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Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.
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Alérgenos , Interleucina-33 , Proteínas de Ligação a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Animais , Caspase 1/metabolismo , Inflamação , Interleucina-1beta/metabolismo , Interleucina-33/genética , Interleucina-33/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Peptídeo Hidrolases/metabolismo , Grânulos de EstresseRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The renewable energy industry demands rechargeable batteries that can be manufactured at low cost using abundant resources while offering high energy density, good safety, wide operating temperature windows, and long lifespans. Utilizing fluorine chemistry to redesign battery configurations/components is considered a critical strategy to fulfill these requirements due to the natural abundance, robust bond strength, and extraordinary electronegativity of fluorine and the high free energy of fluoride formation, which enables the fluorinated components with cost effectiveness, nonflammability, and intrinsic stability. In particular, fluorinated materials and electrode|electrolyte interphases have been demonstrated to significantly affect reaction reversibility/kinetics, safety, and temperature tolerance of rechargeable batteries. However, the underlining principles governing material design and the mechanistic insights of interphases at the atomic level have been largely overlooked. This review covers a wide range of topics from the exploration of fluorine-containing electrodes, fluorinated electrolyte constituents, and other fluorinated battery components for metal-ion shuttle batteries to constructing fluoride-ion batteries, dual-ion batteries, and other new chemistries. In doing so, this review aims to provide a comprehensive understanding of the structure-property interactions, the features of fluorinated interphases, and cutting-edge techniques for elucidating the role of fluorine chemistry in rechargeable batteries. Further, we present current challenges and promising strategies for employing fluorine chemistry, aiming to advance the electrochemical performance, wide temperature operation, and safety attributes of rechargeable batteries.
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Retroviruses and closely related LTR retrotransposons export full-length, unspliced genomic RNA (gRNA) for packaging into virions and to serve as the mRNA encoding GAG and POL polyproteins. Because gRNA often includes splice acceptor and donor sequences used to splice viral mRNAs, retroelements must overcome host mechanisms that retain intron-containing RNAs in the nucleus. Here we examine gRNA expression in Cer1, an LTR retrotransposon in C. elegans which somehow avoids silencing and is highly expressed in germ cells. Newly exported Cer1 gRNA associates rapidly with the Cer1 GAG protein, which has structural similarity with retroviral GAG proteins. gRNA export requires CERV (C. elegans regulator of viral expression), a novel protein encoded by a spliced Cer1 mRNA. CERV phosphorylation at S214 is essential for gRNA export, and phosphorylated CERV colocalizes with nuclear gRNA at presumptive sites of transcription. By electron microscopy, tagged CERV proteins surround clusters of distinct, linear fibrils that likely represent gRNA molecules. Single fibrils, or groups of aligned fibrils, also localize near nuclear pores. During the C. elegans self-fertile period, when hermaphrodites fertilize oocytes with their own sperm, CERV concentrates in two nuclear foci that are coincident with gRNA. However, as hermaphrodites cease self-fertilization, and can only produce cross-progeny, CERV undergoes a remarkable transition to form giant nuclear rods or cylinders that can be up to 5 microns in length. We propose a novel mechanism of rod formation, in which stage-specific changes in the nucleolus induce CERV to localize to the nucleolar periphery in flattened streaks of protein and gRNA; these streaks then roll up into cylinders. The rods are a widespread feature of Cer1 in wild strains of C. elegans, but their function is not known and might be limited to cross-progeny. We speculate that the adaptive strategy Cer1 uses for the identical self-progeny of a host hermaphrodite might differ for heterozygous cross-progeny sired by males. For example, mating introduces male chromosomes which can have different, or no, Cer1 elements.
