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Programmed cell death ligand-1 (PD-L1) is a T cell inhibitory immune checkpoint molecule that interacts with programmed cell death-1 (PD-1) to promote immune escape of tumor cells. Compared with antibody therapies, small molecule drugs show better prospects due to their advantages such as higher bioavailability, better tissue penetration, and reduced risk of immunogenicity. Here, we found that the small molecule demethylzeylasteral (Dem) can significantly downregulate the expression of PD-L1 in colorectal cancer cells and enhance the killing effect of T cells on tumor cells. Mechanistically, Dem binds to the deubiquitinating enzyme USP22 and promotes its degradation, resulting in increased ubiquitination and degradation of PD-L1 through the proteasome pathway. In addition, Dem increased the activity of cytotoxic T cells and reduced the number of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in tumor-infiltrating lymphocytes (TILs), thereby activating the tumor immune microenvironment and inhibiting the growth of subcutaneous MC38 tumors in C57BL/6 mice. Moreover, we also found that the combination of Dem and CTLA4 antibodies can further improve the efficacy of antitumor therapy. Our study reveals the mechanism by which Dem promotes PD-L1 degradation and suggests that the combination of Dem and CTLA4 antibodies may improve the efficacy of immunotherapy.

Abstract Background Dysregulation of lipid metabolism and its consequences on growth performance in young ruminants have attracted attention, especially in the context of alternative feeding strategies. This study aims to elucidate the effects of milk replacer (MR) feeding on growth, lipid metabolism, colonic epithelial gene expression, colonic microbiota composition and systemic metabolism in goat kids compared to breast milk (BM) feeding, addressing a critical knowledge gap in early life nutrition. Methods Ten female goat kids were divided into 2 groups: those fed breast milk (BM group) and those fed a milk replacer (MR group). Over a period of 28 d, body weight was monitored and blood and tissue samples were collected for biochemical, transcriptomic and metabolomic analyses. Profiling of the colonial microbiota was performed using 16S rRNA gene sequencing. Intestinal microbiota transplantation (IMT) experiments in gnotobiotic mice were performed to validate causality. Results MR-fed pups exhibited reduced daily body-weight gain due to impaired lipid metabolism as evidenced by lower serum and liver total cholesterol (TC) and non-esterified fatty acid (NEFA) concentrations. Transcriptomic analysis of the colonic epithelium revealed upregulated genes involved in negative regulation of lipid metabolism, concomitant with microbiota shifts characterized by a decrease in Firmicutes and an increase in Actinobacteria. Specifically, genera such as Bifidobacterium and Prevotella were enriched in the MR group, while Clostridium and Faecalibacterium were depleted. Metabolomics analyses confirmed alterations in bile acid and fatty acid metabolic pathways. IMT experiments in mice recapitulated the metabolic phenotype observed in MR-fed goats, confirming the role of the microbiota in modulating host lipid metabolism. Conclusions Milk replacer feeding in goat kids disrupts lipid metabolism and gut microbiota dynamics, resulting in reduced growth rates and metabolic alterations. These findings highlight the importance of early nutritional intervention on metabolic programming and suggest that modulation of the gut microbiota may be a target for improving growth and metabolic health in ruminants. This study contributes to the understanding of nutritional management strategies in livestock and their impact on animal health and productivity.

Abstract Background Ruminant gut microbiota are critical in ecological adaptation, evolution, and nutrition utilization because it regulates energy metabolism, promotes nutrient absorption, and improves immune function. To study the functional roles of key gut microbiota in sheep and goats, it is essential to construct reference microbial gene catalogs and high-quality microbial genomes database. Results A total of 320 fecal samples were collected from 21 different sheep and goat breeds, originating from 32 distinct farms. Metagenomic deep sequencing and binning assembly were utilized to construct a comprehensive microbial genome information database for the gut microbiota. We successfully generated the largest reference gene catalogs for gut microbiota in sheep and goats, containing over 162 million and 82 million nonredundant predicted genes, respectively, with 49 million shared nonredundant predicted genes and 1138 shared species. We found that the rearing environment has a greater impact on microbial composition and function than the host’s species effect. Through subsequent assembly, we obtained 5810 medium- and high-quality metagenome-assembled genomes (MAGs), out of which 2661 were yet unidentified species. Among these MAGs, we identified 91 bacterial taxa that specifically colonize the sheep gut, which encode polysaccharide utilization loci for glycan and mucin degradation. Conclusions By shedding light on the co-symbiotic microbial communities in the gut of small ruminants, our study significantly enhances the understanding of their nutrient degradation and disease susceptibility. Our findings emphasize the vast potential of untapped resources in functional bacterial species within ruminants, further expanding our knowledge of how the ruminant gut microbiota recognizes and processes glycan and mucins. Video Abstract

Objective: Breast cancer poses a major health risk to millions of females globally. Asiaticoside (AC) is a naturally occurring compound derived from Centella asiatica, a widely used medicinal plant in the oriental countries and has potential antitumor properties. The primary aim of this study was to investigate the anti-cancer effects of synthesized AC at the cellular level and assess its ability to inhibit tumor growth and angiogenesis in breast cancer. Methods: The proliferative capacities of MCF-7 and MDA-MB-231 cells were determined using CCK-8 assay. To analyze invasion and migration, Transwell assays were conducted on the same cell lines. Additionally, apoptosis was analyzed in vitro using flow cytometry. Real-time RT-PCR was used to examine mRNA expression, and Western-blotting assay was employed to examine protein expression. Subcutaneous injection of MDA-MB-231 cells into female BALB/c nude mice was followed by treatment with AC to study its anti-tumor effects in vivo. Results: AC treatment reduced cell proliferation and triggered apoptosis in MCF-7 and MDA-MB-231 cells. The invasive and pro-angiogenesis ability were also impaired upon AC treatment. AC administration also impeded the tumor growth and tumor-associated angiogenesis of MDA-MB-231 cells in nude mice, which was accompanied by the decreased levels of YAP1 and VEGFA. Conclusion: Taken together, our results demonstrated the anti-cancer activity of AC in breast cancer. AC is able to suppress the malignancy of breast cancercells via YAP1/VEGFA signal pathway.

Inflammation is the response of the human body to injury, infection, or other abnormal states, which is involved in the development of many diseases. As a member of the Krüppel-like transcription factors (KLFs) family, KLF4 plays a crucial regulatory role in physiological and pathological processes due to its unique dual domain of transcriptional activation and inhibition. A growing body of evidence has demonstrated that KLF4 plays a pivotal role in the pathogenesis of various inflammatory disorders, including inflammatory bowel disease, osteoarthritis, renal inflammation, pneumonia, neuroinflammation, and so on. Consequently, KLF4 has emerged as a promising new therapeutic target for inflammatory diseases. This review systematically generalizes the molecular regulatory network, specific functions, and mechanisms of KLF4 to elucidate its complex roles in inflammatory diseases. An in-depth study on the biological function of KLF4 is anticipated to offer a novel research perspective and potential intervention strategies for inflammatory diseases.

