Development and application of the physiologically-based toxicokinetic (PBTK) model for ochratoxin A (OTA) in rats and humans.

Ochratoxin A (OTA) is a common fungal toxin frequently detected in food and human plasma samples. Currently, the physiologically based toxicokinetic (PBTK) model plays an active role in dose translation and can improve and enhance the risk assessment of toxins. In this study, the PBTK model of OTA in rats and humans was established based on knowledge of OTA-specific absorption, distribution, metabolism, and excretion (ADME) in order to better explain the disposition of OTA in humans and the discrepancies with other species. The models were calibrated and optimized using the available kinetic and toxicokinetic (TK) data, and independent test datasets were used for model evaluation. Subsequently, sensitivity analyses and population simulations were performed to characterize the extent to which variations in physiological and specific chemical parameters affected the model output. Finally, the constructed models were used for dose extrapolation of OTA, including the rat-to-human dose adjustment factor (DAF) and the human exposure conversion factor (ECF). The results showed that the unbound fraction (Fup) of OTA in plasma of rat and human was 0.02-0.04% and 0.13-4.21%, respectively. In vitro experiments, the maximum enzyme velocity (Vmax) and Michaelis-Menten constant (Km) of OTA in rat and human liver microsomes were 3.86 and 78.17 µg/g min-1, 0.46 and 4.108 µg/mL, respectively. The predicted results of the model were in good agreement with the observed data, and the models in rats and humans were verified. The PBTK model derived a DAF of 0.1081 between rats and humans, whereas the ECF was 2.03. The established PBTK model can be used to estimate short- or long-term OTA exposure levels in rats and humans, with the capacity for dose translation of OTA to provide the underlying data for risk assessment of OTA.

WS-RCNN: Learning to Score Proposals for Weakly Supervised Instance Segmentation.

Weakly supervised instance segmentation (WSIS) provides a promising way to address instance segmentation in the absence of sufficient labeled data for training. Previous attempts on WSIS usually follow a proposal-based paradigm, critical to which is the proposal scoring strategy. These works mostly rely on certain heuristic strategies for proposal scoring, which largely hampers the sustainable advances concerning WSIS. Towards this end, this paper introduces a novel framework for weakly supervised instance segmentation, called Weakly Supervised R-CNN (WS-RCNN). The basic idea is to deploy a deep network to learn to score proposals, under the special setting of weak supervision. To tackle the key issue of acquiring proposal-level pseudo labels for model training, we propose a so-called Attention-Guided Pseudo Labeling (AGPL) strategy, which leverages the local maximal (peaks) in image-level attention maps and the spatial relationship among peaks and proposals to infer pseudo labels. We also suggest a novel training loss, called Entropic OpenSet Loss, to handle background proposals more effectively so as to further improve the robustness. Comprehensive experiments on two standard benchmarking datasets demonstrate that the proposed WS-RCNN can outperform the state-of-the-art by a large margin, with an improvement of 11.6% on PASCAL VOC 2012 and 10.7% on MS COCO 2014 in terms of mAP50, which indicates that learning-based proposal scoring and the proposed WS-RCNN framework might be a promising way towards WSIS.

Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States.

Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.

[Research progress on potential targets-mitochondrial dynamics-related proteins in treatment of myocardial ischemia-reperfusion injury].

Acute myocardial infarction(AMI) is still the leading cause of death worldwide. At present, the treatment of AMI is mainly to restore the cardiac blood supply through myocardial reperfusion. With the widespread use of coronary artery bypass grafting and percutaneous coronary intervention(PCI), myocardial reperfusion injury is a major clinical problem. Mitochondrial dysfunction is an important pathological basis for myocardial ischemic injury. Therefore, mitochondria can be used as an important target against myocardial damage. In this article, we would briefly review the physiological functions of mitochondrial dynamics-related proteins as well as their pathological mechanisms and pharmacological interventions in treatment of myocardial ischemia-reperfusion injury.

Exposure to the BPA-Substitute Bisphenol S Causes Unique Alterations of Germline Function.