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RNA Viral , Retroelementos , Masculino , Feminino , Animais , Retroelementos/genética , Caenorhabditis elegans/genética , Transporte Ativo do Núcleo Celular/genética , Sêmen , Genômica , Citocinas , RNA MensageiroRESUMO
During starvation, organisms modify both gene expression and metabolism to adjust to the energy stress. We previously reported that Caenorhabditis elegans lacing AMP-activated protein kinase (AMPK) exhibit transgenerational reproductive defects associated with abnormally elevated trimethylated histone H3 at lysine 4 (H3K4me3) levels in the germ line following recovery from acute starvation. Here, we show that these H3K4me3 marks are significantly increased at promoters, driving aberrant transcription elongation resulting in the accumulation of R-loops in starved AMPK mutants. DNA-RNA immunoprecipitation followed by high-throughput sequencing (DRIP-seq) analysis demonstrated that a significant proportion of the genome was affected by R-loop formation. This was most pronounced in the promoter-transcription start site regions of genes, in which the chromatin was modified by H3K4me3. Like H3K4me3, the R-loops were also found to be heritable, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK mutant germ lines show considerably more RAD-51 (the RecA recombinase) foci at sites of R-loop formation, potentially sequestering them from their roles at meiotic breaks or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation. The downstream effects of R-loops on DNA damage sensitivity and germline stem cell integrity may account for inappropriate epigenetic modification that occurs in numerous human disorders, including various cancers.
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Caenorhabditis elegans , Epigênese Genética , Instabilidade Genômica , Estruturas R-Loop , Animais , Humanos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Infertilidade/genética , Inanição/metabolismoRESUMO
Subnanometer pores/channels (SNPCs) play crucial roles in regulating electrochemical redox reactions for rechargeable batteries. The delicately designed and tailored porous structure of SNPCs not only provides ample space for ion storage but also facilitates efficient ion diffusion within the electrodes in batteries, which can greatly improve the electrochemical performance. However, due to current technological limitations, it is challenging to synthesize and control the quality, storage, and transport of nanopores at the subnanometer scale, as well as to understand the relationship between SNPCs and performances. In this review, we systematically classify and summarize materials with SNPCs from a structural perspective, dividing them into one-dimensional (1D) SNPCs, two-dimensional (2D) SNPCs, and three-dimensional (3D) SNPCs. We also unveil the unique physicochemical properties of SNPCs and analyse electrochemical couplings in SNPCs for rechargeable batteries, including cathodes, anodes, electrolytes, and functional materials. Finally, we discuss the challenges that SNPCs may face in electrochemical reactions in batteries and propose future research directions.
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The recent focus of cancer therapeutics research revolves around modulating the immunosuppressive tumor microenvironment (TME) to enhance efficacy. The tumor stroma, primarily composed of cancer-associated fibroblasts (CAFs), poses significant obstacles to therapeutic penetration, influencing resistance and tumor progression. Reprogramming CAFs into an inactivated state has emerged as a promising strategy, necessitating innovative approaches. This study pioneers the design of a nanoformulation using pioglitazone, a Food and Drug Administration-approved anti-diabetic drug, to reprogram CAFs in the breast cancer TME. Glutathione (GSH)-responsive dendritic mesoporous organosilica nanoparticles loaded with pioglitazone (DMON-P) are designed for the delivery of cargo to the GSH-rich cytosol of CAFs. DMON-P facilitates pioglitazone-mediated CAF reprogramming, enhancing the penetration of doxorubicin (Dox), a therapeutic drug. Treatment with DMON-P results in the downregulation of CAF biomarkers and inhibits tumor growth through the effective delivery of Dox. This innovative approach holds promise as an alternative strategy for enhancing therapeutic outcomes in CAF-abundant tumors, particularly in breast cancer.
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Neoplasias da Mama , Fibroblastos Associados a Câncer , Nanopartículas , Humanos , Feminino , Pioglitazona/farmacologia , Pioglitazona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Microambiente TumoralRESUMO
We present a dimensional regulating charge transfer strategy to achieve an enhanced electrochemiluminescence (ECL) by constructing a one-dimensional pyrene-based covalent organic framework (1D-COF). The dual-chain-like edge architecture in 1D-COF facilitates the stabilization of aromatic backbones, the enhancement of electronic conjugations, and the decrease of energy loss. The 1D-COF generates enhanced anodic (92.5-fold) and cathodic (3.2-fold) signals with tripropylamine (TPrA) and K2S2O8 as the anodic and cathodic coreactants, respectively, compared with 2D-COF. The anodic and cathodic ECL efficiencies of 1D-COF are 2.08- and 3.08-fold higher than those of 2D-COF, respectively. According to density functional theory (DFT), the rotational barrier energy (ΔE) of 1D-COF enhances sharply with the increase of dihedral angle, suggesting that the architecture in 1D-COF restrains the intramolecular spin of aromatic chains, which facilitates the decrease of nonradiative transitions and the enhancement of ECL. Furthermore, 1D-COF can be used to construct an ECL biosensor for sensitive detection of dopamine.
