Search

Abstract Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH‐triggered charge and size dual switchable nanocage co‐loaded with abemaciclib and IMD‐0354 (PA/PI‐ND) is reported, exhibiting a novel triple‐interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR‐poly(ethylene glycol)‐poly(l‐lysine)‐dimethylmaleic anhydride (NGR‐PEG‐PLL‐DMA, ND) in PA/PI‐ND promotes the pH‐triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI‐ND triple‐interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD‐0354. The dual anti‐tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD‐0354 promoting tumor‐associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI‐ND has improved anti‐tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI‐ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.

Objective: Synaptic plasticity is critical for neurorehabilitation after focal cerebral ischemia. Connexin 43 (Cx43), the main component of the gap junction, has been shown to be pivotal for synaptic plasticity. The objective of this study was to investigate the role of the Cx43 inhibitor (Gap26) and gap junction modifier (GAP-134) in neurorehabilitation and to study their contribution to synaptic plasticity after focal ischemia.Methods: Time course expression of both total and phosphorylated Cx43 (p-Cx43) were detected by western blotting at 3, 7, and 14 d after focal ischemia. Gap26 and GAP-134 were administered starting from 3 d post focal ischemia. Neurological performances were evaluated by balance beam walking test and Y-maze test at 1, 3, and 7 d. Golgi staining and transmission electron microscope (TEM) detection were conducted at 7 d for observing dendritic spine numbers and synaptic ultrastructure, respectively. Immunofluorescent staining was used at 7 d for detection of synaptic plasticity markers, including synaptophysin (SYN) and growth-associated protein-43 (GAP-43).Results: Expression levels of both total Cx43 and p-Cx43 were increased after focal cerebral ischemia, peaking at 7 d. Compared with the MCAO group, Gap26 worsened the neurological behavior and decreased the dendritic spine number while GAP-134 improved the neurobehavior and increased the number of dendritic spines. Moreover, Gap26 further destroyed the synaptic structure, concomitant with downregulated SYN and GAP-43, whereas GAP-134 alleviated synaptic destruction and upregulated SYN and GAP-43.Conclusion: These findings suggested that Cx43 or the gap junction was involved in synaptic plasticity, thereby promoting neural recovery after ischemic stroke. Treatments enhancing gap junctions may be potential promising therapeutic measures for neurorehabilitation after ischemic stroke.

ObjectiveTo identify DNA methylation related biomarkers in patients with breast cancer (BC).Materials and MethodsA total of seven BC methylation studies including 1,438 BC patients or breast tissues were included in this study. An elastic net regularized Cox proportional hazards regression (CPH) model was used to build a multi-5′-C-phosphate-G-3′ methylation panel. The diagnosis and prognosis power of the panel was evaluated and validated using a Kaplan–Meier curve, univariate and multivariable CPH, subgroup analysis. A nomogram containing the panel was developed. The relationships between the panel-based methylation risk and the immune landscape and genomic metrics were investigated.ResultsSixty-eight CpG sites were significantly correlated with the overall survival (OS) of BC patients, and based on the result of penalized CPH, a 28-CpG site based multi CpG methylation panel was found. The prognosis and diagnosis role of the panel was validated in the discovery set, validation set, and six independent cohorts, which indicated that higher methylation risk was associated with poor OS, and the panel outperformed currently available biomarkers and remained an independent factor after adjusting for other clinical features. The methylation risk was negatively correlated with innated and adaptive immune cells, and positively correlated with total mutation load, SCNA, and MATH.ConclusionsWe validated a multi CpG methylation panel that could independently predict the OS of BC patients. The Th2-mediated tumor promotion effect—suppression of innate and adaptive immunity—participated in the progression of high-risk BC. Patients with high methylation risk were associated with tumor heterogeneity and poor survival.

MicroRNAs (miRNAs) are a class of small non-coding RNAs which regulate gene expression at post-transcriptional level. Alterations of miR-186 expression were demonstrated in numerous cancers, shown to play a vital role in oncogenesis, invasion, metastasis, apoptosis, and drug resistance. MiR-186 was documented as a tumor suppressor miRNA in the majority of studies, while conflicting reports verified miR-186 as an oncomir. The contradictory role in cancers may impede the application of miR-186, as well as other dual-functional miRNAs, as a diagnostic and therapeutic target. This review emphasizes the alterations and functions of miR-186 in cancers and discusses the mechanisms behind the contradictory findings. Among these, target abundance and dose-dependent effects of miR-186 are highlighted. The paper aims to review the challenges involved in developing diagnostic and therapeutic strategies for cancer treatment based on dual-functional miRNAs.

