Model informed precision medicine of Chinese herbal medicines formulas-A multi-scale mechanistic intelligent model.

Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine "disease syndrome" and "macro micro" system modeling to facilitate translational research in CHM formulas.

Biomimetic "Gemini nanoimmunoregulators" orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages.

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy. Here, a new type of spatiotemporal biomimetic "Gemini nanoimmunoregulators" was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death (ICD), tumor-associated macrophages (TAMs) phenotype reprogramming and programmed cell death ligand 1 (PD-L1) degradation. The "Gemini nanoimmunoregulators" PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine (mPDA) as nanovectors to deliver metformin (Met) and toll-like receptor 7/8 agonist resiquimod (R848) to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane (RM) inlaid with T7 or M2 peptides. mPDA/Met@RM-T7 (abbreviated as PM@RM-T7) was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity. Meanwhile, PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion. Subsequently, mPDA/R848@RM-M2 (abbreviated as PR@RM-M2) specifically recognized TAMs and reset the phenotype from M2 to M1 state, thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes. This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity, which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis. This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

Relationship between negative air ion and PM2.5 in Quercus variabilis under natural conditions.

In recent years, PM2.5 pollution has become a most important source of air pollution. Prolonged exposure to high PM2.5 concentrations can give rise to severe health issues. Negative air ion (NAI) is an important indicator for measuring air quality, which is collectively known as the 'air vitamin'. However, the intricate and fluctuating meteorological conditions and vegetation types result in numerous uncertainties in the correlation between PM2.5 and NAI. In this study, we collected data on NAI, PM2.5, and meteorological elements through positioning observation during the period of June to September in 2019 and 2020 under the condition of relatively constant leaf area in Quercus variabilis forest, a typical forest in warm temperate zones. We investigated the spatiotemporal variation of PM2.5 and NAI under consistent meteorological conditions, established the correlation between PM2.5 and NAI, and explicated the impact mechanism of PM2.5 on NAI in natural conditions. The results showed that NAI decreased exponentially with the increases in natural PM2.5, with a significant negative correlation (y=1148.79x-0.123). The decrease rates of NAI in PM2.5 concentrations of 0-20, 20-40, 40-80, 80-100 and 100-120 µg·m-3 were 40.1%, 36.2%, 9.4%, 2.4%, 5.1% and 6.8%, respectively. Results of the sensitivity analysis showed that the PM2.5 concentration range of 0-40 µg·m-3 was the sensitive range that affected NAI. Our findings could provide a scientific basis for better understanding the response mechanisms of NAI to environmental factors.

Multiple Treatment of Triple-Negative Breast Cancer Through Gambogic Acid-Loaded Mesoporous Polydopamine.

Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype of breast cancer, characterized by aggressiveness and high recurrence rate. As monotherapy provides limited benefit to TNBC patients, combination therapy emerges as a promising treatment approach. Gambogic acid (GA) is an exceedingly promising anticancer agent. Nonetheless, its application potential is hampered by low drug loading efficiency and associated toxic side effects. To overcome these limitations, using mesoporous polydopamine (MPDA) endowed with photothermal conversion capabilities is considered as a delivery vehicle for GA. Meanwhile, GA can inhibit the activity of heat shock protein 90 (HSP90) to enhance the photothermal effect. Herein, GA-loaded MPDA nanoparticles (GA@MPDA NPs) are developed with a high drug loading rate of 75.96% and remarkable photothermal conversion performance. GA@MPDA NPs combined with photothermal treatment (PTT) significantly inhibit the tumor growth, and effectively trigger the immunogenic cell death (ICD), which thereby increase the number of activated effector T cells (CD8+ T cells and CD4+ T cells) in the tumor, and hoist the level of immune-inflammatory cytokines (IFN-γ, IL-6, and TNF-α). The above results suggest that the combination of GA@MPDA NPs with PTT expected to activate the antitumor immune response, thus potentially enhancing the clinical therapeutic effect on TNBC.

Remodeling the tumor immune microenvironment via siRNA therapy for precision cancer treatment.

