong Rashba SOC is activated for the px bands, which produces spin-valley-flavoured D± valleys paired by time-reversal symmetry, whereas Rashba splitting of the Γ valley is constrained by the pz symmetry. Intriguingly, the giant Stark effect shows the same px-orbital selectiveness, collectively shifting the valence band maximum of the D± Rashba valleys to exceed the Γ Rashba top. Such an orchestrating effect allows us to realize gate-tunable Rashba valley manipulations for two-dimensional hole gases, hallmarked by unconventional even-to-odd transitions in quantum Hall states due to the formation of a flavour-dependent Landau level spectrum. For two-dimensional electron gases, the quantization of the Γ Rashba valley is characterized by peculiar density-dependent transitions in the band topology from trivial parabolic pockets to helical Dirac fermions.

4.
Acc Chem Res ; 57(8): 1149-1162, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38547518

RESUMEN

ConspectusTransition metal-catalyzed reductive cross-coupling of two carbon electrophiles, also known as cross-electrophile coupling (XEC), has transformed the landscape of C-C coupling chemistry. Nickel catalysts, in particular, have demonstrated exceptional performance in facilitating XEC reactions, allowing for diverse elegant transformations by employing various electrophiles to forge C-C bonds. Nevertheless, several crucial challenges remain to be addressed. First, the intrinsic chemoselectivity between two structurally similar electrophiles in Ni-catalyzed C(sp3)-C(sp3) and C(sp2)-C(sp2) cross-coupling has not been well understood; this necessitates an excess of one of the coupling partners to achieve synthetically useful outcomes. Second, the substitution of economically and environmentally benign nonmetal reductants for Zn/Mn can help scale up XEC reactions and avoid trace metals in pharmaceutical products, but research in this direction has progressed slowly. Finally, it is highly warranted to leverage mechanistic insights from Ni-catalyzed XEC to develop innovative thermoredox coupling protocols, specifically designed to tackle challenges associated with difficult substrates such as C(sp3)-H bonds and unactivated alkenes.In this Account, we address the aforementioned issues by reviewing our recent work on the reductive coupling of C-X and C-O electrophiles, the thermoredox strategy for coupling associated with C(sp3)-H bonds and unactivated alkenes, and the use of diboron esters as nonmetal reductants to achieve reductive coupling. We focus on the mechanistic perspectives of the transformations, particularly how the key C-NiIII-C intermediates are generated, in order to explain the chemoselective and regioselective coupling results. The Account consists of four sections. First, we discuss the Zn/Mn-mediated chemoselective C(sp2)-C(sp2) and C(sp3)-C(sp3) bond formations based on the coupling of selected alkyl/aryl, allyl/benzyl, and other electrophiles. Second, we describe the use of diboron esters as versatile reductants to achieve C(sp3)-C(sp3) and C(sp3)-C(sp2) couplings, with an emphasis on the mechanistic consideration for the construction of C(sp3)-C(sp2) bonds. Third, we discuss leveraging C(sp3)-O bonds for effective C(sp3)-C bond formation via in situ halogenation of alcohols as well as the reductive preparation of α-vinylated and -arylated unusual amino esters. In the final section, we illustrate the thermoredox functionalization of challenging C(sp3)-H bonds with aryl and alkyl halides to afford C(sp3)-C bonds by taking advantage of the compatibility of Zn with the oxidant di-tert-butylperoxide (DTBP). Furthermore, we discuss a Ni-catalyzed and SiH/DTBP-mediated hydrodimerization of terminal alkenes to selectively forge head-to-head and methyl branched C(sp3)-C(sp3) bonds. This process, conducted in the presence or absence of catalytic CuBr2, provides a solution to a long-standing challenge: site-selective hydrocoupling of unactivated alkenes to produce challenging C(sp3)-C(sp3) bonds.

