Cancer cell-intrinsic biosynthesis of itaconate promotes tumor immunogenicity.

The Krebs cycle byproduct itaconate has recently emerged as an important metabolite regulating macrophage immune functions, but its role in tumor cells remains unknown. Here, we show that increased tumor-intrinsic cis-aconitate decarboxylase (ACOD1 or CAD, encoded by immune-responsive gene 1, Irg1) expression and itaconate production promote tumor immunogenicity and anti-tumor immune responses. Furthermore, we identify thimerosal, a vaccine preservative, as a specific inducer of IRG1 expression in tumor cells but not in macrophages, thereby enhancing tumor immunogenicity. Mechanistically, thimerosal induces itaconate production through a ROS-RIPK3-IRF1 signaling axis in tumor cells. Further, increased IRG1/itaconate upregulates antigen presentation-related gene expression via promoting TFEB nuclear translocation. Intratumoral injection of thimerosal induced itaconate production, activated the tumor immune microenvironment, and inhibited tumor growth in a T cell-dependent manner. Importantly, IRG1 deficiency markedly impaired tumor response to thimerosal treatment. Furthermore, itaconate induction by thimerosal potentiates the anti-tumor efficacy of adoptive T-cell therapy and anti-PD1 therapy in a mouse lymphoma model. Hence, our findings identify a new role for tumor intrinsic IRG1/itaconate in promoting tumor immunogenicity and provide a translational means to increase immunotherapy efficacy.

Position of meristems and the angles of the cell division plane regulate the uniqueness of lateral organ shape.

Leaf meristem is a cell proliferative zone present in the lateral organ primordia. In this study, we examined how cell proliferative zones in primordia of planar floral organs and polar auxin transport inhibitor (PATI)-treated leaf organs differ from those of non-treated foliage leaves of Arabidopsis thaliana, with a focus on the accumulation pattern of ANGUSTIFOLIA3 (AN3) protein, a key element for leaf meristem positioning. We found that PATI-induced leaf shape changes were correlated with cell division angle but not with meristem positioning/size or AN3 localisation. In contrast, different shapes between sepals and petals compared with foliage leaves were associated with both altered meristem position, due to altered AN3 expression patterns, and different distributions of cell division angles. A numerical simulation showed that meristem position majorly affected the final shape but biased cell division angles had a minor effect. Taken together, these results suggest that the unique shapes of different lateral organs depend on the position of the meristem in the case of floral organs and cell division angles in the case of leaf organs with different auxin flow.

Unlocking reproducible transcriptomic signatures for acute myeloid leukaemia: Integration, classification and drug repurposing.

Acute myeloid leukaemia (AML) is a highly heterogeneous disease, which lead to various findings in transcriptomic research. This study addresses these challenges by integrating 34 datasets, including 26 control groups, 6 prognostic datasets and 2 single-cell RNA sequencing (scRNA-seq) datasets to identify 10,000 AML-related genes (ARGs). We focused on genes with low variability and high consistency and successfully discovered 191 AML signatures (ASs). Leveraging machine learning techniques, specifically the XGBoost model and our custom framework, we classified AML subtypes with both scRNA-seq and bulk RNA-seq data, complementing the ELN2022 classification approach. Our research also identified promising treatments for AML through drug repurposing, with solasonine showing potential efficacy for high-risk AML patients, supported by molecular docking and transcriptomic analyses. To enhance reproducibility and customizability, we developed CSAMLdb, a user-friendly database platform. It facilitates the reuse and personalized analysis of nearly all results obtained in this research, including single-gene prognostics, multi-gene scoring, enrichment analysis, machine learning risk assessment, drug repositioning analysis and literature abstract named entity recognition. CSAMLdb is available at http://www.csamldb.com.

High-Fidelity Sensitive Tracing Circulating Tumor Cell Telomerase Activity.