Abstract Background The role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood. Methods A total of 331 non-demented individuals were included in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition. Results Higher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1. Conclusions These findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Introduction: The epithelial immunomodulation and regeneration are intrinsic critical events against inflammatory bowel disease (IBD). MiR-7 is well documented as a promising regulator in the development of various diseases including inflammatory diseases. Objectives: This study aimed to assess the effect of miR-7 in intestinal epithelial cells (IECs) in IBD. Methods: MiR-7def mice were given dextran sulfate sodium (DSS) to induce enteritis model. The infiltration of inflammatory cells was measured by FCM and immunofluorescence assay. 5′deletion assay and EMSA assays were performed to study the regulatory mechanism of miR-7 expression in IECs. The inflammatory signals and the targets of miR-7 were analyzed by RNA-seq and FISH assay. IECs were isolated from miR-7def, miR-7oe and WT mice to identify the immunomodulation and regeneration capacity. IEC-specific miR-7 silencing expression vector was designed and administered by the tail vein into murine DSS-induced enteritis model to evaluate the pathological lesions of IBD. Results: We found miR-7 deficiency improved the pathological lesions of DSS-induced murine enteritis model, accompanied by elevated proliferation and enhanced transduction of NF-κB/AKT/ERK signals in colonic IECs, as well as decreased local infiltration of inflammatory cells. MiR-7 was dominantly upregulated in colonic IECs in colitis. Moreover, the transcription of pre-miR-7a-1, orchestrated by transcription factor C/EBPα, was a main resource of mature miR-7 in IECs. As for the mechanism, EGFR, a miR-7 target gene, was downregulated in colonic IECs in colitis model and Crohn's disease patients. Furthermore, miR-7 also controlled the proliferation and inflammatory-cytokine secretion of IECs in response to inflammatory-signals through EGFR/NF-κB/AKT/ERK pathway. Finally, IEC-specific miR-7 silencing promoted the proliferation and transduction of NF-κB pathway in IECs and alleviated the pathological damage of colitis. Conclusion: Our results present the unknown role of miR-7/EGFR axis in IEC immunomodulation and regeneration in IBD and might provide clues for the application of miRNA-based therapeutic strategies in colonic diseases.

Abstract Targeting the programmed cell death 1/programmed cell death ligand 1 (PD‐1/PD‐L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4′‐trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD‐L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG‐CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD‐L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor‐infiltrating T‐cell immunity and reduce the immunosuppressive infiltration of myeloid‐derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA‐4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.

Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.

This research investigated the effect of different storage temperatures on the compositional changes, physicochemical characteristics, and functional properties of hawthorn berries. Storage at 25 °C resulted in the gradual decrease of the moisture, hardness, sugar, titratable acid, and colour of hawthorn berries. These changes decreased with decreasing storage temperature, and the minimal changes happened at frozen storage (-18 °C). Similarly, the decreasing rate of ascorbic acid, extractable polyphenol (EPP), and flavonoids during storage also decreased with reducing storage temperature (25 °C > 4 °C > -18 °C). Hydrolysable polyphenol (HPP) was relatively stable during the hawthorn storage, and non-extractable proanthocyanidins (NEPA) increased with decreasing temperature. Ferric reducing antioxidant power (FRAP) of EPP and HPP decreased at 25 °C, while polyphenolic oxidase (PPO) and peroxidase (POD) activities decreased. Decreasing the storage temperature can improve the stability of the nutritional properties, antioxidant capacity, and enzyme activity of hawthorn. The specific storage temperature depends on the final processing conditions and the purposes of the hawthorn berries.

Abstract Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor signalling pathway. In this study, by using morphological observation, fluorescence double staining, LDH release and immunoblot detection, we confirmed for the first time that HGS-ETR1/2 can induce GSDME-mediated pyroptosis in hepatocellular carcinoma cells. Our study found that both inhibition of the AKT signalling pathway and silencing of CPA4 promote pyroptosis, while the overexpression of CPA4 inhibits it. Furthermore, we identified a positive regulatory feedback loop is formed between CPA4 and AKT phosphorylation. Specifically, CPA4 modulates AKT phosphorylation by regulating the expression of the AKT phosphatase PP2A, while inhibition of the AKT signalling pathway leads to a decreased transcription and translation levels of CPA4. Our study reveals a novel mechanism of pyroptosis induced by HGS-ETR1/2, which may provide a crucial foundation for future investigations into cancer immunotherapy.

Autoimmune hepatitis (AIH) is an inflammatory chronic liver disease with persistent and recurrent immune-mediated liver injury. The exact cause of AIH is still not fully understood, but it is believed to be primarily due to an abnormal activation of the immune system, leading to autoimmune injury caused by the breakdown of autoimmune tolerance. Although the pathogenesis of AIH remains unclear, recent studies have shown that abnormalities in amino acid metabolism play significant roles in its development. These abnormalities in amino acid metabolism can lead to remodeling of metabolic processes, activation of signaling pathways, and immune responses, which may present new opportunities for clinical intervention in AIH. In this paper, we first briefly outline the recent progress of clinically relevant research on AIH, focusing on the role of specific amino acid metabolism (including glutamine, cysteine, tryptophan, branched-chain amino acids, etc.) and their associated metabolites, as well as related pathways, in the development of AIH. Furthermore, we discuss the scientific issues that remain to be resolved regarding amino acid metabolism, AIH development and related clinical interventions, with the aim of contributing to the future development of amino acid metabolism-based as a new target for the clinical diagnosis and treatment of AIH.

Abstract Background In colorectal cancer (CRC), the normal tissue adjacent to tumor (NAT) communicates actively with the tumor. Adult stem cells from the colon play a crucial role in the development of the colonic epithelium. In the tumor microenvironment, however, it is unclear what changes have occurred in colonic stem cells derived from NAT. Methods Using an intestinal stem cell culture system, we cultured colonic cells from NAT and paired CRC tissue, as well as cells from healthy tissue (HLT). Clonogenicity and differentiation ability were used to compare the function of clones from NAT, HLT and CRC tissues. RNA high-throughput sequencing of these clones was used to identify the molecular characteristics of NAT-derived clones. Coculture of clones from HLT and CRC was used to assess molecular changes. Results We found that the morphological characteristics, clonogenic ability, and differentiation ability of NAT-derived clones were consistent with those of HLT-derived clones. However, NAT-derived clones changed at the molecular level. A number of genes were specifically activated in NAT. NAT-derived clones enriched pathways related to inflammation and fibrosis, including epithelial mesenchymal transition (EMT) pathway and TGF-beta signaling pathway. Our results also confirmed that NAT-derived clones could recruit fibroblasts in mice. In addition, HLT-derived clones showed high expression of FOSB when cocultured with tumor cells. Conclusions Our results demonstrate that colonic stem cells from NAT in the tumor microenvironment undergo changes at the molecular level, and these molecular characteristics can be maintained in vitro, which can induce fibrosis and an inflammatory response. Video Abstract

Abstract Background The identification of pathogenic mutations in Alzheimer’s disease (AD) causal genes led to a better understanding of the pathobiology of AD. Familial Alzheimer’s disease (FAD) is known to be associated with mutations in the APP, PSEN1, and PSEN2 genes involved in Aβ production; however, these genetic defects occur in only about 10–20% of FAD cases, and more genes and new mechanism causing FAD remain largely obscure. Methods We performed exome sequencing on family members with a FAD pedigree and identified gene variant ZDHHC21 p.T209S. A ZDHHC21T209S/T209S knock-in mouse model was then generated using CRISPR/Cas9. The Morris water navigation task was then used to examine spatial learning and memory. The involvement of aberrant palmitoylation of FYN tyrosine kinase and APP in AD pathology was evaluated using biochemical methods and immunostaining. Aβ and tau pathophysiology was evaluated using ELISA, biochemical methods, and immunostaining. Field recordings of synaptic long-term potentiation were obtained to examine synaptic plasticity. The density of synapses and dendritic branches was quantified using electron microscopy and Golgi staining. Results We identified a variant (c.999A > T, p.T209S) of ZDHHC21 gene in a Han Chinese family. The proband presented marked cognitive impairment at 55 years of age (Mini-Mental State Examination score = 5, Clinical Dementia Rating = 3). Considerable Aβ retention was observed in the bilateral frontal, parietal, and lateral temporal cortices. The novel heterozygous missense mutation (p.T209S) was detected in all family members with AD and was not present in those unaffected, indicating cosegregation. ZDHHC21T209S/T209S mice exhibited cognitive impairment and synaptic dysfunction, suggesting the strong pathogenicity of the mutation. The ZDHHC21 p.T209S mutation significantly enhanced FYN palmitoylation, causing overactivation of NMDAR2B, inducing increased neuronal sensitivity to excitotoxicity leading to further synaptic dysfunction and neuronal loss. The palmitoylation of APP was also increased in ZDHHC21T209S/T209S mice, possibly contributing to Aβ production. Palmitoyltransferase inhibitors reversed synaptic function impairment. Conclusions ZDHHC21 p.T209S is a novel, candidate causal gene mutation in a Chinese FAD pedigree. Our discoveries strongly suggest that aberrant protein palmitoylation mediated by ZDHHC21 mutations is a new pathogenic mechanism of AD, warranting further investigations for the development of therapeutic interventions.

