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In this study, the keyhole dynamic behavior and molten pool flow were investigated to elucidate the effects of oscillating laser on porosity in narrow-gap oscillating laser-MIG hybrid welding of aluminum alloys. A weld with a porosity of 0.08% was produced at the laser oscillating frequency of 600 Hz and diameter of 1 mm, while 2.27% without oscillating laser. Compared to non-oscillating laser, keyhole opening size increased by about 2.3 times and keyhole depth fluctuation was suppressed. The forces acted on the interface between keyhole wall and molten pool became more balanced. The increased vapor recoil pressure overcame the combined closure effect of gravity and molten pool pressure. While applying oscillating laser, the vortex in molten pool was eliminated and the liquid metal flow was more stable. The combined impact force caused by droplets transfer and liquid metal convection due to constraining effect of narrow gap was buffered, which had less effect on molten pool and keyhole stability. The liquid metal tended to flow from the molten pool inside to surface, which favored the escape of bubbles from the molten pool.

Purpose: Renal interstitial fibrosis is a pathological manifestation of the progression of diabetic kidney disease (DKD). Dendrobium officinale polysaccharides (DOP), one of the major active components of Dendrobium officinale, have hypoglycemic and hypolipidemic effects and are used clinically to treat diabetes. However, the role of DOP in delaying DKD progression remains unclear. This study aimed to explore the potential mechanisms by which DOP delays DKD renal interstitial fibrosis. Methods: Using db/db mice as a model of DKD, we administered DOP by gavage and observed its therapeutic effectiveness. Employing ASO technology, we knocked down lncRNA XIST expression in kidney tissues and detected the expression of lncRNA XIST, TGF-β1, and renal interstitial fibrosis-related molecules. Results: DOP was primarily composed of monosaccharides, with 91.57% glucose and 1.41% mannose, forming a spheroid-like structure. It has a high polydispersity index with an Mw/Mn of 6.146, and the polysaccharides are mainly connected by 4-Man(p) and 4-Glc(p) linkages. In the kidneys of db/db mice, lncRNA XIST and TGF-β1 are highly expressed; however, their expression is significantly reduced after gastric infusion with DOP, and upon knockdown of lncRNA XIST, it might delay the progression of renal interstitial fibrosis in DKD. Conclusion: DOP may delay the progression of DKD renal interstitial fibrosis through the regulation of the LncRNA XIST/TGF-β1 related fibrotic pathway. This provides a new perspective for clinical strategies to delay the progression of DKD renal interstitial fibrosis.

Biodegradable magnesium alloy stents have great application potential in the treatment of cardiovascular diseases. However, bare magnesium alloy stents are still limited by some problems such as too fast degradation, poor hemocompatibility, and inability to regulate the behaviors of vascular cells in clinical applications. Surface modifications are highly requested to improve the corrosion resistance and biocompatibility of magnesium alloy stents. Herein, a fucoidan-based coating consisting of MgF2 layer, polydopamine (PDA) and fucoidan was constructed on Mg-Zn-Y-Nd (ZE21B) alloy to improve its corrosion resistance, hemocompatibility and rapid endothelialization for vascular stent application. Compared to bare ZE21B alloy, the modified ZE21B alloy exhibited better corrosion resistance and hemocompatibility. More importantly, the endothelial cells (ECs) and smooth muscle cells (SMCs) exhibited a distinct dose-dependent behaviors towards the fucoidan grafting density. The relatively low fucoidan grafting density promoted the proliferation, spreading and migration of ECs, but suppressed these behaviors of SMCs. The results of in vivo implantation experiments indicated that the fucoidan-based coating modified ZE21B alloy can inhibit intimal hyperplasia, relieve tissue inflammation, and promote the rapid endothelialization. Thus, the fucoidan-based coating provides a simple and effective strategy to develop novel magnesium alloy stents with improved corrosion resistance, good hemocompatibility and pro-endothelialization potential.