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Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.
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COVID-19 , COVID-19/genética , SARS-CoV-2/genética , Evolução Biológica , Mutação , PandemiasRESUMO
Natural organisms have evolved precise sensing systems relying on unique ion channels, which can efficiently perceive various physical/chemical stimuli based on ionic signal transmission in biological fluid environments. However, it is still a huge challenge to achieve extensive applications of the artificial counterparts as an efficient wet sensing platform due to the fluidity of the working medium. Herein, nanofluidic membranes with selective cation transport properties and solid-state organic electrochemical transistors (OECTs) with amplified signals are integrated together to mimic human gustatory sensation, achieving ionic gustatory reagent recognition and a portable configuration. Cu-HHTP nanofluidic membranes with selective cation transport through their uniform micropores are constructed first, followed by assembly with OECTs to form the designed nanofluidic membrane-assisted OECTs (nanofluidic OECTs). As a result, they can distinguish typically ionic gustatory reagents, and even ionic liquids (ILs), demonstrating enhanced gustatory perception performance under a wide concentration range (10-7-10-1 m) compared with those of conventional OECTs. The linear correlations between the response and the reagent concentration further indicate the promising potential for practical application as a next-generation sensing platform. It is suggested that nanofluidic membranes mediated intramembrane cation transport based on the steric hindrance effect, resulting in distinguishable and improved response to multiple ions.
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This study presents the implementation of an evanescent field (EF)-based sensing platform employing a hybrid film composed of graphene oxide (GO) and poly(methyl methacrylate) (PMMA), integrated onto coreless D-shaped fibers (cDsFs). The operational framework of the hybrid film-coated cDsFs (GoP-cDsFs) was comprehensively elucidated through theoretical and experimental analyses. To establish a baseline for comparison, the performance of the cDsFs with the sole inclusion of the PMMA film was investigated. Our investigations underscore the substantive role of graphene oxide in augmenting the evanescent field, thereby generating a synergistic effect that contributes to the overall enhancement of the evanescent field in the device. Consequently, the fabricated GoP-cDsF sensor manifests an outstanding sensitivity of -4.936â nm/°C, rendering it particularly well-suited for applications demanding high-sensitivity temperature sensing. Moreover, the unique attributes of the GoP-cDsF position it as a promising candidate for the measurement of both magnetic and electric fields, presenting an effective strategy for multifunctional sensing applications.
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The unique two-dimensional layered structure of BiOCl makes it highly promising for energy storage applications. In this study, we successfully synthesized BiOCl nanoparticles encapsulated in N-doped carbon nanonecklaces (BiOCl NPs/N-CNNs) using well-established electrospinning and solvothermal substitution. As an anode material for lithium-ion batteries, BiOCl NPs/N-CNNs exhibited enhanced rate performance, delivering a capacity of 220.2 mA h g-1 at 8 A g-1. Furthermore, it demonstrated remarkable long cycle stability, retaining a capacity of 200.5 mA h g-1 after 9000 cycles with a discharge rate of 8.0 A g-1. The superior electrochemical performance can be attributed to the stacked layered structure of BiOCl, facilitated by van der Waals force, as well as the ingenious nanonecklace structures. These structures not only provide fast ion diffusion pathways but also enhance electrolyte penetration and offer more active sites for Li+ insertion and extraction. Additionally, the nanonecklace structure prevents the aggregation of nanopolyhedra, promoting the complete reaction of BiOCl with Li+. Moreover, the unique nanopolyhedron structure alleviates the stress caused by the volume expansion of Bi nanoparticles during cycling and reduces the internal resistance of the electrode.