In order to study the microscopic reaction mechanism and kinetic model of Al/PTFE, a reactive force field (ReaxFF) was used to simulate the interface model of the Al/PTFE system with different oxide layer thicknesses (0 Å, 5 Å, 10 Å), and the thermochemical behavior of Al/PTFE at different heating rates was analyzed by simultaneous thermal analysis (TG-DSC). The results show that the thickness of the oxide layer has a significant effect on the reaction process of Al/PTFE. In the system with an oxide layer thickness of 5 Å, the compactness of the oxide layer changes due to thermal rearrangement, resulting in the diffusion of reactants (fluorine-containing substances) through the oxide layer into the Al core. The reaction mainly occurs between the oxide layer and the Al core. For the 10 Å oxide layer, the reaction only exists outside the interface of the oxide layer. With the movement of the oxygen ions in the oxide layer and the Al atoms in the Al core, the oxide layer moves to the Al core, which makes the reaction continue. By analyzing the reaction process of Al/PTFE, the mechanism function of Al/PTFE was obtained by combining the shrinkage volume model (R3 model) and the three-dimensional diffusion (D3 model). In addition, the activation energy of Al/PTFE was 258.8 kJ/mol and the pre-exponential factor was 2.495 × 1015 min−1. The research results have important theoretical significance and reference value for the in-depth understanding of the microscopic chemical reaction mechanism and the quantitative study of macroscopic energy release of Al/PTFE reactive materials.

Paralytic shellfish toxins (PSTs) are phycotoxins widely distributed worldwide and pose serious marine ecosystems and human health threats. In China's Yellow Sea and the Bohai Sea, Alexandrium spp. has been certified as the major causative dinoflagellate of PSTs, especially in Qinhuangdao, Hebei Province where several poisoning events have been reported, with tens of consumers suffering and some even dying. In terms of these events, mussels contaminated with PSTs were the major cause of consumer poisoning. Therefore, it is vital to reveal the risk of PSTs in these shellfish, which requires scientific opinions on the formation of terminal components of PSTs in mussels. Generally, mussels are not sensitive to PSTs, resulting in the high accumulation of PSTs in their tissues. The PSTs distribute, bio-transfer, and metabolism, and the terminal metabolites pose a risk to consumers. From 2016 to the present, several serious events have occurred in Qinhuangdao caused by PSTs contamination in mussels, which resulted in poisoning by tens of consumers and a huge loss of regional economy. This study exposed purple mussel Mytilus galloprovincialis, the key cultured species of bivalves in Qinhuangdao, to Alexandrium catenella (GY-H25), the predominant producer of PSTs in this area. The accumulation and biotransformation process of PSTs in visceral mass and edible tissue and the accumulation metabolism kinetics were analyzed under exposure to different cell densities by liquid chromatography-tandem mass spectrometry. Our results showed that the growth and toxin production of GY-H25 was stable. The main components of PSTs were N-sulfocarbamoylgonyautoxin (C1 and C2), with the highest algal cell density of 3.5×107 cells/L and the highest production capacity of 2.96 pg STXeq/cell. Toxin-producing algae with the highest production of PSTs per unit volume and algal cell density (22 days) were selected for the exposure experiment. After exposure, the mussel accumulated a high content of PSTs in both visceral mass and edible tissue, with a similar trend in both exposure densities. The whole exposure experiment could be divided into four periods: 0~2 days as the initial exposure period (period Ⅰ); 2~7 days as the period of rapid accumulation (period Ⅱ); 7~12 days as the period of rapid metabolism (period Ⅲ); 12~30 days as the stable period (period Ⅳ). However, the level of PSTs in the visceral mass of mussels in both exposure groups exceeded the maximum residue limit (MRL) of EU (800 μg STX EQ/kg) at the end of the experiment, while that of PSTs in edible flesh was below the MRL. Comparatively, the highest concentration of PSTs in the visceral mass reached 6815.36 μg/kg in the high exposure group, which was 2.61 times that of the low exposure group, with an average accumulation rate of 17.89%, which was significantly higher than that of the low exposure group (13.06%). The results showed that the accumulation of PSTs in the visceral mass and edible tissue of Mytilus galloprovincialis was harmful to its tissues and organs. The toxin excretion rates of the high-and low-concentration groups of PSTs were 74.39 % and 59.15 %, respectively, after 23 days. The average daily elimination rate was 14.4 %, the metabolism rate of Mytilus edulis slowed down in the stable period (period Ⅳ), and some toxins remained in the visceral mass after 23 days of metabolism, which easily formed long-term toxin retention and threatened human life safety. In addition, PSTs in Mytilus galloprovincialis showed a strong biotransformation ability, mainly occurring among C1, C2, and GTX5. According to this research, the transformation pathway from C2 to GTX5 was the main pathway for GTX5 formation during rapid metabolism and stable periods. At the same time, the transformation of C1 to GTX5 was higher than that of C2 to C1, leading to a reduction in the overall proportion of C1. According to the comprehensive evaluation of the metabolic products and toxic equivalence factor (TEF) of GST components in mussels, the metabolic transformation of PSTs in mussels will further promote the formation and proportion of highly toxic GTX5, which will increase the terminal toxicity of PSTs in mussels and may also pose a higher risk to consumers. In this study, compared with the natural conditions, the concentration of toxic algae was far below the harmful algal bloom exposure. The total accumulation of toxins was far lower than the total accumulation of toxins in mussels exposed to harmful algal blooms. Even so, the total amount of residual toxins in the mussel viscera of the high concentration group was still enough to threaten human life safety at the end of the experiment. It was found that the toxin content in the visceral tissue tended to be stable over 12 to 30 days without an obvious downward trend. Even the toxin content increases due to the toxin transformation phenomenon, which means the difficulty in predicting the time required for PSTs in the visceral mass reduced to below the MRLs. Therefore, this study contributes to the scientific assessment of PSTs risk in mussels and provides a basis for establishing regional PSTs monitoring programs.

Infertility affects 10%–20% of the population in most countries, with approximately half of those cases resulting from male infertility. Although millions of infertile men are able to have children with the assistance of reproductive technology, individuals with non-obstructive azoospermia (NOA) syndrome are unable to do so because they lack functional sperm. Therefore, some other strategies for infertile NOA men are still urgently needed. Our current study uses an NOA-like mouse model to optimize microinjection and a subsequent electroporation method to test potential treatment strategies. We showed that the spermatogenetic process could be partially rescued in young Stra8-Rnf20−/− mice with microinjection and subsequent electroporation of Rnf20 plasmids into the testes. All meiotic prophase I stages could be identified, and programmed DNA double-strand break repair factors could successfully be recruited to Stra8-Rnf20−/− spermatocytes after electroporation. Moreover, by including an autophagy inhibitor in the treatment, electroporation significantly improved the spermatogenetic rescue efficiency of adult Stra8-Rnf20−/− mice. Most importantly, infertility caused by Rnf20 depletions could be overcome by electroporation coupled with intracytoplasmic sperm injection. Our studies establish a relative safe and efficient testis electroporation system and provide a promising therapeutic strategy for patients with NOA.