Cadmium (Cd), which is considered an endocrine disruptor, has been linked to the onset of breast cancer (BC). Our recent study demonstrated that Cd-induced BC progression has a strong correlation with miR-374c-5p dysregulation. The aim of our work was to investigate other potential miRNAs involved in Cd-induced BC cell proliferation and metastasis. In our study, the miRNA profiles of Cd-treated T-47D cells (10 μM, 72 h) were analyzed by miRNA-seq, and our results confirmed that miR-3614–5p was the top downregulated miRNA. Moreover, miR-3614–5p mimic transfection significantly decreased the proliferative ability, migration and invasive ability of BC cell lines (T-47D and MCF-7). Furthermore, we analyzed the overlapping genes from our RNA-seq data and predicted targets from the mirDIP database, and twelve genes (ALDH1A3, FBN1, GRIA3, NOS1, PLD5, PTGER4, RASGRF2, RELN, RNF150, SLC17A4, TG, and TXNRD1) were identified as potential binding targets of miR-3614–5p in the current model. Nonetheless, only miR-3614–5p inhibition caused an increase in TXNRD1 expression upon Cd exposure in T-47D and MCF-7 cell lines. Importantly, luciferase reporter assays further verified that miR-3614–5p suppressed the expression of TXNRD1 by directly binding to the 3′-untranslated region (UTR), and TXNRD1 inhibition significantly repressed the proliferation and metastasis capacity of BC cells upon Cd exposure. Together, our findings demonstrated that Cd exposure repressed the expression of miR-3614–5p, thus activating TXNRD1 expression, which promoted the abnormal proliferation and metastasis of BC cells.

Fluoride has received much attention for its predominant bone toxicity in the human body. However, the toxic mechanism of bone injury caused by fluoride exposure remains largely unclear. Bone marrow mesenchymal stem cells (BMSCs) are widely used as model cells for evaluating bone toxicity after environmental toxicant exposure. In this study, BMSCs were exposed to fluoride at 1, 2, and 4 mM for 24 h, and fluoride significantly inhibited cell viability at 2 and 4 mM. A multiomics analysis combining transcriptomics with metabolomics was employed to detect alterations in genes and metabolites in BMSCs treated with 2 mM fluoride. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of transcriptomics profiles identified “lysosomes” as the top enriched pathway, which was severely damaged by fluoride exposure. Lysosomal damage was indicated by decreases in the expression of lysosomal associated membrane protein 2 (LAMP 2) and cathepsin B (CTSB) as well as an increase in pH. Upregulation of the lysosome-related genes Atp6v0b and Gla was observed, which may be attributed to a compensatory lysosomal biogenesis transcriptional response. Interestingly, inhibition of glutathione metabolism was observed in fluoride-treated BMSCs at the metabolomic level. Moreover, an integrative analysis between altered genes, metabolites and lysosome signaling pathways was conducted. Palmitic acid, prostaglandin C2, and prostaglandin B2 metabolites were positively associated with Atp6v0b, a lysosome-related gene. Overall, our results provide novel insights into the mechanism responsible for fluoride-induced bone toxicity.

Cadmium (Cd) is a toxic heavy metal that can facilitate the development and progression of breast cancer (BC). Emerging evidence has indicated that the progression of Cd-exposed BC is related to the dysregulation of microRNAs (miRNAs). The purpose of our study was to investigate the expression pattern and underlying mechanisms of miR-374c-5p in Cd-mediated BC progression. In this study, T-47D cells and MCF-7 cells were treated with different concentrations of Cd (0.1, 1 and 10 μM) for 72 h. MiR-374c-5p expression was downregulated, and transfection of miR-374c-5p mimics significantly decreased BC cell proliferation, migration and invasion induced by 10 μM Cd. Importantly, we used the Cytoscape software plugin cytoHubba to analyse the intersected genes between our RNA-Seq results and the mirDIP database, and six hub genes (CNR1, CXCR4, GRM3, RTN1, SLC1A6 and ZEB1) were identified as potential direct targets of miR-374c-5p in our model; however, luciferase reporter assays indicated that miR-374c-5p only repressed GRM3 by directly binding to its 3′-untranslated region (UTR). Of note, we verified that suppression of N6-methyladenosine (m6A) modification led to miR-374c-5p downregulation by decreasing its RNA transcript stability. Together, these findings demonstrated that m6A modification of pri-miRNA-374c blocks miRNA-374c-5p maturation and then activates GRM3 expression, which drives BC cell metastasis after Cd exposure.