5.
Cereb Cortex ; 34(5)2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38725291

RESUMEN

A widely used psychotherapeutic treatment for post-traumatic stress disorder (PTSD) involves performing bilateral eye movement (EM) during trauma memory retrieval. However, how this treatment-described as eye movement desensitization and reprocessing (EMDR)-alleviates trauma-related symptoms is unclear. While conventional theories suggest that bilateral EM interferes with concurrently retrieved trauma memories by taxing the limited working memory resources, here, we propose that bilateral EM actually facilitates information processing. In two EEG experiments, we replicated the bilateral EM procedure of EMDR, having participants engaging in continuous bilateral EM or receiving bilateral sensory stimulation (BS) as a control while retrieving short- or long-term memory. During EM or BS, we presented bystander images or memory cues to probe neural representations of perceptual and memory information. Multivariate pattern analysis of the EEG signals revealed that bilateral EM enhanced neural representations of simultaneously processed perceptual and memory information. This enhancement was accompanied by heightened visual responses and increased neural excitability in the occipital region. Furthermore, bilateral EM increased information transmission from the occipital to the frontoparietal region, indicating facilitated information transition from low-level perceptual representation to high-level memory representation. These findings argue for theories that emphasize information facilitation rather than disruption in the EMDR treatment.


Asunto(s)
Electroencefalografía , Desensibilización y Reprocesamiento del Movimiento Ocular , Humanos , Femenino , Masculino , Adulto Joven , Adulto , Desensibilización y Reprocesamiento del Movimiento Ocular/métodos , Movimientos Oculares/fisiología , Trastornos por Estrés Postraumático/fisiopatología , Trastornos por Estrés Postraumático/terapia , Trastornos por Estrés Postraumático/psicología , Percepción Visual/fisiología , Memoria/fisiología , Encéfalo/fisiología , Estimulación Luminosa/métodos , Memoria a Corto Plazo/fisiología
6.
Proc Natl Acad Sci U S A ; 119(49): e2209078119, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36445964

RESUMEN

In the history of humanity, most conflicts within and between societies have originated from perceived inequality in resource distribution. How humans achieve and maintain distributive justice has therefore been an intensely studied issue. However, most research on the corresponding psychological processes has focused on inequality aversion and has been largely agnostic of other motives that may either align or oppose this behavioral tendency. Here we provide behavioral, computational, and neuroimaging evidence that distribution decisions are guided by three distinct motives-inequality aversion, harm aversion, and rank reversal aversion-that interact with each other and can also deter individuals from pursuing equality. At the neural level, we show that these three motives are encoded by separate neural systems, compete for representation in various brain areas processing equality and harm signals, and are integrated in the striatum, which functions as a crucial hub for translating the motives to behavior. Our findings provide a comprehensive framework for understanding the cognitive and biological processes by which multiple prosocial motives are coordinated in the brain to guide redistribution behaviors. This framework enhances our understanding of the brain mechanisms underlying equality-related behavior, suggests possible neural origins of individual differences in social preferences, and provides a new pathway to understand the cognitive and neural basis of clinical disorders with impaired social functions.


Asunto(s)
Motivación , Justicia Social , Humanos , Encéfalo , Humanidades , Afecto
7.
BMC Bioinformatics ; 25(1): 183, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724908

RESUMEN

BACKGROUND: In recent years, gene clustering analysis has become a widely used tool for studying gene functions, efficiently categorizing genes with similar expression patterns to aid in identifying gene functions. Caenorhabditis elegans is commonly used in embryonic research due to its consistent cell lineage from fertilized egg to adulthood. Biologists use 4D confocal imaging to observe gene expression dynamics at the single-cell level. However, on one hand, the observed tree-shaped time-series datasets have characteristics such as non-pairwise data points between different individuals. On the other hand, the influence of cell type heterogeneity should also be considered during clustering, aiming to obtain more biologically significant clustering results. RESULTS: A biclustering model is proposed for tree-shaped single-cell gene expression data of Caenorhabditis elegans. Detailedly, a tree-shaped piecewise polynomial function is first employed to fit non-pairwise gene expression time series data. Then, four factors are considered in the objective function, including Pearson correlation coefficients capturing gene correlations, p-values from the Kolmogorov-Smirnov test measuring the similarity between cells, as well as gene expression size and bicluster overlapping size. After that, Genetic Algorithm is utilized to optimize the function. CONCLUSION: The results on the small-scale dataset analysis validate the feasibility and effectiveness of our model and are superior to existing classical biclustering models. Besides, gene enrichment analysis is employed to assess the results on the complete real dataset analysis, confirming that the discovered biclustering results hold significant biological relevance.