Concerns about the safety of Bisphenol A, a chemical found in plastics, receipts, food packaging and more, have led to its replacement with substitutes now found in a multitude of consumer products. However, several popular BPA-free alternatives, such as Bisphenol S, share a high degree of structural similarity with BPA, suggesting that these substitutes may disrupt similar developmental and reproductive pathways. We compared the effects of BPA and BPS on germline and reproductive functions using the genetic model system Caenorhabditis elegans. We found that, similarly to BPA, BPS caused severe reproductive defects including germline apoptosis and embryonic lethality. However, meiotic recombination, targeted gene expression, whole transcriptome and ontology analyses as well as ToxCast data mining all indicate that these effects are partly achieved via mechanisms distinct from BPAs. These findings therefore raise new concerns about the safety of BPA alternatives and the risk associated with human exposure to mixtures.

FTO promotes SREBP1c maturation and enhances CIDEC transcription during lipid accumulation in HepG2 cells.

The fat mass and obesity-associated (FTO) gene is tightly related to body weight and fat mass, and plays a pivotal role in regulating lipid accumulation in hepatocytes. However, the mechanisms underlying its function are poorly understood. Sterol regulatory element binding protein-1c (SREBP1c) is a transcription factor that regulates lipogenesis. Cell death-inducing DFFA (DNA fragmentation factor-α)-like effector c (CIDEC) plays a crucial role in lipid droplets (LDs) size controlling and lipid accumulation. In this report, we first observed that FTO overexpression in HepG2 cells resulted in an increase of lipogenesis and up-regulation of SREBP1c and CIDEC, two key regulatory factors in lipogenesis. In contrast, FTO knockdown in HepG2 cells resulted in a decrease of lipogenesis and down-regulation of SREBP1c and CIDEC expression. Moreover, SREBP1c knockdown resulted in a decrease of lipogenesis in HepG2 cells with FTO overexpression. In addition, FTO demethylation defect mutant presented less transcription of the key genes, and less nuclear translocation and maturation of SREBP1c. Further investigation demonstrated that overexpression of SREBP1c in HepG2 cells also promoted high CIDEC expression. Luciferase reporter assays showed that SREBP1c significantly stimulated CIDEC gene promoter activity. Finally, CIDEC knockdown reduced SREBP1c-induced lipogenesis. In conclusion, our studies suggest that FTO increased the lipid accumulation in hepatocytes by increasing nuclear translocation of SREBP1c and SREBP1c maturation, thus improving the transcriptional activity of LD-associated protein CIDEC. Our studies may provide new mechanistic insight into nonalcoholic fatty liver disease (NAFLD) mediated by FTO.

Mergeomics: a web server for identifying pathological pathways, networks, and key regulators via multidimensional data integration.

BACKGROUND: Human diseases are commonly the result of multidimensional changes at molecular, cellular, and systemic levels. Recent advances in genomic technologies have enabled an outpour of omics datasets that capture these changes. However, separate analyses of these various data only provide fragmented understanding and do not capture the holistic view of disease mechanisms. To meet the urgent needs for tools that effectively integrate multiple types of omics data to derive biological insights, we have developed Mergeomics, a computational pipeline that integrates multidimensional disease association data with functional genomics and molecular networks to retrieve biological pathways, gene networks, and central regulators critical for disease development. RESULTS: To make the Mergeomics pipeline available to a wider research community, we have implemented an online, user-friendly web server ( http://mergeomics. RESEARCH: idre.ucla.edu/ ). The web server features a modular implementation of the Mergeomics pipeline with detailed tutorials. Additionally, it provides curated genomic resources including tissue-specific expression quantitative trait loci, ENCODE functional annotations, biological pathways, and molecular networks, and offers interactive visualization of analytical results. Multiple computational tools including Marker Dependency Filtering (MDF), Marker Set Enrichment Analysis (MSEA), Meta-MSEA, and Weighted Key Driver Analysis (wKDA) can be used separately or in flexible combinations. User-defined summary-level genomic association datasets (e.g., genetic, transcriptomic, epigenomic) related to a particular disease or phenotype can be uploaded and computed real-time to yield biologically interpretable results, which can be viewed online and downloaded for later use. CONCLUSIONS: Our Mergeomics web server offers researchers flexible and user-friendly tools to facilitate integration of multidimensional data into holistic views of disease mechanisms in the form of tissue-specific key regulators, biological pathways, and gene networks.

