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In this study, the effect of cyclic compression on the micromechanical properties of a Zr-based metallic glass (MG) was investigated via nanoindentation. Cyclic compression significantly softened the surface of the sample, with a maximum hardness loss of 19.93%. The number of cyclic compression passes had a greater effect on the hardness of the sample than the cyclic compression load. The elastic modulus exhibited a nonlinear variation upon increasing the cyclic loading or number of passes at a lower loading rate due to the coupling effect of loading rate and cyclic compression treatment. Then, the serration behavior and strain rate sensitivity analysis were applied. The calculated m-values obtained for MGs were all negative and gradually tended to zero upon further cyclic compression treatment. This demonstrated the weakening effect of cyclic compression on the strain rate sensitivity of MG, and the underlying mechanism was discussed. This study provides a process reference for studying the fatigue failure behaviors of MGs from the perspective of mechanical properties, which is useful for understanding their fatigue generation.

Myeloid-derived suppressor cells (MDSCs) occupy a pivotal role in the intricate pathogenesis of the autoimmune disorder, Type 1 diabetes mellitus (T1DM). Since our previous work demonstrated that trichosanthin (TCS), an active compound of Chinese herb medicine Tian Hua Fen, regulated immune response, we aimed to clarify the efficacy and molecular mechanism of TCS in the treatment of T1DM. To this end, T1DM mouse model was established by streptozotocin (STZ) induction. The mice were randomly divided into normal control group (Ctl), T1DM group (STZ), TCS treated diabetic group (STZ + TCS) and insulin-treated diabetic group (STZ + insulin). Our comprehensive evaluation encompassed variables such as blood glucose, glycosylated hemoglobin, body weight, pertinent biochemical markers, pancreatic histopathology, and the distribution of immune cell populations. Furthermore, we meticulously isolated MDSCs from the bone marrow of T1DM mice, probing into the expressions of genes pertaining to the advanced glycation end product receptor (RAGE)/NF-κB signaling pathway through RT-qPCR. Evidently, TCS exhibited a substantial capacity to effectively counteract the T1DM-induced elevation in random blood glucose, glycosylated hemoglobin, and IL-6 levels in plasma. Pathological scrutiny underscored the ability of TCS to mitigate the damage incurred by islets. Intriguingly, TCS interventions engendered a reduction in the proportion of MDSCs within the bone marrow, particularly within the IL-6+ MDSC subset. In contrast, IL-10+ MDSCs exhibited an elevation following TCS treatment. Moreover, we observed a significant down-regulation of relative mRNA of pro-inflammatory genes, including arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), RAGE and NF-κB, within MDSCs due to the influence of TCS. It decreases total MDSCs and regulates the balance between IL-6+ and IL-10+ MDSCs thus alleviating the symptoms of T1DM. TCS also down-regulates the RAGE/NF-κB signaling pathway, making it a promising alternative therapeutic treatment for T1DM. Collectively, our study offered novel insights into the underlying mechanism by which TCS serves as a promising therapeutic intervention for T1DM.

Federated learning has become a prevalent distributed training paradigm, in which local devices collaboratively train learning models without exchanging local data. One of the most dominant frameworks of federated learning (FL) is FedAvg, since it is efficient and simple to implement; here, the first-order information is generally utilized to train the parameters of learning models. In practice, however, the gradient information may be unavailable or infeasible in some applications, such as federated black-box optimization problems. To solve the issue, we propose an innovative zeroth-order adaptive federated learning algorithm without using the gradient information, referred to as ZO-AdaFL, which integrates the zeroth-order optimization algorithm into the adaptive gradient method. Moreover, we also rigorously analyze the convergence behavior of ZO-AdaFL in a non-convex setting, i.e., where ZO-AdaFL achieves convergence to a region close to a stationary point at a speed of O(1/T) (T represents the total iteration number). Finally, to verify the performance of ZO-AdaFL, simulation experiments are performed using the MNIST and FMNIST datasets. Our experimental findings demonstrate that ZO-AdaFL outperforms other state-of-the-art zeroth-order FL approaches in terms of both effectiveness and efficiency.

