Reduced intestinal-to-diffuse conversion and immunosuppressive responses underlie superiority of neoadjuvant immunochemotherapy in gastric adenocarcinoma.

Neoadjuvant immunochemotherapy (NAIC) achieves superior clinical benefits over neoadjuvant chemotherapy (NAC) in multiple types of human cancers, including gastric adenocarcinoma (GAC). However, it is poorly understood how the malignant epithelial cells and tumor immune microenvironment (TIME) might respond distinctly to NAIC and NAC that underlies therapeutic efficacy. Here treatment-naive and paired tumor tissues from multiple centers were subjected to pathological, immunological, and transcriptomic analysis. NAIC demonstrated significantly increased rate of pathological complete response compared to NAC (pCR: 25% vs. 4%, p < 0.05). Interestingly, pretreatment intestinal subtype of Lauren's classification was predictive of pathologic regression following NAIC, but not NAC. A substantial portion of cancers underwent intestinal-to-diffuse transition, which occurred less following NAIC and correlated with treatment failure. Moreover, NAIC prevented reprogramming to an immunosuppressive TIME with less active fibroblasts and exhausted CD8+ T cells, and increased numbers of mature tertiary lymphoid structures. Mechanistically, activation of the tumor necrosis factor alpha (TNFα)/nuclear factor-kappa B (NF-κB) signaling pathway was associated with response to NAIC. Together, NAIC is superior to NAC for locally advanced GAC, likely due to reduced intestinal-to-diffuse conversion and reprogramming to an immuno-active TIME. Modulation of the histological conversion and immunosuppressive TIME could be translatable approaches to improve neoadjuvant therapeutic efficacy.

Stabilization of TGF-ß Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-ß Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance.

Dysregulation of the transforming growth factor-ß (TGF-ß) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-ß receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-ß-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-ß receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-ß signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-ß signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-ß signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-ß signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-ß signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.

In vivo study of chelating agent-modified nano zero-valent iron: Biodistribution and toxicity in mice.

In this study, the distribution and toxicity of nanoscale zero valent iron (nZVI) and nZVIs coated with citric acid and sodium tripolyphosphate (CA-nZVI and STPP-nZVI) in mice were investigated. nZVIs were primarily found in the livers and spleens, followed by the lungs, hearts, and kidneys. Histologic analysis revealed no significant histopathologic abnormalities or lesions in all organs except the liver at 14th d gavage. nZVIs did not have a noticeable impact on the body weight of the mice or the weight of their organs. Compared with the control group, there were no significant changes in hematology indexes in the nZVIs groups. However, the nZVIs groups exhibited varying levels of elevation in alanine aminotransferase, aspartate aminotransferase, and creatinine, suggesting liver and kidney inflammation in mice. The up-regulation of Nuclear Factor erythroid 2-Related Factor 2 and Heme oxygenase 1 in the nZVIs groups may be a response to nZVIs-induced oxidative stress. Immunohistochemical analysis confirmed the inflammatory response induced by the three nZVI groups. Chelating agents did not have a significant impact on the distribution or toxicity of nZVIs in mice. This study contributes to a comprehensive and detailed insight into nZVI toxicity in the environmental field.

Hydrogen-Bond-Network Breakdown Boosts Selective CO2 Photoreduction by Suppressing H2 Evolution.

Conventional strategies for highly efficient and selective CO2 photoreduction focus on the design of catalysts and cocatalysts. In this study, we discover that hydrogen bond network breakdown in reaction system can suppress H2 evolution, thereby improving CO2 photoreduction performance. Photosensitive poly(ionic liquid)s are designed as photocatalysts owing to their strong hydrogen bonding with solvents. The hydrogen bond strength is tuned by solvent composition, thereby effectively regulating H2 evolution (from 0 to 12.6 mmol g-1 h-1). No H2 is detected after hydrogen bond network breakdown with trichloromethane or tetrachloromethane as additives. CO production rate and selectivity increase to 35.4 mmol g-1 h-1 and 98.9 % with trichloromethane, compared with 0.6 mmol g-1 h-1 and 26.2 %, respectively, without trichloromethane. Raman spectroscopy and theoretical calculations confirm that trichloromethane broke the systemic hydrogen bond network and subsequently suppressed H2 evolution. This hydrogen bond network breakdown strategy may be extended to other catalytic reactions involving H2 evolution.