Mergeomics: multidimensional data integration to identify pathogenic perturbations to biological systems.

BACKGROUND: Complex diseases are characterized by multiple subtle perturbations to biological processes. New omics platforms can detect these perturbations, but translating the diverse molecular and statistical information into testable mechanistic hypotheses is challenging. Therefore, we set out to create a public tool that integrates these data across multiple datasets, platforms, study designs and species in order to detect the most promising targets for further mechanistic studies. RESULTS: We developed Mergeomics, a computational pipeline consisting of independent modules that 1) leverage multi-omics association data to identify biological processes that are perturbed in disease, and 2) overlay the disease-associated processes onto molecular interaction networks to pinpoint hubs as potential key regulators. Unlike existing tools that are mostly dedicated to specific data type or settings, the Mergeomics pipeline accepts and integrates datasets across platforms, data types and species. We optimized and evaluated the performance of Mergeomics using simulation and multiple independent datasets, and benchmarked the results against alternative methods. We also demonstrate the versatility of Mergeomics in two case studies that include genome-wide, epigenome-wide and transcriptome-wide datasets from human and mouse studies of total cholesterol and fasting glucose. In both cases, the Mergeomics pipeline provided statistical and contextual evidence to prioritize further investigations in the wet lab. The software implementation of Mergeomics is freely available as a Bioconductor R package. CONCLUSION: Mergeomics is a flexible and robust computational pipeline for multidimensional data integration. It outperforms existing tools, and is easily applicable to datasets from different studies, species and omics data types for the study of complex traits.

The role of shrimp miR-965 in virus infection.

RNAi, mediated by microRNAs (miRNAs), has attracted increasing attention for its important role in cross-talk between host and virus. However, the role of host miRNA in the virus infection in vivo has not been intensively investigated. In this study, the effects of a shrimp miRNA (miR-965) on the white spot syndrome virus (WSSV) infection were characterized. The results indicated that the expression of miR-965 was significantly upregulated in shrimp in response to the WSSV challenge, suggesting its involvement in the virus infection. The miR-965 silencing led to significant increases of WSSV copies and virus-infected shrimp mortality, while the miR-965 overexpression resulted in the decreased WSSV copies and virus-infected shrimp mortality, indicating that miR-965 played a negative role in the WSSV infection. The further data revealed that miR-965 inhibited the virus infection by targeting the viral wsv240 gene, an important gene required for the WSSV infection in shrimp. The results demonstrated that miR-965 could promote the shrimp phagocytosis against virus infection by targeting the shrimp ATG5 (autophagy related 5) gene. Therefore, our findings presented novel evidence to better understand the anfractuous host-virus interactions in vivo.

Translocation of CIDEC in hepatocytes depends on fatty acids.

The CIDEC protein is located in lipid droplets (LDs) and the endoplasmic reticulum (ER) and is induced in fat deposition. However, the binding domain, the functional domain and the underlying mechanism of CIDEC in stimulating lipid accumulation remain unclear. Here, we investigated the subcellular localization and function of pig CIDEC and confirmed CIDEC promotes unilocular development of LDs, reduces the specific surface area (SSA) of LDs and stimulates lipid accumulation in HepG2 cells. By analyzing a series of CIDEC mutants, we showed the N-domain (1-173 amino acid) is involved in LD localization and the C-domain (174-238 amino acid) is necessary for LD fusion. Further analysis indicated that the 106-173 amino acid region includes an ER-binding domain. Moreover, CIDEC stayed in the ER under lipid-deficient conditions and translocated to LDs under fatty acid stimulation suggesting that localization of CIDEC in the ER is before the LD. Our data indicated additional fatty acids stimulated hepatic CIDEC expression and an increasing level of CIDEC induced hepatic LD fusion and lipid accumulation. Our work suggests that CIDEC protects LDs by decreasing the SSA of LDs and is involved in the regulation of hepatic lipid deposition.

