Earth's early continental crust formed from wet and oxidizing arc magmas.

Formation of continental crust has shaped the surface and interior of our planet and generated the land and mineral resources on which we rely. However, how the early continental crust of Earth formed is still debated1-7. Modern continental crust is largely formed from wet and oxidizing arc magmas at subduction zones, in which oceanic lithosphere and water recycle into the mantle8-10. The magmatic H2O content and redox state of ancient rocks that constitute the early continental crust, however, are difficult to quantify owing to ubiquitous metamorphism. Here we combine two zircon oxybarometers11,12 to simultaneously determine magmatic oxygen fugacity (fO2) and H2O content of Archaean (4.0-2.5 billion years ago) granitoids that dominate the early continental crust. We show that most Archaean granitoid magmas were ≥1 log unit more oxidizing than Archaean ambient mantle-derived magmas13,14 and had high magmatic H2O contents (6-10 wt%) and high H2O/Ce ratios (>1,000), similar to modern arc magmas. We find that magmatic fO2, H2O contents and H2O/Ce ratios of Archaean granitoids positively correlate with depth of magma formation, requiring transport of large amounts of H2O to the lower crust and mantle. These observations can be readily explained by subduction but are difficult to reconcile with non-subduction models of crustal formation3-7. We note an increase in magmatic fO2 and H2O content between 4.0 and 3.6 billion years ago, probably indicating the onset of subduction during this period.

THUMPD2 catalyzes the N2-methylation of U6 snRNA of the spliceosome catalytic center and regulates pre-mRNA splicing and retinal degeneration.

The mechanisms by which the relatively conserved spliceosome manages the enormously large number of splicing events that occur in humans (∼200 000 versus ∼300 in yeast) are poorly understood. Here, we show deposition of one RNA modification-N2-methylguanosine (m2G) on the G72 of U6 snRNA (the catalytic center of the spliceosome) promotes efficient pre-mRNA splicing activity in human cells. This modification was identified to be conserved among vertebrates. Further, THUMPD2 was demonstrated as the methyltransferase responsible for U6 m2G72 by explicitly recognizing the U6-specific sequences and structural elements. The knock-out of THUMPD2 eliminated U6 m2G72 and impaired the pre-mRNA splicing activity, resulting in thousands of changed alternative splicing events of endogenous pre-mRNAs in human cells. Notably, the aberrantly spliced pre-mRNA population elicited the nonsense-mediated mRNA decay pathway. We further show that THUMPD2 was associated with age-related macular degeneration and retinal function. Our study thus demonstrates how an RNA epigenetic modification of the major spliceosome regulates global pre-mRNA splicing and impacts physiology and disease.

Cloned antibodies from patients with HIT provide new clues to HIT pathogenesis.

Heparin-induced thrombocytopenia (HIT) is a serious adverse drug reaction characterized by antibodies that recognize platelet factor 4/heparin complexes (PF4/H) and activate platelets to create a prothrombotic state. Although a high percentage of heparin-treated patients produce antibodies to PF4/H, only a subset also makes antibodies that are platelet activating (PA). A close correlation between PA antibodies and the likelihood of experiencing HIT has been demonstrated in clinical studies, but how PA (presumptively pathogenic) and nonactivating (NA) (presumptively benign) antibodies differ from each other at the molecular level is unknown. To address this issue, we cloned 7 PA and 47 NA PF4/H-binding antibodies from 6 patients with HIT and characterized their structural and functional properties. Findings showed that PA clones differed significantly from NA clones in possessing 1 of 2 heavy chain complementarity-determining region 3 (HCDR3) motifs, RX1-2R/KX1-2R/H (RKH) and YYYYY (Y5), in an unusually long complementarity-determining region 3 (≥20 residues). Mutagenic studies showed that modification of either motif in PA clones reduced or abolished their PA activity and that appropriate amino acid substitutions in HCDR3 of NA clones can cause them to become PA. Repertoire sequencing showed that the frequency of peripheral blood IgG+ B cells possessing RKH or Y5 was significantly higher in patients with HIT than in patients without HIT given heparin, indicating expansion of B cells possessing RKH or Y5 in HIT. These findings imply that antibodies possessing RKH or Y5 are relevant to HIT pathogenesis and suggest new approaches to diagnosis and treatment of this condition.

