ABSTRACT
Li-ion batteries (LIBs) for electric vehicles and aviation demand high energy density, fast charging and a wide operating temperature range, which are virtually impossible because they require electrolytes to simultaneously have high ionic conductivity, low solvation energy and low melting point and form an anion-derived inorganic interphase1-5. Here we report guidelines for designing such electrolytes by using small-sized solvents with low solvation energy. The tiny solvent in the secondary solvation sheath pulls out the Li+ in the primary solvation sheath to form a fast ion-conduction ligand channel to enhance Li+ transport, while the small-sized solvent with low solvation energy also allows the anion to enter the first Li+ solvation shell to form an inorganic-rich interphase. The electrolyte-design concept is demonstrated by using fluoroacetonitrile (FAN) solvent. The electrolyte of 1.3 M lithium bis(fluorosulfonyl)imide (LiFSI) in FAN exhibits ultrahigh ionic conductivity of 40.3 mS cm-1 at 25 °C and 11.9 mS cm-1 even at -70 °C, thus enabling 4.5-V graphite||LiNi0.8Mn0.1Co0.1O2 pouch cells (1.2 Ah, 2.85 mAh cm-2) to achieve high reversibility (0.62 Ah) when the cells are charged and discharged even at -65 °C. The electrolyte with small-sized solvents enables LIBs to simultaneously achieve high energy density, fast charging and a wide operating temperature range, which is unattainable for the current electrolyte design but is highly desired for extreme LIBs. This mechanism is generalizable and can be expanded to other metal-ion battery electrolytes.
ABSTRACT
Neutron stars and stellar-mass black holes are the remnants of massive star explosions1. Most massive stars reside in close binary systems2, and the interplay between the companion star and the newly formed compact object has been theoretically explored3, but signatures for binarity or evidence for the formation of a compact object during a supernova explosion are still lacking. Here we report a stripped-envelope supernova, SN 2022jli, which shows 12.4-day periodic undulations during the declining light curve. Narrow Hα emission is detected in late-time spectra with concordant periodic velocity shifts, probably arising from hydrogen gas stripped from a companion and accreted onto the compact remnant. A new Fermi-LAT γ-ray source is temporally and positionally consistent with SN 2022jli. The observed properties of SN 2022jli, including periodic undulations in the optical light curve, coherent Hα emission shifting and evidence for association with a γ-ray source, point to the explosion of a massive star in a binary system leaving behind a bound compact remnant. Mass accretion from the companion star onto the compact object powers the light curve of the supernova and generates the γ-ray emission.
ABSTRACT
Type Ia supernovae (SNe Ia) are thermonuclear explosions of degenerate white dwarf stars destabilized by mass accretion from a companion star1, but the nature of their progenitors remains poorly understood. A way to discriminate between progenitor systems is through radio observations; a non-degenerate companion star is expected to lose material through winds2 or binary interaction3 before explosion, and the supernova ejecta crashing into this nearby circumstellar material should result in radio synchrotron emission. However, despite extensive efforts, no type Ia supernova (SN Ia) has ever been detected at radio wavelengths, which suggests a clean environment and a companion star that is itself a degenerate white dwarf star4,5. Here we report on the study of SN 2020eyj, a SN Ia showing helium-rich circumstellar material, as demonstrated by its spectral features, infrared emission and, for the first time in a SN Ia to our knowledge, a radio counterpart. On the basis of our modelling, we conclude that the circumstellar material probably originates from a single-degenerate binary system in which a white dwarf accretes material from a helium donor star, an often proposed formation channel for SNe Ia (refs. 6,7). We describe how comprehensive radio follow-up of SN 2020eyj-like SNe Ia can improve the constraints on their progenitor systems.
