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.

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.

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.

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.

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.

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.

GBP2 as a potential prognostic predictor with immune-related characteristics in glioma.

Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.

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.

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.

Association of ß-cell function and insulin resistance with pediatric type 2 diabetes among Chinese children.

BACKGROUND: In addition to insulin resistance, impaired insulin secretion has recently been identified as a crucial factor in the pathogenesis of type 2 diabetes mellitus (T2DM). Scarce clinical data exist for pediatric T2DM. AIM: To investigate the association of ß-cell function and insulin resistance with pediatric T2DM in the first Chinese multicenter study. METHODS: This multicenter cross-sectional study included 161 newly diagnosed T2DM children and adolescents between January 2017 and October 2019. Children with normal glycemic levels (n = 1935) were included as healthy control subjects. The homeostasis models (HOMAs) were used to assess the ß-cell function (HOMA2-%B) and insulin resistance (HOMA2-IR) levels. The HOMA index was standardized by sex and age. We performed logistic regression analysis to obtain odds ratios (ORs) for T2DM risk using the standardized HOMA index, adjusted for confounding factors including sex, Tanner stage, T2DM family history, body mass index z-score, and lipid profile. RESULTS: The male-female ratio of newly diagnosed T2DM patients was 1.37:1 (OR = 2.20, P = 0.011), and the mean ages of onset for boys and girls were 12.5 ± 1.9 years and 12.3 ± 1.7 years, respectively. The prevalence of related comorbidities including obesity, elevated blood pressure, and dyslipidemia was 58.2%, 53.2%, and 80.0%, respectively. The T2DM group had lower HOMA2-%B levels (P < 0.001) and higher HOMA2-IR levels (P < 0.001) than the control group. Both the decrease in HOMA2-%B z-score (OR = 8.40, 95%CI: 6.40-11.02, P < 0.001) and the increase in HOMA2-IR z-score (OR = 1.79, 95%CI: 1.60-2.02, P < 0.001) were associated with a higher risk of T2DM, and the decrease in HOMA2-%B z-score always had higher ORs than the increase in HOMA2-IR z-score after adjusting for confounding factors. CONCLUSION: Besides insulin resistance, ß-cell function impairment is also strongly associated with Chinese pediatric T2DM. Gender difference in susceptibility and high comorbidities warrant specific T2DM screening and prevention strategies in Chinese children.

Nrf2 Pathway Ameliorates Bladder Dysfunction in Cyclophosphamide-Induced Cystitis via Suppression of Oxidative Stress.

OBJECTIVE: To investigate the protective effect and molecular mechanism of nuclear factor E2-related factor 2 (Nrf2) pathway in interstitial cystitis (IC). METHODS: We established a mouse model of IC by cyclophosphamide (CYP) in wild-type mice and Nrf2 gene knockout mice. We examined the histological and functional alterations, the changes of oxidative stress markers, and the expression of the antioxidant genes downstream of Nrf2 pathway. RESULTS: After CYP administration, the mice showed urinary frequency and urgency, pain sensitization, decreased contractility, bladder edema, and oxidative stress disorder. Notably, the Nrf2-/- CYP mice had more severe symptoms. The mRNA and protein levels of antioxidant genes downstream of Nrf2 pathway were significantly upregulated in the Nrf2+/+ CYP mice, while there were no significant changes in the Nrf2-/- CYP mice. CONCLUSION: Nrf2 pathway protects bladder injury and ameliorates bladder dysfunction in IC, possibly by upregulating antioxidant genes and inhibiting oxidative stress.

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.

Clinical Effectiveness of Intravenous Peramivir Compared With Oseltamivir in Patients With Severe Influenza A With Primary Viral Pneumonia: A Randomized Controlled Study.