The building extraction method of remote sensing images that uses deep learning algorithms can solve the problems of low efficiency and poor effect of traditional methods during feature extraction. Although some semantic segmentation networks proposed recently can achieve good segmentation performance in extracting buildings, their huge parameters and large amount of calculation lead to great obstacles in practical application. Therefore, we propose a lightweight network (named LRAD-Net) for building extraction from remote sensing images. LRAD-Net can be divided into two stages: encoding and decoding. In the encoding stage, the lightweight RegNet network with 600 million flop (600 MF) is finally selected as our feature extraction backbone net though lots of experimental comparisons. Then, a multiscale depthwise separable atrous spatial pyramid pooling structure is proposed to extract more comprehensive and important details of buildings. In the decoding stage, the squeeze-and-excitation attention mechanism is applied innovatively to redistribute the channel weights before fusing feature maps with low-level details and high-level semantics, thus can enrich the local and global information of the buildings. What's more, a lightweight residual block with polarized self-attention is proposed, it can incorporate features extracted from the space of maps and different channels with a small number of parameters, and improve the accuracy of recovering building boundary. In order to verify the effectiveness and robustness of proposed LRAD-Net, we conduct experiments on a self-annotated UAV dataset with higher resolution and three public datasets (the WHU aerial image dataset, the WHU satellite image dataset and the Inria aerial image dataset). Compared with several representative networks, LRAD-Net can extract more details of building, and has smaller number of parameters, faster computing speed, stronger generalization ability, which can improve the training speed of the network without affecting the building extraction effect and accuracy.

Treg cells can be functionally altered by epigenetic modulators. Here the authors show that the histone H3K36 methyltransferase Setd2 is important for the survival of Treg cells and for the regulation of IL-33 mediated Th2 responses in mice and SETD2 expression is increased in Treg cells from human colorectal cancer tissue.

m6Am is a dynamic and reversible RNA modification found on the mRNA cap. Here the authors report m6Am-seq to directly distinguish m6Am from m6A and identify functional methylation sites.

Abstract Long-term studies have shown that virus infection affects the energy metabolism of host cells, which mainly affects the function of mitochondria and leads to the hydrolysis of ATP in host cells, but it is not clear how virus infection participates in mitochondrial energy metabolism in host cells. In our study, HUVEC cells were infected with HSV-1, and the differentially expressed genes were obtained by microarray analysis and data analysis. The viral gene encoding protein UL16 was identified to interact with host protein ANT2 by immunoprecipitation and mass spectrometry. We also reported that UL16 transfection promoted oxidative phosphorylation of glucose and significantly increased intracellular ATP content. Furthermore, UL16 was transfected into the HUVEC cell model with mitochondrial dysfunction induced by d-Gal, and it was found that UL16 could restore the mitochondrial function of cells. It was first discovered that viral protein UL16 could enhance mitochondrial function in mammalian cells by promoting mitochondrial metabolism. This study provides a theoretical basis for the prevention and treatment of mitochondrial dysfunction or the pathological process related to mitochondrial dysfunction.

Abstract Steroid receptor RNA activator 1 (SRA1) has been described as a novel transcriptional co-activator that affects the migration of cancer cells. Through RT-PCR, we identified that skipping exon 3 of SRA1 produces two isoforms, including the truncated short isoform, SRA1-S, and the long isoform, SRA1-L. However, the effect of these two isomers on the migration of HCC cells, as well as the specific mechanism of exon 3 skipping remain unclear. In this study, we found up regulated expression of SRSF1 and SRA1-L in highly metastatic HCCLM3, as well as in HCCs with SRSF1 demonstrating the strongest correlation with SRA1-L. In contrast, we observed a constitutively low expression of SRA1-S and SRSF1 in lowly metastatic HepG2 cells. Overexpression of SRSF1 or SRA1-L promoted migration and invasion by increasing the expression of CD44, while SRA1-S reversed the effect of SRSF1 and SRA1-L in vitro. In addition, lung metastasis in mice revealed that, knockdown of SRSF1 or SRA1-L inhibited the migration of HCC cells, while SRA1-L overexpression abolished the effect of SRSF1 knockout and instead promoted HCC cells migration in vivo. More importantly, RNA immunoprecipitation and Cross-link immunoprecipitation analyses showed that SRSF1 interacts with exon 3 of SRA1 to up regulate the expression of SRA1-L in HCC cells. RNA pull-down results indicated that SRSF1 could also bind to exon 3 of SRA1 in vitro. Finally, minigene -MS2 mutation experiments showed that mutation of the SRA1 exon 3 binding site for SRSF1 prevented the binding of SRA1 pre-mRNA. In summary, our results provide experimental evidence that SRA1 exon 3 inclusion is up regulated by SRSF1 to promote tumor invasion and metastasis in hepatocellular carcinoma.