ABSTRACT
Polygenic score (PGS) is an important tool for the genetic prediction of complex traits. However, there are currently no resources providing comprehensive PGSs computed from published summary statistics, and it is difficult to implement and run different PGS methods due to the complexity of their pipelines and parameter settings. To address these issues, we introduce a new resource called PGS-Depot containing the most comprehensive set of publicly available disease-related GWAS summary statistics. PGS-Depot includes 5585 high quality summary statistics (1933 quantitative and 3652 binary trait statistics) curated from 1564 traits in European and East Asian populations. A standardized best-practice pipeline is used to implement 11 summary statistics-based PGS methods, each with different model assumptions and estimation procedures. The prediction performance of each method can be compared for both in- and cross-ancestry populations, and users can also submit their own summary statistics to obtain custom PGS with the available methods. Other features include searching for PGSs by trait name, publication, cohort information, population, or the MeSH ontology tree and searching for trait descriptions with the experimental factor ontology (EFO). All scores, SNP effect sizes and summary statistics can be downloaded via FTP. PGS-Depot is freely available at http://www.pgsdepot.net.
Subject(s)
Biostatistics , Multifactorial Inheritance , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Phenotype , Polymorphism, Single Nucleotide , Biostatistics/methodsABSTRACT
Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.
Subject(s)
Demyelinating Diseases , Microglia , Mice , Animals , Microglia/metabolism , Linoleic Acid/metabolism , Autophagy , Demyelinating Diseases/metabolism , RegenerationABSTRACT
Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.
Subject(s)
Alzheimer Disease , Neuromyelitis Optica , Animals , Mice , Humans , Microglia/metabolism , Alzheimer Disease/metabolism , Neuromyelitis Optica/genetics , Neuromyelitis Optica/metabolism , Neuroinflammatory Diseases , Biomarkers/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Receptors, Immunologic/geneticsABSTRACT
The obligate intracellular parasite Toxoplasma gondii causes life-threatening toxoplasmosis to immunocompromised individuals. The pathogenesis of Toxoplasma relies on its swift dissemination to the central nervous system through a 'Trojan Horse' mechanism using infected leukocytes as carriers. Previous work found TgWIP, a protein secreted from Toxoplasma, played a role in altering the actin cytoskeleton and promoting cell migration in infected dendritic cells (DCs). However, the mechanism behind these changes was unknown. Here, we report that TgWIP harbors two SH2-binding motifs that interact with tyrosine phosphatases Shp1 and Shp2, leading to phosphatase activation. DCs infected with Toxoplasma exhibited hypermigration, accompanying enhanced F-actin stress fibers and increased membrane protrusions such as filopodia and pseudopodia. By contrast, these phenotypes were abrogated in DCs infected with Toxoplasma expressing a mutant TgWIP lacking the SH2-binding motifs. We further demonstrated that the Rho-associated kinase (Rock) is involved in the induction of these phenotypes, in a TgWIP-Shp1/2 dependent manner. Collectively, the data uncover a molecular mechanism by which TgWIP modulates the migration dynamics of infected DCs in vitro.
Subject(s)
Cell Movement , Dendritic Cells , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Protein Tyrosine Phosphatase, Non-Receptor Type 6 , Protozoan Proteins , Toxoplasma , Toxoplasma/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Dendritic Cells/metabolism , Dendritic Cells/parasitology , Animals , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Protozoan Proteins/metabolism , Protozoan Proteins/genetics , Humans , Mice , rho-Associated Kinases/metabolism , Toxoplasmosis/metabolism , Toxoplasmosis/parasitology , Toxoplasmosis/pathology , Mice, Inbred C57BLABSTRACT
Pepper (Capsicum annuum) responds differently to high temperature stress (HTS) and Ralstonia solanacearum infection (RSI) but employs some shared transcription factors (TFs), such as CabZIP63 and CaWRKY40, in both cases. How the plant activates and balances these distinct responses, however, was unclear. Here, we show that the protein CaSWC4 interacts with CaRUVBL2 and CaTAF14b and they all act positively in pepper response to RSI and thermotolerance. CaSWC4 activates chromatin of immunity or thermotolerance related target genes of CaWRKY40 or CabZIP63 by promoting deposition of H2A.Z, H3K9ac and H4K5ac, simultaneously recruits CabZIP63 and CaWRKY40 through physical interaction and brings them to their targets (immunity- or thermotolerance-related genes) via binding AT-rich DNA element. The above process relies on the recruitment of CaRUVBL2 and TAF14 by CaSWC4 via physical interaction, which occurs at loci of immunity related target genes only when the plants are challenged with RSI, and at loci of thermotolerance related target genes only upon HTS. Collectively, our data suggest that CaSWC4 regulates rapid, accurate responses to both RSI and HTS by modulating chromatin of specific target genes opening and recruiting the TFs, CaRUVBL2 and CaTAF14b to the specific target genes, thereby helping achieve the balance between immunity and thermotolerance.
