Autophagy, a tightly regulated lysosome-dependent catabolic pathway, is important in the regulation of cancer development and progression and in determining the response of tumor cells to anticancer ...therapy. However, the role of autophagy in leukemia still remains largely unknown. Here we show that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, was released from leukemia cell lines after chemotherapy-induced cytotoxicity and activated autophagy to protect against injury. Treatment with HMGB1-neutralizing antibodies increased the sensitivity of leukemia cells to chemotherapy; whereas, exogenous HMGB1 rendered these cells more resistant to drug-induced cytotoxicity. Moreover, exogenous HMGB1 increased autophagy as evaluated by increased expression of the autophagic marker microtubule-associated protein light chain 3-II, degradation of sequestosome 1 (p62) and autophagosome formation. Furthermore, knockdown or pharmacological inhibition of either phosphoinositide 3-kinase-III or extracellular signal-regulated kinase kinase mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase inhibited HMGB1-induced autophagy. Taken together, these results suggest that HMGB1 release after chemotherapy is a critical regulator of autophagy and a potential drug target for therapeutic interventions in leukemia.
A high-fat diet (HFD) has been previously associated with the development of diseases such as chronic colitis. While chlorogenic acid (CGA) is known to exhibit potent antioxidant, antibacterial, and ...anti-inflammatory properties, little is known about its effects on intestinal inflammation. In this study, we investigated the effects of CGA on intestinal inflammation in an HFD-induced obesity rat model and assessed whether these effects were related to changes in gut microbiota composition. This was achieved by examining physiological and biochemical indicators, the liver transcriptome, and the structure of the fecal microflora. CGA treatment significantly reduced HFD-induced internal organ weight gain, promoted colon tissue repair, downregulated the expression of inflammatory cytokines, and promoted the accumulation of the tight junction protein. KEGG enrichment analysis of differentially expressed genes, applied to data from the RNA-seq of rat liver tissue, revealed that CGA treatment significantly affected amino acid and lipid metabolism in the liver. Furthermore, CGA decreased the abundance of bacteria belonging to the genera Blautia, Sutterella, and Akkermansia and increased butyric acid levels, which were positively correlated with the abundance of Ruminococcus (butyric acid producer). Moreover, the beneficial changes observed in the HFD group were not as pronounced as those in the CGA treatment group. In summary, CGA can alleviate colitis in HFD-induced obesity through its anti-inflammatory effects associated with changes in gut microbiota composition and an increase in the production of short-chain fatty acids and thus can be used as a potential drug for the treatment of this pathology.
•A new numerical method is developed for solving agglomerate coagulation equation over the entire size regime;•The new method is achieved by hybridizing the advantage of IGDMOM and TEMOM, which ...overcomes the shortcoming of IGDMOM for dealing with coagulation kernel;•The new method is verified to achieve the higher precision than recognizable log MOM;•The study provides an alternative tool to resolve collision–coalescence dynamics compared to conventional methods.
The objective of this paper is to derive a model for studying the collision–coalescence dynamics of agglomerates. Accordingly, we first extend the inverse Gaussian distributed method of moments (IGDMOM; J. Atmospheric Sci., 2020, 77(9), 3011–3031) to solve the Smoluchowski coagulation equation for fractal-like agglomerates undergoing Brownian coagulation in the entire size regime. The extended IGDMOM, denoted as E-IGDMOM, is integrated with two solutions, namely Dahneke's solution and the harmonic mean solution, for deriving moment ordinary differential equations (MODEs) for Brownian coagulation in the free molecular regime and in the continuum-slip regime. Comparative analyses demonstrate that the E-IGDMOM achieves nearly the same efficiency as that of the Taylor-series expansion MOM (TEMOM) and the lognormal MOM (log MOM); nevertheless, it has higher precision than that of the log MOM in the free molecular regime and nearly the same precision as that of the TEMOM and log MOM in the transient regime. Regarding the skewness and kurtosis of size distribution functions, compared with the log MOM and IGDMOM, we observe that the E-IGDMOM yields values that are much closer to those of the quadrature MOM.
The refractory tungsten alloys with high ductility/strength/plasticity are highly desirable for a wide range of critical applications. Here we report an interface design strategy that achieves 8.5 mm ...thick W-0.5 wt. %ZrC alloy plates with a flexural strength of 2.5 GPa and a strain of 3% at room temperature (RT) and ductile-to-brittle transition temperature of about 100 °C. The tensile strength is about 991 MPa at RT and 582 MPa at 500 °C, as well as total elongation is about 1.1% at RT and as large as 41% at 500 °C, respectively. In addition, the W-ZrC alloy plate can sustain 3.3 MJ/m(2) thermal load without any cracks. This processing route offers the special coherent interfaces of grain/phase boundaries (GB/PBs) and the diminishing O impurity at GBs, which significantly strengthens GB/PBs and thereby enhances the ductility/strength/plasticity of W alloy. The design thought can be used in the future to prepare new alloys with higher ductility/strength.
Rice planthopper (RPH) populations of Nilaparvata lugens and Sogatella furcifera periodically have erupted across Asia. Predicting RPH population dynamics and identifying their source areas are ...crucial for the management of these migratory pests in China, but the origins of the migrants to temperate and subtropical regions in China remains unclear. In particular, their early migration to China in March and April have not yet been explored due to a lack of research data available from potential source areas, Central Vietnam and Laos. In this study, we examined the population dynamics and migratory paths of N. lugens and S. furcifera in Vietnam and South China in 2012 and 2013. Trajectory modeling showed that in March and April in 2012 and 2013, RPH emigrated from source areas in Central Vietnam where rice was maturing to the Red River Delta and South China. Early migrants originated from Southern Central Vietnam (14–16°N), but later most were from Northern Central Vietnam (16–19°N). Analysis of meteorological and light-trap data from Hepu in April (1977–2013) using generalized linear models showed that immigration increased with precipitation in Southern Central Vietnam in January, but declined with precipitation in Northern Central Vietnam in January. These results determined that the RPH originate from overwintering areas in Central Vietnam, but not from southernmost areas of Vietnam. Winter precipitation, rather than temperature was the most important factor determining the number of RPH migrants. Based on their similar population dynamics and low population densities in Central Vietnam, we further speculated that RPH migrate to track ephemeral food resources whilst simultaneously avoiding predators. Migrations do not seem to be initiated by interspecific competition, overcrowding or host deterioration. Nevertheless, S. furcifera establishes populations earlier than N. lugens South China, perhaps to compensate for interspecific competition. We provide new information that could assist with forecasting outbreaks and implementing control measures against these migratory pests.
Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but ...few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.
Frequency optimization is of great importance in the design of machines and structures subjected to dynamic loading. When the natural frequencies of considered structures are maximized using the ...solid isotropic material with penalization (SIMP) model, artificial localized modes may occur in areas where elements are assigned with lower density values. In this paper, a modified SIMP model is developed to effectively avoid the artificial modes. Based on this model, a new bi-directional evolutionary structural optimization (BESO) method combining with rigorous optimality criteria is developed for topology frequency optimization problems. Numerical results show that the proposed BESO method is efficient, and convergent solid-void or bi-material optimal solutions can be achieved for a variety of frequency optimization problems of continuum structures.
While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant ...tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
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