Early weaning induces intestinal injury, leading to a series of long-term symptoms such as inflammation, malabsorption and diarrhea. In this study, we hypothesized that microbes and their metabolites modulate the host's inflammatory response to early weaning stress in a goat model. A total of 18 female Tibetan goat kids (n = 9) were weaned from their mothers at 28 d (D28) and 60 d (D60) postpartum. D60 and D28 groups were fed the same solid diet ad libitum from weaning to 75 d of age. The colonic epithelium was subject to RNA-sequencing, the caecal digesta metabolomics were assessed by liquid chromatography–tandem mass spectrometry (LC-MS/MS), and the caecal microbiota composition was analysed by 16S ribosomal RNA gene sequencing. We found that early weaning substantially increased the colonic pro-apoptotic gene expression of B-cell lymphoma associated X (Bax), caspase-9, and caspase-3, and decreased the expression of zonula occludens-1 (ZO-1) and claudin-1 (P

ABSTRACT Decreased estrogen level is one of the main causes of lipid metabolism disorders and coronary heart disease in women after menopause. Exogenous estradiol benzoate is effective to some extent in alleviating lipid metabolism disorders caused by estrogen deficiency. However, the role of gut microbes in the regulation process is not yet appreciated. The objective of this study was to investigate the effects of estradiol benzoate supplementation on lipid metabolism, gut microbiota, and metabolites in ovariectomized (OVX) mice and to reveal the importance of gut microbes and metabolites in the regulation of lipid metabolism disorders. This study found that high doses of estradiol benzoate supplementation effectively attenuated fat accumulation in OVX mice. There was a significant increase in the expression of genes enriched in hepatic cholesterol metabolism and a concomitant decrease in the expression of genes enriched in unsaturated fatty acid metabolism pathways. Further screening of the gut for characteristic metabolites associated with improved lipid metabolism revealed that estradiol benzoate supplementation influenced major subsets of acylcarnitine metabolites. Ovariectomy significantly increased the abundance of characteristic microbes that are significantly negatively associated with acylcarnitine synthesis, such as Lactobacillus and Eubacterium ruminantium group bacteria, while estradiol benzoate supplementation significantly increased the abundance of characteristic microbes that are significantly positively associated with acylcarnitine synthesis, such as Ileibacterium and Bifidobacterium spp. The use of pseudosterile mice with gut microbial deficiency greatly facilitated the synthesis of acylcarnitine due to estradiol benzoate supplementation and also alleviated lipid metabolism disorders to a greater extent in OVX mice. IMPORTANCE Our findings establish a role for gut microbes in the progression of estrogen deficiency-induced lipid metabolism disorders and reveal key target bacteria that may have the potential to regulate acylcarnitine synthesis. These findings suggest a possible route for the use of microbes or acylcarnitine to regulate disorders of lipid metabolism induced by estrogen deficiency.

Paralytic shellfish toxins (PSTs) are widely distributed in shellfish along the coast of China, causing a serious threat to consumer health; however, there is still a lack of large-scale systematic investigations and risk assessments. Herein, 641 shellfish samples were collected from March to November 2020, and the PSTs’ toxicity was detected via liquid chromatography–tandem mass spectrometry. Furthermore, the contamination status and potential dietary risks of PSTs were discussed. PSTs were detected in 241 shellfish samples with a detection rate of 37.60%. The average PST toxicities in mussels and ark shells were considerably higher than those in other shellfish. The PSTs mainly included N-sulfonylcarbamoyl toxins (class C) and carbamoyl toxins (class GTX), and the highest PST toxicity was 546.09 μg STX eq. kg−1. The PST toxicity in spring was significantly higher than those in summer and autumn (p < 0.05). Hebei Province had the highest average PST toxicity in spring. An acute exposure assessment showed that consumers in Hebei Province had a higher dietary risk, with mussels posing a significantly higher dietary risk to consumers. This research provides reference for the green and sustainable development of the shellfish industry and the establishment of a shellfish toxin prevention and control system.

Bay scallops (Argopecten irradians; A. irradians) are shellfish with high nutritional and economic value. However, nutritional studies on A. irradians with different shell colors are limited. This study examines the hazardous, nutritional, and taste-contributing compounds during the growth of A. irradians with different shell colors. During the growth of A. irradians, the hazardous contents were below the standard limit. Changes in the nutritional and taste-contributing compounds between months were more significant than shell color. Bay scallops had more fats, total fatty acids, and taste-contributing compounds in August and more proteins, essential fatty acids, vitamin D, vitamin B12, Cu, and Zn in September and October. In October, the golden shell color strain had more proteins, essential fatty acids, vitamin D, vitamin B12, Cu, and Zn, while the purple shell color strain had more taste-contributing compounds. A. irradians had better taste in August and higher nutritional value in September and October. In October, the golden shell color strain has higher nutritional value, and the purple shell color strain has better commercial value and taste. The correlation analysis indicates that the nutritional quality of bay scallops is affected by age (months), shell color, and seawater environment.

Abstract The rock mass is one of the key parameters in engineering design. Accurate rock mass classification is also essential to ensure operational safety. Over the past decades, various models have been proposed to evaluate and predict rock mass. Among these models, artificial intelligence (AI) based models are becoming more popular due to their outstanding prediction results and generalization ability for multiinfluential factors. In order to develop an easy-to-use rock mass classification model, support vector machine (SVM) techniques are adopted as the basic prediction tools, and three types of optimization algorithms, i.e., particle swarm optimization (PSO), genetic algorithm (GA) and grey wolf optimization (GWO), are implemented to improve the prediction classification and optimize the hyper-parameters. A database was assembled, consisting of 80 sets of real engineering data, involving four influencing factors. The three combined models are compared in accuracy, precision, recall, F1 value and computational time. The results reveal that among three models, the GWO-SVC-based model shows the best classification performance by training. The accuracy of training and testing sets of GWO-SVC are 90.6250% (58/64) and 93.7500% (15/16), respectively. For Grades I, II, III, IV and V, the precision value is 1, 0.93, 0.90, 0.92, 0.83, the recall value is 1, 1, 0.93, 0.73, 0.83, and the F1 value is 1, 0.96, 0.92, 0.81, 0.83, respectively. Sensitivity analysis is performed to understand the influence of input parameters on rock mass classification. It shows that the sensitive factor in rock mass quality is the RQD. Finally, the GWO-SVC is employed to assess the quality of rocks from the southeastern ore body of the Chambishi copper mine. Overall, the current study demonstrates the potential of using artificial intelligence methods in rock mass assessment, rendering far better results than the previous reports.