How to effectively transform the pro-oncogenic tumor microenvironments (TME) surrounding a tumor into an anti-tumoral never fails to attract people to study. Small interfering RNA (siRNA) is considered one of the most noteworthy research directions that can regulate gene expression following a process known as RNA interference (RNAi). The research about siRNA delivery targeting tumor cells and TME has been on the rise in recent years. Using siRNA drugs to silence critical proteins in TME was one of the most efficient solutions. However, the manufacture of a siRNA delivery system faces three major obstacles, i.e., appropriate cargo protection, accurately targeted delivery, and site-specific cargo release. In the following review, we summarized the pharmacological actions of siRNA drugs in remolding TME. In addition, the delivery strategies of siRNA drugs and combination therapy with siRNA drugs to remodel TME are thoroughly discussed. In the meanwhile, the most recent advancements in the development of all clinically investigated and commercialized siRNA delivery technologies are also presented. Ultimately, we propose that nanoparticle drug delivery siRNA may be the future research focus of oncogene therapy. This summary offers a thorough analysis and roadmap for general readers working in the field.

Smart nanoparticles for cancer therapy.

Smart nanoparticles, which can respond to biological cues or be guided by them, are emerging as a promising drug delivery platform for precise cancer treatment. The field of oncology, nanotechnology, and biomedicine has witnessed rapid progress, leading to innovative developments in smart nanoparticles for safer and more effective cancer therapy. In this review, we will highlight recent advancements in smart nanoparticles, including polymeric nanoparticles, dendrimers, micelles, liposomes, protein nanoparticles, cell membrane nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, iron oxide nanoparticles, quantum dots, carbon nanotubes, black phosphorus, MOF nanoparticles, and others. We will focus on their classification, structures, synthesis, and intelligent features. These smart nanoparticles possess the ability to respond to various external and internal stimuli, such as enzymes, pH, temperature, optics, and magnetism, making them intelligent systems. Additionally, this review will explore the latest studies on tumor targeting by functionalizing the surfaces of smart nanoparticles with tumor-specific ligands like antibodies, peptides, transferrin, and folic acid. We will also summarize different types of drug delivery options, including small molecules, peptides, proteins, nucleic acids, and even living cells, for their potential use in cancer therapy. While the potential of smart nanoparticles is promising, we will also acknowledge the challenges and clinical prospects associated with their use. Finally, we will propose a blueprint that involves the use of artificial intelligence-powered nanoparticles in cancer treatment applications. By harnessing the potential of smart nanoparticles, this review aims to usher in a new era of precise and personalized cancer therapy, providing patients with individualized treatment options.

Biomimetic Nano-Immunoactivator via Ionic Metabolic Modulation for Strengthened NIR-II Photothermal Immunotherapy.

Reprogramming the immunologically "cold" environment of solid tumors is currently becoming the mainstream strategy to elicit powerful and systemic anticancer immunity. Here, a facile and biomimetic nano-immunnoactivator (CuS/Z@M4T1 ) is detailed by engineering a Zn2+ -bonded zeolitic imidazolate framework-8 (ZIF-8) with CuS nanodots (NDs) and cancer cell membrane for amplified near-infrared-II (NIR-II) photothermal immunotherapy via Zn2+ metabolic modulation. Taking advantage of the NIR-II photothermal effect of CuS NDs and the acidic responsiveness of ZIF-8, CuS/Z@M4T1 rapidly causes intracellular Zn2+ pool overload and disturbs the metabolic flux of 4T1 cells, which effectively hamper the production of heat shock proteins and relieve the resistance of photothermal therapy (PTT). Thus, amplified immunogenic cell death is evoked and initiates the immune cascade both in vivo and in vitro as demonstrated by dendritic cells maturation and T-cell infiltration. Further combination with antiprogrammed death 1 (aPD-1) achieves escalated antitumor efficacy which eliminates the primary, distant tumor and avidly inhibits lung metastasis due to cooperation of enhanced photothermal stimulation and empowerment of cytotoxic T lymphocytes by aPD-1. Collectively, this work provides the first report of using the intrinsic modulation property of meta-organometallic ZIF-8 for enhanced cancer photoimmunotherapy together with aPD-1, thereby inspiring a novel combined paradigm of ion-rich nanomaterials for cancer treatment.

Effect of light intensity on negative air ion under phytotron control.