Resistin reduces mitochondria and induces hepatic steatosis in mice by the protein kinase C/protein kinase G/p65/PPAR gamma coactivator 1 alpha pathway.

UNLABELLED: Obesity is associated with many severe chronic diseases and deciphering its development and molecular mechanisms is necessary for promoting treatment. Previous studies have revealed that mitochondrial content is down-regulated in obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) and proposed that NAFLD and diabetes are mitochondrial diseases. However, the exact mechanisms underlying these processes remain unclear. In this study, we discovered that resistin down-regulated the content and activities of mitochondria, enhanced hepatic steatosis, and induced insulin resistance (IR) in mice. The time course indicated that the change in mitochondrial content was before the change in fat accumulation and development of insulin resistance. When the mitochondrial content was maintained, resistin did not stimulate hepatic fat accumulation. The present mutation study found that the residue Thr464 of the p65 subunit of nuclear factor kappa B was essential for regulating mitochondria. A proximity ligation assay revealed that resistin inactivated peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1α) and diminished the mitochondrial content by promoting the interaction of p65 and PGC-1α. Signaling-transduction analysis demonstrated that resistin down-regulated mitochondria by a novel protein kinase C/protein kinase G/p65/PGC-1α-signaling pathway. CONCLUSION: Resistin induces hepatic steatosis through diminishing mitochondrial content. This reveals a novel pathway for mitochondrial regulation, and suggests that the maintenance of normal mitochondrial content could be a new strategy for treatment of obesity-associated diseases.

Long-term effect of dietary fibre intake on glycosylated haemoglobin A1c level and glycaemic control status among Chinese patients with type 2 diabetes mellitus.

OBJECTIVE: Dietary fibre has been linked to lower levels of glycosylated haemoglobin A1c (HbA1c) among diabetes patients. The present study aimed to evaluate the long-term effect of dietary fibre on HbA1c levels among Chinese patients with type 2 diabetes mellitus. DESIGN: Two cross-sectional surveys were conducted in 2006 and 2011, with the second one being a repeat survey on a sub-sample from the initial one. In both surveys, an in-person interview was conducted to collect information on demographic characteristics and lifestyles following a similar protocol. Dietary intake was assessed with a validated FFQ. Anthropometric measures and biochemical assays were performed at the interview. SETTING: Communities in Pudong New Area of Shanghai, China. SUBJECTS: Chinese patients (n 934) with type 2 diabetes mellitus. RESULTS: An inverse association was observed between dietary fibre and glycaemic status indicated by HbA1c level in both surveys, although it was significant only in the first survey. Among 497 patients participating in both surveys, dietary fibre intake at the first survey was inversely associated with uncontrolled glycaemic status at the second survey, with adjusted odds ratios across the tertiles of intake being 1·00, 0·72 (95 % CI 0·43, 1·21) and 0·58 (95 % CI 0·34, 0·99; P trend = 0·048). The change in fibre intake was slightly associated with glycaemic status, with each increase in tertile scores of intake linked to a 0·138 % (ß = -0·138; 95 % CI -0·002, 0·278) decrease in HbA1c value and a 19 % (OR = 0·81; 95 % CI 0·65, 1·02) reduced risk of uncontrolled glycaemic status at the second survey. CONCLUSIONS: Dietary fibre may have a long-term beneficial effect on HbA1c level among Chinese diabetes patients.

Systematic characterization of the chemical constituents in vitro and in vivo of Qianghuo by UPLC-Q-TOF-MS/MS.