Non-modular fatty acid synthases yield distinct N-terminal acylation in ribosomal peptides.

Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries. However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machinery from other natural product families. Here we report lipoavitides, a class of RiPP/fatty-acid hybrid lipopeptides that display a unique, putatively membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N terminus. The HMP is formed via condensation of isobutyryl-coenzyme A (isobutyryl-CoA) and methylmalonyl-CoA catalysed by a 3-ketoacyl-(acyl carrier protein) synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty-acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.

mTORC2-AKT signaling to PFKFB2 activates glycolysis that enhances stemness and tumorigenicity of intestinal epithelial cells.

Although elevated glycolysis has been widely recognized as a hallmark for highly proliferating cells like stem cells and cancer, its regulatory mechanisms are still being updated. Here, we found a previously unappreciated mechanism of mammalian target of rapamycin complex 2 (mTORC2) in regulating glycolysis in intestinal stem cell maintenance and cancer progression. mTORC2 key subunits expression levels and its kinase activity were specifically upregulated in intestinal stem cells, mouse intestinal tumors, and human colorectal cancer (CRC) tissues. Genetic ablation of its key scaffolding protein Rictor in both mouse models and cell lines revealed that mTORC2 played an important role in promoting intestinal stem cell proliferation and self-renewal. Moreover, utilizing mouse models and organoid culture, mTORC2 loss of function was shown to impair growth of gut adenoma and tumor organoids. Based on these findings, we performed RNA-seq and noticed significant metabolic reprogramming in Rictor conditional knockout mice. Among all the pathways, carbohydrate metabolism was most profoundly altered, and further studies demonstrated that mTORC2 promoted glycolysis in intestinal epithelial cells. Most importantly, we showed that a rate-limiting enzyme in regulating glycolysis, 6-phosphofructo-2-kinase (PFKFB2), was a direct target for the mTORC2-AKT signaling. PFKFB2 was phosphorylated upon mTORC2 activation, but not mTORC1, and this process was AKT-dependent. Together, this study has identified a novel mechanism underlying mTORC2 activated glycolysis, offering potential therapeutic targets for treating CRC.

Biocompatible, Injectable, and Self-Healing Poly(N-vinylpyrrolidone)/Carboxymethyl Cellulose Hydrogel for Drug Release.

Hydrogels have drawn intensive attention as fascinating materials for biomedicine. However, fabricating hydrogels with injectable and self-healing properties remains a challenge. Herein, we reported a biocompatible poly(N-vinylpyrrolidone)/carboxymethyl cellulose (PVP/CMC) hydrogel with excellent injectable and self-healing properties. The PVP/CMC hydrogel exhibits good biocompatible, injectable, and self-healing properties. The sol-gel transition of PVP/CMC hydrogels demonstrates an outstanding self-healing behavior, and the bisected hydrogels can self-heal within 30 s. The hydrogels have a good swelling ratio, and the swelling ratio increases with increasing amount of CMC in PVP and reaches a maximum of 2850% at a 1.0:1.5 PVP and CMC ratio. In addition, the hydrogel possesses excellent drug release capacity, and its drug release rate reaches 70%. Moreover, the release of 4-aminosalicylic acid (4-ASA) in the hydrogel can be controlled by adjusting the proportion of the hydrogel. The PVP/CMC hydrogel with excellent biocompatible, injectable, and self-healing properties has great potential for applications in drug release.