ABSTRACT The maternal gut microbiome affects the duration of pregnancy, delivery, and lactation. It also coordinates the stability of maternal metabolism by regulating and modulating inflammatory cytokines and reproductive hormones. This has been shown in several species; however, the situation in ruminants remains a black box. Here, we aimed to elucidate the relationship between the hindgut microbiota, metabolism, and reproductive hormones in domestic goats (Capra hircus) during nonpregnancy, pregnancy, and lactation stages. The hindgut microbiota was altered during these three stages, with a drastic decrease in the abundance of Family_XIII_AD3011_group in the second and third trimesters of pregnancy. Additionally, a decline in the abundance of Christensenellaceae_R-7_group and Turicibacter was observed from the nonpregnancy stage to late gestation. Family_XIII_AD3011_group and Paeniclostridium were strongly correlated with decreased fecal estradiol and progesterone. Furthermore, we generated a metabolome atlas of the gut and serum from nonpregnancy to lactation to reveal the specific metabolic fingerprints of each physiological stage. Several specific gut metabolites, including carnitine C8:1, γ-aminobutyric acid, and indole-3-carboxylic acid, were negatively correlated with the fecal and serum estradiol concentrations. In contrast, 2′-deoxyinosine, deoxyadenosine, and 5′-deoxyadenosine were positively correlated with the fecal and serum estradiol concentrations. The levels of 2′-deoxyinosine, deoxyadenosine, and 5′-deoxyadenosine in fecal samples were positively correlated with Family_XIII_AD3011_group. Other serum metabolites, such as (±)12-HEPE (hydroxy eicosapentaenoic acid), (±)15-HEPE, (±)18-HEPE, cytidine, uracil, and 5-hydroxyindole-3-acetic acid, were negatively correlated with the serum concentrations of estradiol and progesterone. Finally, Corynebacterium and Clostridium_sensu_stricto_1 in the fecal samples were positively correlated with the abundance of 11,12-EET (epoxy-eicosatrienoic acid), (±)18-HEPE, (±)15-HEPE, and (±)12-HEPE in the serum. IMPORTANCE Our findings revealed that the activity of Family_XIII_AD3011_group and Corynebacterium is strongly correlated with the beneficial regulation of physiological hormones and metabolic changes during pregnancy and lactation. These findings are key for guiding targeted microbial therapeutic approaches to modulate microbiomes in gestating and lactating mammals.

Icariin (ICA) is a kind of natural flavonoid compound monomer, which is derived from the extract of dried stems and leaves of Epimedium. Modern pharmacological studies have found that ICA has broad bioactive function in affecting the biological processes of a variety of cancers, including breast cancer, colorectal cancer, hepatocellular carcinoma, esophageal cancer and other cancers, which indicates that ICA has promising application value in the treatment of cancer patients in the future. Nevertheless, the targets and molecular mechanisms of ICA in cancer treatment have not been elucidated in detail. Therefore, in this review, we systematically summarizes the current research progress of ICA in a series of cancers. In particular, an emphasis is placed on the mechanism of ICA and its future development direction, aiming at providing relevant theoretical basis for the development and application of ICA in the future cancer treatment strategies.

Plants can rapidly close stomata to restrict pathogen entry into leaves. Here the authors show that phosphorylation of villin3 by mitogen-activated protein kinases modulates actin remodeling to activate stomatal defense in Arabidopsis.

Influencer marketing acquires customers who follow their favorite celebrities, who have shared beliefs and opinions. This research explores the self-motives and influencer-related factors that lead to influencer congruence. Influenced customers subsequently recommend those influencers to others. No concrete scale of recommendation is available so far. This research also conceptualizes, develops, and validates a scale for recommendations. In this study, 451 respondents answered questions about the influencers they follow. Normality, reliability, and validity were used for hypothesis testing. Results show the positive and direct impacts of all proposed hypotheses. The findings contribute to the literature by presenting a balanced approach to studying two parallel yet integral aspects of influencer marketing: the influencer and the consumer.

Abstract In recent years, tomato mottle mosaic virus (ToMMV) has become one of the most important viral pathogens affecting solanaceous crop production in Yunnan, Hainan, and Shandong provinces of China, often causing huge yield reductions. To provide farmers and vegetable industry with reliable and easy-to-use ToMMV detection methods, we immunized BALB/c mice with purified ToMMV and obtained six hybridoma cell lines (i.e., 2D6, 9C12, 26A10, 3A4, 23A4 and 17B11) that secrete anti-ToMMV monoclonal antibodies (MAbs) through the hybridoma technology. Using these MAbs as the detection antibody, we developed three serological assays: antigen-coated-plate enzyme-linked immunosorbent assay (ACP-ELISA), dot enzyme-linked immunosorbent assay (dot-ELISA) and tissue print enzyme-linked immunosorbent assay (tissue print-ELISA) for ToMMV detection. Our test results showed that these three newly developed serological methods can be used to specifically detect ToMMV infection in plant samples, but not tobacco mosaic virus, tomato mosaic virus, cucumber green mottle mosaic virus and cucumber mosaic virus. Sensitivity analyses further showed that ACP-ELISA and dot-ELISA can be used to detect ToMMV infection in plant crude extracts diluted at 1:81,920 and 1:40,960 (weight/volume, g/mL), respectively. Surprisingly, the detection limit of the developed dot-ELISA was 26 times higher than that of traditional RT-PCR. Using field-collected plant samples, we have demonstrated that these three new serological methods are accurate and easy-to-use for large-scale detection of ToMMV in fields.

MicroRNAs (miRNAs) are a class of small noncoding RNA that can regulate physiological and pathological processes through post-transcriptional regulatory gene expression. As an important member of the miRNAs family, microRNA-7 (miR-7) was first discovered in 2001 to play an important regulatory role in tissue and organ development. Studies have shown that miR-7 participates in various tissue and organ development processes, tumorigenesis, aging, and other processes by regulating different target molecules. Notably, a series of recent studies have determined that miR-7 plays a key regulatory role in the occurrence of inflammation and related diseases. In particular, miR-7 can affect the immune response of the body by influencing T cell activation, macrophage function, dendritic cell (DC) maturation, inflammatory body activation, and other mechanisms, which has important potential application value in the intervention of related diseases. This article reviews the current regulatory role of miR-7 in inflammation and related diseases, including viral infection, autoimmune hepatitis, inflammatory bowel disease, and encephalitis. It expounds on the molecular mechanism by which miR-7 regulates the occurrence of inflammatory diseases. Finally, the existing problems and future development directions of miR-7-based intervention on inflammation and related diseases are discussed to provide new references and help strengthen the understanding of the pathogenesis of inflammation and related diseases, as well as the development of new strategies for clinical intervention.

Soil–cement–bentonite (SCB) backfill has been widely used in constructing cut-off walls to inhibit groundwater movement in contaminated sites. This study prepares SCB backfill with fixed fluidity. We conducted a series of experiments to investigate the engineering characteristics and microscopic mechanism of the backfill. The results indicate that the water content in the slurry was more sensitive to the bentonite content. The unconfined compression strength (UCS) value increased with an increase in the cement content, and the change with an increase in bentonite content was not noticeable. The permeability coefficient decreased distinctly with an increase in the cement and bentonite contents. The porosity of the SCB backfill increased with increasing bentonite content and decreased with increasing cement content. The UCS of SCB backfill was linearly and negatively correlated with the porosity; the permeability coefficient was not significantly related to the porosity. The percentage of micro- and small-pore throats in the backfill increased with increasing bentonite and cement contents. As cement and bentonite content increased by 6% in the backfill, the proportion of micro- and small-pore throats increased by 0.7% and 1.2%, respectively. The percentage of micro- and small-pore throats is deduced to be more suitable as a characterization parameter for the permeability of the SCB backfill. The overall results of this study show that the reasonably proportioned SCB backfill has potential as an eco-friendly and cost-effective material. Based on the requirements of strength and permeability coefficient (UCS > 100 kPa, 28 days permeability coefficient −7 cm/s), we suggested using a backfill with 12% bentonite and 9% cement as the cut-off wall mix ratio.

Maize chlorotic mottle virus (MCMV) is the only species in the Mahromovirus genus and is often co-infected with one or several viruses of the Potyvirus genus, posing a great threat to the global maize industry. Effective viral integrated management measures are dependent on the timely and proper detection of the causal agent of the disease. In this work, six super-sensitive and specific monoclonal antibodies (mAbs) against MCMV were first prepared using purified MCMV virions as the immunogen. Then, the Dot enzyme-linked immunosorbent assay (Dot-ELISA) was established based on the obtained mAbs, and it can detect MCMV in infected maize leaf crude extracts diluted up to 1:10,240-fold (w/v, g/mL). Furthermore, a rapid and user-friendly Au nanoparticle-based immunochromatographic test strip (AuNP-ICTS) based on paired mAbs 7B12 and 17C4 was created for monitoring MCMV in point-of-care tests, and it can detect the virus in a 25,600-fold dilution (w/v, g/mL) of MCMV-infected maize leaf crude extracts. The whole test process for ICTS was completed in 10 min. Compared with conventional reverse transcription-polymerase chain reaction (RT-PCR), the detection endpoint of both serological methods is higher than that of RT-PCR, especially the Dot-ELISA, which is 12.1 times more sensitive than that of RT-PCR. In addition, the detection results of 20 blinded maize samples by the two serological assays were consistent with those of RT-PCR. Therefore, the newly created Dot-ELISA and AuNP-ICTS exhibit favorable application potential for the detection of MCMV in plant samples.