Subject(s)
Capsicum , Ralstonia solanacearum , Thermotolerance , Capsicum/genetics , Chromatin/genetics , Chromatin/metabolism , Disease Resistance/genetics , Gene Expression Regulation, Plant , Gene Silencing , Plant Diseases/genetics , Plant Growth Regulators/metabolism , Plant Immunity/genetics , Plant Proteins/genetics , Plant Proteins/metabolism , Ralstonia solanacearum/genetics , Ralstonia solanacearum/metabolismABSTRACT
Although evolutionary fates and expression patterns of duplicated genes have been extensively investigated, how duplicated genes co-regulate a biological process in polyploids remains largely unknown. Here, we identified two gsdf (gonadal somatic cell-derived factor) homeologous genes (gsdf-A and gsdf-B) in hexaploid gibel carp (Carassius gibelio), wherein each homeolog contained three highly conserved alleles. Interestingly, gsdf-A and gsdf-B transcription were mainly activated by dmrt1-A (dsx- and mab-3-related transcription factor 1) and dmrt1-B, respectively. Loss of either gsdf-A or gsdf-B alone resulted in partial male-to-female sex reversal and loss of both caused complete sex reversal, which could be rescued by a nonsteroidal aromatase inhibitor. Compensatory expression of gsdf-A and gsdf-B was observed in gsdf-B and gsdf-A mutants, respectively. Subsequently, we determined that in tissue culture cells, Gsdf-A and Gsdf-B both interacted with Ncoa5 (nuclear receptor coactivator 5) and blocked Ncoa5 interaction with Rora (retinoic acid-related orphan receptor-alpha) to repress Rora/Ncoa5-induced activation of cyp19a1a (cytochrome P450, family 19, subfamily A, polypeptide 1a). These findings illustrate that Gsdf-A and Gsdf-B can regulate male differentiation by inhibiting cyp19a1a transcription in hexaploid gibel carp and also reveal that Gsdf-A and Gsdf-B can interact with Ncoa5 to suppress cyp19a1a transcription in vitro. This study provides a typical case of cooperative mechanism of duplicated genes in polyploids and also sheds light on the conserved evolution of sex differentiation.
Subject(s)
Gonads , Sex Differentiation , Animals , Cell Differentiation/genetics , Female , Fish Proteins/genetics , Fishes/genetics , Gene Expression Regulation, Developmental , Gonads/metabolism , Male , Polyploidy , Sex Differentiation/genetics , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Transition metal-containing materials with aggregation-induced emission (AIE) have brought new opportunities for the development of biological probes, optoelectronic materials, stimuli-responsive materials, sensors, and detectors. Coordination compounds containing the platinum metal have emerged as a promising option for constructing effective AIE platinum complexes. In this review, we classified AIE platinum complexes based on the number of ligands. We focused on the development and performance of AIE platinum complexes with different numbers of ligands and discussed the impact of platinum ion coordination and ligand structure variation on the optoelectronic properties. Furthermore, this review analyzes and summarizes the influence of molecular geometries, stacking models, and aggregation environments on the optoelectronic performance of these complexes. We provided a comprehensive overview of the AIE mechanisms exhibited by various AIE platinum complexes. Based on the unique properties of AIE platinum complexes with different numbers of ligands, we systematically summarized their applications in electronics, biological fields, etc. Finally, we illustrated the challenges and opportunities for future research on AIE platinum complexes, aiming at giving a comprehensive summary and outlook on the latest developments of functional AIE platinum complexes and also encouraging more researchers to contribute to this promising field.