Ecological assessment of stream water polluted by phosphorus chemical plant: Physiological, biochemical, and molecular effects on zebrafish (Danio rerio) embryos.

The rapid development of the phosphorus chemical industry has caused serious pollution problems in the regional eco-environment. However, understanding of their ecotoxic effects remains limited. This study aimed to investigate the developmental toxicity of a stream polluted by a phosphorus chemical plant (PCP) on zebrafish embryos. For this, zebrafish embryos were exposed to stream water (0, 25, 50, and 100% v/v) for 96 h, and developmental toxicity, oxidative stress, apoptosis, and DNA damage were assessed. Stream water-treated embryos exhibited decreased hatching rates, heart rates, and body lengths, as well as increased mortality and malformation rates. The general morphology score system indicated that the swim bladder and pigmentation were the main abnormal morphological endpoints. Stream water promoted antioxidant enzymes (superoxide dismutase (SOD), peroxidase (POD), and glutathione peroxidase (GPx)), lipid peroxidation, and DNA damage. It also triggered apoptosis in the embryos' heads, hearts, and spines by activating apoptotic enzymes (Caspase-3 and Caspase-9). Additionally, stream water influenced growth, oxidative stress, and apoptosis-related 19 gene expression. Notably, tyr, sod (Mn), and caspase9 were the most sensitive indicators of growth, oxidative stress, and apoptosis, respectively. The current trial concluded that PCP-polluted stream water exhibited significant developmental toxicity to zebrafish embryos, which was regulated by the oxidative stress-mediated activation of endogenous apoptotic signaling pathways.

Removal of bisphenol A in a heterogeneous Fenton system via biochar synthesized using different Fe precursors: Properties, effects, and mechanisms.

The reactivity and mechanism of the Fe-doped biochar (FeBC) Fenton reaction are typically influenced by the amount and type of Fe species in materials. This study investigated the effects of different Fe precursors (FeSO4, Fe(NO)3, FeCl2, and FeCl3) used to prepare Fenton catalyst FeBCs (FeSBC, FeNBC, FeC2BC, and FeC3BC) on the physicochemical characteristics, pH resistance, and reactivity for bisphenol A (BPA) removal. In addition to the FeSBC/H2O2 (0.007 min-1) system, FeNBC/H2O2 (1.143 min-1), FeC2BC/H2O2 (0.278 min-1), and FeC3BC/H2O2 (0.556 min-1) completely removed BPA within 20 min under the optimal conditions (FeBCs: 0.1 g/L; H2O2: 1 mM; BPA: 20 mg/L; pH 3). FeBCs/H2O2 systems demonstrated good stability and resistance to inorganic anions and natural organic matter under appropriate initial pH conditions. However, FeC2BC and FeC3BC exhibited better pH applicability than FeNBC. Characterization results indicated that the physicochemical properties of FeBCs were dependent on the Fe precursor, which correlated with the degree of Fe corrosion and the production of distinct reactive oxygen species (ROS). Quenching experiments and electron spin resonance detection results indicated that OH, 1O2, and O2- species were all engaged in BPA removal; the ROS concentrations were significantly influenced by the initial pH and Fe precursor. The results indicate that Fe precursors significantly impact the performance and characteristics of Fe-based biochar materials, which are tailorable to specific applications.

Excessive nucleic acid R-loops induce mitochondria-dependent epithelial cell necroptosis and drive spontaneous intestinal inflammation.

