RESUMEN
The probability of finding a spherical "hole" of a given radius r contains crucial structural information about many-body systems. Such hole statistics, including the void conditional nearest-neighbor probability functions GV(r), have been well studied for hard-sphere fluids in d-dimensional Euclidean space Rd. However, little is known about these functions for hard-sphere crystals for values of r beyond the hard-sphere diameter, as large holes are extremely rare in crystal phases. To overcome these computational challenges, we introduce a biased-sampling scheme that accurately determines hole statistics for equilibrium hard spheres on ranges of r that far extend those that could be previously explored. We discover that GV(r) in crystal and hexatic states exhibits oscillations whose amplitudes increase rapidly with the packing fraction, which stands in contrast to GV(r) that monotonically increases with r for fluid states. The oscillations in GV(r) for 2D crystals are strongly correlated with the local orientational order metric in the vicinity of the holes, and variations in GV(r) for 3D states indicate a transition between tetrahedral and octahedral holes, demonstrating the power of GV(r) as a probe of local coordination geometry. To further study the statistics of interparticle spacing in hard-sphere systems, we compute the local packing fraction distribution f(Ïl) of Delaunay cells and find that, for d ≤ 3, the excess kurtosis of f(Ïl) switches sign at a certain transitional global packing fraction. Our accurate methods to access hole statistics in hard-sphere crystals at the challenging intermediate length scales reported here can be applied to understand the important problem of solvation and hydrophobicity in water at such length scales.
RESUMEN
Burkitt's lymphoma (BL) is a rare and highly aggressive B-cell non-Hodgkin lymphoma. Although the outcomes of patients with BL have greatly improved, options for patients with relapsed and refractory BL are limited. Therefore, there is an urgent need to improve BL therapeutics and to develop novel drugs with reduced toxicity. In this study, we demonstrated that enolase 1 (ENO1) is a potential novel drug target for BL treatment. We determined that ENO1 was aberrantly upregulated in BL, which was closely related to its invasiveness and poor clinical outcomes. Furthermore, using RNA interference, we demonstrated that ENO1 depletion significantly inhibited cell proliferation and invasion both in vitro and in vivo. Mechanistically, we established that ENO1 knockdown suppressed the PI3K-AKT and epithelial-mesenchymal transition (EMT) signaling pathways by reducing plasminogen (PLG) recruitment, plasmin (PL) generation, and TGF-ß1 activation. Addition of activated TGF-ß1 protein to the culture medium of shENO1 cells reversed the inhibitory effects on cell proliferation and invasion, as well as those on the PI3K-AKT and EMT signaling pathways. Notably, our research led to the discovery of a novel ENO1-PLG interaction inhibitor, Ciwujianoside E (L-06). L-06 effectively disrupts the interaction between ENO1 and PLG, consequently reducing PL generation and suppressing TGF-ß1 activation. In both in vitro and in vivo experiments, L-06 exerted impressive antitumor effects. In summary, our study elucidated the critical role of ENO1 in BL cell proliferation and invasion and introduced a novel ENO1 inhibitor, which holds promise for improving the treatment of patients with BL in the future.
Asunto(s)
Linfoma de Burkitt , Proliferación Celular , Proteínas de Unión al ADN , Transición Epitelial-Mesenquimal , Invasividad Neoplásica , Fosfopiruvato Hidratasa , Plasminógeno , Factor de Crecimiento Transformador beta1 , Proteínas Supresoras de Tumor , Fosfopiruvato Hidratasa/metabolismo , Humanos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Animales , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/patología , Linfoma de Burkitt/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Plasminógeno/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Masculino , Ratones Desnudos , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Ratones , Ratones Endogámicos BALB C , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Biomarcadores de TumorRESUMEN
Fever is a serious condition that can lead to various consequences ranging from prolonged illness to death. Tetrastigma hemsleyanum Diels et Gilg (T. hemsleyanum) has been used for centuries to treat fever, but the specific chemicals responsible for its antipyretic effects are not well understood. This study aimed to isolate and identify the chemicals with antipyretic bioactivity in T. hemsleyanum extracts and to provide an explanation for the use of T. hemsleyanum as a Chinese herbal medicine for fever treatment. Our results demonstrate that kaempferol 3-rutinoside (K3OR) could be successfully isolated and purified from the roots of T. hemsleyanum. Furthermore, K3OR exhibited a significant reduction in rectal temperature in a mouse model of fever. Notably, a 4 µM concentration of K3OR showed more effective antipyretic effects than ibuprofen and acetaminophen. To explore the underlying mechanism, we conducted an RNA sequencing analysis, which revealed that PXN may act as a key regulator in the fever process induced by lipopolysaccharide (LPS). In the mouse model of fever, K3OR significantly promoted the secretion of IL-6 and TNF-α during the early stage in the LPS-treated group. However, during the middle to late stages, K3OR facilitated the elimination of IL-6 and TNF-α in the LPS-treated group. Overall, our study successfully identified the chemicals responsible for the antipyretic bioactivity in T. hemsleyanum extracts, and it answered the question as to why T. hemsleyanum is used as a traditional Chinese herbal medicine for treating fever. These findings contribute to a better understanding of the therapeutic potential of T. hemsleyanum in managing fever, and they provide a basis for further research and development in this field.