ABSTRACT
To explore whether granulosa cell (GC)-derived exosomes (GC-Exos) and follicular fluid-derived exosomes (FF-Exos) have functional similarities in follicle development and to establish relevant experiments to validate whether GC-Exos could serve as a potential substitute for follicular fluid-derived exosomes to improve folliculogenesis. GC-Exos were characterized. MicroRNA (miRNA) profiles of exosomes from human GCs and follicular fluid were analyzed in depth. The signature was associated with folliculogenesis, such as phosphatidylinositol 3 kinases-protein kinase B signal pathway, mammalian target of rapamycin signal pathway, mitogen-activated protein kinase signal pathway, Wnt signal pathway, and cyclic adenosine monophosphate signal pathway. A total of five prominent miRNAs were found to regulate the above five signaling pathways. These miRNAs include miRNA-486-5p, miRNA-10b-5p, miRNA-100-5p, miRNA-99a-5p, and miRNA-21-5p. The exosomes from GCs and follicular fluid were investigated to explore the effect on folliculogenesis by injecting exosomes into older mice. The proportion of follicles at each stage is counted to help us understand folliculogenesis. Exosomes derived from GCs were isolated successfully. miRNA profiles demonstrated a remarkable overlap between the miRNA profiles of FF-Exos and GC-Exos. The shared miRNA signature exhibited a positive influence on follicle development and activation. Furthermore, exosomes derived from GCs and follicular fluid promoted folliculogenesis in older female mice. Exosomes derived from GCs had similar miRNA profiles and follicle-promoting functions as follicular fluid exosomes. Consequently, GC-Exos are promising for replacing FF-Exos and developing new commercial reagents to improve female fertility.
Subject(s)
Exosomes , Granulosa Cells , MicroRNAs , Ovarian Follicle , Animals , Female , Humans , Mice , Exosomes/genetics , Exosomes/metabolism , Follicular Fluid/metabolism , Granulosa Cells/metabolism , MicroRNAs/genetics , Ovarian Follicle/metabolism , Signal TransductionABSTRACT
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a widespread gastrointestinal inflammatory disorder with globally increasing incidence. Clostridioides difficile infection (CDI) often occurs in patients with intestinal dysbiosis, such as after antibiotic therapy. Patients with IBD have increased incidence of CDI and the clinical outcome of IBD is reportedly worsened by CDI. However, the underlying reasons remain poorly understood. METHODS: We performed a retrospective single-center and a prospective multicenter analysis of CDI in patients with IBD, including genetic typing of C difficile isolates. Furthermore, we performed a CDI mouse model to analyze the role of the sorbitol metabolization locus that we found distinguished the main IBD- and non-IBD-associated sequence types (STs). Moreover, we analyzed sorbitol concentration in the feces of patients with IBD and healthy individuals. RESULTS: We detected a significant association of specific lineages with IBD, particularly increased abundance of ST54. We found that in contrast to the otherwise clinically predominant ST81, ST54 harbors a sorbitol metabolization locus and was able to metabolize sorbitol in vitro and in vivo. Notably, in the mouse model, ST54 pathogenesis was dependent on intestinal inflammation-induced conditions and the presence of sorbitol. Furthermore, we detected significantly increased sorbitol concentrations in the feces of patients with active IBD vs patients in remission or healthy controls. CONCLUSIONS: Sorbitol and sorbitol utilization in the infecting C difficile strain play major roles for the pathogenesis and epidemiology of CDI in patients with IBD. CDI in patients with IBD may thus be avoided or improved by elimination of dietary sorbitol or suppression of host-derived sorbitol production.