Altered lipid metabolism in macrophages is associated with various important inflammatory conditions. Although lipid metabolism is an important target for therapeutic intervention, the metabolic requirement involved in lipid accumulation during pro-inflammatory activation of macrophages remains incompletely characterized. We show here that macrophage activation with IFNγ results in increased aerobic glycolysis, iNOS-dependent inhibition of respiration, and accumulation of triacylglycerol. Surprisingly, metabolite tracing with 13C-labeled glucose revealed that the glucose contributed to the glycerol groups in triacylglycerol (TAG), rather than to de novo synthesis of fatty acids. This is in stark contrast to the otherwise similar metabolism of cancer cells, and previous results obtained in activated macrophages and dendritic cells. Our results establish a novel metabolic pathway whereby glucose provides glycerol to the headgroup of TAG during classical macrophage activation.

Abstract Background Antimicrobial resistance (AMR) has been a worldwide public health concern. Current widespread AMR pollution has posed a big challenge in accurately disentangling source-sink relationship, which has been further confounded by point and non-point sources, as well as endogenous and exogenous cross-reactivity under complicated environmental conditions. Because of insufficient capability in identifying source-sink relationship within a quantitative framework, traditional antibiotic resistance gene (ARG) signatures-based source-tracking methods would hardly be a practical solution. Results By combining broad-spectrum ARG profiling with machine-learning classification SourceTracker, here we present a novel way to address the question in the era of high-throughput sequencing. Its potential in extensive application was firstly validated by 656 global-scale samples covering diverse environmental types (e.g., human/animal gut, wastewater, soil, ocean) and broad geographical regions (e.g., China, USA, Europe, Peru). Its potential and limitations in source prediction as well as effect of parameter adjustment were then rigorously evaluated by artificial configurations with representative source proportions. When applying SourceTracker in region-specific analysis, excellent performance was achieved by ARG profiles in two sample types with obvious different source compositions, i.e., influent and effluent of wastewater treatment plant. Two environmental metagenomic datasets of anthropogenic interference gradient further supported its potential in practical application. To complement general-profile-based source tracking in distinguishing continuous gradient pollution, a few generalist and specialist indicator ARGs across ecotypes were identified in this study. Conclusion We demonstrated for the first time that the developed source-tracking platform when coupling with proper experiment design and efficient metagenomic analysis tools will have significant implications for assessing AMR pollution. Following predicted source contribution status, risk ranking of different sources in ARG dissemination will be possible, thereby paving the way for establishing priority in mitigating ARG spread and designing effective control strategies.

Abstract Background Perilla frutescens is well known for its high α-linolenic acid (ALA) accumulation in seeds and medicinal values as well as a source of edible and general-purpose oils. However, the regulatory mechanisms of the biosynthesis of fatty acid in its seeds remain poorly understood due to the lacking of sequenced genome. For better understanding the regulation of lipid metabolism and further increase its oil content or modify oil composition, time-course transcriptome and lipid composition analyses were performed. Results Analysis of fatty acid content and composition showed that the α-linolenic acid and oleic acid accumulated rapidly from 5 DAF to 15 DAF and then kept relatively stable. However, the amount of palmitic acid and linoleic acid decreased quickly from 5 DAF to 15DAF. No significant variation of stearic acid content was observed from 5 DAF to 25DAF. Our transcriptome data analyses revealed that 110,176 unigenes were generated from six seed libraries at 5, 10, 20 DAF. Of these, 53 (31 up, 22 down) and 653 (259 up, 394 down) genes showed temporal and differentially expression during the seed development in 5 DAF vs 10 DAF, 20 vs 10 DAF, respectively. The differentially expressed genes were annotated and found to be involved in distinct functional categories and metabolic pathways. Deep mining of transcriptome data led to the identification of key genes involved in fatty acid and triacylglycerol biosynthesis and metabolism. Thirty seven members of transcription factor family AP2, B3 and NFYB putatively involved in oil synthesis and deposition were differentially expressed during seed development. The results of qRT-PCR for selected genes showed a strong positive correlation with the expression abundance measured in RNA-seq analysis. Conclusions The present study provides valuable genomic resources for characterizing Perilla seed gene expression at the transcriptional level and will extend our understanding of the complex molecular and cellular events of oil biosynthesis and accumulation in oilseed crops.

Background/Aims: Alzheimer disease (AD) is a common neurodegenerative disease that is characterized by the deposition of beta-amyloid peptide and formation of intracellular neurofibrillary tangles. Due to the failure of various clinical trials of novel drugs for AD, effective drugs for AD treatment are urgently required. Methods: In this study, we used the classic APP/PS1 mouse model to explore the neuroprotective effects of a new compound, bajijiasu, and the mechanisms involved. Behavioral tests and western blotting were performed to assess the beneficial effects of bajijiasu in APP/PS1 mice. Results: Morris water maze and Y-maze test results showed that oral administration of bajijiasu (35 mg/kg/day and 70 mg/kg/day) improved learning and memory abilities in APP/PS1 mice. Bajijiasu reduced ROS and MDA levels in both the hippocampus and cortex. Moreover, western blotting results showed that bajijiasu protected neurons from apoptosis, elevated the expression levels of neurotrophic factors, and alleviated endoplasmic reticulum stress in both the hippocampus and cortex. Conclusion: These results indicate that the mechanisms underlying the effects of bajijiasu on AD might be related to beta-amyloid-downstream pathologies, particularly endoplasmic reticulum stress.

