Cancer development in hepatocytes by long-term induction of hypoxic hepatocellular carcinoma cell (HCC)-derived exosomes in vivo and in vitro

Hypoxic tumor cell-derived exosomes play a key role in the occurrence, development, and metastasis of tumors. However, the mechanism of hypoxia-mediated metastasis remains unclear. In this study, hypoxic hepatocellular carcinoma cell (HCC-LM3)-derived exosomes (H-LM3-exos) were used to induce hepatocytes (HL-7702) over a long term (40 passages in 120 days). A nude mouse experiment further verified the effect of H-LM3-exos on tumor growth and metastasis. The process of cancer development in hepatocytes induced by H-LM3-exos was analyzed using both biological and physical techniques, and the results showed that the proliferation and soft agar growth abilities of the transformed cells were enhanced. The concentration of tumor markers secreted by transformed cells was increased, the cytoskeleton was disordered, and the migration ability was enhanced and was accompanied by epithelial−mesenchymal transition (EMT). Transcriptome results showed that differentially expressed genes between transformed cells and hepatocytes were enriched in cancer-related signaling pathways. The degree of cancer development in transformed cells was enhanced by an increase in H-LM3-exos-induced passages. Nude mice treated with different concentrations of H-LM3-exos showed different degrees of tumor growth and liver lesions. The physical properties of the cells were characterized by atomic force microscopy. Compared with the hepatocytes, the height and roughness of the transformed cells were increased, while the adhesion and elastic modulus were decreased. The changes in physical properties of primary tumor cells and hepatocytes in nude mice were consistent with this trend. Our study linking omics with the physical properties of cells provides a new direction for studying the mechanisms of cancer development and metastasis

Transcriptome and HS-SPME-GC-MS analysis of key genes and flavor components associated with beef marbling

Wagyu cattle are well-known for their rich marbling. Qinchuan cattle have slower-depositing marbling than Wagyu cattle. However, because of an increase in the consumer demand for high-quality beef and the increasingly stringent standards of beef quality, improving the marbling grade of Qinchuan cattle has become particularly crucial. Therefore, we here considered castrated crossbred Wagyu cattle (crossed with Qinchuan cattle) as the research subjects. Flavor substances in the longissimus dorsi muscle (LDM) of A1 and A5 grades were detected through headspace-solid-phase microextraction-gas chromatography–mass spectrometry (HS-SPME-GC-MS) and electronic nose (E-nose) analysis. Fat deposition-regulating functional genes in both groups were identified through RNA sequencing (RNA-seq) and Weighted gene co-expression network analysis (WGCNA). The results showed that the intramuscular fat (IMF) was significantly higher in A5-grade beef (32.96 ± 1.88) than in A1-grade beef (10.91 ± 1.07) (p < 0.01). In total, 41 and 39 flavor compounds were detected in A1 and A5 grade beef, respectively. Seven aroma compounds were identified base on odor activity values (OAVs) ≥ 1, namely decanal, hexanal, nonanal, heptanol, 1-octen-3-ol, pentanol, and hexanoic acid-methyl ester. Additionally, FABP4, PLIN1, LIPE, ACACA, and CIDEA were the key genes primarily involved in cholesterol metabolism, sterol metabolism, and the PPAR signaling pathway in the two grades of beef. This study attempted to offer comprehensive information on marbling formation-associated candidate genes and gene-enriched pathways, which provides data for future research in beef cattle breeding and beef quality improvement

A three-dimensional network of graphene/silicon/graphene sandwich sheets as anode for Li-ion battery

Abstract(#br)A freestanding porous three-dimensional (3D) network composed of graphene/silicon/graphene sandwich sheets is proposed to prevent the expansion induced pulverization for Si-based anode in a lithium-ion battery. The architecture ensures the attachment of Si active material, improves the conductivity, and absorbs the Si volume expansions. The 3D Graphene and Si in this architecture work synergistically to contribute to the capacity, while the nanoscale of Si lowers the expansion during lithiation. And the 3D graphene with an interconnected skeleton, in addition to active material, also acts as the current collector as well as a stable support for Si

Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China

Abstract Background The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations. Methods Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped. Results Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A. Conclusion Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings enhance our understanding of HIV-1 evolution and are valuable for the development and implementation of a comprehensive public health approach to HIV-1 DR prevention and treatment in the region. </jats:sec