Dynamic tracing of intracellular telomerase activity plays a crucial role in cancer cell recognition and correspondingly in earlier cancer diagnosis and personalized precision therapy. However, due to the complexity of the required reaction system and insufficient loading of reaction components into cells, achieving a high-fidelity determination of telomerase activity is still a challenge. Herein, an Aptamer-Liposome mediated Telomerase activated poly-Molecular beacon Arborescent Nanoassembly(ALTMAN) approach was described for direct high-fidelity visualization of telomerase activity. Briefly, intracellular telomerase activates molecular beacons, causing their hairpin structures to unfold and produce fluorescent signals. Furthermore, multiple molecular beacons can self-assemble, forming arborescent nanostructures and leading to exponential amplification of fluorescent signals. Integrating the enzyme-free isothermal signal amplification successfully increased the sensitivity and reduced interference by leveraging the skillful design of the molecular beacon and the extension of the telomerase-activated TTAGGG repeat sequence. The proposed approach enabled ultrasensitive visualization of activated telomerase exclusively with a prominent detection limit of 2 cells·µL-1 and realized real-time imaging of telomerase activity in living cancer cells including blood samples from breast cancer patients and urine samples from bladder cancer patients. This approach opens an avenue for establishing a telomerase activity determination and in situ monitoring technique that can facilitate both telomerase fundamental biological studies and cancer diagnostics.

Development of α-Tocopherol Loaded PLGA Nanoparticles and Its Evaluation as a Novel Immune Adjuvant.

With the continuous development of preventive and therapeutic vaccines, traditional adjuvants cannot provide sufficient immune efficacy and it is of high necessity to develop safe and effective novel nanoparticle-based vaccine adjuvants. α-Tocopherol (TOC) is commonly used in oil-emulsion adjuvant systems as an immune enhancer, yet its bioavailability is limited by poor water solubility. This study aims to develop TOC-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TOC-PLGA NPs) to explore the potential of TOC-PLGA NPs as a novel nanoparticle-immune adjuvant. TOC-PLGA NPs are prepared by a nanoprecipitation method and their physicochemical properties are characterized. It is shown that TOC-PLGA NPs are 110.8 nm, polydispersity index value of 0.042, and Zeta potential of -13.26 mV. The encapsulation efficiency and drug loading of NPs are 82.57% and 11.80%, respectively, and the cumulative release after 35 days of in vitro testing reaches 47%. Furthermore, TOC-PLGA NPs demonstrate a superior promotion effect on RAW 264.7 cell proliferation compared to PLGA NPs, being well phagocytosed and also promoting antigen uptake by macrophages. TOC-PLGA NPs can strongly upregulate the expression of co-stimulatory surface molecules and the secretion of cytokines. In conclusion, TOC-PLGA NPs can be a novel vaccine adjuvant with excellent biocompatibility and significant immune-enhancing activity.

Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling.

Intracellular delivery of messenger RNA (mRNA)-based cancer vaccine has shown great potential to elicit antitumor immunity. To achieve robust antitumor efficacy, mRNA encoding tumor antigens needs to be efficiently delivered and translated in dendritic cells with concurrent innate immune stimulation to promote antigen presentation. Here, by screening a group of cationic lipid-like materials, we developed a minimalist nanovaccine with C1 lipid nanoparticle (LNP) that could efficiently deliver mRNA in antigen presenting cells with simultaneous Toll-like receptor 4 (TLR4) activation and induced robust T cell activation. The C1 nanovaccine entered cells via phagocytosis and showed efficient mRNA-encoded antigen expression and presentation. Furthermore, the C1 lipid nanoparticle itself induced the expression of inflammatory cytokines such as IL-12 via stimulating TLR4 signal pathway in dendritic cells. Importantly, the C1 mRNA nanovaccine exhibited significant antitumor efficacy in both tumor prevention and therapeutic vaccine settings. Overall, our work presents a C1 LNP-based mRNA cancer nanovaccine with efficient antigen expression as well as self-adjuvant property, which may provide a platform for developing cancer immunotherapy for a wide range of tumor types.

Bone Marrow Stimulation Does Not Lead to Lower Retear Rates, Better Functional Outcomes, or Higher Complication Rates at Short-Term Follow-Up for Arthroscopic Rotator Cuff Repair: A Meta-analysis of Randomized Controlled Trials.