Abstract The relaxation behaviors of thin polymer films show a strong dependence on temperature and film thickness. Direct quantitative detection of the relaxation behaviors of thin polymer films at nanometer scale by traditional instruments is however challenging. In this study, we employed atomic force microscopy (AFM)-based force-distance curve to study the relaxation dynamics and the film thickness dependence of glass transition temperature (T g ) for normal thin polystyrene (PS) films supported on silicon substrate. The adhesion force (Fad) between AFM tip and normal thin PS film surfaces was quantitatively detected in situ under the variation of temperature and film thickness. The T g of normal thin PS film was successfully obtained by the abrupt variation of Fad under temperature stimulation. Our result showed that the T g of normal thin PS films decreased with the decreasing film thickness. The study here could be beneficial for understanding the relaxation dynamics of normal thin polymer films.

An accurate intrinsic structural model is essential to describing the high-temperature deformation behavior of metal materials. Support Vector Regression (SVR) has strong regression analysis capabilities, but its application research in constructing constitutive models of 25CrMo4 steel still needs to be improved. In this study, we use grid search, particle swarm optimization, improved genetic algorithm, and improved gray wolf optimization to optimize SVR parameters. A constitutive relationship model for 25CrMo4 steel under high-temperature compression based on SVR was established through training using experimental data models. The predicted data of SVR constitutive models with different optimization algorithms were compared with experimental data. Statistical values, such as average absolute percentage error (AAPE), mean absolute percentage error (MAPE), and correlation coefficient (R2), were introduced to evaluate the accuracy of each model. The particle swarm optimization-SVR model achieved the best performance, with an AAPE of 0.455 38, MAPE of 0.489 09%, and R2 of 0.999 74. Furthermore, compared to other models, it requires the least time. This model has a higher accuracy than other commonly used instantaneous models. These findings can provide a basis for selecting appropriate deformation parameters and preventing hot working defects of 25CrMo4 steel, thus helping to improve the manufacturing process and material properties. [ABSTRACT FROM AUTHOR]

Summary: Mammalian oocytes not fertilized immediately after ovulation can undergo ageing and a rapid decline in quality. The addition of antioxidants can be an efficient approach to delaying the oocyte ageing process. Onion peel extract (OPE) contains quercetin and other flavonoids with natural antioxidant activities. In this study, we investigated the effect of OPE on mouse oocyte ageing and its mechanism of action. The oocytes were aged in vitro in M16 medium for 16 h after adding OPE at different concentrations (0, 50, 100, 200, and 500 μg/ml). The addition of 100 μg/ml OPE reduced the oocyte fragmentation rate, decreased the reactive oxygen species (ROS) level, increased the glutathione (GSH) level, and improved the mitochondrial membrane potential compared with the control group. The addition of OPE also increased the expression of SOD1 , CAT , and GPX3 genes, and the caspase-3 activity in OPE-treated aged oocytes was significantly lower than that in untreated aged oocytes and similar to that in fresh oocytes. These results indicated that OPE delayed mouse oocyte ageing by reducing oxidative stress and apoptosis and enhancing mitochondrial function. [ABSTRACT FROM AUTHOR]

Healthy seed germination is important for improving the yield and quality of maize, but the molecular mechanisms regulating maize seed germination are still unclear. Significant progress has been made in the study of rice quality functional genomics, with the cloning of many important genes related to the regulation of rice quality traits. Selecting crop varieties with high and stable yields, as well as improving quality and economic benefits, has become a long-term topic while facing the continuous increasing population and the adverse effects of environmental changes. Therefore, developing fragrant rice varieties, strengthening the breeding of high-quality conventional indica rice, and developing functional rice with special nutritional value or specific needs of specific populations are important directions for future rice breeding. [Extracted from the article]