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Cancer stem cells (CSCs) make up a small population of cancer cells, primarily responsible for tumor initiation, metastasis, and drug resistance. They overexpress Arg-Gly-Asp (RGD) binding integrin receptors that play crucial roles in cell proliferation and stemness through interaction with the extracellular matrix. Here, we showed that monodisperse polymeric tadpole nanoparticles covalently coupled with different RGD densities regulated colon CSC proliferation and stemness in a RGD density-dependent manner. These tadpoles penetrated deeply and evenly into tumor spheroids and specifically entered cells with cancer stem markers CD24 and CD133. Low RGD density tadpoles triggered integrin α5 expression that further activated TGF-ß3 and TGF-ß2 signaling pathways, confirmed by the increase of pERK and Bcl-2 protein levels. This process is associated with the RGD cluster presentation controlled by the RGD density on the tadpole surface.
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Proliferação de Células , Células-Tronco Neoplásicas , Oligopeptídeos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Humanos , Animais , Nanoestruturas/química , Linhagem Celular Tumoral , Nanopartículas/químicaRESUMO
An efficient and chemodivergent synthesis of highly functionalized 1,4-dihydropyridazines and pyrazoles has been accomplished via base-promoted annulation between hydrazones and alkyl 2-aroyl-1-chlorocyclopropanecarboxylates, respectively. This transition-metal-free domino reaction proceeded rapidly under mild basic conditions, affording potentially bioactive 1,4-dihydropyridazine and pyrazole derivatives in moderate yields. The conversion of 1,4-dihydropyridazine to pyrazole was confirmed by adjusting the quantity of the base.
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Herein, a transition-metal-free phosphorylation of benzyl fluorides with P(O)-H compounds is disclosed. In the presence of tBuOK, various benzyl fluorides react with P(O)-H compounds to produce the corresponding benzyl phosphine oxides, phosphinates, and phosphonates in good to high yields. This base-promoted phosphorylation reaction offers a facile and general strategy for the construction of a C(sp3)-P bond.
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Visible light-induced aza-6π electrocyclization was developed for the synthesis of aza-arenes from nitroarenes with diverse aldehydes. This protocol allows the reduction of nitroarenes by B2nep2 and subsequent 6π-electrocyclization of the in situ formed imine under visible light. An array of 6- and multi-substituted phenanthridines were constructed in moderate to good yields under purple LEDs at room temperature. A wide scope of substrates with diverse functional groups were well tolerated. In addition, the synthetic utility of this methodology was further demonstrated in the late-stage functionalization of celecoxib.
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An efficient method was developed for the one-pot construction of C-B and C-I via visible light-induced transformation of nitroarenes. This protocol relies on the photochemical properties of nitroarenes under visible light, followed by reduction with B2pin2 and diazotization with tBuONO. An array of arylboronates and iodobenzenes were constructed smoothly after excitation with purple LEDs at room temperature. In addition, the synthetic utility of this method was further demonstrated in the late-stage modification of a drug molecule. The advantages of this strategy include metal-free system, mild reaction conditions and acceptable substrate scope.
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BACKGROUND: Achieving full revascularization via percutaneous coronary intervention (PCI) may enhance the prognosis of individuals diagnosed with acute coronary syndrome (ACS) and multivessel coronary disease (MVD). The present work focused on investigating whether PCI should be performed during staged or index procedures for non-culprit lesions. METHODS: Electronic databases, such as PubMed, EMBASE, the Cochrane Library, and Web of Science, were systematically explored to locate studies contrasting immediate revascularization with staged complete revascularization for patients who experienced ACS and MVD without cardiac shock. The outcome measures comprised major adverse cardiovascular events (MACEs), all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stroke, and unplanned ischemia-driven revascularization (UIDR). RESULTS: Nine randomized controlled trials involving 3550 patients, including 1780 who received immediate complete revascularization (ICR) and 1770 who received staged complete revascularization (SCR), were included in the analysis. The ICR group had lower MACEs (RR: 0.73, 95% CI: 0.61~0.87, P = 0.0004), MI (RR: 0.53, 95% CI: 0.37~0.77, P = 0.0008), and UIDR (RR: 0.64, 95% CI: 0.50~0.81, P = 0.0003) than did the SCR group. All-cause mortality, CVD incidence, and stroke incidence did not significantly differ between the two groups. According to our subgroup analyses based on the time window of the SCR, the ICR group had significantly fewer MACEs (RR: 0.70, 95% CI: 0.56~0.88, P = 0.003), MI (RR: 0.53, 95% CI: 0.37~0.77, P = 0.0002), and UIDR (RR: 0.56, 95% CI: 0.40~0.77, P = 0.0004) than did the subgroup of patients who were between discharge and 45 days. CONCLUSION: Compared with patients in the SCR group, patients in the ICR group had decreased MACEs, MI, and UIDR, especially between discharge and 45 days. All-cause mortality and CVD incidence were not significantly different between the two groups.