Asunto(s)
Caenorhabditis elegans , Análisis de la Célula Individual , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Animales , Análisis de la Célula Individual/métodos , Análisis por Conglomerados , Perfilación de la Expresión Génica/métodos , Algoritmos
8.
J Cell Mol Med ; 28(11): e18370, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38818568

RESUMEN

The Finkel-Biskis-Jinkins Osteosarcoma (c-Fos; encoded by FOS) plays an important role in several cardiovascular diseases, including atherosclerosis and stroke. However, the relationship between FOS and venous thromboembolism (VTE) remains unknown. We identified differentially expressed genes in Gene Expression Omnibus dataset, GSE48000, comprising VTE patients and healthy individuals, and analysed them using CIBERSORT and weighted co-expression network analysis (WGCNA). FOS and CD46 expressions were significantly downregulated (FOS p = 2.26E-05, CD64 p = 8.83E-05) and strongly linked to neutrophil activity in VTE. We used GSE19151 and performed PCR to confirm that FOS and CD46 had diagnostic potential for VTE; however, only FOS showed differential expression by PCR and ELISA in whole blood samples. Moreover, we found that hsa-miR-144 which regulates FOS expression was significantly upregulated in VTE. Furthermore, FOS expression was significantly downregulated in neutrophils of VTE patients (p = 0.03). RNA sequencing performed on whole blood samples of VTE patients showed that FOS exerted its effects in VTE via the leptin-mediated adipokine signalling pathway. Our results suggest that FOS and related genes or proteins can outperform traditional clinical markers and may be used as diagnostic biomarkers for VTE.


Asunto(s)
Biología Computacional , MicroARNs , Neutrófilos , Proteínas Proto-Oncogénicas c-fos , Tromboembolia Venosa , Humanos , MicroARNs/genética , MicroARNs/sangre , MicroARNs/metabolismo , Neutrófilos/metabolismo , Tromboembolia Venosa/genética , Tromboembolia Venosa/metabolismo , Tromboembolia Venosa/sangre , Biología Computacional/métodos , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Regulación de la Expresión Génica , Masculino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Femenino , Biomarcadores/sangre , Biomarcadores/metabolismo
9.
Cancer Immunol Immunother ; 73(8): 140, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833011

RESUMEN

OBJECTIVES: To investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP). RESULTS: Among the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0-53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40-0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30-0.79, p < 0.0001). CONCLUSION: ORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Femenino , Persona de Mediana Edad , Anciano , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Neoplasia Residual , Antígeno B7-H1/antagonistas & inhibidores , Anciano de 80 o más Años , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Incidencia , Metástasis de la Neoplasia , Estudios de Seguimiento , Estudios Retrospectivos
10.
Magn Reson Med ; 91(3): 886-895, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38010083

RESUMEN

PURPOSE: Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. METHODS: The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. RESULTS: Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. CONCLUSION: The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.


Asunto(s)
Neoplasias Encefálicas , Ácido Láctico , Humanos , Espectroscopía de Resonancia Magnética/métodos , Fantasmas de Imagen , Neoplasias Encefálicas/diagnóstico por imagen , Treonina
11.
J Med Virol ; 96(2): e29439, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38294104

RESUMEN

Hepatitis B virus (HBV) infection is a serious global health problem. After the viruses infect the human body, the host can respond to the virus infection by coordinating various cellular responses, in which mitochondria play an important role. Evidence has shown that mitochondrial proteins are involved in host antiviral responses. In this study, we found that the overexpression of TIM22 and TIM29, the members of the inner membrane translocase TIM22 complex, significantly reduced the level of intracellular HBV DNA and RNA and secreted HBV surface antigens and E antigen. The effects of TIM22 and TIM29 on HBV replication and transcription is attributed to the reduction of core promoter activity mediated by the increased expression of SRSF1 which acts as a suppressor of HBV replication. This study provides new evidence for the critical role of mitochondria in the resistance of HBV infection and new targets for the development of treatment against HBV infection.