Negative air ion (NAI) is an important index for measuring air quality and has been widely recognized to be influenced by photosynthesis processes. However, vegetation type and light intensity are also known to impact NAI, contributing to significant uncertainties in the relationship between light and NAI. In this paper, we selected Pinus bungeana, Platycladus orientalis and Buxus sinica as research subjects and obtained their NAI, light intensity, and meteorological data through synchronous observation under the relatively stable condition of the phytotron. We analyzed the change characteristics of NAI and the difference of NAI production ability in needle and broadleaf vegetation under different light intensities. Finally, we determined the relationship and underlying mechanism governing light intensity and NAI using diverse tree species. The results showed that the influence of light on NAI was significant. In the environment without vegetation, the influence of different light intensities on NAI was not significant, and the mean NAI concentration was 310 ions·cm-3. Conversely, in the presence of vegetation, NAI showed a "single-peak" trend with increasing light intensity. The NAI concentration of the three tree species was significantly higher than under different light intensities when vegetation was not present. The NAI promoting ability of P. bungeana was the highest (675 ions·cm-3), followed by P. orientalis (478 ions·cm-3) and B. sinica (430 ions·cm-3), which increased by 117.5%, 53.9% and 38.6% compared to the environment without vegetation. The NAI growth rate was significantly different between needle and broadleaf vegetation based on the specific tridimensional green biomass. Additionally, the NAI growth rates of P. bungeana and P. orientalis were 647 and 295 ions·cm-3·m-3, respectively, which were 3.06 and 1.39 times that of B. sinica (211 ions·cm-3·m-3). The piecewise equation fitting effect of NAI and light intensity was better for different tree species, the determination coefficients (R2) of P. bungeana, P. orientalis and B. sinica were 0.926, 0.916 and 0.880, and the root mean square errors (RMSE) were 7.157, 6.008 and 5.389 ion·cm-3, respectively. Altogether, our study provides a theoretical basis as well as technical support for the construction of healthy vegetation stands, the selection of preferred tree species, and the optimization of vegetation models, and promotes air quality and the provision of ecosystem functions and services.

Seasonal variations of plant water use in the karst desertification control.

Understanding the water use characteristics of plants is crucial for the sustainability of forest water management and vegetation restoration. The vegetation restoration program in the karst desertification areas of southwest China has been implemented for more than two decades, and remarkable achievements have been made in ecological restoration. However, the water use characteristics of revegetation are still poorly understood. We investigated the water uptake patterns and water use efficiency of four woody plants (Juglans regia, Zanthoxylum bungeanum, Eriobotrya japonica, and Lonicera japonica) using stable isotopes (δ2H, δ18O, and δ13C) in combination with the MixSIAR model. The results showed that plants responded to seasonal changes in soil moisture with flexible water uptake patterns. Differences in water use sources among the four plant species during the growing season indicated the occurrence of hydrological niche separation, which is the key to vegetation symbiosis. Throughout the study period, groundwater made the lowest contribution to plants (9.39 %~16.25 %), and fissure soil water made the highest contribution (39.74 %~64.71 %). Among them, shrubs and vines were more dependent on fissure soil water compared to trees (50.52 %~64.71 %). Furthermore, plant foliar δ13C was higher in the dry season than in the rainy season. Evergreen shrubs (-27.94 ‰) exhibited higher water use efficiency compared to other tree species (-30.48 ‰~-29.04 ‰). The water use efficiency of four plants showed seasonal variation and was influenced by the water availability caused by soil moisture. Our study demonstrates that fissure soil water is an important water source for karst desertification revegetation and that seasonal changes in water use characteristics are influenced by species-level water uptake patterns and water use strategies. This study provides a reference for vegetation restoration and water resource management in karst areas.

Does Lumbar Interbody Fusion Modality Affect the Occurrence of Complications in an Osteoporotic Spine Under Whole-Body Vibration? A Finite Element Study.

OBJECTIVE: To evaluate the effects of 3 lumbar interbody fusion techniques on the occurrence of complications in an osteoporotic spine under whole-body vibration. METHODS: A previously developed and validated nonlinear finite element model of L1-S1was modified to develop anterior lumbar interbody fusion (ALIF), posterior lumbar interbody fusion (PLIF), and transforaminal lumbar interbody fusion (TLIF) models with osteoporosis. In each model, the lower surface of the sacrum was absolutely fixed, a follower load of 400N was applied through the axis of the lumbar spine, and an axial sinusoidal vertical load of ±40N (5 Hz) was imposed on the superior surface of L1, to perform a transient dynamic analysis. The maximal values of intradiscal pressure, shear stress on annulus substance, disc bulge, facet joint stress, and screw and rod stress, along with their dynamic response curves, were collected. RESULTS: Among these 3 models, the TLIF model generated the greatest screw and rod stress, and the PLIF model generated the greatest cage-bone interface stress. At the L3-L4 level, compared with the other 2 models, the maximal values and dynamic response curves of intradiscal pressure, shear stress of annulus ground substance, and disc bulge were all lower in the ALIF model. However, the facet contact stress at the adjacent segment in the ALIF model was higher than that in the other 2 models. CONCLUSIONS: In an osteoporotic spine under whole-body vibration, TLIF has the highest risk of screw and rod breakage, PLIF has the highest risk of cage subsidence, and ALIF has the lowest risk of upper adjacent disc degeneration, but the highest risk of adjacent facet joint degeneration.