Summary: Developing low cost, yet high-voltage electrolyte is significant to improve the energy density and practicability of lithium metal batteries (LMBs). Low concentration electrolyte has significant merits in terms of cost and viscosity; however, their poor compatibility with high-voltage LMBs hinders its applications. Here, we develop a diluted low concentration electrolyte by replacing solvating cosolvent with a non-solvating cosolvent to facilitate the interaction between BF4− and Li+, resulting in optimized interfacial chemistry and suppressed side reaction. Thus, the high-loading Li-LiCoO2 full cells (20.4 mg cm−2) deliver outstanding cycling stability and rate performance at a cutoff voltage of 4.6 V. More impressively, a Li-LiCoO2 pouch cell achieves an energy density of more than 400 Wh kg−1 under practical conditions with thin Li (50 μm) and lean electrolyte (2.7 g Ah−1). This work provides a rational approach to design a low concentration electrolyte, which can be extended to other high voltage battery systems.

Cadmium (Cd) is a carcinogen that stimulates breast cancer (BC) progression. Rapamycin is a macrolide antibiotic produced by Streptomyces hygroscopicus that possesses a wide array of pharmacological activities, including anti-BC activity. However, the effects of rapamycin on Cd-increased BC progression and the underlying mechanism have not been fully elucidated. Here, we hypothesize that rapamycin antagonizes Cd-induced BC cell proliferation and metastasis by directly modulating ACSS2. In this study, we found that rapamycin efficiently inhibited Cd-induced proliferation, invasion and migration in MCF-7 and T47-D cells. Moreover, a surface plasmon resonance (SPR) assay confirmed that rapamycin directly binds to the ACSS2 protein with a calculated equilibrium dissociation constant (KD) of 18.3 μM. Molecular docking showed that there are three binding sites in the ACSS2 protein and that rapamycin binds at the coenzyme A (COA) binding site with a docking score of − 12.26 and a binding free energy of − 26.34 kcal/mol. More importantly, rapamycin suppresses Cd-induced BC progression by activating ACSS2. After cells were cotreated with an ACSS2 inhibitor, the effects of rapamycin were abolished. In conclusion, our findings suggest that rapamycin suppresses Cd-augmented BC progression by upregulating ACSS2, and ACSS2 may serve as a direct target of rapamycin for inhibiting xenobiotic (e.g., Cd)-mediated BC progression.

This data set contains the data used in Twarog et al. (2021) to examine the robustness and utility of response surface models in drug combination analysis. It includes simulated experimental data for the evaluation of traditional index methods, as well as a processed library of interaction metrics evaluated on the Merck OncoPolyPharmacology Screen (O'Neil et al., 2016), the scripts used to implement those metrics on all tested combinations in that screen, and scripts to evaluate the performance of those metrics in comparison with real-world mechanistic classifications. Finally, the data set includes data from several published and unpublished drug combination experiments, and scripts which allow the analyses of those experiments to be replicated and applied to new data.

Summary: Although insulin is a life-saving medicine, administration by daily injection remains problematic. Our goal was to exploit the power of DNA-encoded libraries to identify molecules with insulin-like activity but with the potential to be developed as oral drugs. Our strategy involved using a 104-member DNA-encoded library containing 160 Traditional Chinese Medicines (nDEL) to identify molecules that bind to and activate the insulin receptor. Importantly, we used the natural ligand, insulin, to liberate bound molecules. Using this selection method on our relatively small, but highly diverse, nDEL yielded a molecule capable of both binding to and activating the insulin receptor. Chemical analysis showed this molecule to be a polycyclic analog of the guanidine metformin, a known drug used to treat diabetes. By using our protocol with other, even larger, DELs we can expect to identify additional organic molecules capable of binding to and activating the insulin receptor.