Asunto(s)
Virus de la Hepatitis B , Hepatitis B , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Factores de Empalme Serina-Arginina , Humanos , Antígenos e de la Hepatitis B/genética , Antígenos e de la Hepatitis B/metabolismo , Antígenos de Superficie de la Hepatitis B/metabolismo , Virus de la Hepatitis B/fisiología , Factores de Empalme Serina-Arginina/metabolismo , Replicación Viral , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales/metabolismo
12.
Opt Express ; 32(11): 19626-19644, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38859093

RESUMEN

X-ray mirrors, which are essential for constructing synchrotron radiation light sources, are highly required for full-range spatial wavelength errors. This paper investigated power-law non-Newtonian fluids and pointed out that both three-body removal and shear removal existed in the shear thickening polishing process. Subsequently, this paper calculates the shear force of the power-law non-Newtonian fluid polishing fluid in polishing the surface with different frequency errors. It establishes an MRR model of shear thickening polishing in the frequency domain by combining it with the Archard equation. Then, this model is also applied to optimize the polishing fluid formulation and processing parameters. Finally, the removal effect of the optimized polishing fluid on the mid-frequency ripple error is experimentally verified. On Ф50 mm monocrystalline silicon, the removal of mid-frequency ripple error with a spatial wavelength of 1 mm was achieved by shear thickening polishing technique while converging the surface roughness to 0.14 nm. Finally, the experimental results were applied to monocrystalline silicon with a length of 500 mm. This work provides a new research idea for the existing shear thickening polishing process. It provides theoretical and technical support for removing the mid- and high-frequency errors in high-precision X-ray mirrors.

13.
J Nutr ; 154(2): 535-542, 2024 02.
Artículo en Inglés | MEDLINE | ID: mdl-38072153

RESUMEN

BACKGROUND: Intrauterine growth restriction (IUGR) resulted in high mortality and many physiological defects of piglets, causing huge economic loss in the swine industry. Lactobacillus amylovorus (L. amylovorus) was identified as one of the main differential bacteria between IUGR and normal piglets. However, the effects of L. amylovorus on the growth performance and intestinal health in IUGR piglets remained unclear. OBJECTIVES: This study aimed to investigate the promoting effects of L. amylovorus Mafic1501, a new strain isolated from normal piglets, on the growth performance and intestinal barrier functions in IUGR piglets. METHODS: Newborn mice or piglets were assigned into 3 groups: CON (normal birth weight, control), IUGR (low birth weight), and IUGR+L. amy (low birth weight), administered with sterile saline or L. amylovorus Mafic1501, respectively. Growth performance, lactose content in the digesta, intestinal lactose transporter, and barrier function parameters were profiled. IPEC-J2 cells were cultured to verify the effects of L. amylovorus Mafic1501 on lactose utilization and intestinal barrier functions. RESULTS: L. amylovorus Mafic1501 elevated body weight and average daily gain of IUGR mice and piglets (P < 0.05). The lactose content in the ileum was decreased, whereas gene expression of glucose transporter 2 (GLUT2) was increased by L. amylovorus Mafic1501 in IUGR piglets during suckling period (P < 0.05). Besides, L. amylovorus Mafic1501 promoted intestinal barrier functions by increasing the villus height and relative gene expressions of tight junctions (P < 0.05). L. amylovorus Mafic1501 and its culture supernatant decreased the lactose level in the medium and upregulated gene expressions of transporter GLUT2 and tight junction protein Claudin-1 of IPEC-J2 cells (P < 0.05). CONCLUSION: L. amylovorus Mafic1501 improved the growth performance of IUGR piglets by promoting the lactose utilization in small intestine and enhancing intestinal barrier functions. Our results provided the new evidence of L. amylovorus Mafic1501 for its application in the swine industry.


Asunto(s)
Retardo del Crecimiento Fetal , Lactobacillus acidophilus , Femenino , Humanos , Animales , Porcinos , Ratones , Retardo del Crecimiento Fetal/metabolismo , Lactosa/farmacología , Lactosa/metabolismo , Peso al Nacer , Funcion de la Barrera Intestinal , Intestino Delgado/metabolismo , Animales Recién Nacidos
14.
Langmuir ; 40(18): 9761-9774, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38663878