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AIMS: The present meta-analysis focused on investigating whether bivalirudin plus post-PCI infusion was safer and more effective than heparin monotherapy in patients who developed ST-segment elevation myocardial infarction (STEMI) and who underwent primary percutaneous coronary intervention (PCI). METHODS: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were systemically searched to identify randomized controlled trials (RCTs) comparing bivalirudin and heparin for treating STEMI patients who underwent primary PCI. The Cochrane quality assessment tool was used to assess the quality of the enrolled studies. The primary and secondary outcomes included net adverse clinical events (NACEs, comprising all-cause death or major bleeding), major adverse cardiovascular events (MACEs, comprising all-cause death, stroke, MI, and TVR), in-stent thrombosis (IST), and bleeding of Bleeding Academic Research Consortium (BARC) types 2, 3, and 5. RESULTS: The four RCTs, comprising 10,695 events, included 5350 patients who received bivalirudin combined with post-PCI infusion and 5345 patients who received heparin monotherapy. Compared with those in the heparin group, the number of NACEs (RR 0.84, 95% CI 0.73-0.96, P = 0.009), MACEs (RR 0.82, 95% CI 0.67-0.99, P = 0.04), and ISTs (RR 0.66, 95% CI 0.49-0.91, P < 0.0001) in the bivalirudin group was significantly lower. There were no significant differences in all-cause death, cardiac death, stroke, MI, TVR, or BARC type 2, 3, or 5 bleeding between the two groups. CONCLUSION: In STEMI patients undergoing primary PCI, bivalirudin plus post-PCI infusion significantly reduced the incidence of NACEs, MACEs, and ISTs compared with heparin monotherapy, without increasing the risk of MI or TVR. Bivalirudin may also contribute to a potential reduction in stroke, death, and BARC type 2, 3, and 5 bleeding rates.
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The biphenyl molecule (C12H10) acts as a fundamental molecular backbone in the stereoselective synthesis of organic materials due to its inherent twist angle causing atropisomerism in substituted derivatives and in molecular mass growth processes in circumstellar environments and combustion systems. Here, we reveal an unconventional low-temperature phenylethynyl addition-cyclization-aromatization mechanism for the gas-phase preparation of biphenyl (C12H10) along with ortho-, meta-, and para-substituted methylbiphenyl (C13H12) derivatives through crossed molecular beams and computational studies providing compelling evidence on their formation via bimolecular gas-phase reactions of phenylethynyl radicals (C6H5CC, X2A1) with 1,3-butadiene-d6 (C4D6), isoprene (CH2C(CH3)CHCH2), and 1,3-pentadiene (CH2CHCHCHCH3). The dynamics involve de-facto barrierless phenylethynyl radical additions via submerged barriers followed by facile cyclization and hydrogen shift prior to hydrogen atom emission and aromatization to racemic mixtures (ortho, meta) of biphenyls in overall exoergic reactions. These findings not only challenge our current perception of biphenyls as high temperature markers in combustion systems and astrophysical environments, but also identify biphenyls as fundamental building blocks of complex polycyclic aromatic hydrocarbons (PAHs) such as coronene (C24H12) eventually leading to carbonaceous nanoparticles (soot, grains) in combustion systems and in deep space thus affording critical insight into the low-temperature hydrocarbon chemistry in our universe.