Asymmetric and zwitterionic Blatter diradicals.

Asymmetric diradical molecular systems with different resonance mechanisms are largely unexplored. Herein, two conjugated asymmetric diradicals with Blatter and phenoxyl moieties (pBP and mBP) have been synthesized and studied in depth. A complete set of spectroscopic, X-ray crystallographic and magnetic techniques, together with quantum chemical calculations, have been used. The para-isomer (pBP) bears diradical and zwitterionic resonant forms, the latter by a electron delocalization mechanism, which are synergistically integrated by a sequence of nitrogen, provided by the Blatter moiety imine and amine (of different acceptor nature). In the meta-isomer (mBP), the zwitterionic form promoted in pBP by the lone-pair electron of the amine nitrogen is not available, yet it possesses a pseudo-hyperconjugation effect where the N lone pair mediates in a bonding coupling in a counter homolytic bond scission mechanism. Both electronic effects converge to promote medium diradical characters and narrow singlet-triplet gaps to the two electronic isomers. All these aspects delineate the subtle balance that shapes the electronic structure of open-shell molecules, which is even more challenging in the case of asymmetric systems, such as those described here with asymmetric phenoxyl-Blatter diradicals.

Assessment of soil redistribution in a typical karst catchment using 137Cs.

An effective assessment of soil erosion and redistribution is a prerequisite for soil erosion control and is critical to achieving sustainable development goals. The most typical landscape in the karst region of Southwest China is found in the peak-cluster depression area, but little attention has been given to the soil redistribution here. A typical karst peak-cluster depression catchment water area in Southwest China was selected, and 137Cs technology was used to evaluate the soil redistribution rate and soil erosion process along a total transect (hillslope, depression and sinkhole) in the catchment. The results showed that the distribution of 137Cs had a high spatial variability on the total transect of the catchment (CV = 60.04%), the middle slope was the most severely eroded (highest erosion rate of 13.49 t ha-1 yr-1), and the area between the bottom slope and the depression was the primary sedimentary area on the surface in the catchment. The distribution of soil properties on the hillslope was affected by the process of soil redistribution. According to the distribution of the 137Cs soil profile, the soil profile of the hillslope was uniform, and signs of historical tillage activities were evident; the historical tillage activities of depressions were in the range of 0-20 cm depth, while the 137Cs in the sinkhole was mostly distributed in the shallow layers and decreased exponentially with depth, reflecting the depositional characteristics of noncultivated soil. In addition, this study found evidence of underground soil loss in sinkholes since the 1960s; the shallow sediment of these sinkholes mainly came from depressions, with an average deposition rate of 11.77 t ha-1 yr-1. Human disturbance and land-use change controlled recent changes in soil redistribution. The soil erosion rate of the hillslopes in catchments was extremely low (average erosion rate of 1.92 t ha-1 yr-1). The rocky desertification of hillslopes occurred before 1960; it was not a short-term contemporary process that occurred only during recent decades. This study showed that underground soil loss mainly occurred through sinkholes for a short period of time (100 years). These research results are of great significance for understanding the evolution of rocky desertification and the process of soil erosion.

Biomechanical Effect of Osteoporosis on Adjacent Segments After Anterior Cervical Corpectomy and Fusion.

