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Primary lung cancer is one of the most common malignant tumors in China. Approximately 60% of lung cancer patients have distant metastasis at the initial diagnosis, so it is necessary to find new tumor markers for early diagnosis and individualized treatment. Tumor markers contribute to the early diagnosis of lung cancer and play important roles in early detection and treatment, as well as in precision medicine, efficacy monitoring, and prognosis prediction. The pathological diagnosis of lung cancer in small biopsy specimens determines whether there are tumor cells in the biopsy and tumor type. Because biopsy is traumatic and the compliance of patients with multiple biopsies is poor, liquid biopsy has become a hot research direction. Liquid biopsies are advantageous because they are nontraumatic, easy to obtain, reflect the overall state of the tumor, and allow for real-time monitoring. At present, liquid biopsies mainly include circulating tumor cells, circulating tumor DNA, exosomes, microRNA, circulating RNA, tumor platelets, and tumor endothelial cells. This review introduces the research progress and clinical application prospect of liquid biopsy technology for lung cancer.

Noroviruses (NoVs) and rotaviruses (RVs), the two most important causes of viral acute gastroenteritis, are found to recognise histo-blood group antigens (HBGAs) as receptors or ligands for attachment. Human HBGAs are highly polymorphic containing ABO, secretor and Lewis antigens. In addition, both NoVs and RVs are highly diverse in how they recognise these HBGAs. Structural analysis of the HBGA-binding interfaces of NoVs revealed a conserved central binding pocket (CBP) interacting with a common major binding saccharide (MaBS) of HBGAs and a variable surrounding region interacting with additional minor binding saccharides. The conserved CBP indicates a strong selection of NoVs by the host HBGAs, whereas the variable surrounding region explains the diverse recognition patterns of different HBGAs by NoVs and RVs as functional adaptations of the viruses to human HBGAs. Diverse recognition of HBGAs has also been found in bacterial pathogen Helicobacter pylori. Thus, exploratory research into whether such diverse recognitions also occur for other viral and bacterial pathogens that recognise HBGAs is warranted.

Background Sepsis is a life-threatening condition that is characterized by multiorgan dysfunction and caused by dysregulated cytokine networks, which are closely associated with sepsis progression and outcomes. However, currently available treatment strategies that target cytokines have failed. Thus, this study aimed to investigate the interplay between genetically predicted circulating concentrations of cytokines and the outcomes of sepsis and to identify potential targets for sepsis treatment. Methods Data related to 35 circulating cytokines in 31,112 individuals (including 11,643 patients with sepsis) were included in genome-wide association studies (GWASs) from the UK Biobank and FinnGen consortia. A bidirectional two-sample Mendelian randomization (MR) analysis was performed using single nucleotide polymorphisms (SNPs) to evaluate the causal effects of circulating cytokines on sepsis outcomes and other cytokines. Results A total of 35 inflammatory cytokine genes were identified in the GWASs, and 11 cytokines, including Interleukin-1 receptor antagonist (IL-1ra), macrophage inflammatory protein 1 (MIP1α), IL-16, et al., were associated with sepsis outcome pairs according to the selection criteria of the cis-pQTL instrument. Multiple MR methods verified that genetically predicted high circulating levels of IL-1ra or MIP1α were negatively correlated with genetic susceptibility to risk of sepsis, including sepsis (28-day mortality), septicaemia, streptococcal and pneumonia-derived septicaemia ( P  ≤ 0.01). Furthermore, genetic susceptibility of sepsis outcomes except sepsis (28-day mortality) markedly associated with the circulating levels of five cytokines, including active plasminogen activator inhibitor (PAI), interleukin 7 (IL-7), tumour necrosis factor alpha (TNF-α), beta nerve growth factor (NGF-β), hepatic growth factor (HGF) ( P  < 0.05). Finally, we observed that the causal interaction network between MIP1α or IL-1ra and other cytokines ( P  < 0.05). Conclusions This comprehensive MR analysis provides insights into the potential causal mechanisms that link key cytokines, particularly MIP1α, with risk of sepsis, and the findings suggest that targeting MIP1α may be a potential strategy for preventing sepsis.

