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Abstract Background Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. Methods A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. Results Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. Conclusions These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Abstract Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether‐linked phosphatidylethanolamine (ePE) and a marked increase in ether‐linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate‐15‐lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI‐knockdown cells, while SELENOI overexpression can partially rescue GPX4‐knockdown‐induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.

Abstract Lithium (Li) dendrite growth significantly deteriorates the performance and shortens the operation life of lithium metal batteries. Capturing the intricate dynamics of surface localized and rapid mass transport at the electrolyte–electrode interface of lithium metal is essential for the understanding of the dendrite growth process, and the evaluation of the solutions mitigating the dendrite growth issue. Here we demonstrate an approach based on an ultrasensitive tilted fiber Bragg grating (TFBG) sensor which is inserted close to the electrode surface in a working lithium metal battery, without disturbing its operation. Thanks to the superfine optical resonances of the TFBG, in situ and rapid monitoring of mass transport kinetics and lithium dendrite growth at the nanoscale interface of lithium anodes have been achieved. Reliable correlations between the performance of different natural/artificial solid electrolyte interphases (SEIs) and the time-resolved optical responses have been observed and quantified, enabling us to link the nanoscale ion and SEI behavior with the macroscopic battery performance. This new operando tool will provide additional capabilities for parametrization of the batteries’ electrochemistry and help identify the optimal interphases of lithium metal batteries to enhance battery performance and its safety.

Abstract Challenges in enabling next-generation rechargeable batteries with lower cost, higher energy density, and longer cycling life stem not only from combining appropriate materials, but from optimally using cell components. One-size-fits-all approaches to operational cycling and monitoring are limited in improving sustainability if they cannot utilize and capture essential chemical dynamics and states of electrodes and electrolytes. Herein we describe and show how the use of tilted fiber Bragg grating (TFBG) sensors to track, via the monitoring of both temperature and refractive index metrics, electrolyte-electrode coupled changes that fundamentally control lithium sulfur batteries. Through quantitative sensing of the sulfur concentration in the electrolyte, we demonstrate that the nucleation pathway and crystallization of Li2S and sulfur govern the cycling performance. With this technique, a critical milestone is achieved, not only towards developing chemistry-wise cells (in terms of smart battery sensing leading to improved safety and health diagnostics), but further towards demonstrating that the coupling of sensing and cycling can revitalize known cell chemistries and break open new directions for their development.

Abstract Ulcerative colitis (UC) is currently the most common inflammatory bowel disease (IBD). Due to its diverse and complex causes, there is no cure at present, and researchers are constantly exploring new therapies. In recent years, nano-selenium particle(SeNP) has attracted wide attention due to excellent biological activities. Therefore, in this study, for the first time, we used a natural polysaccharide, Eucommia ulmoides polysaccharide (EUP), modified SeNP to get EUP-SeNP with a size of about 170 nm, and its effect on 3% dextran sulphate sodium (DSS) induced colitis was explored. Our results showed that colon intestinal histology, intestinal mucosal barrier, inflammatory cytokines and intestinal microbiome composition were changed after EUP-SeNP treatment in colitis mice. Specifically, it was also shown that oral treatment of EUP-SeNP could relieve the degree of DSS-induced colitis in mice by restoring weight loss, reducing disease activity index (DAI), enhancing colon antioxidant capacity and regulating intestinal microbiome composition. In addition, we verified the mechanism in intestinal epithelial cell lines, showing that EUP-SeNP inhibited LPS-induced activation of the TRL-4/NF-κB signaling pathway in intestinal epithelial cell lines. To some extend, our study provides therapeutic reference for the treatment of IBD.

Abstract Background Formyl peptide receptor 2 (Fpr2) plays a crucial role in colon homeostasis and microbiota balance. Commensal E. coli is known to promote the regeneration of damaged colon epithelial cells. The aim of the study was to investigate the connection between E. coli and Fpr2 in the recovery of colon epithelial cells. Results The deficiency of Fpr2 was associated with impaired integrity of the colon mucosa and an imbalance of microbiota, characterized by the enrichment of Proteobacteria in the colon. Two serotypes of E. coli, O22:H8 and O91:H21, were identified in the mouse colon through complete genome sequencing. E. coli O22:H8 was found to be prevalent in the gut of mice and exhibited lower virulence compared to O91:H21. Germ-free (GF) mice that were pre-orally inoculated with E. coli O22:H8 showed reduced susceptibility to chemically induced colitis, increased proliferation of epithelial cells, and improved mouse survival. Following infection with E. coli O22:H8, the expression of Fpr2 in colon epithelial cells was upregulated, and the products derived from E. coli O22:H8 induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency increased susceptibility to chemically induced colitis, delayed the repair of damaged colon epithelial cells, and heightened inflammatory responses. Additionally, the population of E. coli was observed to increase in the colons of Fpr2 −/− mice with colitis. Conclusion Commensal E. coli O22:H8 stimulated the upregulation of Fpr2 expression in colon epithelial cells, and the products from E. coli induced migration and proliferation of colon epithelial cells through Fpr2. Fpr2 deficiency led to an increased E. coli population in the colon and delayed recovery of damaged colon epithelial cells in mice with colitis. Therefore, Fpr2 is essential for the effects of commensal E. coli on colon epithelial cell recovery.