Abstract Patterned nanostructures with ultrasmall features endow functional devices with unique nanoconfinement and performance enhancements. The increasing demand for miniaturization has stimulated the development of sub‐100 nm nanopatterning techniques. Beyond conventional lithography—which is limited by unavoidable factors—advanced patterning techniques have been reported to produce nanoscale features down to molecular or even atomic scale. In this review, unconventional techniques for sub‐100 nm nanopatterning are discussed, in particular the principles by which to achieve the desired patterns (among other important issues). Such techniques can be classified into three categories: template‐replica, template‐induced, and template‐free techniques. Moreover, multi‐dimensional nanostructures consist of various building materials, the unique properties of which are summarized. Finally, the remaining challenges and opportunities for large‐scale patterning, the improvement of device performance, the multi‐dimensional nanostructures of biocompatible materials, molecular‐scale patterning, and the carbon footprint requirements for future nanofabrication processes are discussed.

Lung cancer is a commonly diagnosed cancer and the leading cause of cancer-related deaths, posing a serious health risk. Despite new advances in immune checkpoint and targeted therapies in recent years, the prognosis for lung cancer patients, especially those in advanced stages, remains poor. MicroRNAs (miRNAs) have been shown to modulate tumor development at multiple levels, and as such, miRNA mimics and molecules aimed at regulating miRNAs have shown promise in preclinical development. More importantly, miRNA-based therapies can also complement conventional chemoradiotherapy, immunotherapy, and targeted therapies to reverse drug resistance and increase the sensitivity of lung cancer cells. Furthermore, small interfering RNA (siRNA) and miRNA-based therapies have entered clinical trials and have shown favorable development prospects. Therefore, in this paper, we review recent advances in miRNA-based therapies in lung cancer treatment as well as adjuvant therapy and present the current state of clinical lung cancer treatment. We also discuss the challenges facing miRNA-based therapies in the clinical application of lung cancer treatment to provide new ideas for the development of novel lung cancer therapies.

Intermittent fasting (IF) is becoming a prevailing topic worldwide, as it can cause changes in the body’s energy metabolism processes, improve health, and affect the progression of many diseases, particularly in the circumstance of oncology. Recent research has shown that IF can alter the energy metabolism of tumor cells, thereby inhibiting tumor growth and improving antitumor immune responses. Furthermore, IF can increase cancer sensitivity to chemotherapy and radiotherapy and reduce the side effects of these traditional anticancer treatments. IF is therefore emerging as a promising approach to clinical cancer treatment. However, the balance between long-term benefits of IF compared with the harm from insufficient caloric intake is not well understood. In this article, we review the role of IF in tumorigenesis and tumor therapy, and discuss some scientific problems that remain to be clarified, which might provide some assistance in the application of IF in clinical tumor therapy.

Abstract Background Drug repositioning, the strategy of unveiling novel targets of existing drugs could reduce costs and accelerate the pace of drug development. To elucidate the novel molecular mechanism of known drugs, considering the long time and high cost of experimental determination, the efficient and feasible computational methods to predict the potential associations between drugs and targets are of great aid. Methods A novel calculation model for drug-target interaction (DTI) prediction based on network representation learning and convolutional neural networks, called DLDTI, was generated. The proposed approach simultaneously fused the topology of complex networks and diverse information from heterogeneous data sources, and coped with the noisy, incomplete, and high-dimensional nature of large-scale biological data by learning the low-dimensional and rich depth features of drugs and proteins. The low-dimensional feature vectors were used to train DLDTI to obtain the optimal mapping space and to infer new DTIs by ranking candidates according to their proximity to the optimal mapping space. More specifically, based on the results from the DLDTI, we experimentally validated the predicted targets of tetramethylpyrazine (TMPZ) on atherosclerosis progression in vivo. Results The experimental results showed that the DLDTI model achieved promising performance under fivefold cross-validations with AUC values of 0.9172, which was higher than the methods using different classifiers or different feature combination methods mentioned in this paper. For the validation study of TMPZ on atherosclerosis, a total of 288 targets were identified and 190 of them were involved in platelet activation. The pathway analysis indicated signaling pathways, namely PI3K/Akt, cAMP and calcium pathways might be the potential targets. Effects and molecular mechanism of TMPZ on atherosclerosis were experimentally confirmed in animal models. Conclusions DLDTI model can serve as a useful tool to provide promising DTI candidates for experimental validation. Based on the predicted results of DLDTI model, we found TMPZ could attenuate atherosclerosis by inhibiting signal transductions in platelets. The source code and datasets explored in this work are available at https://github.com/CUMTzackGit/DLDTI .

Abstract Background Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4−/− mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 knockdown using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

Apolipoprotein C2 (ApoC2) is a key activator of lipoprotein lipase for plasma triglyceride metabolism. ApoC2-deficient patients present with severe hypertriglyceridemia and recurrent acute pancreatitis, for whom the only effective treatment is the infusion of normal plasma containing ApoC2. However, since ApoC2 has a fast catabolic rate, a repeated infusion is required, which limits its clinical use. To explore a safe and efficient approach for ApoC2 deficiency, we herein established an adeno-associated virus expressing human ApoC2 (AAV-hApoC2) to evaluate the efficacy and safety of gene therapy in ApoC2-deficient hypertriglyceridemic hamsters. Administration of AAV-hApoC2 via jugular or orbital vein in adult and neonatal ApoC2-deficient hamsters, respectively, could prevent the neonatal death and effectively improve severe hypertriglyceridemia of ApoC2-deficient hamsters without side effects in a long-term manner. Our novel findings in the present study demonstrate that AAV-hApoC2-mediated gene therapy will be a promising therapeutic approach for clinical patients with severe hypertriglyceridemia caused by ApoC2 deficiency.

Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level and play critical roles in regulating physiological function, and are becoming worldwide research hot spot in brain development and diseases. However, the exact value of miRNAs in brain physiological and pathological processes remain to be fully elucidated, which is vital for the application of miRNAs as diagnostic, prognostic, and therapeutic biomarkers for brain diseases. MicroRNA-7 (miR-7), as a highly expressed miRNA molecule in the mammalian brain, is well documented to play a critical role in development of various diseases. Importantly, accumulating evidence has shown that miR-7 is involved in a range of developmental and pathological processes of brain. Expressively, miR-7, encoded by three genes located different chromosomes, is dominantly expressed in neurons with sensory or neurosecretory. Moreover, the expression of miR-7 is regulated at three levels including gene transcription, process of primary and precursor sequence and formation of mature sequence. Physiologically, miR-7 principally governs the physiological development of Pituitary gland, Optic nervous system and Cerebral cortex. Pathologically, miR-7 can regulate multiple genes thereby manipulating the process of various brain diseases including neurodegenerative diseases, neuroinflammation, and mental disorders and so on. These emerging studies have shown that miR-7, a representative member of miRNA family, might be a novel intrinsic regulatory molecule involved in the physiological and pathological process of brain. Therefore, in-depth studies on the role of miR-7 in brain physiology and pathology undoubtedly not only provide a light on the roles of miRNAs in brain development and diseases, but also are much helpful for ultimate development of therapeutic strategies against brain diseases. In this review, we provide an overview of current scientific knowledge regarding the expression and function of miR-7 in development and disease of brain and raise many issues involved in the relationship between miR-7 and brain physiological and pathological processes.