BACKGROUND: Adjacent segmental degeneration (ASD) is one common long-term complication of anterior cervical corpectomy and fusion (ACCF), and osteoporosis is one basic disease in the elderly. After ACCF, patients may experience osteoporosis with age. However, the influence of osteoporosis on ASD remains unclear. The purpose of this study was to determine whether osteoporosis could affect the development of ASD following ACCF. METHODS: Three finite element models of the cervical spine, including 1 normal model, 1 ACCF model, and 1 ACCF with osteoporosis model, were constructed. ACCF was simulated at the C4-C6 level. A 73.6 N follower load and a 1 Nm moment were imposed on the normal model, and the same follower load together with an adjusted moment was applied to the ACCF model and the ACCF with osteoporosis model, to simulate movement in each direction. The range of motion, intradiscal pressure, shear stress on anulus fibrosus, and facet joint stress at C3-C4 and C6-C7 levels of the models were calculated. RESULTS: In this study, the normal model was well validated. In flexion, extension, right lateral bending, and right axial rotation, the overall range of motion was 8.92°, 19.7°, 15.37°, and 45.27° in the normal model, and the adjusted moment was 1.4 Nm, 2.7 Nm, 1.1 Nm, and 2.6 Nm in the ACCF model, and 1.3 Nm, 2.5 Nm, 1.1 Nm, and 2.4 Nm in the ACCF with osteoporosis model. Despite of a few exceptions, the maximum values of the outcome measurements were mostly found in the ACCF model, and the minimum values in the normal model. Compared with the ACCF model, most of the outcome measurements were decreased in the ACCF with osteoporosis model. CONCLUSIONS: Osteoporosis can retard the adverse influence of ACCF on adjacent segments.

Mesoporous Silica Nanoparticles-Based Nanoplatforms: Basic Construction, Current State, and Emerging Applications in Anticancer Therapeutics.

In recent years, researchers are developing novel nanoparticles for diagnostic applications using imaging techniques and for therapeutic purposes through drug delivery techniques. The unique physical and chemical properties of mesoporous silica nanoparticles (MSNs) make it possible to integrate a variety of commonly used therapeutic and imaging agents to construct a multimodal synergistic anticancer drug delivery system. Herein, recent advances in MSNs synthesis for drug delivery and smart response applications are reviewed. First, synthetic strategies for the fabrication of ordered MSNs, hollow MSNs, core-shell structured MSNs, dendritic MSNs, and biodegradable MSNs are outlined. Then, the recent research progress in designing functional MSN materials with various controlled release mechanisms in anticancer therapy is discussed, and new properties are introduced to suggest the latest design requirements as drug delivery materials. The review also highlights significant achievements in bioimaging using MSNs and their multifunctional counterparts as delivery vehicles. Finally, personal views on key directions for future work in this area are presented.

Aquatic resistance training repercussions on the dynamic stability in volleyball athletes / Repercussões do treino de resistência aquático sobre a estabilidade dinâmica dos atletas de vôlei / Repercusiones del entrenamiento de resistencia acuática en la estabilidad dinámica de los atletas de voleibol

ABSTRACT Introduction Resistance training is considered a practical pathway for increasing strength and speed. Objective Explore the aquatic resistance training on the dynamic stability in volleyball athletes. Methods Using aquatic resistance training reinforcement, 20 first-level national male volleyball athletes were randomly divided into control and experimental groups. The time of the experiment was ten weeks. In the end, lower limb muscle strength, jumping ability, dynamic stability, and muscle pain were compared. Residual effects were also checked six weeks after the end of the experiment. Results The aquatic resistance training group stopped training for six weeks, peak torque at 60°/s, 180°s of relative knee extension, jump height, full arm swing, and all three phases of the high jump were significantly better than the preliminary test; water entry speed in the vertical direction was also significantly better one week after training. Conclusion Aquatic resistance training can significantly improve the dynamic stability of the lower limbs, and its effect can be maintained up to 6 weeks after completion. It is recommended to apply resistance enhancement training to maintain fitness, especially for long periods. Evidence Level II; Therapeutic Studies - Investigating the result.

RESUMO Introdução O treino de resistência é considerado um meio eficaz para aumento de força e a velocidade. Objetivo Explorar as repercussões do treino de resistência aquática sobre a estabilidade dinâmica dos atletas de vôlei. Métodos 20 atletas de primeiro nível nacionais de vôlei masculino, foram divididos aleatoriamente em um grupo de treinamento para controle e outro grupo experimental com reforço utilizando treino de resistência aquático. O tempo do experimento foi de 10 semanas. Ao final, foram comparadas força muscular do membro inferior, capacidade de salto, estabilidade dinâmica, dor muscular. Foram verificados também os efeitos residuais em seis semanas após o término do experimento. Resultados O grupo de treino de resistência aquática parou de treinar por 6 semanas, com pico de torque a 60°/s, 180°s de extensão relativa do joelho, a altura de salto, o balanço completo dos braços e as três fases do salto em altura foram significativamente melhores do que o teste primário; a velocidade de entrada na água na direção vertical também foi significativamente melhor uma semana após o treinamento. Conclusão O treino de resistência aquático pode melhorar significativamente a estabilidade dinâmica dos membros inferiores e seu efeito pode ser mantido até 6 semanas após o término. Recomenda-se aplicar o treino de aprimoramento da resistência para manter o condicionamento físico, especialmente por longos períodos. Nível de evidência II; Estudos Terapêuticos - Investigação de Resultados.