BACKGROUND: High-quality evidence confirms that the clinical efficacy of peramivir in severe influenza patients with primary viral pneumonia is lacking. To optimize clinical medication, we evaluate the different efficacy between peramivir and oseltamivir in the treatment of severe influenza A with primary viral pneumonia. METHODS: A single-center, randomized, controlled trial was conducted during the Chinese influenza season from December 2018 to April 2019 in patients with severe influenza A with primary viral pneumonia. A total of 40 inpatients were enrolled and treated with either intravenous peramivir (300 mg, once daily for 5 days) or oral oseltamivir (75 mg, twice daily for 5 days). RESULTS: The duration of influenza virus nucleic acid positivity in the oseltamivir group and the peramivir group was 2.95 days and 2.80 days, respectively. The remission times of clinical symptoms in the oseltamivir group and the peramivir group were 3.90 days and 3.25 days, respectively. In addition, the remission time of cough symptoms in the peramivir group (63.89 hours) was shorter than that in the oseltamivir group (75.53 hours). There was no significant difference between these values (P > .05). The remission time of fever symptoms in the oseltamivir group was 23.67 hours, which was significantly longer than that in the peramivir group (12.32 hours) (P = .034). CONCLUSIONS: Peramivir is no less effective than oseltamivir in the treatment of severe influenza A with primary viral pneumonia, and patients treated with peramivir had significantly shorter remission times of fever symptoms than those treated with oseltamivir.

Effect of autoflation on the prognosis of otitis media with effusion in children / 中华耳鼻咽喉头颈外科杂志

Objective: To investigate the effect of autoinflation on the prognosis of OME in children. Methods: Total of 325 pediatric patients, age ranged from 3 to 8 years, with OME(486 ears)diagnosed in our department from January 2019 to January 2020 were collected. Among them, 177 were males, 148 were females. Disease course ranged from 25 to 86 days. According to watchful waiting and autoinflation application during follow-up, these children were divided into two groups including 183 cases(271 ears) and 142 cases(215 ears), respectively. The average auditory threshold and tympanogram curve type in two groups were analyzed in the period of 3 months follow-up, and the recovery of OME was evaluated. Results: At the end of 1- and 2- month follow-up, the auditory threshold of patients in autoinflation group was significantly lower than that in watchful waiting group (t=2.139 5 and 2.680 6, P<0.05). However, at the end of 3- month follow-up, there was no significant difference between two groups (t=1.158 5, P>0.05). At the end of 1-, 2- and 3- month follow-up, 89 (33%, 89/271), 200 (74%, 200/271), 220 (81%, 220/271) and 176 (82%, 176/215), 178 (83%, 178/215), 183 (85%, 183/215) ears in watchful waiting group and autoinflation group had a hearing threshold <20 dB HL, respectively, in which ears with auditory threshold<20 dB HL in watchful waiting group were significantly less than those in autoinflation group at the end of 1 and 2 month follow-up (P<0.05), However, ears with auditory threshold<20 dB HL in watchful waiting group were not significantly different from that in the autoflation group at the end of 3- month follow-up (P>0.05). The proportion of ears with type A tympanogram curve was 74%(159/215), 79%(170/215), and 85%(183/215) at the end of 1-, 2- and 3- month follow-up in autoinflation group and 36%(98/271), 71%(192/271) and 76%(206/271) in watchful waiting group, respectively. Proportion of ears with type A tympanogram curve in autoflation group was significantly higher than that in watchful waiting group (P<0.05). Conclusion: Autoinflation can improve the hearing of children with OME in early stage, restore normal middle ear pressure, increase recovery rate, and reduce the choice of surgical treatment of OME.

[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.

Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell-Dependent Endothelial Cell Apoptosis.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.

Shrimp miR-965 induced the human melanoma stem-like cell apoptosis and inhibited their stemness by disrupting the MCL-1-ER stress-XBP1 feedback loop in a cross-species manner.