  Increasing amounts of data also showed that many bacterial and other viral pathogens rely on a carbohydrate receptor for infection [17]. [...]the requirement of a carbohydrate receptor could be a convergent factor in the evolution of these bacterial and viral pathogens.\\n One possibility is that a functional co-receptor necessary for norovirus replication is missing in the cell culture, although failures of additional downstream steps of viral replication also may be the reason. In the laboratory a single residue mutation around receptor-binding interfaces can result in a change of HBGA binding patterns [8], [29]. [...]it would be of significance to explore whether the consensus receptor binding patterns can switch between two genotypes in nature and whether GII.4 noroviruses will continue to dominate or will be replaced by other genotypes in future epidemics.

Plant cold acclimation (CA) is a genetically complex phenomenon involving gene regulation and expression. Little is known about the cascading pattern of gene regulatroy network and the link between genes and metabolites during CA. (DOKM) is an important medicinal and ornamental plant and hypersensitive to low temperature. Here, we used the large scale metabolomic and transcriptomic technologies to reveal the response to CA in DOKM seedlings based on the physiological profile analyses. Lowering temperature from 4 to -2°C resulted in significant increase ( < 0.01) in antioxidant activities and electrolyte leakage (EL) during 24 h. The fitness CA piont of 0°C and control (20°C) during 20 h were firstly obtained according to physiological analyses. Subsequently, massive transcriptome and metabolome reprogramming occurred during CA. The gene to metabolite network demonstrated that the CA associated processes are highly energy demanding through activating hydrolysis of sugars, amino acids catabolism and citrate cycle. The expression levels of 2,767 genes were significantly affected by CA, including 153-fold upregulation of CBF transcription factor, 56-fold upregulation of MAPKKK16 protein kinase. Moreover, the gene interaction and regulation network analysis revealed that the CA as an active process, was regulated at the transcriptional, post-transcriptional, translational and post-translational levels. Our findings highligted a comprehensive regulatory mechanism including cold signal transduction, transcriptional regulation, and gene expression, which contributes a deeper understanding of the highly complex regulatory program during CA in DOKM. Some marker genes identified in DOKM seedlings will allow us to understand the role of each individual during CA by further functional analyses.

Acute coronary syndromes (ACS) remain life-threatening disorders, which are associated with high morbidity and mortality. Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in the response to clopidogrel treatment, in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y 12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19, which affect the pharmacokinetics of clopidogrel. While the US Food and Drug Administration has issued a boxed warning for CYP2C19 poor metabolizers because of potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug–drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability, and how they are interrelated, is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence the pharmacokinetics and pharmacodynamics of clopidogrel and how they mechanistically contribute to inter-individual differences in the response to clopidogrel treatment.

DNA and histone modifications have notable effects on gene expression 1 . Being the most prevalent internal modification in mRNA, the N 6 -methyladenosine (m 6 A) mRNA modification is as an important post-transcriptional mechanism of gene regulation 2 – 4 and has crucial roles in various normal and pathological processes 5 – 12 . However, it is unclear how m 6 A is specifically and dynamically deposited in the transcriptome. Here we report that histone H3 trimethylation at Lys36 (H3K36me3), a marker for transcription elongation, guides m 6 A deposition globally. We show that m 6 A modifications are enriched in the vicinity of H3K36me3 peaks, and are reduced globally when cellular H3K36me3 is depleted. Mechanistically, H3K36me3 is recognized and bound directly by METTL14, a crucial component of the m 6 A methyltransferase complex (MTC), which in turn facilitates the binding of the m 6 A MTC to adjacent RNA polymerase II, thereby delivering the m 6 A MTC to actively transcribed nascent RNAs to deposit m 6 A co-transcriptionally. In mouse embryonic stem cells, phenocopying METTL14 knockdown, H3K36me3 depletion also markedly reduces m 6 A abundance transcriptome-wide and in pluripotency transcripts, resulting in increased cell stemness. Collectively, our studies reveal the important roles of H3K36me3 and METTL14 in determining specific and dynamic deposition of m 6 A in mRNA, and uncover another layer of gene expression regulation that involves crosstalk between histone modification and RNA methylation. METTL14 recognizes the trimethyl mark on lysine 36 of histone H3 that directs m 6 A modifications co-transcriptionally.