Oxidative stress, which can be activated by a variety of environmental risk factors, has been implicated as an important pathogenic factor for inflammatory bowel disease (IBD). However, how oxidative stress drives IBD onset remains elusive. Here, we found that oxidative stress was strongly activated in inflamed tissues from both ulcerative colitis patients and Crohn's disease patients, and it caused nuclear-to-cytosolic TDP-43 transport and a reduction in the TDP-43 protein level. To investigate the function of TDP-43 in IBD, we inducibly deleted exons 2 to 3 of Tardbp (encoding Tdp-43) in mouse intestinal epithelium, which disrupted its nuclear localization and RNA-processing function. The deletion gave rise to spontaneous intestinal inflammation by inducing epithelial cell necroptosis. Suppression of the necroptotic pathway with deletion of Mlkl or the RIP1 inhibitor Nec-1 rescued colitis phenotypes. Mechanistically, disruption of nuclear TDP-43 caused excessive R-loop accumulation, which triggered DNA damage and genome instability and thereby induced PARP1 hyperactivation, leading to subsequent NAD+ depletion and ATP loss, consequently activating mitochondrion-dependent necroptosis in intestinal epithelial cells. Importantly, restoration of cellular NAD+ levels with NAD+ or NMN supplementation, as well as suppression of ALKBH7, an α-ketoglutarate dioxygenase in mitochondria, rescued TDP-43 deficiency-induced cell death and intestinal inflammation. Furthermore, TDP-43 protein levels were significantly inversely correlated with γ-H2A.X and p-MLKL levels in clinical IBD samples, suggesting the clinical relevance of TDP-43 deficiency-induced mitochondrion-dependent necroptosis. Taken together, these findings identify a unique pathogenic mechanism that links oxidative stress to intestinal inflammation and provide a potent and valid strategy for IBD intervention.

Non-modular Fatty Acid Synthases Yield Unique Acylation in Ribosomal Peptides.

Recent efforts in genome mining of ribosomally synthesized and post-translationally modified peptides (RiPPs) have expanded the diversity of post-translational modification chemistries 1, 2 . However, RiPPs are rarely reported as hybrid molecules incorporating biosynthetic machineries from other natural product families 3-8 . Here, we report lipoavitides, a class of RiPP/fatty acid hybrid lipopeptides that display a unique, membrane-targeting 4-hydroxy-2,4-dimethylpentanoyl (HMP)-modified N -terminus. The HMP is formed via condensation of isobutyryl-CoA and methylmalonyl-CoA catalyzed by a 3-ketoacyl-ACP synthase III enzyme, followed by successive tailoring reactions in the fatty acid biosynthetic pathway. The HMP and RiPP substructures are then connected by an acyltransferase exhibiting promiscuous activity towards the fatty acyl and RiPP substrates. Overall, the discovery of lipoavitides contributes a prototype of RiPP/fatty acid hybrids and provides possible enzymatic tools for lipopeptide bioengineering.

Major complications after ultrasound-guided liver biopsy: An annual audit of a Chinese tertiary-care teaching hospital.

BACKGROUND: As ultrasound-guided percutaneous liver biopsy (PLB) has become a standard and important method in the management of liver disease in our country, a periodical audit of the major complications is needed. AIM: To determine the annual incidence of major complications following ultrasound-guided PLB and to identify variables that are significantly associated with an increased risk of major complications. METHODS: A total of 1857 consecutive cases of PLB were included in our hospital from January 2021 to December 2021. The major complication rate and all-cause 30-d mortality rate were determined. Multivariate analyses were performed by logistic regression to investigate the risk factors associated with major complications and all-cause 30-d mortality following ultrasound-guided PLB. RESULTS: In this audit of 1857 liver biopsies, 10 cases (0.53%) of major complications occurred following ultrasound-guided PLB. The overall all-cause mortality rate at 30 d after PLB was 0.27% (5 cases). Two cases (0.11%) were attributed to major hemorrhage within 7 d after liver biopsy. Fibrinogen less than 2 g/L [odds ratio (OR): 17.226; 95% confidence interval (CI): 2.647-112.102; P = 0.003], post-biopsy hemoglobin level (OR: 0.963; 95%CI: 0.942-0.985; P = 0.001), obstructive jaundice (OR: 6.698; 95%CI: 1.133-39.596; P = 0.036), application of anticoagulants/antiplatelet medications (OR: 24.078; 95%CI: 1.678-345.495; P = 0.019) and age (OR: 1.096; 95%CI: 1.012-1.187; P = 0.025) were statistically associated with the incidence of major complications after PLB. CONCLUSION: In conclusion, the results of this annual audit confirmed that ultrasound-guided PLB can be performed safely, with a major complication rate within the accepted range. Strict patient selection and peri-biopsy laboratory assessment are more important than procedural factors for optimizing the safety outcomes of this procedure.