Abstract An ultrathin and flexible metamaterial absorber (MA) with triple absorption peaks is presented in this paper. The proposed absorber has been designed in such a way that three absorption peaks are located at 8.5, 13.5, and 17 GHz (X and Ku bands) with absorption of 99.9%, 99.5%, and 99.9%, respectively. The proposed structure is only 0.4 mm thick, which is approximately 1/88, 1/55, and 1/44 for the respective free space wavelengths of absorption frequency in various bands. The MA is also insensitive due to its symmetric geometry. In addition, the proposed structure exhibits minimum 86% absorption (TE incidence) within 60° angle of incidence. For TM incidence, the proposed absorber exhibits more than 99% absorptivity up to 60° incidence. Surface current and electric field distributions were investigated to analyze the mechanism governing absorption. Parameter analyses were performed for absorption optimization. Moreover, the performance of the MA was experimentally demonstrated in free space on a sample under test with 20 × 30 unit cells fabricated on a flexible dielectric. Under normal incidence, the fabricated MA exhibits near perfect absorption at each absorption peak for all polarization angles, and the experimental results were found to be consistent with simulation results. Due to its advantages of high-efficiency absorption over a broad range of incidence angles, the proposed absorber can be used in energy harvesting and electromagnetic shielding.

Non-essential proteins for viral replication affect host cell metabolism, while the function of the UL43 protein of herpes simplex virus 1 (HSV-1) is not clear. Herein, we performed a comprehensive microarray analysis of HUVEC cells infected with HSV-1 and its UL43-deficient mutant and found significant variation in genes associated with cellular energy metabolic pathways. The localization of UL43 protein in host cells and how it affects cellular energy metabolism pathways were further investigated. Internalization analysis showed that the UL43 protein could be endocytosis-mediated by YPLF motif (aa144–147) and localized to mitochondria. At the same time, more ATP was produced by coupling with mitochondrial small G protein ARF-like 2 (ARL2) GTPase, which triggered the phosphorylation of ANT1 (SLC25A4) to affect the opening degree of mitochondrial permeability transition pore (mPTP), and significantly promoted the aerobic oxidation and oxidative phosphorylation of glucose. Our study shows that UL43 mediates the improvement of host cell metabolism after HSV-1 infection. Additionally, UL43 protein could be a valuable ATP-stimulating factor for mammalian cells.

The slow proliferation rate and poor osteodifferentiation ability of inflammatory periodontal membrane stem cells extracted from periodontitis tissues (i-PDLSCs) account for poor efficiency in treating inflammatory bone loss. Exosomes reportedly have inducible and relatively stable components, allowing them to promote inflammatory bone repair, but obtaining i-PDLSCs exosomes with the ability to promote osteodifferentiation is challenging. In the present study, i-PDLSCs were extracted from periodontal membrane tissues of patients with severe periodontitis, and in vitro induction with gallic acid (GA) significantly promoted the proliferative activity of i-PDLSCs at a concentration of 10 mM, with TC0 of 11.057 mM and TC50 of 67.56 mM for i-PDLSCs. After mRNA sequencing, we found that GA could alleviate oxidative stress in i-PDLSCs and increase its mitochondrial membrane potential and glucose aerobic metabolism level, thus promoting the osteodifferentiation of i-PDLSCs. After exosomes of i-PDLSCs after GA induction (i-EXO-GA) were isolated by differential centrifugation, we found that 200 ug/mL of i-EXO-GA could remarkably promote the osteodifferentiation of i-PDLSCs. Overall, our results suggest that GA induction can enhance the proliferation and osteodifferentiation in primary cultures of i-PDLSCs in vitro, mediated by alleviating oxidative stress and glycometabolism levels in cells, which further influences the osteodifferentiation-promoting ability of i-EXO-GA. Overall, we provide a viable cell and exosome induction culture method for treating inflammatory alveolar defects associated with periodontitis.