The Chinese herb Qianghuo is an antiphlogistic herb with many effects and complex components. In this study, the chemical composition of Qianghuo and its components in rat plasma after oral administration were investigated using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). The extracts, blank plasma, and plasma containing the drug were analyzed by mass spectrometry, and data collected in both positive and negative ion modes were analyzed using Masslynx software, and the structures were confirmed by combining the compound fragment ions and mass spectrometry cleavage pathways. A total of 62 in vitro chemical components were identified, including 27 coumarins, 18 organic acids, 5 amino acids, 5 glycosides, 2 flavonoids, 4 nucleotides, and 1 ester, which were summarized from the obtained compounds in terms of their possible cleavage patterns. Among the identified 31 compounds in rat plasma, 21 were prototypes, mostly coumarins, organic acids, and flavonoids, and 10 were metabolites, which were mainly generated via hydroxylation and methylation pathways. Based on these, this study provides a theoretical foundation for quality control and basic research on Qianghuo medicinal substances.

Strong Intervalley Scattering-Induced Renormalization of Electronic and Thermal Transport Properties and Selection Rule Analysis in 2D Tellurium.

The electron-phonon interaction (EPI) and phonon-phonon interactions are ubiquitous in promising two-dimensional (2D) semiconductors, determining both electronic and thermal transport properties. In this work, based on ab initio calculations, the effects of intervalley scattering on EPI and higher-order four-phonon interactions of α-Te and ß-Te are investigated. Through the proposed selection rules for scattering channels and calculations of full electron-phonon scattering rates, we demonstrate that multiple nearly degenerate local valleys/peaks produce more scattering channels, resulting in stronger intervalley scattering over intravalley scattering. The lattice thermal conductivities of α-Te and ß-Te are decreased by as much as 10.9% and 30.8% by considering EPI under the carrier concentration of 2 × 1013 cm-2 (n-type) at 300 K compared to those limited by three-phonon scattering, respectively. However, when further considering four-phonon scattering, EPI reduces the lattice thermal conductivities by 2.6% and 19.4% for α-Te and ß-Te, respectively. Furthermore, it is revealed that the four-phonon interaction is more dominant in phonon transport for α-Te than that for ß-Te due to the presence of an acoustic-optical phonon gap in α-Te. Finally, we demonstrate strong intervalley scattering induces significant renormalization effects from EPI on all the constituent parameters of thermoelectric performance. Our results show the contributions of intervalley scattering to the electronic properties as well as thermal transport properties in band-convergent thermoelectric materials are essential and highlight the potential of monolayer tellurium as a promising candidate for advanced thermoelectric applications.

Ultra-Confined Phonon Polaritons and Strongly Coupled Microcavity Exciton Polaritons in Monolayer MoSi2N4 and WSi2N4.

The 2D semiconductors are an ideal platform for exploration of bosonic fluids composed of coupled photons and collective excitations of atoms or excitons, primarily due to large excitonic binding energies and strong light-matter interaction. Based on first-principles calculations, it is demonstrated that the phonon polaritons formed by two infrared-active phonon modes in monolayer MoSi2N4 and WSi2N4 possess ultra-high confinement factors of around ≈105 and 103, surpassing those of conventional polaritonic thin-film materials by two orders of magnitude. It is observed that the first bright exciton possesses a substantial binding energies of 750 and 740 meV in these two monolayers, with the radiative recombination lifetimes as long as 25 and 188 ns, and the Rabi splitting of the formed cavity-exciton polaritons reaching 373 and 321 meV, respectively. The effective masses of the cavity exciton polaritons are approximately 10-5me, providing the potential for high-temperature quantum condensation. The ultra-confined and ultra-low-loss phonon polaritons, as well as strongly-coupled cavity exciton polaritons with ultra-small polaritonic effective masses in these two monolayers, offering the flexible control of light at the nanoscale, probably leading to practical applications in nanophotonics, meta-optics, and quantum materials.

Characterising global antimicrobial resistance research explains why One Health solutions are slow in development: An application of AI-based gap analysis.