RESUMEN

Stimuli-responsive behaviors and controlled release in liposomes are pivotal in nanomedicine. To this end, we present an approach using a photoresponsive azobenzene nanocluster (AzDmpNC), prepared from azobenzene compounds through melting and aggregation. When integrated with liposomes, they form photoresponsive vesicles. The morphology and association with liposomes were investigated by using transmission electron microscopy. Liposomes loaded with calcein exhibited a 9.58% increased release after UV exposure. To gain insights into the underlying processes and elucidate the mechanisms involved. The molecular dynamic simulations based on the reactive force field and all-atom force field were employed to analyze the aggregation of isomers into nanoclusters and their impacts on phospholipid membranes, respectively. The results indicate that the nanoclusters primarily aggregate through π-π and T-stacking forces. The force density inside the cis-isomer of AzDmpNC formed after photoisomerization is lower, leading to its easier dispersion, rapid diffusion, and penetration into the membrane, disrupting the densification.


Asunto(s)
Compuestos Azo , Liposomas , Simulación de Dinámica Molecular , Compuestos Azo/química , Compuestos Azo/efectos de la radiación , Liposomas/química , Nanopartículas/química , Rayos Ultravioleta , Fluoresceínas/química , Procesos Fotoquímicos
15.
Anticancer Drugs ; 35(1): 55-62, 2024 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-37823256

RESUMEN

Sorafenib has been approved for advance hepatocellular carcinoma (HCC), however, drug resistance often occurred. Therefore, it is of great significance to clarify the underlying mechanisms of sorafenib resistance and to find out the effective strategies to overcome sorafenib resistance. The expression of HCG18 was detected by qPCR, MTT, colony formation, flow cytometry and TUNEL assay were used to explore the function of HCG18 on sorafenib resistance in HCC. RNA pull-down, RNA immunoprecipitation, immunofluorescence labeling, luciferase reporter assay, western blot and qPCR were used to investigate the mechanism of HCG18 regulating sorafenib resistance in HCC. Our results showed that HCG18 was significantly increased in HCC, which resulted in shorter 5-year survival for patients with HCC. Sorafenib can induce the expression of HCG18, suggesting HCG18 might be involved in sorafenib resistance in HCC. Further analysis showed that knockdown of HCG18 can reduce viability and increase apoptosis of HCC cells. Mechanistically, HCG18 can bind to USP15, further regulated the protein stability of p65, TAB2 and TAB3, and nuclear location of p65, which finally modulated the NF-κB signaling. Our findings showed that HCG18 played an important role in sorafenib resistance in HCC. And knockdown of HCG18 can promote the sensitivity of HCC cells to sorafenib, inferring that targeting HCG18 might be an effective strategy to overcome sorafenib resistance in HCC.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Sorafenib/farmacología , Neoplasias Hepáticas/genética , Resistencia a Antineoplásicos , ARN/farmacología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismo , Proteasas Ubiquitina-Específicas/farmacología
16.
Circ Res ; 131(7): 601-615, 2022 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-36052690

RESUMEN

BACKGROUND: Racial differences in metabolomic profiles may reflect underlying differences in social determinants of health by self-reported race and may be related to racial disparities in coronary heart disease (CHD) among women in the United States. However, the magnitude of differences in metabolomic profiles between Black and White women in the United States has not been well-described. It also remains unknown whether such differences are related to differences in CHD risk. METHODS: Plasma metabolomic profiles were analyzed using liquid chromatography-tandem mass spectrometry in the WHI-OS (Women's Health Initiative-Observational Study; 138 Black and 696 White women), WHI-HT trials (WHI-Hormone Therapy; 156 Black and 1138 White women), MESA (Multi-Ethnic Study of Atherosclerosis; 114 Black and 219 White women), JHS (Jackson Heart Study; 1465 Black women with 107 incident CHD cases), and NHS (Nurses' Health Study; 2506 White women with 136 incident CHD cases). First, linear regression models were used to estimate associations between self-reported race and 472 metabolites in WHI-OS (discovery); findings were replicated in WHI-HT and validated in MESA. Second, we used elastic net regression to construct a racial difference metabolomic pattern (RDMP) representing differences in the metabolomic patterns between Black and White women in the WHI-OS; the RDMP was validated in the WHI-HT and MESA. Third, using conditional logistic regressions in the WHI (717 CHD cases and 719 matched controls), we examined associations of metabolites with large differences in levels by race and the RDMP with risk of CHD, and the results were replicated in Black women from the JHS and White women from the NHS. RESULTS: Of the 472 tested metabolites, levels of 259 (54.9%) metabolites, mostly lipid metabolites and amino acids, significantly differed between Black and White women in both WHI-OS and WHI-HT after adjusting for baseline characteristics, socioeconomic status, lifestyle factors, baseline health conditions, and medication use (false discovery rate <0.05); similar trends were observed in MESA. The RDMP, composed of 152 metabolites, was identified in the WHI-OS and showed significantly different distributions between Black and White women in the WHI-HT and MESA. Higher RDMP quartiles were associated with an increased risk of incident CHD (odds ratio=1.51 [0.97-2.37] for the highest quartile comparing to the lowest; Ptrend=0.02), independent of self-reported race and known CHD risk factors. In race-stratified analyses, the RDMP-CHD associations were more pronounced in White women. Similar patterns were observed in Black women from the JHS and White women from the NHS. CONCLUSIONS: Metabolomic profiles significantly and substantially differ between Black and White women and may be associated with CHD risk and racial disparities in US women.