This study aimed to explore the therapeutic effects of adipose-derived stem cells (ADSCs)-based microtissues (MTs) on erectile dysfunction (ED) in streptozotocin (STZ)-induced diabetic rats. Fifty-six 8-week-old Sprague-Dawley rats received intraperitoneal injection of STZ (60 mg kg−1 ), and 8 weeks later, the determined diabetic rats randomly received intracavernous (IC) injection of phosphate buffer solution (PBS), ADSCs, or MTs. Another eight normal rats equally got IC injection of PBS. MTs were generated with a hanging drop method, and the injected cells were tracked in ADSC- and MT-injected rats. Four weeks after the treatments, intracavernous pressure (ICP), histopathological changes in corpus cavernosum (CC), and functional proteins were measured. Rat cytokine antibody array was used to detect ADSCs or MTs lysate. The results showed that MTs expressed vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and tumor necrosis factor-stimulated gene-6 (TSG-6). MTs injection had a higher retention than ADSCs injection and MTs treatment improved ICP, neuronal nitric oxide synthase (nNOS) expression, smooth muscle, and endothelial contents in diabetic rats, ameliorated local inflammation in CC better. Thus, our findings demonstrate that IC injection of MTs improves erectile function and histopathological changes in STZ-induced diabetic rats and appears to be more promising than traditional ADSCs. The underlying mechanisms involve increased cell retention accompanied with neuroprotection and anti-inflammatory behaviors of the paracrine factors.

Background: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. Methods: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg−1·min−1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg−1·d−1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. Results: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0.05). All these cellular and molecular effects induced by Ang II in the hearts of mice were reduced by DAPT treatment. Interestingly, Ang II stimulated Hey1, a known Notch target, but did not affect the expression of Hey2, another Notch target gene. Conclusions: A Jagged1-Hey1 signal might mediate the impairment of angiogenesis induced by Ang II during cardiac hypertrophy.

C18H16ClN2O2Cu, monoclinic, C2/c (no. 15), a = 23.330(5) Å, b = 7.1347(14) Å, c = 10.328(2) Å, β = 108.33(3)°, V = 1632.0(6) Å3, Z = 4, Rgt(F) = 0.0275, wRref(F2) = 0.0763, T = 296(2) K.

C24H36Br2N8Cd, monoclinic, P21/c (no. 14), a = 9.6915(4) Å, b = 7.6614(2) Å, c = 19.0851(8) Å, β = 100.529(4)°, V = 1393.21(9) Å3, Z = 2, Rgt(F) = 0.0744, wRref(F2) = 0.1823, T = 293(2) K.

C60H51N16O16Cl3Co2, monoclinic, P21/n (no. 14), a = 35.652(4) Å, b = 14.1314(16) Å, c = 25.141(3) Å, β = 105.113(2)°, V = 12228(3) Å3, Z = 8, Rgt(F) = 0.0651, wRref(F2) = 0.1663, T = 103(2) K.

Posterior long-segment spinal fusion may lead to proximal junctional kyphosis (PJK). The present study sought to identify the appropriate fusion levels required in order to prevent PJK using finite element analysis. A finite element model was constructed based on the whole-spine computed tomography findings of a healthy adult. Nine commonly used posterior spinal fusion methods were selected. Stress on the annulus fibrosis fibers, the posterior ligamentous complex, and the vertebrae after various spinal fusions in the upright position were compared. This study was divided into two groups: non-fusion and fusion. In the former, the stress between the T10 and the upper thoracic vertebrae was higher. Comparing thoracic and lumbar segments in the fusion group, the peak stress values of the upper instrumented vertebrae (UIV) were mainly observed in T2 and L2 whilst those of the UIV+1 were observed in T10 and L2. After normalization, the peak stress values of the UIV and UIV+1 were located in T2 and L2. Similarly, the peak stress values of the annulus fibrosus at the upper adjacent level were on T10 and L2 after normalization. However, the peak stress values of the interspinal/supraspinal complex forces were concentrated on T11, T12, and L1 after normalization whilst the peak stress value of the pedicle screw was on T2. Controversy remains over the fusion of T10, and this study simulated testing conditions with gravitational loading only. However, further assessment is needed prior to reaching definitive conclusions.

This research mainly studies the factors influencing the efficiency of energy utilization. Firstly, by calculating Moran’sI and local indicators of spatial association (LISA) of energy efficiency of regions in mainland China, we found that energy efficiency shows obvious spatial autocorrelation and spatial clustering phenomena. Secondly, we established the spatial quantile autoregression (SQAR) model, in which the energy efficiency is the response variable with seven influence factors. The seven factors include industrial structure, resource endowment, level of economic development etc. Based on the provincial panel data (1998–2016) of mainland China (data source: China Statistical Yearbook, Statistical Yearbook of provinces), the findings indicate that level of economic development and industrial structure have a significant role in promoting energy efficient. Resource endowment, government intervention and energy efficiency show a negative correlation. However, the negative effect of government intervention is weakened with the increase of energy efficiency. Lastly, we compare the results of SQAR with that of ordinary spatial autoregression (SAR). The empirical result shows that the SQAR model is superior to SAR model in influencing factors analysis of energy efficiency.