PURPOSE: To determine the effect of bone marrow stimulation (BMS) on retear rates, functional outcomes, and complication rates in patients who underwent arthroscopic rotator cuff repair (RCR) through a meta-analysis of randomized controlled trials. METHODS: PubMed, EMBASE, Web of Science, and The Cochrane Library were searched on March 25, 2023. Two evaluators independently screened the literature, extracted data, and assessed the methodologic quality of the enrolled studies. Meta-analysis was conducted using RevMan software, version 5.4. RESULTS: A total of 7 randomized controlled trials with 638 patients were included. The evaluation of rotator cuff tendon integrity was conducted using distinct imaging modalities. Specifically, 259 patients underwent magnetic resonance imaging whereas 208 patients underwent ultrasound. Additionally, a subset of 95 patients underwent either of these modalities; however, the precise distribution between these 2 modalities was not explicitly delineated. Compared with RCR alone, RCR combined with BMS provided similar retear rates (P = .51, I2 = 46%), Constant-Murley scores (P = .14, I2 = 0%), American Shoulder and Elbow Surgeons (standardized shoulder assessment form) scores (P = .56, I2 = 0%), Western Ontario Rotator Cuff Index scores (P = .20, I2 = 0%), visual analog scale scores (P = .19, I2 = 0%), forward flexion (P = .18, I2 = 0%), external rotation (P = .62, I2 = 0%), severe complication rates (P = .56, I2 = 0%), and mild complication rates (P = .10, I2 = 0%). CONCLUSIONS: Compared with the outcomes observed after isolated arthroscopic RCR, arthroscopic RCR with BMS showed comparable results in terms of retear rate, functional outcomes, and incidence of complications. LEVEL OF EVIDENCE: Level II, meta-analysis of Level I and II studies.

5-Fluorouracil for the Treatment of Pustulosis Caused by Vascular Occlusion After Receiving Filler Injection.

With the increase of cosmetic injections in recent years, complications, like filler embolism, had also increased. The pustulosis, as a result of vascular occlusion and hypoxia, requires a long treatment cycle and often develops pigmentation and scarring, leaved patients with bad memories and affected esthetics. In this study, we report three cases of pustulosis after hyaluronic acid injection. We used 5-fluorouracil preparations to heal the pustulosis and the pustules resolved in an average of 24 hours.Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Comprehensive Multi-drug Strategy for the Management of Foreign Body Granuloma Following Mesotherapy.

BACKGROUND: Mesotherapy is a medical technique that administers cosmetic nutrients directly to the dermis through microdrop injections for aesthetic purposes. Its application has become increasingly widespread. However, there have also been a growing number of reported cases of multiple foreign body granulomas following mesotherapy. It is crucial to find an effective and safe treatment. METHODS: In this study, 31 patients with facial foreign body granuloma after mesotherapy were included. A mixture of 5-fluorouracil, lidocaine injection , and normal saline was prepared in a ratio of 1:1:4 and injected subcutaneously. Triamcinolone acetonide, 5-fluorouracil, lidocaine injection, and normal saline were prepared in a ratio of 2:5:3:10. Subcutaneous injections were administered to each papule using a 34G needle. The treatments were scheduled at intervals of 10-14 days. Color Doppler ultrasound was used to evaluate the condition before the initial treatment and after the final treatment. RESULTS: The preoperative ultrasonography revealed diffuse hypoechoic areas in the dermis of the facial skin. After an average of 2-4 treatment sessions, a significant improvement was observed in all patients' appearance, with reduced redness and swelling, softened nodules, absence of pain and itching symptoms, and no evident abnormal echo on ultrasound examination. During a follow-up period ranging from 1 to 8 months, no recurrence or adverse reactions were reported. CONCLUSION: This technique demonstrates clear efficacy. And this formulation effectively reduces the dosage of triamcinolone acetonide and minimizes the risk of adverse reactions such as skin atrophy. Therefore, it can be considered an effective treatment for multiple foreign body granulomas following mesotherapy. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

FBXO11 amplifies type I interferon signaling to exert antiviral effects by facilitating the assemble of TRAF3-TBK1-IRF3 complex.