BACKGROUND: Melanoma is a type of aggressive skin cancer with a poor survival rate. The resistance to conventional therapy of this disease is, at least in part, attributed to its cancer stem cell population. However, the mechanism of survival and stemness maintenance of cancer stem cells remains to be investigated. METHODS: Tumorsphere formation assay was used to study the stem-like property of melanoma stem-like cells (MSLC). Chromatin immunoprecipitation (ChIP), promoter luciferase reporter assay were included for exploring the role of MCL-1 in MSLC and electrophoretic mobility shift assay were used to evaluate the interaction between shrimp miR-965 and human Ago2 protein. Melanoma xenograft nude mice were used to study the inhibition of tumor development. RESULTS: In the present study, our results showed that myeloid cell leukemia sequence 1 (MCL-1) knocking down induced ER stress and apoptosis, and the expression reduction of stemness associated genes in MSLC, which implied a significant role of MCL-1 in MSLC. Further study indicated that ER stress agonist (tunicamycin) treatment in MSLC results in the translocation of XBP1, an ER stress sensor, into the nucleus to induce MCL-1 expression through direct binding to the - 313- to - 308-bp region of MCL-1 promoter. In addition, we found that a shrimp-derived miRNA (shrimp miR-965) could interact with the human Ago2 protein and suppressed the human MCL-1 expression by binding to the 3' UTR of MCL-1 mRNA, thereby inhibiting the MSLC proliferation and stemness in vitro and in vivo in a cross-species manner. CONCLUSION: In conclusion, we identified an important role of MCL-1-ER stress-XBP1 feedback loop in the stemness and survival maintenance of MSLC, and shrimp miR-965, a natural food derived miRNA, could regulate MSLC stemness and survival by targeting MCL-1 and disrupting the balance of MCL-1-ER stress-XBP1 feedback loop. In conclusion, this study indicated an important mechanism of the regulation of MSLC stemness and survival, otherwise it also demonstrated the significance of cross-species-derived miRNA as promising natural drugs in melanoma therapy.

Differential metabolic and multi-tissue transcriptomic responses to fructose consumption among genetically diverse mice.

Understanding how individuals react differently to the same treatment is a major concern in precision medicine. Metabolic challenges such as the one posed by high fructose intake are important determinants of disease mechanisms. We embarked on studies to determine how fructose affects differential metabolic dysfunctions across genetically dissimilar mice, namely, C57BL/6 J (B6), DBA/2 J (DBA) and FVB/NJ (FVB), by integrating physiological and gene regulatory mechanisms. We report that fructose has strain-specific effects, involving tissue-specific gene regulatory cascades in hypothalamus, liver, and white adipose tissues. DBA mice showed the largest numbers of genes associated with adiposity, congruent with their highest susceptibility to adiposity gain and glucose intolerance across the three tissues. In contrast, B6 and FVB mainly exhibited cholesterol phenotypes, accompanying the largest number of adipose genes correlating with total cholesterol in B6, and liver genes correlating with LDL in FVB mice. Tissue-specific network modeling predicted strain-and tissue-specific regulators such as Fgf21 (DBA) and Lss (B6), which were subsequently validated in primary hepatocytes. Strain-specific fructose-responsive genes revealed susceptibility for human diseases such that genes in liver and adipose tissue in DBA showed strong enrichment for human type 2 diabetes and obesity traits. Liver and adipose genes in FVB were mostly related to lipid traits, and liver and adipose genes in B6 showed relevance to most cardiometabolic traits tested. Our results show that fructose induces gene regulatory pathways that are tissue specific and dependent on the genetic make-up, which may underlie interindividual variability in cardiometabolic responses to high fructose consumption.

Predicting the weld width from high-speed successive images of the weld zone using different machine learning algorithms during laser welding.

The dynamic behavior of the keyhole and molten pool is associated with the quality of weld seam. In this study, an on-line visual monitoring system is devised to photograph the keyhole and molten pool during external magnetic field assisted laser welding on the AISI 2205 duplex stainless steel plates. Seven features are defined to describe the morphology of the keyhole and molten pool. Then, the principal component analysis (PCA) algorithm is applied to reduce the dimensions of these features to obtain different number of principal components (PCs). Three different machine learning algorithms, i.e. the back propagation neural network (BPNN), the radial based function neural network (RBFNN) and the support vector regression (SVR), are utilized to fit the relationship between the chosen PCs and the weld width. Finally, the global and local prediction accuracy of these three machine learning algorithms are compared under different number of PCs. Results illustrated that data dimensionality reduction is helpful to improve the modeling efficiency. Machine learning algorithms can be exploited to predict the weld quality during laser welding with high accuracy. Among them, the BPNN model performs best and SVR model performs better than RBFNN model in this research. This work aims to model the relation between the features in weld zone and the weld quality with different machine learning algorithms, and provides a guideline of model selection for laser welding on-line monitoring and a necessary foundation for realizing intelligent welding with advanced algorithm.