RESUMEN Introducción El entrenamiento de resistencia se considera una forma eficaz de aumentar la fuerza y la velocidad. Objetivo Explorar las repercusiones del entrenamiento de resistencia acuática en la estabilidad dinámica de los atletas de voleibol. Métodos 20 atletas masculinos de voleibol de primer nivel nacional, fueron divididos aleatoriamente en un grupo de entrenamiento de control y otro grupo experimental con refuerzo mediante entrenamiento de resistencia acuática. El tiempo del experimento fue de 10 semanas. Al final, se comparó la fuerza muscular de las extremidades inferiores, la capacidad de salto, la estabilidad dinámica y el dolor muscular. También se comprobaron los efectos residuales a las seis semanas de finalizar el experimento. Resultados El grupo de entrenamiento de resistencia acuática dejó de entrenar durante 6 semanas, el pico máximo de torque a 60°/s, la extensión relativa de la rodilla a 180°s, la altura del salto, el balanceo completo del brazo y las tres fases del salto de altura fueron significativamente mejores que en la prueba primaria; la velocidad de entrada al agua en la dirección vertical también fue significativamente mejor una semana después del entrenamiento. Conclusión El entrenamiento de resistencia acuática puede mejorar significativamente la estabilidad dinámica de los miembros inferiores y su efecto puede mantenerse hasta 6 semanas después de su realización. Se recomienda aplicar un entrenamiento de mejora de la resistencia para mantener la forma física, especialmente durante largos periodos. Nivel de evidencia II; Estudios terapéuticos - Investigación de resultados.

Topological patterns of motor networks in Parkinson's disease with different sides of onset: A resting-state-informed structural connectome study.

Parkinson's disease (PD) has a characteristically unilateral pattern of symptoms at onset and in the early stages; this lateralization is considered a diagnostically important diagnosis feature. We aimed to compare the graph-theoretical properties of whole-brain networks generated by using resting-state functional MRI (rs-fMRI), diffusion tensor imaging (DTI), and the resting-state-informed structural connectome (rsSC) in patients with left-onset PD (LPD), right-onset PD (RPD), and healthy controls (HCs). We recruited 26 patients with PD (13 with LPD and 13 with RPD) as well as 13 age- and sex-matched HCs. Rs-fMRI and DTI were performed in all subjects. Graph-theoretical analysis was used to calculate the local and global efficiency of a whole-brain network generated by rs-fMRI, DTI, and rsSC. Two-sample t-tests and Pearson correlation analysis were conducted. Significantly decreased global and local efficiency were revealed specifically in LPD patients compared with HCs when the rsSC network was used; no significant intergroup difference was found by using rs-fMRI or DTI alone. For rsSC network analysis, multiple network metrics were found to be abnormal in LPD. The degree centrality of the left precuneus was significantly correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) score and disease duration (p = 0.030, r = 0.599; p = 0.037, r = 0.582). The topological properties of motor-related brain networks can differentiate LPD and RPD. Nodal metrics may serve as important structural features for PD diagnosis and monitoring of disease progression. Collectively, these findings may provide neurobiological insights into the lateralization of PD onset.