As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1–V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2′-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1–MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.

Introduction: The body’s ability to metabolize nicotine and the disposition of nicotine in the brain are important determinants of its exposure. Limited knowledge about the near real-time changes of neurochemicals during the brain nicotine metabolic process hinders the recognition of its multiple neuropharmacological effects.Methods: An online microdialysis coupled with UHPLC-HRMS/MS method for the in vivo multi-analysis of nicotine metabolites and several neurotransmitters in rat brain was developed. Whether the systemic modulation of metabolic enzyme CYP2B would modulate nicotine pharmacokinetics and local neurochemical effects was further investigated.Results: The dynamic profiles of over 10 nicotine metabolites and neurotransmitters were simultaneously obtained after a single injection of nicotine (2 mg·kg−1, i.p.) using the new method. Proadifen pretreatment (50 mg·kg−1·d−1, i.p., 4 days) caused significant inhibition of brain CYP2B1 activity. When exposed to nicotine, the brain Cmax of nicotine was 1.26 times higher and the levels of nicotine metabolites, nornicotine, and nicotine-N-oxide, were decreased by 85.3% and 34.4% in proadifen-pretreated rats. The higher level of brain nicotine induced a greater release of dopamine, serotonin, glutamate, and γ-amino-butyric acid in the nucleus accumbens. The concentrations of nicotine and dopamine were positively correlated, and the average levels of γ-amino-butyric acid and serotonin were 2.7 and 1.2 times higher, respectively, under the inhibition of nicotine metabolism.Discussion: These results demonstrated that inhibiting nicotine metabolism in rats can enhance the residence of brain nicotine and its local neurotransmitter effects. The metabolic activity of nicotine under different physiological conditions could regulate nicotine’s bioavailability and its resulting pharmacology.

Cancer stem cells (CSCs) have been increasingly recognized in recent years. CSCs from human neural tumors are one of the root causes of metastatic tumor progression, therapeutic resistance and recurrence. However, there is a lack of comprehensive literature that systematically consolidates the biomarkers specific to CSCs in neurological cancers. Therefore, this review provides a comprehensive summary of cancer stem cell (CSC) biomarkers for neurological tumors such as glioma, meningioma, medulloblastoma and neurofibroma. It also points out the possible functions of these biomarkers in diagnosis, treatment and prognosis, providing a broader perspective. First, we quantitatively screened key words such as CSCs, biomarkers, and expression by bibliometric analysis and clarified the intrinsic connections between the key words. Then, we describe the CSC biomarkers of major neurological tumors and their pathway mechanisms, and provide an in-depth analysis of the commonalities and differences with the biomarkers of non-CSCs. In addition, many studies have shown that antipsychotic drugs can inhibit tumor growth and reduce the expression of CSC biomarkers, which facilitates targeted therapy against tumors in the nervous system. Therefore, this study will focus on the biomarkers of CSCs in the nervous system, hoping to provide guidance for future in-depth exploration and monitoring of neurological tumors for clinical applications.

Chemo-mechanical stress within Li-based batteries detrimentally affects the performance and lifetime of these devices. Here, the authors propose an operando technique using optical fibers embedded in electrodes for internal stress monitoring of cells containing either solid or liquid electrolytes.

Human cathelicidin antimicrobial peptide LL-37 (LL-37) is an antimicrobial peptide derived from its precursor protein hCAP18, which is an only cathelicidin in human. LL-37 not only serves as a mediator of innate immune defense against invading microorganisms, but it also plays an essential role in tissue homeostasis, regenerative processes, regulation of proinflammatory responses, and inhibition of cancer progression. Therefore, LL-37 has been considered as a drug lead for diseases. However, high levels of LL-37 may reduce cell viability and promote apoptosis of osteoblasts, vascular smooth muscle cells, periodontal ligament cells, neutrophils, airway epithelial cells and T cells. Recent evidence reveals that LL-37-derived short peptides possess similar biological activities as the whole LL-37 with reduced cytotoxicity. Thus, such small molecules constitute a pool of potential therapeutic agents for diseases.

