Allergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.

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.

Author Correction: Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Fluorine Chemistry in Rechargeable Batteries: Challenges, Progress, and Perspectives.

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.

The CERV protein of Cer1, a C. elegans LTR retrotransposon, is required for nuclear export of viral genomic RNA and can form giant nuclear rods.

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.

Unscheduled epigenetic modifications cause genome instability and sterility through aberrant R-loops following starvation.

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.

Electrochemical coupling in subnanometer pores/channels for rechargeable batteries.

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.

A Pioglitazone Nanoformulation Designed for Cancer-Associated Fibroblast Reprogramming and Cancer Treatment.

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.

One-Dimensional Covalent Organic Framework with Improved Charge Transfer for Enhanced Electrochemiluminescence.

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.

ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-ß1 activation.

OBJECTIVE: Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-ß1 (TGF-ß1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-ß1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-ß1 bioavailability and its impact on CLD progression. DESIGN: RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1-KO and Fxr-KO mice, patient liver tissue and computer simulations. RESULTS: Expression of LTGF-ß1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1-KO mice. In HSCs, overexpression of ECM1 prevented LTGF-ß1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-ß1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-ß1 activation while KTFR treatment reversed Ecm1-KO-mediated and Fxr-KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-ß1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. CONCLUSION: Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-ß1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD.

A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

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.

Cascading CRISPR/Cas and Nanozyme for Enhanced Organic Photoelectrochemical Transistor Detection with Triple Signal Amplification.

Innovative signal amplification and transduction play pivotal roles in bioanalysis. Herein, cascading CRISPR/Cas and the nanozyme are integrated with electronic amplification in an organic photoelectrochemical transistor (OPECT) to enable triple signal amplification, which is exemplified by the miRNA-triggered CRISPR/Cas13a system and polyoxometalate nanozyme for OPECT detection of miRNA-21. The CRISPR/Cas13a-enabled release of glucose oxidase could synergize with peroxidase-like SiW12 to induce catalytic precipitation on the photogate, inhibiting the interfacial mass transfer and thus the significant suppression of the channel current. The as-developed OPECT sensor demonstrates good sensitivity and selectivity for miRNA-21 detection, with a linear range from 1 fM to 10 nM and an ultralow detection limit of 0.53 fM. This study features the integration of bio- and nanoenzyme cascade and electronic triple signal amplification for OPECT detection.

Nanofluidic Membrane-Assisted Organic Electrochemical Transistors for Bioinspired Gustatory Sensation Based on Selective Cation Transport.

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.

Tuning Work Function of Fe2N@C Nanosheets by Co Doping for Enhanced Lithium Storage.

Transition metal nitrides (TMNs) with high theoretical capacity and excellent electrical conductivity have great potential as anode materials for lithium-ion batteries (LIBs), but suffer from poor rate performance due to the slow kinetics. Herein, taking the Fe2N for instance, Co doping is utilized to enhance the work function of Fe2N, which accelerates the charge transfer and strengthens the adsorption of Li+ ions. The Fe2N nanoparticles with various Co dopants are anchoring on the surface of honeycomb porous carbon foam (named Cox-Fe2N@C). Co-doping can enlarge the work function of pristine Fe2N and thereby optimize the charging/discharging kinetics. The work function can be increased from 5.23 eV (pristine Fe2N) to 5.67 eV for Co0.3-Fe2N@C and 5.56 eV for Co0.1-Fe2N@C. As expected, the Co0.1-Fe2N@C electrode exhibits the highest specific capacity (673 mA h g-1 at 100 mA g-1) and remarkable rate capability (375 mA h g-1 at 5 000 mA g-1), outperforming most reported TMNs electrodes. Therefore, this work provides a promising strategy to design and regulate anode materials for high-performance and even commercially available LIBs.

Enhanced evanescent field via integration of a graphene oxide/poly(methyl methacrylate) hybrid film on coreless D-shaped fibers.

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 -4.936 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.

Magnetic tuning with minimal thermal drift in high-Q microspheres coated with magnetorheological polydimethylsiloxane.

Integration of whispering-gallery-mode (WGM) resonators with high-quality factors (Q) into advanced timing, oscillator, and sensing systems demands a platform that enables precise resonance frequency modulation. This study investigates the tuning characteristics of magnetorheological polydimethylsiloxane (MR-PDMS) coated microspheres (µ-spheres) employed as magnetic microresonators, achieving a Q value of 107 at the 1550 nm wavelength. Magnetic WGM resonators not only endow the device with magnetic adjustability but also markedly improve thermal resistance. Experimental findings reveal that the magnetic µ-sphere demonstrates a sensitivity of -32.53 MHz/mT, outperforming conventional magnetic WGM resonators. Furthermore, analysis of the temperature dependence shows a reduction in fluctuation to -2.85 MHz/K, thereby greatly enhancing the sensor's practical detection limit.

N-Doped Carbon Nanonecklaces with Encapsulated BiOCl Nanoparticles as High-Rate Anodes for Lithium-Ion Batteries.

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.

RGD Density on Tadpole Nanostructures Regulates Cancer Stem Cell Proliferation and Stemness.

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.

A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations.

AIM: Sodium-glucose co-transporter-2 inhibitors (SGLT-2is) are used to maintain glycaemic control as well as for their beneficial cardiovascular and renal effects in diabetes patients. However, increased risk of amputation and peripheral artery disease (PAD) have been observed with the use of some SGLT-2is. A meta-analysis was conducted to understand the effect of SGLT-2is on amputation and PAD events using data from randomized controlled trials (RCT). MATERIALS AND METHODS: A systematic literature review was conducted using Medline and Central databases for RCTs that involved the administration of SGLT-2is versus placebo/active comparators to diabetic patients. The primary outcome was amputation events and PAD. A random-effects model was used to calculate the pooled odds ratio, and subgroup analyses was performed. RESULTS: A total of 51 RCTs were included in the meta-analysis with data from 97 589 patients. Meta-analysis of the data showed that there was a significant increase in PAD risk (p = 0.04) but no significant increase in amputation risk with SGLT-2i use versus placebo/active comparators (p = 0.43). Subgroup analyses demonstrated no significant difference between SGLT-2i type, duration of treatment or patient risk factors on amputation or PAD incidence. However, length of drug treatment (> 100 weeks) was associated with a significant increase in both PAD and amputation risks in the SGLT-2i treatment groups. CONCLUSIONS: The results of the meta-analysis showed no significant association between SGLT-2i use and PAD and amputation risks in diabetic patients when used for shorter treatment durations.

Direct Construction of 1,4-Dihydropyridazines and Pyrazoles via Annulation of Alkyl 2-Aroyl-1-chlorocyclopropanecarboxylates.

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.

Base-Promoted Nucleophilic Phosphorylation of Benzyl Fluorides via C(sp3)-F Cleavage.

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.