Abstract Background Accumulating evidence has documented that microRNA-7 (miR-7) plays an important role in the pathology of various diseases. However, the potential role of miR-7 in brain tissue inflammation (BTI) remains unclear. Methods We detected the expression of miR-7 in LPS-induced murine BTI model and observed the possible effects of miR-7 deficiency on the pathology of BTI. To elucidate the mechanism, the target gene of miR-7 was screened out by Gene chip assay and its potential roles in BTI were evaluated by Western blot, immunofluorescence, and RNAi assay, respectively. Results MiR-7 was upregulated in brain tissue in BTI mice and its deficiency could significantly aggravate the pathology of brain tissue. Moreover, RORα, a new target molecule of miR-7, was upregulated in brain tissue from miR-7 deficiency BTI mice. Of note, downregulation of RORα could remarkably exacerbate the pathology of brain tissue and elevate the transduction of NF-κB and ERK1/2 signaling pathways in brain tissue from miR-7 deficiency BTI mice. Furthermore, RORα and miR-7 were dominantly co-expressed in neurons of BTI mice. Finally, RORα synergized with miR-7 to control the inflammatory reaction of neuronal cells in response to LPS stimulation. Conclusions MiR-7 expression is upregulated in BTI model. Moreover, miR-7 synergizes with its target gene RORα to control the inflammation reaction of neurons, thereby orchestrating the pathology of BTI.

This study applied an artifact-centric view to investigate the consequences of enterprise social media usage. It investigates how enterprise social media usage influences employee creativity. A moderated mediation model is developed based on social exchange theory. The empirical sample of 238 employees is used to test the proposed model. Results of the empirical analysis performed using PROCESS macro of SPSS indicate that enterprise social media usage positively impacts employee creativity via the mediating mechanisms (i.e., leader-member exchange and support for innovation). Furthermore, social media usage frequency negatively moderates this impact of enterprise social media usage on employee creativity via leader-member exchange. Interestingly, the empirical analysis reveals that the impact of enterprise social media usage frequency strengthens the indirect effect that enterprise social media usage has on employee creativity via perceived support for innovation.

Plum pox virus (PPV) is a causal agent of the stone fruit tree sharka disease that often causes enormous economic losses. Due to its worldwide distribution and economic importance, rapid and reliable diagnostic technologies are becoming increasingly important for successful management of sharka disease. In this study, we have produced two super-sensitive and specific anti-PPV monoclonal antibodies (i.e., MAbs 13H4 and 4A11). Using these two MAbs, we have now developed a dot enzyme-linked immunosorbent assay (dot-ELISA) and a colloidal gold immunochromatographic strip (CGICS) assay. These two technologies can be used to quickly and reliably detect PPV. The results of these sensitivity assays confirmed that the dot-ELISA and CGICS assays could detect PPV infection in apricot tree leaf crude extracts diluted up to 1:5120 and 1:6400 (w/v), respectively. Further analyses using field-collected apricot tree leaf samples showed that the detection endpoint of the dot-ELISA was ~26 times above that obtained through RT-PCR, and the CGICS was as sensitive as RT-PCR. This present study is to broaden the knowledge about detection limits of dot-ELISA and CGICS for PPV monitoring. We consider that these newly developed dot-ELISA and CGICS are particularly useful for large scale PPV surveys in fields.

The contamination of 2,2’,4,4’-Tetrabrmodiphenyl ether (BDE-47) and perfluorooctanoic acid (PFOA) has drawn a worldwide attention over the risks in ecological and food safety. In this work, blue mussel (Mytilus galloprpvincialis) was employed to investigate the combined effects of BDE-47 (10 ng mL-1) and PFOA (100 ng mL-1) on tissue distribution, accumulation, elimination, and toxicity. Results suggested that BDE-47 and PFOA accumulated mostly in digestive gland, followed by gills and gonad, and M. galloprovincialis displayed higher accumulation capacity to BDE-47 than PFOA. Co-exposure treatment reduced the accumulation of BDE-47, and enhanced the accumulation of PFOA. Furthermore, biochemical and histopathological tests revealed that the aggravated toxicity in co-exposure groups was mainly attributed to the oxidative stress and damage of tissue structure. This work could be helpful to get a better understanding of the combined behaviors and cumulative risks of BDE-47 and PFOA in marine ecosystem.

Harmful algal blooms in Chinese waters have caused serious domoic acid (DA) contamination in shellfish. Although shellfish are at particular risk of dietary exposure to DA, there have been no systematic DA risk assessments in Chinese coastal waters. A total of 451 shellfish samples were collected from March to November 2020. The presence of DA and four of its isomers were detected using liquid chromatography–tandem mass spectrometry. The spatial-temporal distribution of DA occurrence and its potential health risks were examined. DA was detected in 198 shellfish samples (43.90%), with a maximum level of 942.86 μg/kg. DA was recorded in all 14 shellfish species tested and Pacific oysters (Crassostrea gigas) showed the highest average DA concentration (82.36 μg/kg). The DA concentrations in shellfish showed distinct spatial-temporal variations, with significantly higher levels of occurrence in autumn than in summer and spring (p < 0.01), and particularly high occurrence in Guangdong and Fujian Provinces. The detection rates and maximum concentrations of the four DA isomers were low. While C. gigas from Guangdong Province in September showed the highest levels of DA contamination, the risk to human consumers was low. This study improves our understanding of the potential risk of shellfish exposure to DA-residues.

A holistic view of scientific literacy-related literature was generated based on bibliometric analysis. The purpose was to provide insight into and knowledge on evolving knowledge fronts and to highlight the turning points in the existing literature between 1980 and 2019. Scientific literacy in society can potentially help to answer unsolved riddles of socio-scientific issues (SSI) to enable people to become smart and responsible global citizens. Specifically, two decades before and after the year 2000 was taken into account as it comprised the most noticeable revolutionary developments in terms of economics, technology, culture, and society. Interestingly, the attention paid to scientific literacy significantly increased after the financial crisis of 2008. International Journal of Science Education and the Journal of Research in Science Teaching were observed to be the top-cited and top publishing journals, respectively. Similarly, Jonathan Osborne, Rosalind Driver, and Norman G. Lederman were recorded as the most cited and most published authors, respectively, during the study period. Alarmingly, most of the literature evolved in and was dominated by the Western region, indicating the need to understand the regional-cultural complexities of the East and the rest of the world. The recent evolving clusters, with titles of literacy (as a concept), learning progression, and informal reasoning, were observed to be currently active knowledge areas in the evolution of the intellectual structure of scientific literacy-related literature. However, no recent trend or emerging research direction was noticed in the last decade, even though new and digital media (including immersive media) have revolutionized the communication channels and public understanding of science and socio-scientific issues.

In order to study the morphology characteristics of the PTFE/Al reactive shaped charge jet and the chemical reaction during the jet formation, PTFE/Al reactive liners with aluminum particle sizes of 5 μm and 100 μm were prepared. The parameters of the Johnson–Cook constitutive model of PTFE/Al reactive materials (RMs) were obtained through quasi-static compression experiments and SHPB (Split Hopkinson Pressure Bar) experiments. X-ray imaging technology was used to photograph the shape of reactive shaped charges jet at two different time points. The AUTODYN secondary development technology was used to simulate the jet formation, and the simulation results are compared with the experimental results. The results show that the simulation results are close to the experimental results, and the error is in the range of 4–8%. Through analysis, it is observed that the RMs reacted during the PTFE/Al reactive shaped charge jet formation, and due to the convergence of the inner layer of the liner during the jet formation, the chemical reaction of the jet is from inside to outside. Secondly, the particle size of aluminum powder has an influence on the chemical reaction and morphology of the jet. During the jet formation, there were fewer RMs reacted when the PTFE/Al reactive liners were prepared with 100 μm aluminum powder. Compared with 5 μm aluminum powder, when the aluminum powder is 100 μm, the morphology of the jet is more condensed, which is conducive to generating greater penetration depth.