Asunto(s)
Enfermedad Coronaria , Aminoácidos , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/epidemiología , Femenino , Hormonas , Humanos , Lípidos , Factores de Riesgo , Estados Unidos/epidemiología
17.
Biomacromolecules ; 25(2): 729-740, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38263676

RESUMEN

Intervertebral disk degeneration is a common disease with an unknown etiology. Currently, tissue engineering is considered to be an important method for intervertebral disk repair. Although transplanted stem cells may disrupt the repair process because of apoptosis caused by the oxidative microenvironment. Herein, bone marrow mesenchymal stem cell (BMSC) and Neochlorogenic acid (Ncg) were encapsulated into a GelMA hydrogel as a carrier to protect transplanted stem cells. Ncg effectively inhibited the oxidative stress process and reduced the apoptosis rate. A 5% GelMA hydrogel had a large pore size and porosity that provided an enhanced survival space for cells. An in vivo assessment showed that treatment with GelMA + BMSC + Ncg produced greater repair of degenerated intervertebral disks than that found in other model groups. Thus, this study may help contribute to improving stem cell transplantation for treating intervertebral disk degeneration.


Asunto(s)
Ácido Clorogénico/análogos & derivados , Degeneración del Disco Intervertebral , Disco Intervertebral , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Ácido Quínico/análogos & derivados , Humanos , Degeneración del Disco Intervertebral/terapia , Hidrogeles/farmacología , Trasplante de Células Madre Mesenquimatosas/métodos , Células de la Médula Ósea
18.
Lupus ; 33(2): 155-165, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38182135

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex autoimmune connective tissue disease (CTD) that is an important cause of devastating pulmonary arterial hypertension (PAH), and persistent progression of PAH can lead to right heart failure, predicting a poor prognosis for SLE patients. Right ventricular-pulmonary arterial (RV-PA) coupling with echocardiography has been demonstrated to be a noninvasive alternative method for evaluating PAH patients' predictive outcomes. Whether the ratio of right ventricular stroke volume (RVSV) to right ventricular end-systolic volume (RVESV) measured by three-dimensional echocardiography (3DE) is a new index of RV-PA coupling has not been discussed as a new predictor for the clinical outcome of systemic lupus erythematosus-associated pulmonary arterial hypertension (SLE-PAH). METHODS: From June 2019 to February 2023, 46 consecutive patients with SLE-PAH were enrolled prospectively, and their clinical data and echocardiographs were studied and analyzed. The control group consisted of 30 healthy subjects matched for age, sex, and body surface area (BSA). The main endpoints of this study were a composite of all-cause mortality and adverse clinical events. Baseline clinical characteristics and echocardiographic assessments were analyzed. RESULTS: During a median of 24 months (IQR 18-31), 16 of 46 SLE-PAH patients (34.7%) experienced endpoint-related events. At baseline, patients who experienced mortality or adverse events had a worse WHO functional class (WHO FC) and lower anti-double-stranded DNA (dsDNA) antibody levels. The right ventricular (RV) systolic dysfunction in SLE-PAH subjects was significantly worse than that in the healthy control group, especially in SLE-PAH patients in the endpoint event group. Compared to controls, patients with SLE-PAH had a lower RVSV/RVESV ratio. In the group comparison, patients who had experienced an endpoint event had a sequentially worse ratio (1.86 (1.65-2.3) versus 1.30 (1.09-1.46) versus 0.64 (0.59-0.67), p < .001). There were statistically significant associations between the RVSV/RVESV ratio to routine RV systolic function and clinical parameters. The RVSV/RVESV ratio was negatively correlated with the WHO FC (r = -0.621, p < .001) and positively correlated with the anti-dsDNA level. The ROC curve showed that the optimal cutoff for RVSV/RVESV < 0.712 determined a higher risk of poor prognosis. Kaplan‒Meier survival curves showed that an RVSV/RVESV ratio >0.712 was associated with more favorable long-term outcomes. CONCLUSIONS: The 3DE-derived SV/ESV ratio as a noninvasive alternative surrogate of RV-PA coupling was an eximious indicator for identifying endpoint events in SLE-PAH patients and can provide a diagnostic basis for clinical intervention.