Background This study aimed to investigate the effect of systemic inflammation, assessed by high sensitivity C‐reactive protein (hs‐CRP) levels, on prediabetes progression and regression in middle‐aged and older adults based on the China Health and Retirement Longitudinal Study (CHARLS). Methods Participants with prediabetes from CHARLS were followed up 4 years later with blood samples collected for measuring fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The level of hs‐CRP was assessed at baseline and categorized into tertiles (low, middle, and high groups). Prediabetes at baseline and follow‐up was defined primarily according to the American Diabetes Association (ADA) criteria. Logistic regression models were used to estimate the odds ratios (ORs) and confidence intervals (CIs). We also performed stratified analyses according to age, gender, BMI, the presence of hypertension, and the disease history of heart disease and dyslipidemia and sensitivity analyses excluding a subset of participants with incomplete data. Results Of the 2,874 prediabetes included at baseline, 834 participants remained as having prediabetes, 146 progressed to diabetes, and 1,894 regressed to normoglycemia based on ADA criteria with a 4 year follow‐up. After multivariate logistics regression analysis, prediabetes with middle (0.67–1.62 mg/L) and high (>1.62 mg/L) hs‐CRP levels had an increased incidence of progressing to diabetes compared with prediabetes with low hs‐CRP levels (<0.67 mg/L; OR = 1.846, 95%CI: 1.129–3.018; and OR = 1.632, 95%CI: 0.985–2.703, respectively), and the incidence of regressing to normoglycemia decreased (OR = 0.793, 95%CI: 0.645–0.975; and OR = 0.769, 95%CI: 0.623–0.978, respectively). Stratified analyses and sensitivity analyses showed consistent results. Conclusions Low levels of hs‐CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes. This study found that low levels of hs‐CRP are associated with a high incidence of regression from prediabetes to normoglycemia and reduced odds of progression to diabetes. Subgroup analyses showed a stronger association between hs‐CRP and type 2 diabetes in women than in men. Thus, prediabetes may need to be closely monitored in middle‐aged and older women with elevated hs‐CRP. In addition, whether a lower cutoff value for hs‐CRP elevation in women should be proposed is a question worthy of future research.

Pathological cardiac hypertrophy involves multiple regulators and several signal transduction pathways. Currently, the mechanisms of it are not well understood. Differentially expressed in FDCP 6 homolog (DEF6) was reported to participate in immunity, bone remodeling, and cancers. The effects of DEF6 on pathological cardiac hypertrophy, however, have not yet been fully characterized. We initially determined the expression profile of DEF6 and found that DEF6 was upregulated in hypertrophic hearts and cardiomyocytes. Our in vivo results revealed that DEF6 deficiency in mice alleviated transverse aortic constriction (TAC)-induced cardiac hypertrophy, fibrosis, dilation and dysfunction of left ventricle. Conversely, cardiomyocyte-specific DEF6-overexpression aggravated the hypertrophic phenotype in mice under chronic pressure overload. Similar to the animal experiments, the in vitro data showed that adenovirus-mediated knockdown of DEF6 remarkably inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas DEF6 overexpression exerted the opposite effects. Mechanistically, exploration of the signal pathways showed that the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase 1/2 (ERK1/2) cascade might be involved in the prohypertrophic effect of DEF6. Coimmunoprecipitation and GST (glutathione S-transferase) pulldown analyses demonstrated that DEF6 can directly interact with small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), and the Rac1 activity assay revealed that the activity of Rac1 is altered with DEF6 expression in TAC-cardiac hypertrophy and PE-triggered cardiomyocyte hypertrophy. In the end, western blot and rescue experiments using Rac1 inhibitor NSC23766 and the constitutively active mutant Rac1(G12V) verified the requirement of Rac1 and MEK1/2-ERK1/2 activation for DEF6-mediated pathological cardiac hypertrophy. Our study substantiates that DEF6 acts as a deleterious regulator of cardiac hypertrophy by activating the Rac1 and MEK1/2-ERK1/2 signaling pathways, and suggests that DEF6 may be a potential treatment target for heart failure.

Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignancies worldwide. The incidence of CRC has been increasing, especially in young people. Although great advances have been made in managing CRC, the prognosis is unfavorable. Numerous studies have shown that berberine (BBR) is a safe and effective agent presenting significant antitumor effects. Nevertheless, the detailed underlying mechanism in treating CRC remains indistinct. In this review, we herein offer beneficial evidence for the utilization of BBR in the management and treatment of CRC, and describe the underlying mechanism(s). The review emphasizes several therapeutic effects of BBR and confirms that BBR could suppress CRC by modulating gene expression, the cell cycle, the inflammatory response, oxidative stress, and several signaling pathways. In addition, BBR also displays antitumor effects in CRC by regulating the gut microbiota and mucosal barrier function. This review emphasizes BBR as a potentially effective and safe drug for CRC therapy.