BackgroundThe rapid growth of social media as an information channel has made it possible to quickly spread inaccurate or false vaccine information, thus creating obstacles for vaccine promotion. ObjectiveThe aim of this study is to develop and evaluate an intelligent automated protocol for identifying and classifying human papillomavirus (HPV) vaccine misinformation on social media using machine learning (ML)–based methods. MethodsReddit posts (from 2007 to 2017, N=28,121) that contained keywords related to HPV vaccination were compiled. A random subset (2200/28,121, 7.82%) was manually labeled for misinformation and served as the gold standard corpus for evaluation. A total of 5 ML-based algorithms, including a support vector machine, logistic regression, extremely randomized trees, a convolutional neural network, and a recurrent neural network designed to identify vaccine misinformation, were evaluated for identification performance. Topic modeling was applied to identify the major categories associated with HPV vaccine misinformation. ResultsA convolutional neural network model achieved the highest area under the receiver operating characteristic curve of 0.7943. Of the 28,121 Reddit posts, 7207 (25.63%) were classified as vaccine misinformation, with discussions about general safety issues identified as the leading type of misinformed posts (2666/7207, 36.99%). ConclusionsML-based approaches are effective in the identification and classification of HPV vaccine misinformation on Reddit and may be generalizable to other social media platforms. ML-based methods may provide the capacity and utility to meet the challenge involved in intelligent automated monitoring and classification of public health misinformation on social media platforms. The timely identification of vaccine misinformation on the internet is the first step in misinformation correction and vaccine promotion.

Group 3 innate lymphoid cells (ILC3s) have important functions in inflammatory bowel disease. Here, the authors show that TL1A/DR3 signalling stimulates ILC3s to produce GM-CSF, thereby recruiting inflammatory cells, which results in subsequent IL-23-dependent loss of ILC3s and further intestinal inflammation.

The potential advantages of recombinant microbes as oral drug carriers for curing diseases have attracted much attention. The use of recombinant oil microbes as living cell liposomes to carry polypeptide drugs may be an ideal polypeptide oral drug delivery system. GM4-ΔTS was constructed by LFH-PCR from Rhodotorula glutinis GM4, which was screened and preserved in our laboratory, and then transferred into choline-phosphate cytidylyltransferase (CCT), which is a rate-limiting enzyme for lecithin synthesis. The results showed that the CCT gene was highly expressed in the GM4-ΔTS strain and could significantly increase fatty acid and lecithin contents in GM4-ΔTS-PGK1-CCT. Moreover, insulin, H22-LP, and α-MSH were successfully introduced into cells in vitro, and the strain no longer proliferated in vivo, for safe and controllable polypeptide drug delivery. In vivo, normal mice were intragastrically administered with recombinant strains carrying insulin and α-MSH, and different levels of polypeptide drugs were detected in serum and tissue, respectively. Then, recombinant strains carrying insulin were administered to type II diabetes mellitus mice. The results showed that the strains could effectively reduce blood glucose levels in mice, which indicated that the recombinant strains could carry insulin into the body, and the drug effect was remarkable. Therefore, recombinant GM4-ΔTS-PGK1-CCT strains were successfully used as living cell liposomes to carry insulin, H22-LP, and α-MSH peptides into the body for the first time; additionally, these strains have enhanced safety, controllability, and efficacy.

In this paper, a theoretical numerical analysis of the thermodynamics second law in ammonia/ethylene counter-flow diffusion flames is carried out. The combustion process, which includes heat and mass transfer, as well as a chemical reaction, is simulated based on a detailed chemical reaction model. Entropy generation and exergy loss due to various reasons in ammonia/ethylene and argon/ethylene flames are calculated. The effects of ammonia addition on the thermodynamics efficiency of combustion are investigated. Based on thermodynamics analysis, a parameter, the lowest emission of pollutant (LEP), is proposed to establish a relationship between the available work and pollutant emissions produced during the combustion process. Chemical reaction paths are also analyzed by combining the chemical entropy generation, and some important chemical reactions and substances are identified. The numerical results reveal that ammonia addition has a significant enhancement on heat transfer and chemical reaction in the flames, and the total exergy loss rate increases slightly at first and then decreases with an increase in ammonia concentration. Considering the factors of thermodynamic efficiency, the emissions of CO2 and NOx reach a maximum when ammonia concentration is near 10% and 30%, respectively. In terms of the chemical reaction path analysis, ammonia pyrolysis and nitrogen production increase significantly, while ethylene pyrolysis and carbon monoxide production decrease when ammonia is added to hydrocarbon diffusion flames.

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D.

In this work, a single-band metamaterial absorber (MA) based on a three dimensional (3D) resonant structure is presented. The unit cell is composed of a standing gear-shaped resonator, which is embedded in the dielectric substrate. The proposed 3D MA is ultrathin with a total thickness of 2.3 mm, corresponding 0.077λ0 at its center frequency. The simulation results demonstrate a high absorption peak at 10.1 GHz with absorptivity of 99.9%. The proposed 3D MA is insensitive to the polarization of the incident wave due to its rotationally symmetric structure. Moreover, the proposed 3D MA exhibits a wide-incident-angle stability, as absorptivity of more than 85% can be achieved for both TE and TM incidences with incident angle up to 60°. Most importantly, multiband electromagnetic wave absorption of the stereo MA can be enabled by adjusting the structural parameters of the standing gear. The proposed structure is compatible with 3D printing technology and has potential applications in electromagnetic shielding.