Deregulation of DUX4 and ERG in acute lymphoblastic leukemia

Chromosomal rearrangements deregulating hematopoietic transcription factors are common in acute lymphoblastic leukemia (ALL).1,2 Here, we show that deregulation of the homeobox transcription factor gene DUX4 and the ETS transcription factor gene ERG are hallmarks of a subtype of B-progenitor ALL that comprises up to 7% of B-ALL. DUX4 rearrangement and overexpression was present in all cases, and was accompanied by transcriptional deregulation of ERG, expression of a novel ERG isoform, ERGalt, and frequent ERG deletion. ERGalt utilizes a non-canonical first exon whose transcription was initiated by DUX4 binding. ERGalt retains the DNA-binding and transactivating domains of ERG, but inhibits wild-type ERG transcriptional activity and is transforming. These results illustrate a unique paradigm of transcription factor deregulation in leukemia, in which DUX4 deregulation results in loss-of-function of ERG, either by deletion or induction of expression of an isoform that is a dominant negative inhibitor of wild type ERG function

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Seismic analysis of gravity dam-reservoir-foundation systems using scaled boundary finite element method

A gravity dam is designed to retain water by using its self-weight to resist hydro-pressure of the reservoir. When an earthquake occurs, the energy emanated from the earthquake source may reach the dam site and cause the dam to vibrate. The earthquake action at the site is often the most critical loading case in the design of gravity dams. The estimation of the dynamic responses of gravity dams to earthquakes is necessary for achieving optimal upgrades and maintenance, and for improving our confidence in knowing that a dam will survive the impact of an earthquake of a specified magnitude. This thesis develops an efficient approach to the seismic analysis of gravity dam-reservoir-foundation systems with an emphasis on the seismic input modelling and adaptive damage simulation of dams. The whole system is divided into a bounded domain including the dam body and adjacent parts of reservoir and foundation, and an unbounded domain of reservoir and an unbounded domain of foundation. The dynamic properties of the unbounded domains are simulated by artificial boundaries formulated in the framework of Scaled Boundary Finite Element Method (SBFEM). The seismic waves are considered as plane waves in both two-dimensional and three-dimensional media. The seismic waves are inputted to the bounded domains by means of the Domain Reduction Method (DRM) through a single layer of elements adjacent to the interface between the bounded domain and the unbounded domain of foundation. The fully automatic quadtree/octree mesh technique is employed to discretize the complex geometry of the bounded domain including the dam and geological features in the foundation. The scaled boundary finite element method is applied in the bounded domain and overcomes the issue of hanging node faced by standard finite elements. The continuum damage mechanics is applied to model concrete and rocks as quasi-brittle materials. An h-adaptive strategy is developed for damage analysis to improve the computational efficiency. A progressive damage process is simulated through a series of optimal meshes. The proposed strategy simplifies the implementation of the adaptive analysis in automatic mesh refinement and data transfer. As the final outcome of this thesis, an automatic and efficient SBFEM formulation for seismic analysis of gravity dam-reservoir-foundation interaction systems has been developed. Case studies of gravity dams are performed

Research Progress on Calcium Ion in Gametophytic Self-Incompatibility

Calcium ions are involved in plant self-incompatibility response as important signaling substances in cells. In the sporophytic self-incompatibility response, Ca2+ enters the stigma papilla cells and plays a key role in inhibiting incompatible pollen tube growth. In the gametophytic self-incompatibility reaction of Papaveraceae, the female determinants in the style (PrsS) and the male determinants in the pollen (PrpS) recognize each other, promote extracellular Ca2+ influx into the incompatible pollen tube, destroy the calcium ion gradient at the tip of the pollen tube, and inhibit the pollen tube growth. In the S-RNase-based Rosaceae game-tophytic self-incompatibility response, it is still unclear how the S-RNase interacts with the male determinant and how the S-RNase specifically degrades the RNA in the pollen tube. Therefore, we reviewed the research progress on the role of Ca2+ in self-incompatibility and, based on our research results, proposed a role model of Ca2+ as a signal substance in the gametophyte self-incompatibility response in Rosaceae