Local delivery of gambogic acid to improve anti-tumor immunity against oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) accounts for nearly 90% of oral cavity malignancies. However, despite significant advances in the last four decades, little improvement has been achieved in the overall survival rates for OSCC patients. While gambogic acid (GA) is a potential candidate compound for treating a variety of malignancies, its anti-cancer impact on OSCC has not to be completely investigated. The tumor immune microenvironment (TIME) has been proven to play a crucial role in the prognosis of cancer patients. Although there are few reports on the T cell activation effect of GA, the regulation of GA on the TIME of OSCC has barely been studied yet. In this study, GA was applied to treat OSCC-bearing mice through in situ controlled release. First, GA-loaded mPEG2000-PCL micelles (GA-MIC) were prepared by the thin-film hydration method to improve the aqueous dispersibility of GA. Second, poly(D, l-lactide)-poly(ethylene glycol)-poly(D, l-lactide) (PLEL) was synthesized for thermosensitive hydrogel preparation. Third, GA-MIC was mixed with PLEL to form an injectable therapeutic hydrogel (GA-MIC-GEL). The anti-tumor and TIME regulation effects of GA-MIC-GEL on tumor-bearing mice were further examined. The results showed that the thermosensitive GA-MIC-GEL with sensitive sol-gel transition characteristics could form hydrogel at 37 °C within 24 s, facilitating the local delivery and sustained GA release. Biochemical, hematological, and pathological analysis proved that GA-MIC-GEL has good biological safety. Moreover, GA-MIC-GEL promoted an obvious regression of both primary and distant tumors on the OSCC mouse models. Mechanically, GA-MIC-GEL down-regulated the expression of PD-1, increased the frequency of cytotoxic T cells and reduced the immunosuppressive cellular components, which boosted the anti-tumor immunity of OSCC-bearing mice. The constructed thermosensitive hydrogel for local delivery of GA has provided a safe and effective strategy with great potential for OSCC therapy.

Caveolin-1 signaling-driven mitochondrial fission and cytoskeleton remodeling promotes breast cancer migration.

Mitochondria are highly dynamic organelles that constantly divide and fuse to maintain their proper structure and function. Cancer cells are often accompanied by an imbalance of mitochondrial fusion and fission, cancer progression is greatly affected by this imbalance. Here, we found that high-metastatic breast cancer MDA-MB-231 cells possess higher caveolin-1 (Cav-1) expression compared with low-metastatic breast cancer MCF-7 cells or normal breast epithelial MCF-10A cells. Downregulation of Cav-1 decreases the migratory and invasive abilities of MDA-MB-231 cells. Our results further demonstrated that downregulation of Cav-1 facilitated DRP1 and MFN2 to translocate to mitochondria, increasing the inhibitory phosphorylation level of DRP1 at Ser637 by protein kinase A (PKA), resulting in mitochondria elongation. We also showed that downregulation of Cav-1 significantly reduced the Rac1 activity by affecting intracellular reactive oxygen species (ROS) generation, which then inhibited F-actin formation. Based on these findings, we proposed that Cav-1 mediated mitochondrial fission-affected intracellular ROS generation and activated Rho GTPases, leading to F-actin-dependent formation of lamellipodia and promotion of breast cancer motility.

Evaluation of the Glymphatic System Using the DTI-ALPS Index in Patients with Spontaneous Intracerebral Haemorrhage.

Objective: To investigate the function of the human glymphatic system (GS) in patients with spontaneous intracerebral haemorrhage (sICH) using diffusion tensor imaging analysis along with the perivascular space (DTI-ALPS). Methods: Twenty patients with sICH and 31 healthy controls (HCs) were recruited for DTI and susceptibility-weighted imaging scanning. The diffusivity along the perivascular spaces, as well as the projection fibres and association fibres, was evaluated separately. The DTI-ALPS index of each subject was also calculated. Two-sample t-tests and paired t-tests were performed to analyse the difference in ALPS scores between patients and HCs, as well as that between the lesion side and contralateral side. Pearson correlation analysis was used to observe the relationship between disease duration and GS function. Results: The DTI-ALPS index on the lesion side was significantly lower than that of the contralateral side in patients with sICH (p < 0.01, t = -5.77), and it was also significantly lower than that of the ipsilateral side of HCs (p < 0.01, t = -9.50). No significant differences were found in the DTI-ALPS index on the nonlesion side between patients and HCs (p = 0.96, t = 0.05) or between the left and right cerebral hemispheres of HCs (p = 0.41, t = -0.83). The DTI-ALPS index of the lesion side in patients with sICH was significantly correlated with disease duration (p = 0.018, r = 0.537). Conclusions: The present study confirmed that GS dysfunction on the ipsilateral side of the lesion is impaired in patients with haemorrhagic stroke, indicating that the GS may be a separate system in the left and right cerebral hemispheres. The DTI-ALPS index can reflect disease duration. These findings have significant implications for understanding sICH from a new perspective.

Erratum: Microenvironment Activatable Nanoprodrug Based on Gripper-like Cyclic Phenylboronic Acid to Precisely and Effectively Alleviate Drug-induced Hepatitis: Erratum.

[This corrects the article DOI: 10.7150/thno.61214.].