As the key component of host innate antiviral immunity, type I interferons (IFN-Is) exert multiple antiviral effects by inducing hundreds of IFN-stimulated genes. However, the precise mechanism involved in host sensing of IFN-I signaling priming is particularly complex and remains incompletely resolved. This research identified F-box protein 11 (FBXO11), a component of the E3-ubiquitin ligase SKP/Cullin/F-box complex, acted as an important regulator of IFN-I signaling priming and antiviral process against several RNA/DNA viruses. FBXO11 functioned as an essential enhancer of IFN-I signaling by promoting the phosphorylation of TBK1 and IRF3. Mechanistically, FBXO11 facilitated the assembly of TRAF3-TBK1-IRF3 complex by mediating the K63 ubiquitination of TRAF3 in a NEDD8-dependent manner to amplify the activation of IFN-I signaling. Consistently, the NEDD8-activating enzyme inhibitor MLN4921 could act as a blocker for FBXO11-TRAF3-IFN-I axis of signaling. More significantly, examination of clinical samples of chronic hepatitis B virus (HBV) infection and public transcriptome database of severe acute respiratory syndrome coronavirus-2-, HBV-, and hepatitis C virus-infected human samples revealed that FBXO11 expression was positively correlated with the stage of disease course. Taken together, these findings suggest that FBXO11 is an amplifier of antiviral immune responses and might serve as a potential therapeutic target for a number of different viral diseases.

Value Added Conversion of Ethanol on Morphologically Controlled and Defect-Engineered Titanium Dioxide Nanorods.

Developing an environmentally benign and highly effective strategy for the value-added conversion of biomass platform molecules such as ethanol has emerged as a significant challenge and opportunity. This challenge stems from the need to harness renewable solar energy and conduct thermodynamically unfavorable reactions at room temperature. To tackle this challenge, one-dimensional titanium dioxide photocatalysts have been designed and fabricated to achieve a remarkable photocatalytic selectivity of almost 100 % for transforming ethanol into value-added 1,1-diethoxyethane, contrasting the primary production of acetaldehyde in titanium dioxide nanoparticles. By incorporating a Pt co-catalyst and infusing oxygen vacancies into the one-dimensional catalyst, the ethanol transformation rate was doubled to 128.8 mmol g-1 h-1 with respect to that of its unmodified counterpart (about 66.7 mmol g-1 h-1 ). The underlying mechanism for this high conversion and selectivity resides in the narrowed bandgap of the catalyst and the prolonged lifetime of the photo-generated carriers. This is a promising strategy for the photocatalytic transformation of essential biomass platform molecules that intertwines morphological control and defect engineering.

New Insights into Selective Singlet Oxygen Production via the Typical Electroactivation of Oxygen for Water Decontamination.

Selective production of singlet oxygen (1O2) as an electrophilic oxidant is crucial for the precise control of chemical targets in environmental fields. Herein, we proposed a strategy to construct a redox interface on electrodes, which can in situ produce inorganic metal hydroperoxides with appropriate oxidative ability during oxygen activation. Benefiting from atomic Cu sites (CuN4) in a copper-carbon aerogel electrode, almost complete production of 1O2 was achieved, thereby refraining the competitive formation of other reactive oxygen species. The fast electron transfer rate between CuN4 and electrogenerated H2O2 promoted the in situ formation of copper hydroperoxide (N4-Cu-OOH), thereby selectively and efficiently oxidizing intermediate O2•- to 1O2. The optimized production of 1O2 was up to 2583 µmol L-1 without additional chemical reagents. We further considered the high production of 1O2 for efficiently removing electron-rich organic pollutants from a complex water matrix. Fast kinetics was achieved and considered for removing various pollutants with electron-donating substituents in a nonradical oxidation pathway. The BPA degradation efficiency is less susceptible to the coexisting natural organic matter (NOM) and inorganic ions. Specifically, the kinetic constant for BPA removal is 34 times higher than that for a nanoparticle of a copper-carbon electrode while producing a hydroxyl radical. Our findings highlight the innovative interfacial surface engineering of an electrocatalytic O2 activation system to selectively generate 1O2 for future potential applications.

Candidate Gene of NOS3, MMP3, AGT, and AGT1R and Pathway Analyses for Platelet Reactivity and Clinical Outcomes of Repeat Revascularization After First PCI in Chinese Patients.