In this study, we conducted three sets of analouge experiments, i.e., the pilot experiment with homogeneous quartz sand with frontal ramp, scaled experiments with embedded layer of silicone and/or frontal ramp, for the Shuangyushi area in the north western Sichuan Foreland Basin.It suggests that the north western Sichuan Foreland Basin is dominated with two-layer style of deformation, in particular, with pop-up in deep strata which is controlled by the basal decollement and frontal ramp.It should be noted that the frontal ramp has significant influence on the undistributed deformation and related fault-style occurred at the overlying sequences, which are in favor of formation for a pathway system between Lower Cambrian Qiongzhushi Formation and Mesozoic carbonate/dolomite reservoir.In contrast to duplex as a result of multistage deformation in the thrust-and-fold-belt, the north western Sichuan Foreland Basin is characterized with gentle deformation, as a result of forelandward propagation deformation in Cenozoic, and thus with a better quality of hydrocarbon preservation.Analogue experiments have been a powerful and indispensable tool to help us understand the thrust-fold-belt and foreland basin, as well as their hydrocarbon accumulation, from nature to models.

BackgroundHepatocellular carcinoma (HCC) is one of the most lethal human tumors with extensive intratumor heterogeneity (ITH). Serine protease 3 (PRSS3) is an indispensable member of the trypsin family and has been implicated in the pathogenesis of several malignancies, including HCC. However, the paradoxical effects of PRSS3 on carcinogenesis due to an unclear molecular basis impede the utilization of its biomarker potential. We hereby explored the contribution of PRSS3 transcripts to tumor functional heterogeneity by systematically dissecting the expression of four known splice variants of PRSS3 (PRSS3-SVs, V1~V4) and their functional relevance to HCC.MethodsThe expression and DNA methylation of PRSS3 transcripts and their associated clinical relevance in HCC were analyzed using several publicly available datasets and validated using qPCR-based assays. Functional experiments were performed in gain- and loss-of-function cell models, in which PRSS3 transcript constructs were separately transfected after deleting PRSS3 expression by CRISPR/Cas9 editing.ResultsPRSS3 was aberrantly differentially expressed toward bipolarity from very low (PRSS3Low) to very high (PRSS3High) expression across HCC cell lines and tissues. This was attributable to the disruption of PRSS3-SVs, in which PRSS3-V2 and/or PRSS3-V1 were dominant transcripts leading to PRSS3 expression, whereas PRSS3-V3 and -V4 were rarely or minimally expressed. The expression of PRSS3-V2 or -V1 was inversely associated with site-specific CpG methylation at the PRSS3 promoter region that distinguished HCC cells and tissues phenotypically between hypermethylated low-expression (mPRSS3-SVLow) and hypomethylated high-expression (umPRSS3-SVHigh) groups. PRSS3-SVs displayed distinct functions from oncogenic PRSS3-V2 to tumor-suppressive PRSS3-V1, -V3 or PRSS3-V4 in HCC cells. Clinically, aberrant expression of PRSS3-SVs was translated into divergent relevance in patients with HCC, in which significant epigenetic downregulation of PRSS3-V2 was seen in early HCC and was associated with favorable patient outcome.ConclusionsThese results provide the first evidence for the transcriptional and functional characterization of PRSS3 transcripts in HCC. Aberrant expression of divergent PRSS3-SVs disrupted by site-specific CpG methylation may integrate the effects of oncogenic PRSS3-V2 and tumor-suppressive PRSS3-V1, resulting in the molecular diversity and functional plasticity of PRSS3 in HCC. Dysregulated expression of PRSS3-V2 by site-specific CpG methylation may have potential diagnostic value for patients with early HCC.

Recent explorations reveal a great potential for oil and gas resources in the northwestern Sichuan foreland basin. However, constrained by multi-phase tectonic activities of the Longmenshan-West Sichuan foreland system and the deep burial of the piedmont belt, there remain many uncertainties in the interpretation of petroleum structure models in the foreland concealed tectonic belt. Based on the geometry-kinematics-dynamic similarity theory between the foreland prototype of the northwestern Sichuan and the sandbox analogue model, two groups of controlled experiments were carried out (including standard scaled experiments and analogue experiments with a ramp-flat structure). The fold-thrust belt and foreland basin of the western Sichuan are controlled by two sets of main detachments of the Middle-Lower Triassic gypsum salt and the Lower Cambrian mudstone, leading the layered-style propagation to the foreland in the Late-Middle Cenozoic. The ramp-flat structure plays a profound influence on deep thrust and pop-up structures in the northwestern Sichuan foreland basin. Analogue results combined with seismic interpretation of the northwestern Sichuan illustrates that the main exploration potential may rely on the Paleozoic blind thrust and pop-up structures caused by the latest propagation to the northwestern Sichuan foreland basin.