The current state of artificial intelligence in endoscopic diagnosis of early esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor of the digestive tract. The most effective method of reducing the disease burden in areas with a high incidence of esophageal cancer is to prevent the disease from developing into invasive cancer through screening. Endoscopic screening is key for the early diagnosis and treatment of ESCC. However, due to the uneven professional level of endoscopists, there are still many missed cases because of failure to recognize lesions. In recent years, along with remarkable progress in medical imaging and video evaluation technology based on deep machine learning, the development of artificial intelligence (AI) is expected to provide new auxiliary methods of endoscopic diagnosis and the treatment of early ESCC. The convolution neural network (CNN) in the deep learning model extracts the key features of the input image data using continuous convolution layers and then classifies images through full-layer connections. The CNN is widely used in medical image classification, and greatly improves the accuracy of endoscopic image classification. This review focuses on the AI-assisted diagnosis of early ESCC and prediction of early ESCC invasion depth under multiple imaging modalities. The excellent image recognition ability of AI is suitable for the detection and diagnosis of ESCC and can reduce missed diagnoses and help endoscopists better complete endoscopic examinations. However, the selective bias used in the training dataset of the AI system affects its general utility.

Enhanced organic pollutant removal in saline wastewater by a tripolyphosphate-Fe0/H2O2 system: Key role of tripolyphosphate and reactive oxygen species generation.

The effects of tripolyphosphate (TPP) on organic pollutant degradation in saline wastewater using Fe0/H2O2 were systematically investigated to elucidate its mechanism and the main reactive oxygen species (ROS). Organic pollutant degradation was dependent on the Fe0 and H2O2 concentration, Fe0/TPP molar ratio, and pH value. The apparent rate constant (kobs) of TPP-Fe0/H2O2 was 5.35 times higher than that of Fe0/H2O2 when orange II (OGII) and NaCl were used as the target pollutant and model salt, respectively. The electron paramagnetic resonance (EPR) and quenching test results showed that •OH, O2•-, and 1O2 participated in OGII removal, and the dominant ROS were influenced by the Fe0/TPP molar ratio. The presence of TPP accelerates Fe3+/Fe2+ recycling and forms Fe-TPP complexes, which ensures sufficient soluble Fe for H2O2 activation, prevents excessive Fe0 corrosion, and thereby inhibits Fe sludge formation. Additionally, TPP-Fe0/H2O2/NaCl maintained a performance similar to those of other saline systems and effectively removed various organic pollutants. The OGII degradation intermediates were identified using high-performance liquid chromatography-mass spectrometry (HPLC-MS) and density functional theory (DFT), and possible degradation pathways for OGII were proposed. These findings provide a facile and cost-effective Fe-based AOP method for removing organic pollutants from saline wastewater.

Labour-Market Characteristics and Self-Rated Health: Evidence from the China Health and Retirement Longitudinal Study.