CARD19, a Novel Regulator of the TAK1/NF-κB Pathway in Self-Reactive B Cells.

The caspase recruitment domain family member (CARD)11-Bcl10-Malt1 signalosome controls TGF-ß-activated kinase 1 (TAK1) activation and regulates BCR-induced NF-κB activation. In this study, we discovered that CARD19 interacted with TAK1 and inhibited TAB2-mediated TAK1 ubiquitination and activation. Although CARD19 deficiency in mice did not affect B cell development, it enhanced clonal deletion, receptor editing, and anergy of self-reactive B cells, and it reduced autoantibody production. Mechanistically, CARD19 deficiency increased BCR/TAK1-mediated NF-κB activation, leading to increased expression of transcription factors Egr2/3, as well as the E3 ubiquitin ligases c-Cbl/Cbl-b, which are known inducers of B cell tolerance in self-reactive B cells. RNA sequencing analysis revealed that although CARD19 deficiency did not affect the overall Ag-induced gene expression in naive B cells, it suppressed BCR signaling and increased hyporesponsiveness of self-reactive B cells. As a result, CARD19 deficiency prevented Bm12-induced experimental systemic lupus erythematosus. In summary, CARD19 negatively regulates BCR/TAK1-induced NF-κB activation and its deficiency increases Egr2/3 and c-Cbl/Cbl-b expression in self-reactive B cells, thereby enhancing B cell tolerance.

Hyperactivation of SREBP induces pannexin-1-dependent lytic cell death.

Sterol-regulatory element binding proteins (SREBPs) are a conserved transcription factor family governing lipid metabolism. When cellular cholesterol level is low, SREBP2 is transported from the endoplasmic reticulum to the Golgi apparatus where it undergoes proteolytic activation to generate a soluble N-terminal fragment, which drives the expression of lipid biosynthetic genes. Malfunctional SREBP activation is associated with various metabolic abnormalities. In this study, we find that overexpression of the active nuclear form SREBP2 (nSREBP2) causes caspase-dependent lytic cell death in various types of cells. These cells display typical pyroptotic and necrotic signatures, including plasma membrane ballooning and release of cellular contents. However, this phenotype is independent of the gasdermin family proteins or mixed lineage kinase domain-like (MLKL). Transcriptomic analysis identifies that nSREBP2 induces expression of p73, which further activates caspases. Through whole-genome CRISPR-Cas9 screening, we find that Pannexin-1 (PANX1) acts downstream of caspases to promote membrane rupture. Caspase-3 or 7 cleaves PANX1 at the C-terminal tail and increases permeability. Inhibition of the pore-forming activity of PANX1 alleviates lytic cell death. PANX1 can mediate gasdermins and MLKL-independent cell lysis during TNF-induced or chemotherapeutic reagents (doxorubicin or cisplatin)-induced cell death. Together, this study uncovers a noncanonical function of SREBPs as a potentiator of programmed cell death and suggests that PANX1 can directly promote lytic cell death independent of gasdermins and MLKL.

siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice.

Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

PIN1P1 is activated by CREB1 and promotes gastric cancer progression via interacting with YBX1 and upregulating PIN1.

Long noncoding RNAs (lncRNAs) play critical roles in the carcinogenesis and progression of cancers. However, the role and mechanism of the pseudogene lncRNA PIN1P1 in gastric carcinoma remain unclear. The expression and effects of lncRNA PIN1P1 in gastric cancer were investigated. The transcriptional regulation of CREB1 on PIN1P1 was determined by ChIP and luciferase assays. The mechanistic model of PIN1P1 in gastric cancer was further explored by RNA pull-down, RIP and western blot analysis. PIN1P1 was overexpressed in gastric cancer tissues, and upregulated PIN1P1 predicted poor prognosis in patients. CREB1 was directly combined with the promoter region of PIN1P1 to promote the transcription of PIN1P1. CREB1-mediated enhanced proliferation, migration and invasion could be partially reversed by downregulation of PIN1P1. Overexpressed PIN1P1 promoted the proliferation, migration and invasion of gastric cancer cells, whereas decreased PIN1P1 showed the opposite effects. PIN1P1 directly interacted with YBX1 and promoted YBX1 protein expression, leading to upregulation of PIN1, in which E2F1 may be involved. Silencing of YBX1 during PIN1P1 overexpression could partially rescue PIN1 upregulation. PIN1, the parental gene of PIN1P1, was elevated in gastric cancer tissues, and its upregulation was correlated with poor patient outcomes. PIN1 facilitated gastric cancer cell proliferation, migration and invasion. To sum up, CREB1-activated PIN1P1 could promote gastric cancer progression through YBX1 and upregulating PIN1, suggesting that it is a potential target for gastric cancer.