Environmental pH change is a challenge for growth and health of aquatic animals. In this study, the juveniles of Pacific white shrimp Litopenaeus vannamei were exposed to a higher pH 9.5 or a lower pH 6.5 versus a normal pH (pH 8.0) as the control for four weeks. Growth performance, antioxidant capacity, immune functions, and intestinal histological damage and microbiota were evaluated. The weight gain rate was significantly decreased in shrimp at pH 9.5 compared with the control shrimp at pH 8.0. The antioxidant capacities of shrimp as activities of SOD, GSH-Px, GST and MDA contents shown at pH 9.5 or pH 6.5 were significantly reduced relative to the control shrimp. The expressions of immune-related genes, including anti-lipopolysaccharide factor, lysozyme, protein toll, immune deficiency, and hemocyte protein-glutamine gamma-glutamyltransferase, were down-regulated and the intestine tissues were distorted. Histology analysis showed that shrimp gut epithelial cells at pH 6.5 separated from the basement membrane, while epithelial cell necrosis were found in shrimp at pH 9.5. The diversity of intestine microbiota was disturbed with lower Shannon and higher Simpson indices in shrimp at pH 6.5 than the control shrimp, but no differences were found in shrimp at pH 9.5. The intestine barrier functions were weakened as the KEGG analysis shown, where functions for protein or carbohydrate digestion and absorption at pH 6.5, and for antibiotics biosynthesis, including streptomycin, penicillin, cephalosporin, novobiocin, ansamycins and vancomycin, at pH 9.5 in shrimp were significantly decreased. All finding in this study suggest that long-term lower or higher pH stress could adversely affect gut microbiota functions, thus leading to shrimp reduced growth, immunity and antioxidant capacity, and even intestine histology damage. Keywords: Litopenaeus vannamei, pH stress, Health, Histology, Intestine microbiota

The red flour beetle, Tribolium castaneum, is a major agriculture pest of stored grain, cereal products and peanuts for human consumption. It is reported that heat shock protein 18.3 of T. castaneum (Tchsp18.3) plays a significant role in stress resistance, development and reproduction. However, the regulatory systems of Tchsp18.3 remain unknown. Therefore, we compared the global transcriptome profiles of RNA interference (RNAi)-treated larvae (ds-Tchsp18.3) and control larvae of T. castaneum using RNA sequencing. Overall, we obtained 14 154 435 sequence reads aligned with 13 299 genes. Additionally, 569 differentially expressed genes (DEGs) were identified from the ds-Tchsp18.3 and control groups, of which 246 DEGs were annotated in the 47 Gene Ontology (GO) functional groups and 282 DEGs were assigned to 147 Kyoto Encyclopedia of Genes and Genomes (KEGG) biological signaling pathways. The DEGs encoding viperin, dorsal, Hdd11, PGRP2, defensin1 and defensin2 were simultaneously related to immunity and stress responses, which suggests that cross-talk might exist between the immunity and stress responses of T. castaneum. The knockdown of Tchsp18.3 gene expression suppressed the antioxidant activity process, which most likely modulated the effects of Tchsp18.3 on development and reproduction. Furthermore, the DEGs, including Blimp-1, Gld, Drm, Kinesin-14, Pthr2, Delta(11)-like and EGF-like domain protein 2, were also associated with the development and reproduction of ds-Tchsp18.3 insects. Additionally, knockdown of Tchsp18.3 amplified the serine protease (SP) signaling pathway to further regulate stress responses and innate immunity as well as development and reproduction of the red flour beetles. These results provide valuable insight into the molecular regulatory mechanism of Tchsp18.3 involved in insect physiology and further facilitate the research of suitable and sustainable management for pest control.