Subject(s)
Clostridioides difficile , Clostridium Infections , Inflammatory Bowel Diseases , Animals , Mice , Retrospective Studies , Sorbitol/therapeutic use , Prospective Studies , Inflammatory Bowel Diseases/therapy , Clostridium Infections/epidemiology , Clostridium Infections/drug therapy , Bacteria/geneticsABSTRACT
5,10-Dimethyl-5,10-dihydrophenazine (MP) is utilized as an effective auxochrome, leveraging its highly conjugated structure to enhance the photophysical and photochemical properties of fluorophores. As illustrated in the difluoride-boron complex and coumarin fluorophores, the extensive conjugation of MP auxochrome substantially red-shifts the absorption/emission wavelengths and increases Stokes shift due to the intensified intramolecular charge transfer effect; notably, MP auxochrome effectively improves fluorophores' photostability by mitigating photooxidative reactions through enhanced electron density delocalization on nitrogen atoms and increased ionization potential. Importantly, MP-based fluorophores demonstrate applicability in stimulated emission depletion nanomicroscopy, showcasing their utility in lipid droplet labeling.
ABSTRACT
Accurate detection of labile analytes through activity based fluorogenic sensing is meaningful but remains a challenge because of nonrapid reaction kinetic. Herein, we present a signaling reporter engineering strategy to accelerate azoreduction reaction by positively charged fluorophore promoted unstable anion recognition for rapidly sensing sodium dithionite (Na2S2O4), a kind of widespread used but harmful inorganic reducing agent. Its quick decomposition often impedes application reliability of traditional fluorogenic probes in real samples because of their slow responses. In this work, four azo-based probes with different charged fluorophores (positive, zwitterionic, neutral, and negative) were synthesized and compared. Among of them, with sequestration effect of positively charged anthocyanin fluorophore for dithionite anion via electrostatic attraction, the cationic probe Azo-Pos displayed ultrafast fluorogenic response (â¼2 s) with the fastest response kinetic (kpos' = 0.373 s-1) that is better than other charged ones (kzwi' = 0.031 s-1, kneu' = 0.013 s-1, kneg' = 0.003 s-1). Azo-Pos was demonstrated to be capable to directly detect labile Na2S2O4 in food samples and visualize the presence of Na2S2O4 in living systems in a timely fashion. This new probe has potential as a robust tool to fluorescently monitor excessive food additives and biological invasion of harmful Na2S2O4. Moreover, our proposed accelerating strategy would be versatile to develop more activity-based sensing probes for quickly detecting other unstable analytes of interest.
Subject(s)
Fluorescent Dyes , Fluorescent Dyes/chemistry , Humans , Dithionite/chemistry , Azo Compounds/chemistry , KineticsABSTRACT
Amplified nanoprobes based on hybridization chain reaction (HCR) have been widely developed for the detection of intracellular low abundance mRNA. However, the formed chain-like assembly decorated with fluorophore would be degraded rapidly by endogenous enzyme, resulting in failure of the long-term fluorescence imaging. To address this issue, herein, a composite signal-amplifying strategy that integrates HCR into protein-binding signal amplification (HPSA) was communicated for the in situ imaging of mRNA by avoiding signal fluctuation. Different from conventional HCR-based nanoprobes (HCR-nanoprobe), the HCR was used as the signal-triggered mode and the amplifying signal generated from in situ fluorophore-protein binding in cells, which can maintain high stability of the signal for a long time. As a proof-of-principle, a nanobeacon based on HPSA (HPSA-nanobeacon) was constructed to detect TK1 mRNA. Taking advantage of the double signal-amplifying mode, the endogenous TK1 mRNA was sensitively detected and the fluorescence signal was maintained for more than 8 h in HepG2 cells. The attempt in this work provides a new option to the current signal-amplifying strategy for sensing nucleic acid targets with high stability, significantly enhancing the acquisition of intracellular molecular information.