Asunto(s)
Antocianinas , Antipiréticos , Medicamentos Herbarios Chinos , Flavonas , Animales , Ratones , Temperatura Corporal , Factor de Necrosis Tumoral alfa/genética , Antipiréticos/farmacología , Antipiréticos/uso terapéutico , Interleucina-6 , Quempferoles/farmacología , Medicamentos Herbarios Chinos/farmacología , Lipopolisacáridos , Fiebre/tratamiento farmacológico , Flavonas/farmacología , Flavonas/uso terapéutico , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: People with schizophrenia often face challenges such as lower psychological resilience, reduced self-worth, and increased social stigma, hindering their recovery. Mindfulness-Based Cognitive Therapy (MBCT) has shown promise in boosting psychological resilience and self-esteem while diminishing stigma. However, MBCT demands professional involvement and substantial expenses, adding to the workload of professionals and the financial strain on patients. Mixed-mode Mindfulness-Based Cognitive Therapy (M-MBCT) integrates both "face-to-face" and "self-help" approaches to minimize staff effort and costs. This study aims to assess the impact of M-MBCT on the psychological resilience, self-esteem, and stigma in schizophrenia patients. METHODS: This randomized, controlled, parallel-group, assessor-blinded clinical trial enrolled 174 inpatients with schizophrenia. Participants were randomly assigned to either the experimental or control group. The experimental group underwent an 8-week M-MBCT intervention, while the control group received standard treatment. Data collection employed the Connor-Davidson Resilience Scale (CD-RISC), Internalized Stigma of Mental Illness Scale (ISMI), and Rosenberg Self-Esteem Scale (RSES) before and after the intervention. Post-intervention, significant differences in ISMI, CD-RISC, and RSES scores were observed between the experimental and control groups. RESULTS: In the experimental group, ISMI scores notably decreased, while CD-RISC and RSES scores significantly increased (P < 0.05). Multiple linear regression analysis identified age, education, and family history of mental illness as significant factors related to stigma (P < 0.05). Additionally, correlation analysis indicated a significant negative relationship between the reduction in CD-RISC scores and the reduction in ISMI scores (P < 0.05). CONCLUSION: M-MBCT effectively enhanced psychological resilience and self-esteem while diminishing stigma in individuals with schizophrenia. M-MBCT emerges as a promising treatment option for schizophrenia sufferers. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trial Registry on 03/06/2023 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2300069071).
Asunto(s)
Terapia Cognitivo-Conductual , Atención Plena , Pruebas Psicológicas , Resiliencia Psicológica , Esquizofrenia , Humanos , Esquizofrenia/terapia , Estigma Social , Pacientes Internos , AutoimagenRESUMEN
The knowledge of exact analytical functional forms for the pair correlation function g2(r) and its corresponding structure factor S(k) of disordered many-particle systems is limited. For fundamental and practical reasons, it is highly desirable to add to the existing database of analytical functional forms for such pair statistics. Here, we design a plethora of such pair functions in direct and Fourier spaces across the first three Euclidean space dimensions that are realizable by diverse many-particle systems with varying degrees of correlated disorder across length scales, spanning a wide spectrum of hyperuniform, typical nonhyperuniform, and antihyperuniform ones. This is accomplished by utilizing an efficient inverse algorithm that determines equilibrium states with up to pair interactions at positive temperatures that precisely match targeted forms for both g2(r) and S(k). Among other results, we realize an example with the strongest hyperuniform property among known positive-temperature equilibrium states, critical-point systems (implying unusual 1D systems with phase transitions) that are not in the Ising universality class, systems that attain self-similar pair statistics under Fourier transformation, and an experimentally feasible polymer model. We show that our pair functions enable one to achieve many-particle systems with a wide range of translational order and self-diffusion coefficients D, which are inversely related to one another. One can design other realizable pair statistics via linear combinations of our functions or by applying our inverse procedure to other desirable functional forms. Our approach facilitates the inverse design of materials with desirable physical and chemical properties by tuning their pair statistics.