Asunto(s)
Ecocardiografía Tridimensional , Hipertensión Pulmonar , Lupus Eritematoso Sistémico , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Humanos , Hipertensión Pulmonar/etiología , Lupus Eritematoso Sistémico/complicaciones , Ecocardiografía Tridimensional/métodos , Ecocardiografía , Disfunción Ventricular Derecha/etiología
19.
Inorg Chem ; 63(24): 11487-11493, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38833379

RESUMEN

We report the first room-temperature synthesis of ternary CdTeSe magic-size clusters (MSCs) that have mainly the surface ligand oleate (OA). The MSCs display sharp optical absorption peaking at ∼399 nm and are thus referred to as MSC-399. They are made from prenucleation-stage samples of binary CdTe and CdSe, which are prepared by two reactions in 1-octadecene (ODE) of cadmium oleate (Cd(OA)2) and tri-n-octylphosphine chalcogenide (ETOP, E = Te and Se) at 25 °C for 120 min and 80 °C for 15 min, respectively. When the two binary samples are mixed at room temperature and dispersed in a mixture of toluene (Tol) and octylamine (OTA), the CdTeSe MSC-399 develops. Also, when the CdSe sample is added to CdTe MSC-371 in a dispersion, the transformation from CdTe MSC-371 to CdTeSe MSC-399 is seen. We propose that the MSCs develop from their precursor compounds (PCs) that are relatively transparent in optical absorption, such as CdTeSe MSC-399 from CdTeSe PC-399 and CdTe MSC-371 from CdTe PC-371. The formation of CdTeSe PC-399 undergoes monomer substitution and not anion exchange, which is the reaction of CdTe PC-371 and the CdSe monomer to produce CdTeSe PC-399 and the CdTe monomer. Our study provides evidence of monomer substitution for the transformation from binary CdTe to ternary CdTeSe PCs.

20.
Inorg Chem ; 63(25): 11852-11859, 2024 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-38856980

RESUMEN

The efficiency of electrochemical nitrate (NO3-) reduction to ammonia (NH3) still remains a challenge due to the sluggish kinetics of the complex eight-electron reduction process and competitive hydrogen evolution reaction (HER). Herein, we designed new three-dimensional (3D) porous Cu/Cu2+1O nanosheet arrays (Cu/Cu2+1O NSA) by coupling a template-directed method with in situ electroreduction. Thanks to the 3D porous structure and in-plane heterojunctions, Cu/Cu2+1O NSA can provide abundant active sites and a good interfacial effect, obtaining the maximum Faradaic efficiency (FE) of ammonia (88.09%) and high yield rate of 0.2634 mmol h-1 cm-2, which is higher than that of CuO nanosheets (77.81% and 0.2188 mmol h-1 cm-2) and CuO nanoparticles (34.60% and 0.0692 mmol h-1 cm-2). Experimental results and DFT simulations show that the interface effect of Cu/Cu2+1O can decrease the reaction energy barrier of the key step (*NO to *NOH) and can greatly inhibit the competitive hydrogen evolution reaction, thereby achieving excellent electrocatalytic performance for nitrate-to-ammonia conversion.

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