Structural and molecular basis for urea recognition by Prochlorococcus.

Nitrogen (N) is an essential element for microbial growth and metabolism. The growth and reproduction of microorganisms in more than 75% of areas of the ocean are limited by N. Prochlorococcus is numerically the most abundant photosynthetic organism on the planet. Urea is an important and efficient N source for Prochlorococcus. However, how Prochlorococcus recognizes and absorbs urea still remains unclear. Prochlorococcus marinus MIT 9313, a typical Cyanobacteria, contains an ABC-type transporter, UrtABCDE, which may account for the transport of urea. Here, we heterologously expressed and purified UrtA, the substrate-binding protein of UrtABCDE, detected its binding affinity toward urea, and further determined the crystal structure of the UrtA/urea complex. Molecular dynamics simulations indicated that UrtA can alternate between "open" and "closed" states for urea binding. Based on structural and biochemical analyses, the molecular mechanism for urea recognition and binding was proposed. When a urea molecule is bound, UrtA undergoes a state change from open to closed surrounding the urea molecule, and the urea molecule is further stabilized by the hydrogen bonds supported by the conserved residues around it. Moreover, bioinformatics analysis showed that ABC-type urea transporters are widespread in bacteria and probably share similar urea recognition and binding mechanisms as UrtA from P. marinus MIT 9313. Our study provides a better understanding of urea absorption and utilization in marine bacteria.

Radiotherapy-Driven Nanoprobes Targeting for Visualizing Tumor Infiltration Dynamics and Inducing Ferroptosis in Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSCs) significantly hinder the immune response to tumor radiotherapy (RT) because of their massive accumulation in tumors after RT, resulting in immunosuppression and poor clinical prognosis. Herein, we developed an anti-PD-L1 antibody-conjugated iron oxide nanoprobe (Fe3O4-αPD-L1) to target and induce ferroptosis in MDSCs, thereby alleviating RT resistance. Overexpression of PD-L1 in MDSCs following RT enables noninvasive in vivo magnetic resonance and positron emission tomography imaging using 89Zr-labeled nanoprobes to track the movement of MDSCs and their infiltration into the tumor. After uptake by MDSCs that infiltrated the tumor, Fe3O4-αPD-L1 nanoprobes were mainly found within the lysosome and triggered the Fenton reaction, resulting in the generation of abundant reactive oxygen species. This process leads to ferroptosis of MDSCs, characterized by lipid peroxidation and mitochondrial dysfunction, and effectively reprograms the immunosuppressive environment within the tumor following RT. This study highlights a strategy for monitoring and regulating the fate of MDSCs to alleviate RT resistance and ultimately achieve improved treatment outcomes.

Treatment discontinuation in older people with multiple sclerosis.

PURPOSE OF REVIEW: The aim of this review was to examine the evidence for disease-modifying therapies (DMTs) discontinuation in older people with multiple sclerosis (MS). We first summarized aging-associated biological changes that influence MS progression and DMT effectiveness, and then summarized recent evidence in evaluating clinical outcomes of discontinuing DMTs in older people with MS. RECENT FINDINGS: Recent findings provide mixed evidence regarding the outcomes of DMT discontinuation in older people with MS. Retrospective observational studies suggested older age and longer stable duration on DMT before DMT discontinuation were associated with lower risk of relapse in people with MS. However, one randomized clinical trial did not demonstrate the noninferiority of DMT discontinuation. SUMMARY: The available clinical evidence examining DMT discontinuation in older people with MS remains inconclusive. More robust evidence from clinical trials and real-world data will be necessary to guide clinical decisions regarding DMT discontinuation in older people with MS.

Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis.

Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.

Laparoscopic Right Hemi-hepatectomy of the Bile Duct-Obstructed Area Guided by Real-Time Fluorescence Imaging.

BACKGROUND: The regions of the liver with cholestasis caused by biliary tumors or thrombosis can be distinctly identified using indocyanine green (ICG) fluorescence imaging.1 The authors' team reported the application of bile-duct obstructed area imaging (BOAI) to assist open hepatectomy for intrahepatic cholangiocarcinoma (ICC) combined with intrahepatic bile duct obstruction previously.2 This video is the first report of real-time BOAI-guided three-dimensional (3D) laparoscopic hepatectomy using a 3D-4K fluorescence imaging system. METHODS: A 65-year-old man was admitted to the authors' institution with clonorchiasis. Preoperative computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) showed an obstruction and diffuse dilation of the right hepatic duct. A 15-min retention of ICG (ICG R15) was performed 5 days before the operation, with a 3.3% result. Preoperative planning involved performing laparoscopic right hemi-hepatectomy with regional lymph node dissection assisted by visualization technology.3 During the procedure, significant fluorescence accumulation in the right liver was shown by fluorescence imaging. With the guidance of real-time BOAI (Fig. 1), the regions of biliary obstruction were precisely resected, and the middle hepatic vein (MHV) was passively and adequately exposed on the cutting plane. Fig. 1 Administration steps for real-time bile duct-obstructed area imaging. A ICG is injected intravenously 3-5 days before operation at a dose of 0.5 mg/kg. B ICG is accumulated in the whole liver within a few minutes after injection. C ICG is selectively absorbed by the liver and excreted into the intestines, whereby it is retained in areas of biliary obstruction RESULTS: The histopathologic diagnosis indicated high-grade intraepithelial neoplasia of the right bile duct tumor without lymph node metastases and clonorchiasis. The duration of the operation was 300 min, with an intraoperative blood loss of 50 ml. No postoperative complications occurred, and the patient was discharged after 7 days. CONCLUSION: Laparoscopic right hemi-hepatectomy for the bile-duct obstructed area with the guidance of real-time BOAI is feasible and effective.

Palladium-Catalyzed Carbonylation Reaction of Indole/Pyrrole Involving HCFO-1233zd (E).

3-Indole-3-one is a key intermediate in the synthesis of many drugs and plays an important role in synthetic chemistry and biochemistry. A new method for synthesizing trifluoromethylated 3-indoleketones by Pd(0)-catalyzed carbonylation was introduced. In the absence of additives, 1-chloro-3,3,3-trifluoropropyl (an inexpensive and environmentally friendly synthetic block of trifluoromethyl) reacts with indole and carbon monoxide to generate trifluoromethylindole ketones with good yields, regioselectivity, and chemical selectivity; furthermore, the products exhibit strong resistance to basic functional groups, such as alkynes, aldehydes, and esters. In addition to the conversion of indole compounds into corresponding products, pyrrole and heteroindole may be suitable for corresponding chemical transformations. This study provides a synthetic method for the further construction of trifluoromethylated 3-indole ketones.

Structural features and substrate engagement in peptide-modifying radical SAM enzymes.

In recent years, the biological significance of ribosomally synthesized, post-translationally modified peptides (RiPPs) and the intriguing chemistry catalyzed by their tailoring enzymes has garnered significant attention. A subgroup of bacterial radical S-adenosylmethionine (rSAM) enzymes can activate C-H bonds in peptides, which leads to the production of a diverse range of RiPPs. The remarkable ability of these enzymes to facilitate various chemical processes, to generate and harbor high-energy radical species, and to accommodate large substrates with a high degree of flexibility is truly intriguing. The wide substrate scope and diversity of the chemistry performed by rSAM enzymes raise one question: how does the protein environment facilitate these distinct chemical conversions while sharing a similar structural fold? In this review, we discuss recent advances in the field of RiPP-rSAM enzymes, with a particular emphasis on domain architectures and substrate engagements identified by biophysical and structural characterizations. We provide readers with a comparative analysis of six examples of RiPP-rSAM enzymes with experimentally characterized structures. Linking the structural elements and the nature of rSAM-catalyzed RiPP production will provide insight into the functional engineering of enzyme activity to harness their catalytic power in broader applications.