The global health crisis posed by increasing antimicrobial resistance (AMR) implicitly requires solutions based a One Health approach, yet multisectoral, multidisciplinary research on AMR is rare and huge knowledge gaps exist to guide integrated action. This is partly because a comprehensive survey of past research activity has never performed due to the massive scale and diversity of published information. Here we compiled 254,738 articles on AMR using Artificial Intelligence (AI; i.e., Natural Language Processing, NLP) methods to create a database and information retrieval system for knowledge extraction on research perfomed over the last 20 years. Global maps were created that describe regional, methodological, and sectoral AMR research activities that confirm limited intersectoral research has been performed, which is key to guiding science-informed policy solutions to AMR, especially in low-income countries (LICs). Further, we show greater harmonisation in research methods across sectors and regions is urgently needed. For example, differences in analytical methods used among sectors in AMR research, such as employing culture-based versus genomic methods, results in poor communication between sectors and partially explains why One Health-based solutions are not ensuing. Therefore, our analysis suggest that performing culture-based and genomic AMR analysis in tandem in all sectors is crucial for data integration and holistic One Health solutions. Finally, increased investment in capacity development in LICs should be prioritised as they are places where the AMR burden is often greatest. Our open-access database and AI methodology can be used to further develop, disseminate, and create new tools and practices for AMR knowledge and information sharing.

Sanguinarine modulates microglial function via PPARγ activation and protects against CNS demyelination.

Microglia aggregate in regions of active inflammation and demyelination in the CNS of multiple sclerosis (MS) patients and are considered pivotal in the disease process. Targeting microglia is a promising therapeutic approach for myelin repair. Previously, we identified two candidates for microglial modulation and remyelination using a Connectivity Map (CMAP)-based screening strategy. Interestingly, with results that overlapped, sanguinarine (SAN) emerged as a potential drug candidate to modulate microglial polarization and promote remyelination. In the current study, we demonstrate the efficacy of SAN in mitigating the MS-like experimental autoimmune encephalomyelitis (EAE) in a dose-dependent manner. Meanwhile, prophylactic administration of a medium dose (2.5 mg/kg) significantly reduces disease incidence and ameliorates clinical signs in EAE mice. At the cellular level, SAN reduces the accumulation of microglia in the spinal cord. Morphological analyses and immunophenotyping reveal a less activated state of microglia following SAN administration, supported by decreased inflammatory cytokine production in the spinal cord. Mechanistically, SAN skews primary microglia towards an immunoregulatory state and mitigates proinflammatory response through PPARγ activation. This creates a favorable milieu for the differentiation of oligodendrocyte progenitor cells (OPCs) when OPCs are incubated with conditioned medium from SAN-treated microglia. We further extend our investigation into the cuprizone-induced demyelinating model, confirming that SAN treatment upregulates oligodendrocyte lineage genes and increases myelin content, further suggesting its pro-myelination effect. In conclusion, our data propose SAN as a promising candidate adding to the preclinical therapeutic arsenal for regulating microglial function and promoting myelin repair in CNS demyelinating diseases such as MS.

[Dual-Perspective Analysis of the Warming Effect of the Methane Emissions from Animal Husbandry in China].

Accurate quantitative evaluation of the greenhouse effects of methane(CH4) is the foundation for developing effective mitigation strategies. This study was the first to quantitatively evaluate the warming effects of the CH4 emissions from animal husbandry in China using the recently proposed climate metric GWP-star(GWP*), which is designed for short-lived climate pollutants(SLCP), and to compare the results with the commonly used climate metric global warming potential(GWP). The results showed:CH4emissions from animal husbandry in China decreased from 957.0×105 t in 2000 to 764.0×105 t. The GWP results showed that the greenhouse effect of CH4 emissions from animal husbandry in China was increasing between 2015 and 2019, and the GWP* results showed that it decreased compared to that 20 years ago. The amount of reduction was equivalent to removing the warming of 2.1×108 t of carbon dioxide. Under the GWP evaluation system, achieving carbon neutrality in the livestock industry in China requires eliminating or offsetting stable annual CH4 emissions from increased carbon sinks. Instead, under the GWP* evaluation system, China's livestock industry could achieve its carbon neutrality in the short term by effectively reducing CH4 emissions by only 0.3% per year. In the case that the livestock industry in China continues to take effective emission reduction measures, the reduction target under the GWP* metric will be reached earlier than that under GWP. Still, the choice of GWP or GWP* requires careful consideration of the objectives of evaluation, the time scale of assessment, and practical operability.