Subject(s)
Nucleic Acid Hybridization , RNA, Messenger , Humans , RNA, Messenger/analysis , RNA, Messenger/metabolism , RNA, Messenger/genetics , Hep G2 Cells , Optical Imaging , Fluorescent Dyes/chemistry , Protein Binding , Nucleic Acid Amplification Techniques/methods , Thymidine KinaseABSTRACT
A noninvasive sampling technology was conceived, employing a disposable acupuncture needle in conjunction with high-resolution mass spectrometry (termed as noninvasive direct sampling extractive electrospray ionization mass spectrometry, NIDS-EESI-MS) to scrutinize the epidermal mucus of Nile tilapia for insights into the metabolic dysregulation induced by polypropylene nano- and microplastics. This analytical method initiates with the dispensing of an extraction solvent onto the needles coated with the mucus sample, almost simultaneously applying a high voltage to generate analyte ions. This innovative strategy obliterates the necessitation for laborious sample preparation, thereby simplifying the sampling process. Employing this technique facilitated the delineation of a plethora of metabolites, encompassing, but not confined to, amino acids, peptides, carbohydrates, ketones, fatty acids, and their derivatives. Follow-up pathway enrichment analysis exposed notable alterations within key metabolic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, lysine degradation, as well as the biosynthesis and metabolism of valine, leucine, and isoleucine pathways in Nile tilapia, consequent to increased concentrations of polypropylene nanoplastics. These metabolic alterations portend potential implications such as immune suppression, among other deleterious outcomes. This trailblazing application of this methodology not only spares aquatic life from sacrifice but also inaugurates an ethical paradigm for conducting longitudinal studies on the same organisms, facilitating detailed investigations into the long-term effects of environmental pollutants. This technique enhances the ability to observe and understand the subtle yet significant impacts of such contaminants over time.
Subject(s)
Cichlids , Microplastics , Mucus , Polypropylenes , Animals , Microplastics/analysis , Polypropylenes/chemistry , Cichlids/metabolism , Mucus/metabolism , Mucus/chemistry , Epidermis/metabolism , Epidermis/chemistry , Spectrometry, Mass, Electrospray IonizationABSTRACT
The response rate of anti-PD1 therapy is limited, and the influence of anti-PD1 therapy on cancer patients is unclear. To address these challenges, we conducted a longitudinal analysis of plasma proteomic changes with anti-PD1 therapy in non-small cell lung cancer (NSCLC), alveolar soft part sarcoma (ASPS), and lymphoma patients. We included 339 plasma samples before and after anti-PD1 therapy from 193 patients with NSCLC, ASPS, or lymphoma. The plasma proteins were detected using data-independent acquisition-mass spectrometry and customable antibody microarrays. Differential proteomic characteristics in responders (R) and non-responders (NR) before and after anti-PD1 therapy were elucidated. A total of 1019 proteins were detected using our in-depth proteomics platform and distributed across 10-12 orders of abundance. By comparing the differential plasma proteome expression between R and NR groups, 50, 206, and 268 proteins were identified in NSCLC, ASPS, and lymphoma patients, respectively. Th17, IL-17, and JAK-STAT signal pathways were identified upregulated in NR group, while cellular senescence and transcriptional misregulation pathways were activated in R group. Longitudinal proteomics analysis revealed the IL-17 signaling pathway was downregulated after treatment. Consistently, many proteins were identified as potential combinatorial therapeutic targets (e.g., IL-17A and CD22). Five noninvasive biomarkers (FLT4, SFTPB, GNPTG, F5, and IL-17A) were further validated in an independent lymphoma cohort (n = 39), and another three noninvasive biomarkers (KIT, CCL3, and TNFSF1) were validated in NSCLC cohort (n = 76). Our results provide molecular insights into the anti-PD1 therapy in cancer patients and identify new therapeutic strategies for anti-PD1-resistant patients.