MicroRNAs (miRNAs) are widely present in many organisms and regulate the expression of genes in various biological processes such as cell differentiation, metabolism, and development. Numerous studies have shown that miRNAs are abnormally expressed in tumor tissues and are closely associated with tumorigenesis. MiRNA-based cancer gene therapy has consistently shown promising anti-tumor effects and is recognized as a new field in cancer treatment. So far, some clinical trials involving the treatment of malignancies have been carried out; however, studies of miRNA-based cancer gene therapy are still proceeding slowly. Therefore, furthering our understanding of the regulatory mechanisms of miRNA can bring substantial benefits to the development of miRNA-based gene therapy or other combination therapies and the clinical outcome of patients with cancer. Recent studies have revealed that the aberrant expression of miRNA in tumors is associated with promoter sequence mutation, epigenetic alteration, aberrant RNA modification, etc., showing the complexity of aberrant expression mechanisms of miRNA in tumors. In this paper, we systematically summarized the regulation mechanisms of miRNA expression in tumors, with the aim of providing assistance in the subsequent elucidation of the role of miRNA in tumorigenesis and the development of new strategies for tumor prevention and treatment.

Abstract Dual-specificity phosphatases (DUSPs) are a subset of protein tyrosine phosphatases (PTPs), many of which dephosphorylate the residues of phosphor-serine/threonine and phosphor-tyrosine on mitogen-activated protein kinases (MAPKs), and hence are also referred to as MAPK phosphatases (MKPs). Homologue of Vaccinia virus H1 phosphatase gene clone 5 (HVH-5), also known as DUSP8, is a unique member of the DUSPs family of phosphatases. Accumulating evidence has shown that DUSP8 plays an important role in phosphorylation-mediated signal transduction of MAPK signaling ranging from cell oxidative stress response, cell apoptosis and various human diseases. It is generally believed that DUSP8 exhibits significant dephosphorylation activity against JNK, however, with the deepening of research, plenty of new literature reports that DUSP8 also has effective dephosphorylation activity on p38 MAPK and ERKs, successfully affects the transduction of MAPKs pathway, indicating that DUSP8 presents a unknown diversity of DUSPs family on distinct corresponding dephosphorylated substrates in different biological events. Therefore, the in-depth study of DUSP8 not only throws a new light on the multi-biological function of DUSPs, but also is much valuable for the reveal of complex pathobiology of clinical diseases. In this review, we provide a detail overview of DUSP8 phosphatase structure, biological function and expression regulation, as well as its role in related clinical human diseases, which might be help for the understanding of biological function of DUSP8 and the development of prevention, diagnosis and therapeutics in related human diseases.

The abnormal regulation and expression of microRNA (miRNA) are closely related to the aging process and the occurrence and development of aging-related diseases. Lethal-7 (let-7) was discovered in Caenorhabditis elegans (C. elegans) and plays an important role in development by regulating cell fate regulators. Accumulating evidence has shown that let-7 is elevated in aging tissues and participates in multiple pathways that regulate the aging process, including affecting tissue stem cell function, body metabolism, and various aging-related diseases (ARDs). Moreover, recent studies have found that let-7 plays an important role in the senescence of B cells, suggesting that let-7 may also participate in the aging process by regulating immune function. Therefore, these studies show the diversity and complexity of let-7 expression and regulatory functions during aging. In this review, we provide a detailed overview of let-7 expression regulation as well as its role in different tissue aging and aging-related diseases, which may provide new ideas for enriching the complex expression regulation mechanism and pathobiological function of let-7 in aging and related diseases and ultimately provide help for the development of new therapeutic strategies.

A polymer of tetrafluoroethylene, hexafluoropropylene, and vinylidene fluoride- (THV) based reactive materials (RMs) was designed to improve their density and energy release efficiency. The mechanical performances, fracture mechanisms, thermal behavior, energy release behavior, and reaction energy of four types of RMs (26.5% Al/73.5% PTFE, 5.29% Al/80% W/14.71% PTFE, 62% Hf/38% THV, 88% Hf/12% THV) were systematically researched by conducting compressive tests, scanning electron microscope (SEM), differential scanning calorimeter, thermogravimetric (DSC/TG) tests and ballistic experiments. The results show that the THV-based RMs have a unique strain softening effect, whereas the PTFE-based RMs have a remarkable strain strengthening effect, which is mainly caused by the different glass transition temperatures. Thermal analysis indicates that the THV-based RMs have more than one exothermic peak because of the complex component in THV. The energy release behavior of RMs is closely related to their mechanical properties, which could dominate the fragmentation behavior of materials. The introduction of tungsten (W) particles to PTFE RMs could not only enhance the density but also elevate the reaction threshold of RMs, whereas the reaction threshold of THV-based RMs is decreased when increasing Hf particles content. As such, under current conditions, the THV-based RMs (88% Hf/12% THV) with a high density of 7.83 g/cm3 are adapted to release a lot of energy in thin, confined spaces.

Paralytic shellfish toxins (PSTs) are an increasingly important source of pollution. Bivalves, as the main transmission medium, accumulate and metabolize PSTs while protecting themselves from damage. At present, the resistance mechanism of bivalves to PSTs is unclear. In this study, Mytilus galloprovincialis and Argopecten irradians were used as experimental shellfish species for in situ monitoring. We compared the inflammatory-related gene responses of the two shellfish during PSTs exposure by using transcriptomes. The results showed that the accumulation and metabolism rate of PSTs in M. galloprovincialis was five-fold higher than that in A. irradians. The inflammatory balance mechanism of M. galloprovincialis involved the co-regulation of the MAPK-based and AMPK-based anti-inflammatory pathways. A. irradians bore a higher risk of death because it did not have the balance system, and the regulation of apoptosis-related pathways such as the PI3K-AKT signaling pathway were upregulated. Taken together, the regulation of the inflammatory balance coincides with the ability of bivalves to cope with PSTs. Inflammation is an important factor that affects the metabolic pattern of PSTs in bivalves. This study provides new evidence to support the studies on the resistance mechanism of bivalves to PSTs.

Accumulating research has documented that microRNA-21 (miR-21) plays an important role in the development of human colorectal carcinoma (CRC). Our recent work also showed that antisense oligonucleotides (ASOs) against miR-21 can impair the growth of CRC cells in vitro. However, the potential role of miR-21 in gene therapy against CRC remains to be fully elucidated. Here, we further observed the effect of ASOs against miR-21 on the growth and metastasis of CRC in vivo using a xenograft model of human CRC. We found that ASOs could effectively inhibit the growth and metastasis of CRC in vivo, accompanied by downregulated expression of miR-21 and reduced transduction of the AKT and ERK pathway. Mechanically, global gene expression analysis showed that the expression of DUSP8, a novel target of miR-21, was upregulated in tumor mass. Furthermore, overexpression of DUSP8 could remarkably suppress the proliferation and migration of CRC cells in vitro. Finally, downregulation of DUSP8 could abrogate the effects of ASOs against miR-21 on the proliferation and migration of CRC cells, as well as altered transduction of the AKT and ERK signaling pathway. Together, these data suggest that ASOs against miRNAs are an attractive and potential therapeutic for the treatment of human CRC and warrant further development. Keywords: miR-21, ASOs, colorectal carcinoma, growth, DUSP8