PURPOSE: Major disadvantages of the percutaneous coronary intervention (PCI) are the high occurrence of repeat revascularization due to restenosis and disease progression. The current study aimed to identify indicators that can predict the risk of repeat revascularization. METHODS: A total of 143 patients who underwent PCI and had genetic test results were enrolled. We retrospectively reviewed their medical records after the first PCI. P2Y12 reaction unit (PRU) test results were obtained by VerifyNow; 4 candidate genes (NOS3, MMP3, AGT, and AGT1R) and 380 genes related to platelet activation-related processes and clopidogrel activity were selected for analysis. Repeat revascularization and in-stent restenosis (ISR) were used as clinical outcomes, and PRU and ADP aggregation rates were used as platelet function outcomes in analysis. RESULTS: After the first PCI, the incidence of repeat revascularization at 18, 30, and 42 months was 14.1% (20/142), 17.5% (24/137), and 39.7% (31/78), respectively. In the candidate gene analysis, rs7830 (NOS3) was associated with both ADP aggregation rate and 18- and 30-month ISR, and rs 62,275,847 (AGTR1) was associated with both ADP aggregation rate and 30-month ISR. In the pathway, gene-set analysis, the linkage rs471683 and rs7785386 of GNAI1|GNAT3 were associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30 months. Rs1715389 of GNAI1|GNAT3 was associated with both PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30 months. Rs7313458 of ITPR2 was associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 18 months. CONCLUSIONS: The genetic polymorphisms of rs7830 (NOS3), rs62275874 (AGTR1), linkage rs471683 and rs7785386 (GNAI1|GNAT3), rs1715389 (GNAI1|GNAT3), and rs7313458 (ITPR2) may lead to an increased risk of in-stent restenosis and revascularization after the first PCI in Chinese patients by affecting the efficacy of clopidogrel. The above six SNP may be used as potential genetic biomarkers for high risk of in-stent restenosis and revascularization after the first PCI in Chinese patients.

Adjusting grain boundary within NiCo2O4rod arrays by phosphating reaction for efficient hydrogen production.

In this work, the density and electronic structures of the metal active sites in NiCo2O4nanorod arrays were concurrently tuned by controlling the sample's exposure time in a phosphorization process. The results showed that both the density and electronic structure of the active adsorption sites played a key role towards the catalytic activity for water splitting to produce hydrogen. The optimal catalyst exhibited 81 mV overpotential for hydrogen evolution reaction (HER) at 10 mA cm-2and 313 mV overpotential towards oxygen evolution reaction at 50 mA cm-2. The assembled electrode delivered a current density of 50 mA cm-2at 1.694 V in a fully functional water electrolyzer. The further results of theoretical density functional theory calculations revealed the doping of P elements lowered down the H adsorption energies involved in the water splitting process on the various active sites of P-NiCo2O4-10 catalyst, and thus enhanced its HER catalytic activities.

Electronic Control of Traditional Iron-Carbon Electrodes to Regulate the Oxygen Reduction Route to Scale Up Water Purification.

Shifting four-electron (4e-) oxygen reduction in fuel cell technology to a two-electron (2e-) pathway with traditional iron-carbon electrodes is a critical step for hydroxyl radical (HO•) generation. Here, we fabricated iron-carbon aerogels with desired dimensions (e.g., 40 cm × 40 cm) as working electrodes containing atomic Fe sites and Fe3C subnanoclusters. Electron-donating Fe3C provides electrons to FeN4 through long-range activation for achieving the ideal electronic configuration, thereby optimizing the binding energy of the *OOH intermediate. With an iron-carbon aerogel benefiting from finely tuned electronic density, the selectivity of 2e- oxygen reduction increased from 10 to 90%. The resultant electrode exhibited unexpectedly efficient HO• production and fast elimination of organics. Notably, the kinetic constant kM for sulfamethoxazole (SMX) removal is 60 times higher than that in a traditional iron-carbon electrode. A flow-through pilot device with the iron-carbon aerogel (SA-Fe0.4NCA) was built to scale up micropolluted water decontamination. The initial total organic carbon (TOC) value of micropolluted water was 4.02 mg L-1, and it declined and maintained at 2.14 mg L-1, meeting the standards for drinking water quality in China. Meanwhile, the generation of emerging aromatic nitrogenous disinfection byproducts (chlorophenylacetonitriles) declined by 99.2%, satisfying the public safety of domestic water. This work provides guidance for developing electrochemical technologies to satisfy the flexible and economic demand for water purification, especially in water-scarce areas.