Synthesis and biological evaluation of novel 1,2,3,4-tetrahydro-ß-carboline derivatives as potential antibacterial agents.

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-ß-carboline (THßC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THßC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THßC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs.

The important role of whole-process computed tomography guidance for percutaneous gastrostomy in esophageal cancer patients who are unsuitable for or have had unsuccessful attempts with endoscopic and fluoroscopic gastrostomy.

PURPOSE: To explore the value of clinical application with the whole process computed tomography (CT) guided percutaneous gastrostomy in esophageal tumor patients. MATERIALS AND METHODS: A consecutive series of 32 esophageal tumor patients in whom endoscopic gastrostomy or fluoroscopy guided gastrostomy were considered too dangerous or impossible due to the esophagus complete obstruction, complicate esophageal mediastinal fistula, esophageal trachea fistula or severe heart disease. All of the 32 patients were included in this study from 2 medical center and underwent the gastrostomy under whole process CT guided. RESULTS: All of the gastrostomy procedure was finished successfully under whole process CT guided and the technical success rate was 100%. The average time for each operation was 27 min. No serious complications occurred and the minor complications occurred in 3 patients, including local infection, severe hyperplasia of granulation tissue and tube dislodgment. There were no procedure related deaths. CONCLUSION: The technical success rate of whole process CT guided percutaneous gastrostomy is high and the complication is low. This technique can be used feasible and effectively in some special patients.

A novel anti-PD-L1/IL-15 immunocytokine overcomes resistance to PD-L1 blockade and elicits potent antitumor immunity.

Despite the demonstrated immense potential of immune checkpoint inhibitors in various types of cancers, only a minority of patients respond to these therapies. Immunocytokines designed to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME) and block the immune checkpoint simultaneously may provide a strategic advantage over the combination of two single agents. To increase the response rate to checkpoint blockade, in this study, we developed a novel immunocytokine (LH01) composed of the antibody against programmed death-ligand 1 (PD-L1) fused to interleukin (IL)-15 receptor alpha-sushi domain/IL-15 complex. We demonstrate that LH01 efficiently binds mouse or human PD-L1 and maintains IL-15 stimulatory activity. In syngeneic mouse models, LH01 showed improved antitumor efficacy and safety versus anti-PD-L1 plus LH02 (Fc-sushi-IL15) combination and overcame resistance to anti-PD-L1 treatment. Mechanistically, the dual anti-immunosuppressive function of LH01 activated both the innate and adaptive immune responses and induced a favorable and immunostimulatory TME. Furthermore, combination therapy with LH01 and bevacizumab exerts synergistic antitumor effects in an HT29 colorectal xenograft model. Collectively, our results provide supporting evidence that fusion of anti-PD-L1 and IL-15 might be a potent strategy to treat patients with cold tumors or resistance to checkpoint blockade.

CD40L-Activated DC Promotes Th17 Differentiation and Inhibits Th2 Differentiation in Sepsis-Induced Lung Injury via cGAS-STING Signaling.

Immune hemostasis due to an infection plays a vital role in sepsis-induced multiple organ dysfunction. Dendritic cells (DC) and T helper (Th) cells are the key members of the immune system maintaining immune homeostasis. This study aimed to explore the effect and mechanism of CD40L on the activation of DC and activated DC-induced Th2/Th17 differentiation. A CD40L knockout and cecal ligation and puncture (CLP) mouse model was established via cecal ligation. HE staining was used to evaluate the pathological changes. The gene expressions were studied using quantitative real-time polymerase chain reaction (qRT-PCR), while a transwell system was used to perform the co-culture of DC and T-cells. Flow cytometry was performed to detect the subtype of T and DC cells. ELISA was used to assess the amount of inflammatory factors. CD40L was highly expressed in the plasma of CLP mice. Knock out of CD40L inhibited the activation of DC cell and Th17 differentiation while promoting the Th2 differentiation. The mechanistic investigations revealed that CD40L promoted the activation of cGAS-STING pathway. Rescue experiments indicated that CD40L mediated DC activation via cGAS-STING signaling. Moreover, co-culturing of CD and CD+4 T-cells demonstrated that silencing of CD40L in DC suppressed the DC activation and inhibited Th17 differentiation while promoting Th2 differentiation. These findings revealed a relationship between CD40L, DC activation, and Th2/Th17 differentiation balance in sepsis-induced acute lung injury for the first time. These findings are envisaged to provide novel molecular targets for sepsis-induced lung injury treatment.