The cytokine like protein FAM3D (Fam3D in mice) is highly expressed in the digestive tract with unknown role in colon pathophysiology. Here, by using gene deficient mice, the authors show that Fam3D is critically involved in colon homeostasis, host defense against colitis-associated carcinogenesis, and the balance of microbiota.

An amendment to this paper has been published and can be accessed via the original article.

We use analog experiments to investigate the influence of rapid filling of a foreland basin system during the development of a fold-and-thrust belt, in particular, the change of erosion–sedimentation along the strike in the Longmenshan foreland basin. A negative relationship between wedge geometries and the magnitude of erosion can be found; increased erosion results in out-of-sequence thrusting and fault reactivation in the wedge hinterland, to limit the forelandward propagation of the wedge. In contrast, increased sedimentation facilitates the forelandward propagation of the wedge. We focus on a natural example of the Longmenshan foreland basin, where a change in erosion–sedimentation along the strike during the Late Cretaceous to Cenozoic is well documented. The comparison between our model and seismic sections indicates that such along-strike variation results in a rejuvenated foreland basin restricted to the southwestern part of the western Sichuan Basin in the Cenozoic.

Selenium (Se) is one of the essential trace elements that plays a biological role in the body, mainly in the form of selenoproteins. Selenoproteins can be involved in the regulation of oxidative stress, endoplasmic reticulum (ER) stress, antioxidant defense, immune and inflammatory responses and other biological processes, including antioxidant, anti-inflammation, anti-apoptosis, the regulation of immune response and other functions. Over-loading or lack of Se causes certain damage to the body. Se deficiency can reduce the expression and activity of selenoproteins, disrupt the normal physiological function of cells and affect the body in antioxidant, immunity, toxin antagonism, signaling pathways and other aspects, thus causing different degrees of damage to the body. Se intake is mainly in the form of dietary supplements. Due to the important role of Se, people pay increasingly more attention to Se-enriched foods, which also lays a foundation for better research on the mechanism of selenoproteins in the future. In this paper, the synthesis and mechanism of selenoproteins, as well as the role and mechanism of selenoproteins in the regulation of diseases, are reviewed. Meanwhile, the future development of Se-enriched products is prospected, which is of great significance to further understand the role of Se.

Chronic inflammation is a causative factor of many cancers, although it originally acts as a protective host response to the loss of tissue homeostasis. Many inflammatory conditions predispose susceptible cells, most of which are of epithelial origin, to neoplastic transformation. There is a close correlation between digestive tract (DT) cancer and chronic inflammation, such as esophageal adenocarcinoma associated with Barrett’s esophagus, helicobacter pylori infection as the cause of stomach cancer, hepatitis leading to liver cirrhosis and subsequent cancer, and colon cancer linking to inflammatory bowel diseases and schistosomiasis . A prominent feature of malignant transformation of DT tract epithelial cells is their adoption of somatic gene mutations resulting in abnormal expression of proteins that endow the cells with unlimited proliferation as well as increased motility and invasive capabilities. Many of these events are mediated by Gi-protein coupled chemoattractant receptors (GPCRs) including formyl peptide receptors (FPRs in human, Fprs in mice). In this article, we review the current understanding of FPRs (Fprs) and their function in DT cancer types as well as their potential as therapeutic targets.

The destabilization of zein gel particles by salt ions seriously limits their practical application. In this study, zein gel particles exhibiting excellent stability to salt ions were developed by grafting gum arabic with tannic acid. Gum arabic (GA) was first coated onto the surface of zein gel particles, followed by addition of tannic acid to further reinforce non-covalent cross-linking between GA and the zein gel particle surface. The stability of the gel particle dispersions was characterized by Turbiscan analysis, gel particle diameter changes and visual inspection of phase separation. The tannic acid-treated zein–GA gel particles were highly protected from precipitation or aggregation in the presence of NaCl (0–3 mol/L) at different pH values (4.0, 7.0 or 8.5). The gel particles prepared in this study will therefore have broader applicability in different pH and salt ions ion environments.

Background Drug addiction is a serious problem worldwide and is infuenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. Methods A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. Results Both single-SNP and haplotype tests revealed associations between illicit drug use and several immunerelated genes in the major histocompatibility complex (MHC) region (SNP association: log10BF=15.135, p=1.054e18; haplotype association: log10BF=20.925, p=2.065e-24). These genes may afect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide signifcant associations between rs3782886 (SNP association: log10BF=8.726, p=4.842e-11) in BRAP and rs671 (SNP association: log10BF=7.406, p=9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide signifcant association (haplotype association: log10BF=7.607, p=3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. Conclusions These fndings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches. [ABSTRACT FROM AUTHOR]