In the face of labour-force ageing, understanding labour-market characteristics and the health status of middle-aged and older workers is important for sustainable social and economic development. Self-rated health (SRH) is a widely-used instrument to detect health problems and predict mortality. This study investigated labour-market characteristics that may have an impact on the SRH among Chinese middle-aged and older workers, using data from the national baseline wave of the China Health and Retirement Longitudinal Study. The analytical sample included 3864 individuals who at the time held at least one non-agricultural job. Fourteen labour-market characteristics were clearly defined and investigated. Multiple logistic regression models of the associations of each labour-market characteristic with SRH were estimated. Seven labour-market characteristics were associated with higher odds of poor SRH when controlled for age and sex. Employment status and earned income remained significantly associated with poor SRH, when controlling for all the sociodemographic factors and health behaviours. Doing unpaid work in family businesses is associated with 2.07 (95% CI, 1.51-2.84) times probability of poor SRH, compared with employed individuals. Compared with more affluent individuals (highest quintile of earned income), people in the fourth and fifth quintiles had 1.92 (95% CI, 1.29-2.86) times and 2.72 (95% CI, 1.83-4.02) times higher chance, respectively, of poor SRH. In addition, residence type and region were important confounders. Measures improving adverse working conditions should be taken to prevent future risk of impaired health among the Chinese middle-aged and older workforce.

Distinctive adsorption and desorption behaviors of temporal and post-treatment heavy metals by iron nanoparticles in the presence of microplastics.

There are increasing concerns about microplastic (MP) pollution in the natural environment. Consequently, numerous physicochemical and toxicological studies have been conducted on the effects of MPs. However, few studies have concerned the potential impact of MPs on contaminated site remediation. We herein investigated the influence of MPs on the temporary and post heavy metal removal by iron nanoparticles, including pristine and sulfurized nano zero-valent irons (nZVI and S-nZVI). MPs inhibited adsorption of most heavy metals during the treatment of iron nanoparticles, and facilitated their desorption, such as Pb (II) from nZVI and Zn (II) from S-nZVI. However, such effects presented by MPs was usually less than those by dissolved oxygen (DO). Most desorption cases are irrelevant to the reduced formats of heavy metals involving redox reactions, such as Cu (I) or Cr (III), suggesting that the influence of MPs on metals are limited to those binding with iron nanoparticles through surface complexation or electrostatic interaction. As another common factor, natural organic matter (NOM) had almost no influence on the heavy metal desorption. These insights shed lights for enhanced remediation of heavy metals by nZVI/S-NZVI in the presence of MPs.

Genome mining unveils a class of ribosomal peptides with two amino termini.

The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual ( S )- N 2 , N 2 -dimethyl-1,2-propanediamine (Dmp)-modified C -terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C -terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C -terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.

Genome mining unveils a class of ribosomal peptides with two amino termini.

The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual (S)-N2,N2-dimethyl-1,2-propanediamine (Dmp)-modified C-terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC from Microbacterium paraoxydans DSM 15019 was selected for experimental characterization. Derived from a C-terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to the C-terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.

N-doped porous bowl-like carbon with superhigh external surface area for ultrafast degradation of bisphenol A: Key role of site exposure degree.

High-temperature nitrogen (N) doping boosts the activity of biochars for peroxymonosulfate (PMS) activation, but the N heat loss causes the unsatisfactory catalytic efficiency. Improving the surface area for obtaining the high exposure of N sites is a promising solution. Herein, a soft template-KHCO3 etching strategy is used to synthesize the N-doped porous bowl-like carbon (NPBC) with ultrahigh external surface area (1610.8 m2 g-1). The bowl-like structure eliminates inert bulk interior and allows unobstructed mass transfer of reactants onto both outer and inner surfaces, while the large pore channels by KHCO3 etching further improves the exposure degree of limited N sites. Although NPBC has only 0.43% N content, 93.1% of bisphenol A (BPA) is removed within 1 min through the electron-transfer pathway by fully utilizing the N active centers, and the kinetic rate constant (k) reaches 5.29 min-1, exceeding reported values by 2-270 times. Moreover, the NPBC/PMS system possesses excellent applicability for various organics and conditions, effectively mineralizes BPA and reduces effluent biotoxicity. A quantitative index W representing N exposure degree is first proposed and shows high linearity with the k values of BPA degradation (R2=0.992, 0 

Identifying the E2F3-MEX3A-KLF4 signaling axis that sustains cancer cells in undifferentiated and proliferative state.

Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression. Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues. The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids. Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A. Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis. MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage. Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation. Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.