NRG1 regulates Fra-1 transcription and metastasis of triple-negative breast cancer cells via the c-Myc ubiquitination as manipulated by ERK1/2-mediated Fbxw7 phosphorylation.

Neuregulin 1 (NRG1), an EGF family member, is expressed in most breast cancers. It promotes breast cancer growth and metastasis in HER2 receptor expressing breast cancer. However, its role in triple-negative breast cancer (TNBC) has not been extensively investigated. In this study, we observed that NRG1 knockdown resulted in the suppression of TNBC cells (MDA-MB-231 cell and MDA-MB-468 cell) metastasis and downregulation of Fra-1 (FOS-like 1, AP-1 transcription factor subunit, which is an overexpressed transcription factor in TNBC and acts as a coordinator of metastasis). In addition, the transcriptional regulation of Fra-1 by NRG1 was mediated by ERK1/2-induced recruitment of c-Myc (MYC proto-oncogene, transcription factor) to the promoter of Fra-1. Furthermore, c-Myc was targeted by an E3 ligase Fbxw7 and its ubiquitination and degradation by Fbxw7 was regulated by NRG1 expression and ERK1/2-mediated Fbxw7 phosphorylation that results in the dissociation and nuclear import of c-Myc. Taken together, the results of our study demonstrated that NRG1 regulates the Fra-1 expression to coordinate the TNBC metastasis via the novel ERK1/2-Fbxw7-c-Myc pathway and targeting NRG1 expression could be a potential therapeutic strategy for TNBC.

FRAT1 promotes the angiogenic properties of human glioblastoma cells via VEGFA.

Glioblastoma is a common central nervous system tumor and despite considerable advancements in treatment patient prognosis remains poor. Angiogenesis is a significant prognostic factor in glioblastoma, anti­angiogenic treatments represent a promising therapeutic approach. Vascular endothelial growth factor A (VEGFA) is a predominant regulator of angiogenesis and mounting evidence suggests that the Wnt signaling pathway serves a significant role in tumor angiogenesis. As a positive regulator of the Wnt/ß­catenin signaling pathway, frequently rearranged in advanced T­cell lymphomas­1 (FRAT1) is highly expressed in human glioblastoma and is significantly associated with glioblastoma growth, invasion and migration, as well as poor patient prognosis. Bioinformatics analysis demonstrated that both VEGFA and FRAT1 were highly expressed in most tumor tissues and associated with prognosis. However, whether and how FRAT1 is involved in angiogenesis remains to be elucidated. In the present study, the relationship between FRAT1 and VEGFA in angiogenesis was investigated using the human glioblastoma U251 cell line. Small interfering RNAs (siRNAs) were used to silence FRAT1 expression in U251 cells, and the mRNA and protein expression levels of VEGFA, as well as the concentration of VEGFA in U251 cell supernatants, were determined using reverse transcription­quantitative PCR, western blotting and ELISA. A tube formation assay was conducted to assess angiogenesis. The results demonstrated that siRNA knockdown significantly decreased the protein expression levels of FRAT1 in U251 cells and markedly decreased the mRNA and protein expression levels of VEGFA. Furthermore, the concentration of VEGFA in the cell supernatant was significantly reduced and angiogenesis was suppressed. These results suggested that FRAT1 may promote VEGFA secretion and angiogenesis in human glioblastoma cells via the Wnt/ß­catenin signaling pathway, supporting the potential use of FRAT1 as a promising therapeutic target in human glioblastoma.