Antibodies that target both group 1 and group 2 influenza A viruses are valuable for therapeutic and vaccine development, but only a few have been reported to date. Here, we describe a new VH1-69 antibody 27F3 that broadly recognizes heterosubtypic hemagglutinins (HAs) from both group 1 and group 2 influenza A viruses. Structural characterization of 27F3 Fab with A/California/04/2009 (H1N1) hemagglutinin illustrates that 27F3 shares the key binding features observed in other VH1-69 antibodies to the HA stem. Compared to other VH1-69 antibodies, the 27F3 VH domain interacts with the HA stem in a distinct orientation, which alters its epitope and may have influenced its breadth. The diverse rotations of VH1-69 antibodies on the HA stem epitope highlight the different ways that this antibody family can evolve to broadly neutralize influenza A viruses. These results have important implications for understanding how to elicit broad antibody responses against influenza virus.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the clinical treatment for tumor. However, the low response rate of ICIs remains the major obstacle for curing patients and effective approaches for patients with primary or secondary resistance to ICIs remain lacking. In this study, immune stimulating agent unmethylated CG-enriched (CpG) oligodeoxynucleotide (ODN) was locally injected into the tumor to trigger a robust immune response to eradicate cancer cells, while anti-CD25 antibody was applied to remove immunosuppressive regulatory T cells, which further enhanced the host immune activity to attack tumor systematically. The combination of CpG and anti-CD25 antibody obtained notable regression in mouse melanoma model. Furthermore, rechallenge of tumor cells in the xenograft model has resulted in smaller tumor volume, which demonstrated that the combinational treatment enhanced the activity of memory T cells. Remarkably, this combinational therapy presented significant efficacy on multiple types of tumors as well and was able to prevent relapse of tumor partially. Taken together, our combinational immunotherapy provides a new avenue to enhance the clinical outcomes of patients who are insensitive or resistant to ICIs treatments.

Nearly half of all Asian non-small cell lung cancer (NSCLC) patients harbour epidermal growth factor receptor (EGFR) mutations, and first-generation EGFR tyrosine kinase inhibitors (TKIs) are one of the first-line treatments that have improved the outcomes of these patients. Unfortunately, 20% of these patients can not benefit from the treatment. The basis of this primary resistance is poorly understood. Therefore, overcoming EGFR-TKI primary resistance and maintaining the efficacy of TKIs has become a key issue. β-Elemene, a sesquiterpene compound extracted from Curcuma aromatica Salisb. (wenyujing), has shown potent antitumor effects. In this research, we found that β-elemene combined with erlotinib enhanced the cytotoxicity of erlotinib to primary EGFR-TKI-resistant NSCLC cells with EGFR mutations and that ferroptosis was involved in the antitumor effect of the combination treatment. We found that lncRNA H19 was significantly downregulated in primary EGFR-TKI-resistant NSCLC cell lines and was upregulated by the combination treatment. Overexpression or knockdown of H19 conferred sensitivity or resistance to erlotinib, respectively, in both in vitro and in vivo studies. The high level of H19 enhanced the cytotoxicity of erlotinib by inducing ferroptosis. In conclusion, our data showed that β-elemene combined with erlotinib could enhance sensitivity to EGFR-TKIs through induction of ferroptosis via H19 in primary EGFR-TKI-resistant lung cancer, providing a promising strategy to overcome EGFR-TKI resistance in NSCLC patients.

Although some important advances have been achieved in clinical and diagnosis in the past few years, the management of non-small cell lung cancer (NSCLC) is ultimately dissatisfactory due to the low overall cure and survival rates. Epidermal growth factor (EGFR) has been recognized as a carcinogenic driver and is a crucial pharmacological target for NSCLC. DMU-212, an analog of resveratrol, has been reported to have significant inhibitory effects on several types of cancer. However, the effect of DMU-212 on lung cancer remains unclear. Therefore, this study aims to determine the effects and underlying mechanism of DMU-212 on EGFR-mutant NSCLC cells. The data found that the cytotoxicity of DMU-212 on three EGFR-mutant NSCLC cell lines was significantly higher than that of normal lung epithelial cell. Further study showed that DMU-212 can regulate the expression of cell cycle-related proteins including p21 and cyclin B1 to induce G2/M phase arrest in both H1975 and PC9 cells. Moreover, treatment with DMU-212 significantly promoted the activation of AMPK and simultaneously down-regulated the expression of EGFR and the phosphorylation of PI3K, Akt and ERK. In conclusion, our study suggested that DMU-212 inhibited the growth of NSCLCs via targeting of AMPK and EGFR.