Subject(s)
Anti-Infective Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Lymphoma , Humans , Interleukin-17 , Carcinoma, Non-Small-Cell Lung/drug therapy , Proteomics , Lung Neoplasms/drug therapy , Penicillins , Biomarkers , Transferases (Other Substituted Phosphate Groups)ABSTRACT
Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase , Brain Ischemia , White Matter , Animals , Male , Mice , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Brain Ischemia/metabolism , Chronic Disease , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Neuroinflammatory Diseases/drug therapy , Neuroinflammatory Diseases/metabolism , Neuroinflammatory Diseases/pathology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , White Matter/drug effects , White Matter/pathology , White Matter/metabolismABSTRACT
MAIN CONCLUSION: A stable genetic transformation system for Erigeron breviscapus was developed. We cloned the EbYUC2 gene and genetically transformed it into Arabidopsis thaliana and E. breviscapus. The leaf number, YUC2 gene expression, and the endogenous auxin content in transgenic plants were significantly increased. Erigeron breviscapus is a prescription drug for the clinical treatment of cardiovascular and cerebrovascular diseases. The rosette leaves have the highest content of the major active compound scutellarin and are an important component in the yield of E. breviscapus. However, little is known about the genes related to the leaf number and flowering time of E. breviscapus. In our previous study, we identified three candidate genes related to the leaf number and flowering of E. breviscapus by combining resequencing data and genome-wide association study (GWAS). However, their specific functions remain to be characterized. In this study, we cloned and transformed the previously identified full-length EbYUC2 gene into Arabidopsis thaliana, developed the first stable genetic transformation system for E. breviscapus, and obtained the transgenic plants overexpressing EbYUC2. Compared with wild-type plants, the transgenic plants showed a significant increase in the number of leaves, which was correlated with the increased expression of EbYUC2. Consistently, the endogenous auxin content, particularly indole-3-acetic acid, in transgenic plants was also significantly increased. These results suggest that EbYUC2 may control the leaf number by regulating auxin biosynthesis, thereby laying a foundation for revealing the molecular mechanism governing the leaf number and flowering time of E. breviscapus.
Subject(s)
Arabidopsis , Erigeron , Erigeron/genetics , Arabidopsis/genetics , Genome-Wide Association Study , Indoleacetic Acids , Plant Leaves/genetics , Plants, Genetically Modified , Transformation, GeneticABSTRACT
MAIN CONCLUSION: The oxidosqualene cyclases (OSCs) generating triterpenoid skeletons in Cyclocarya paliurus were identified for the first time, and two uridine diphosphate (UDP)-glycosyltransferases (UGTs) catalyzing the glycosylation of flavonoids were characterized. Cyclocarya paliurus, a native rare dicotyledonous plant in China, contains an abundance of triterpenoid saponins and flavonoid glycosides that exhibit valuable pharmaceutical effects in preventing hypertension, hyperlipidemia, and diabetes. However, the molecular mechanism explaining the biosynthesis of triterpenoid saponin and flavonoid glycoside in C. paliurus remains unclear. In this study, the triterpene content in different tissues and the expression pattern of genes encoding the key enzymes associated with triterpenoid saponin and flavonoid glycoside biosynthesis were studied using transcriptome and metabolome analysis. The eight upstream oxidosqualene cyclases (OSCs) involved in triterpenoid saponin biosynthesis were functionally characterized, among them CpalOSC6 catalyzed 2,3;22,23-dioxidosqualene to form 3-epicabraleadiol; CpalOSC8 cyclized 2,3-oxidosqualene to generate dammarenediol-II; CpalOSC2 and CpalOSC3 produced ß-amyrin and CpalOSC4 produced cycloartenol, while CpalOSC2-CpalOSC5, CpalOSC7, and CpalOSC8 all produced lanosterol. However, no catalytic product was detected for CpalOSC1. Moreover, two downstream flavonoid uridine diphosphate (UDP)-glycosyltransferases (UGTs) (CpalUGT015 and CpalUGT100) that catalyze the last step of flavonoid glycoside biosynthesis were functionally elucidated. These results uncovered the key genes involved in the biosynthesis of triterpenoid saponins and flavonoid glycosides in C. paliurus that could be applied to produce flavonoid glycosides and key triterpenoid saponins in the future via a synthetic strategy.