Standard- vs. low-dose rivaroxaban in patients with atrial fibrillation: a systematic review and meta-analysis.

PURPOSE: Low-dose rivaroxaban is often given to patients with atrial fibrillation (AF) around the world, but the rationale for its use remains unclear. We aimed to compare the efficacy and safety of standard- or low-dose rivaroxaban in patients with AF through systematic review of literature with meta-analysis. METHODS: We searched PubMed, Web of Science, EMBASE, Clinical Trials.gov, the Cochrane Library, and Bayer trial website from inception of each database until June 2020. Randomized controlled trials (RCTs) and cohort studies were included in the meta-analysis. A random-effects model was employed to calculate the pooled effect estimates. RESULTS: Two RCTs and 17 cohort studies were included in the qualitative analysis. Indirect comparison of RCTs showed no significant difference between the two rivaroxaban dosages in risk of efficacy or safety outcomes (p > 0.05). Indirect comparison of cohort studies showed a lower risk of MACE among Caucasians in standard-dose group (HR 0.779; 95% CI 0.687-0.884; p < 0.001). Bleeding outcomes did not differ significantly between the two dosage regimens in Asian or Caucasian populations, except that the standard dose was associated with higher risk of major bleeding among elderly Caucasian patients (HR 1.329; 95% CI 1.141-1.547; p < 0.001). The quality of evidence was rated ranging from very low to low for all the efficacy and safety outcomes. CONCLUSION: In Caucasians with AF, standard-dose rivaroxaban may prevent MACE significantly better than low-dose treatment. Further studies in Asians are needed to verify the advantages of the standard dose.

Non-vitamin K antagonist oral anticoagulants in venous thromboembolism patients: a meta-analysis of real-world studies.

BACKGROUND: The real-world studies on recurrent venous thromboembolism (VTE) and bleeding events of non-vitamin K antagonist oral anticoagulants (NOACs) in VTE patients have reported conflicting findings. Our study aimed to provide the direct comparison evidence of different NOACs for VTE patients in clinical practice settings. METHODS: Search of the medical literature was conducted using PubMed, Web of Science, EMBASE, Clinical Trials.gov, and the Cochrane Library from inception to March 22, 2021. Among the 19,996 citations retrieved, a total of 63,144 patients from 6 studies were analyzed. Clinical outcomes included recurrent VTE, death, and different bleeding events. RESULTS: Adjusted hazard ratio (HR) analysis suggested that apixaban had significant lower bleeding riskthan rivaroxaban (major, minor and any bleeding: HR = 0.61, 0.56, 0.70; p = 0.008, < 0.0001, 0.006, respectively), but no statistics difference found in recurrent VTE events (HR = 1.02, 95% confidence interval (CI) 0.71-1.47, p = 0.93). There was no significant difference of major bleeding between dabigatran and rivaroxaban (odds ratios (OR) = 0.41, 95% CI 0.09-1.90, p = 0.25), apixaban and dabigatran (OR 0.64, 95% CI 0.15-2.72, p = 0.83). No significant difference was found in the comparison of edoxaban and other NOACs in VTE recurrence, major bleeding and composite outcome. CONCLUSIONS: In the prevention of bleeding events, apixaban was associated with a lower risk than rivaroxaban, but equivalent efficacy for different NOACs in prevention of recurrent VTE. Evidence generated from the meta-analysis based on real-world data can help to guide selection between apixaban and rivaroxaban in routine clinical practice. TRIAL REGISTRATION: This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology statements and was registered with PROSPERO (CRD42019140553).

High-Resolution Small RNAs Landscape Provides Insights into Alkane Adaptation in the Marine Alkane-Degrader Alcanivorax dieselolei B-5