Expression and Clinical Significance of MAGE-A Proteins and mRNA in Lung Cancer Patients: A Retrospective Study.

Objective: This study investigated the expression and clinical significance of Melanoma Associated Antigen (MAGE)-A proteins and mRNA in patients with non-small cell lung cancer (NSCLC). Methods: A retrospective study was conducted, and we selected a cohort of 88 NSCLC patients treated at our hospital from January 2015 to January 2020. Adjacent tissues were chosen as controls. The expression of MAGE-A proteins in lung cancer and adjacent tissues was assessed via Western blot, while MAGE-As mRNA expression was measured using RT-PCR. Results: The relative expression levels of MAGE-A proteins and mRNA in NSCLC tissues were significantly higher than those in adjacent tissues (P < .05), with values of (0.343 ± 0.101) and (0.728 ± 0.112), respectively. Furthermore, MAGE-As protein expression was significantly higher in stage III - IV lung cancer compared to stage I - II (P < .05). No significant differences were observed in MAGE-A protein expression concerning gender, age, tumor diameter, pathological type, and differentiation degree (P > .05). The relative expression of MAGE-As mRNA was significantly higher in clinical stage III - IV and moderately differentiated lung cancer tissues compared to stage I - II and well-differentiated tissues (P < .05). No significant differences were found in MAGE-As mRNA expression concerning gender, age, tumor diameter, and pathological type (P > .05). Patients with high MAGE-As mRNA expression had a significantly shorter median overall survival of 33 months (95% CI: 31.64-34.36) compared to those with low MAGE-As mRNA expression (P < .05). However, no significant difference was observed in median overall survival between patients with high and low MAGE-As protein expression (P > .05). Conclusions: In NSCLC, the up-regulation of MAGE-A proteins and mRNA is associated with clinical stage and differentiation degree, warranting further investigation.

Low concentrations of tetrabromobisphenol A promote the biofilm formation of methicillin-resistant Staphylococcus aureus.

The effect and underlying mechanism of tetrabromobisphenol A (TBBPA), a plastic additive, on biofilm formation of methicillin-resistant Staphylococcus aureus (MRSA USA300) remain unknown. This study first investigated the impact of different concentrations of TBBPA on the growth and biofilm formation of USA300. The results indicated that a low concentration (0.5 mg/L) of TBBPA promoted the growth and biofilm formation of USA300, whereas high concentrations (5 mg/L and 10 mg/L) of TBBPA had inhibitory effects. Further exploration revealed that the low concentration of TBBPA enhance biofilm formation by promoting the synthesis of extracellular proteins, release of extracellular DNA (eDNA), and production of staphyloxanthin. RTqPCR analysis demonstrated that the low concentration of TBBPA upregulated genes associated with extracellular protein synthesis (sarA, fnbA, fnbB, aur) and eDNA formation (atlA) and increased the expression of genes involved in staphyloxanthin biosynthesis (crtM), suggesting a potential mechanism for enhanced resistance of USA300 to adverse conditions. These findings shed light on how low concentrations of TBBPA facilitate biofilm formation in USA300 and highlight the indirect impact of plastic additives on pathogenic bacteria in terms of human health. In the future, in-depth studies about effects of plastic additives on pathogenicity of pathogenic bacteria should be conducted. CAPSULE: The protein and eDNA contents in biofilms of methicillin-resistant Staphylococcus aureus are increased by low concentrations of TBBPA.