[This corrects the article DOI: 10.1371/journal.pone.0170630.].

Drug resistance constitutes one of the main obstacles for clinical recovery of acute myeloid leukemia (AML) patients. Therefore, the treatment of AML requires new strategies, such as adding a third drug. To address whether GATA2 could act as a regulator of chemotherapy resistance in human leukemia cells, we observed KG1a cells and clinical patients' AML cells with a classic drug (Cerubidine) and Gefitinib. After utilizing chemotherapy, the expression of GATA2 and its target genes (EVI, SCL and WT1) in surviving AML cells and KG1a cells were significantly enhanced to double and quadrupled compared to its original level respectively. Furthermore, with continuous chemotherapeutics, AML cells with GATA2 knockdown or treated with GATA2 inhibitor (K1747) almost eliminated with dramatically reduced expression of WT1, SCL, EVI, and significantly increased apoptotic population. Therefore, we propose that reducing GATA2 expression or inhibition of its transcription activity can relieve the drug resistance of acute myeloid leukemia cells and it would be helpful for eliminating the leukemia cells in patients.

Our prior study found that transforming growth factor beta-induced (TGFBI) is an important negative regulator in TLR-induced inflammation. However, whether TGFBI may affect inflammation during lipopolysaccharide (LPS)-induced endotoxin tolerance (ET) is still unclear.This study aimed to investigate whether TGFBI was involved in the mechanisms of ET in human through dampening nuclear factor-kappa B (NF-κB) mediated pathway. ET models of isolated healthy volunteers peripheral blood mononuclear cells (PBMCs) were established by pretreating with a low dose of LPS to observe the changes of TGFBI expression during ET induction, compared with ten healthy controls. Moreover, a vector-based short hairpin RNA expression system was used to specifically inhibit TGFBI expression to further explore its role in ET induction. The expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The responses to LPS were determined by the activation of NF-κB, the production of tumor necrosis factor-α (TNF-α) and Nitric Oxide (NO), which were analysed by enzyme-linked immuno sorbent assay (ELISA).The results showed that TGFBI expression in the ET group obviously increased; ET also led to a hyporesponse of PBMCs to LPS with less activation of NF-κB, less production of TNF-α and NO, as well as more expression of TGFBI than those of non-ET group. Moreover, the inhibitory effect was partly refracted in plasmid TGFBI short hairpin RNA (pTGFBI-shRNA) transfected PBMCs. Meanwhile, the absence of TGFBI caused abnormal enhancement of inflammatory cytokine production and it was involved in ET induction through dampening NF-κB mediated pathway.Therefore, TGFBI may be a new target for the clinical treatment of inflammatory disorders.

Recently, a number of studies have demonstrated the potential beneficial role for novel anti-diabetic GLP-1 receptor agonists (GLP-1RAs) in the skeleton metabolism in diabetic rodents and patients. In this study, we evaluated the impacts of the synthetic GLP-1RA Liraglutide on bone mass and quality in osteoporotic rats induced by ovariectomy (OVX) but without diabetes, as well as its effect on the adipogenic and osteoblastogenic differentiation of bone marrow stromal cells (BMSCs). Three months after sham surgery or bilateral OVX, eighteen 5-month old female Wistar rats were randomly divided into three groups to receive the following treatments for 2 months: (1) Sham + normal saline; (2) OVX + normal saline; and (3) OVX + Liraglutide (0.6 mg/day). As revealed by micro-CT analysis, Liraglutide improved trabecular volume, thickness and number, increased BMD, and reduced trabecular spacing in the femurs in OVX rats; similar results were observed in the lumbar vertebrae of OVX rats treated with Liraglutide. Following in vitro treatment of rat and human BMSCs with 10 nM Liraglutide, there was a significant increase in the mRNA expression of osteoblast-specific transcriptional factor Runx2 and the osteoblast markers alkaline phosphatase (ALP) and collagen α1 (Col-1), but a significant decrease in peroxisome proliferator-activated receptor γ (PPARγ). In conclusion, our results indicate that the anti-diabetic drug Liraglutide can exert a bone protective effect even in non-diabetic osteoporotic OVX rats. This protective effect is likely attributable to the impact of Liraglutide on the lineage fate determination of BMSCs.