Alkanes are widespread in the ocean, and Alcanivorax is one of the most ubiquitous alkane-degrading bacteria in the marine ecosystem. Small RNAs (sRNAs) are usually at the heart of regulatory pathways, but sRNA-mediated alkane metabolic adaptability still remains largely unknown due to the difficulties of identification. Here, differential RNA sequencing (dRNA-seq) modified with a size selection (~50-nt to 500-nt) strategy was used to generate high-resolution sRNAs profiling in the model species Alcanivorax dieselolei B-5 under alkane (n-hexadecane) and non-alkane (acetate) conditions. As a result, we identified 549 sRNA candidates at single-nucleotide resolution of 5'-ends, 63.4% of which are with transcription start sites (TSSs), and 36.6% of which are with processing sites (PSSs) at the 5'-ends. These sRNAs originate from almost any location in the genome, regardless of intragenic (65.8%), antisense (20.6%) and intergenic (6.2%) regions, and RNase E may function in the maturation of sRNAs. Most sRNAs locally distribute across the 15 reference genomes of Alcanivorax, and only 7.5% of sRNAs are broadly conserved in this genus. Expression responses to the alkane of several core conserved sRNAs, including 6S RNA, M1 RNA and tmRNA, indicate that they may participate in alkane metabolisms and result in more actively global transcription, RNA processing and stresses mitigation. Two novel CsrA-related sRNAs are identified, which may be involved in the translational activation of alkane metabolism-related genes by sequestering the global repressor CsrA. The relationships of sRNAs with the characterized genes of alkane sensing (ompS), chemotaxis (mcp, cheR, cheW2), transporting (ompT1, ompT2, ompT3) and hydroxylation (alkB1, alkB2, almA) were created based on the genome-wide predicted sRNA-mRNA interactions. Overall, the sRNA landscape lays the ground for uncovering cryptic regulations in critical marine bacterium, among which both the core and species-specific sRNAs are implicated in the alkane adaptive metabolisms.

Genotype-guided antiplatelet treatment versus conventional therapy: A systematic review and meta-analysis.

AIM: This meta-analysis was carried out to explore if a personalized antiplatelet strategy based on genotyping is superior to conventional therapy. METHODS: PubMed, Web of Science, EMBASE and the Cochrane Library were searched from the inception of each database to 5 May 2020. Studies reporting endpoints in genotype-guided treatment group and conventional treatment group were included. The endpoint results were presented as the risk ratio (RR), with 95% confidence interval (CI). RESULTS: A total of 10 561 patients from 16 studies (eight randomized controlled trials [RCT] and eight cohort studies) were included in the meta-analysis. The rates of major adverse cardiovascular events (MACE), stent thrombosis and myocardial infarction (MI) were significantly lower in the genotype-guided group than in the conventional treatment group (RR 0.56, 95% CI 0.44-0.73, P < .0001; RR 0.40, 95% CI 0.24-0.67, P = .0005; RR 0.45, 95% CI 0.35-0.58, P < .00001, respectively). A significant difference was found between the two groups in major bleeding (RR 0.73, 95% CI 0.55-0.98, P = .04), which was not robust after sensitivity analysis. CONCLUSION: Genotype-guided antiplatelet treatment could decrease the risk of MACE, stent thrombosis and MI in patients with coronary artery disease or undergoing percutaneous coronary intervention, without increasing the risk of bleeding over a long follow-up period. The decreased risk of efficacy outcomes was more obvious in cohort studies. Well-organized RCTs and clinical trials are required to verify the benefit of genotype-guided therapy.

Noncanonical Role of FBXO6 in Regulating Antiviral Immunity.

The evolutionarily conserved F-box family of proteins are well known for their role as the key component of SKP1-Cullin1-F-box (SCF) E3 ligase in controlling cell cycle, cell proliferation and cell death, carcinogenesis, and cancer metastasis. However, thus far, there is only limited investigation on their involvement in antiviral immunity. In contrast to the canonical function of FBXO6 associated with SCF E3 ligase complex, we report, in this study, that FBXO6 can also potently regulate the activation of IFN-I signaling during host response to viral infection by targeting the key transcription factor IFN-regulatory factor 3 (IRF3) for accelerated degradation independent of SCF in human embryonic kidney cells (HEK293T) and human lung cancer epithelial cells (A549). Structure and function delineation has further revealed that FBXO6 interacts with IAD domain of IRF3 through its FBA region to induce ubiquitination and degradation of IRF3 without the involvement of SCF. Thus, our studies have identified a general but, to our knowledge, previously unrecognized role and a novel noncanonical mechanism of FBXO6 in modulating IFN-I-mediated antiviral immune responses, which may protect the host from immunopathology of overreactive and harmful IFN-I production.