ABSTRACT
The TOC and TIC complexes are essential translocons that facilitate the import of the nuclear genome-encoded preproteins across the two envelope membranes of chloroplast, but their exact molecular identities and assembly remain unclear. Here, we report a cryoelectron microscopy structure of TOC-TIC supercomplex from Chlamydomonas, containing a total of 14 identified components. The preprotein-conducting pore of TOC is a hybrid ß-barrel co-assembled by Toc120 and Toc75, while the potential translocation path of TIC is formed by transmembrane helices from Tic20 and YlmG, rather than a classic model of Tic110. A rigid intermembrane space (IMS) scaffold bridges two chloroplast membranes, and a large hydrophilic cleft on the IMS scaffold connects TOC and TIC, forming a pathway for preprotein translocation. Our study provides structural insights into the TOC-TIC supercomplex composition, assembly, and preprotein translocation mechanism, and lays a foundation to interpret the evolutionary conservation and diversity of this fundamental translocon machinery.
Subject(s)
Algal Proteins , Chlamydomonas , Chloroplasts , Chloroplasts/metabolism , Cryoelectron Microscopy , Intracellular Membranes/metabolism , Protein Transport , Chlamydomonas/chemistry , Chlamydomonas/cytology , Multiprotein Complexes/metabolism , Algal Proteins/metabolismABSTRACT
The emergence of hypervirulent clade 2 Clostridioides difficile is associated with severe symptoms and accounts for >20% of global infections. TcdB is a dominant virulence factor of C. difficile, and clade 2 strains exclusively express two TcdB variants (TcdB2 and TcdB4) that use unknown receptors distinct from the classic TcdB. Here, we performed CRISPR/Cas9 screens for TcdB4 and identified tissue factor pathway inhibitor (TFPI) as its receptor. Using cryo-EM, we determined a complex structure of the full-length TcdB4 with TFPI, defining a common receptor-binding region for TcdB. Residue variations within this region divide major TcdB variants into 2 classes: one recognizes Frizzled (FZD), and the other recognizes TFPI. TFPI is highly expressed in the intestinal glands, and recombinant TFPI protects the colonic epithelium from TcdB2/4. These findings establish TFPI as a colonic crypt receptor for TcdB from clade 2 C. difficile and reveal new mechanisms for CDI pathogenesis.
Subject(s)
Bacterial Toxins , Clostridioides difficile , Bacterial Proteins/chemistry , Bacterial Toxins/chemistry , Clostridioides difficile/genetics , Lipoproteins/geneticsABSTRACT
RNA polymerase II (RNAPII) transcription involves initiation from a promoter, transcriptional elongation through the gene, and termination in the terminator region. In bacteria, terminators often contain specific DNA elements provoking polymerase dissociation, but RNAPII transcription termination is thought to be driven entirely by protein co-factors. We used biochemical reconstitution, single-molecule studies, and genome-wide analysis in yeast to study RNAPII termination. Transcription into natural terminators by pure RNAPII results in spontaneous termination at specific sequences containing T-tracts. Single-molecule analysis indicates that termination involves pausing without backtracking. The "torpedo" Rat1-Rai1 exonuclease (XRN2 in humans) greatly stimulates spontaneous termination but is ineffectual on other paused RNAPIIs. By contrast, elongation factor Spt4-Spt5 (DSIF) suppresses termination. Genome-wide analysis further indicates that termination occurs by transcript cleavage at the poly(A) site exposing a new 5' RNA-end that allows Rat1-Rai1 loading, which then catches up with destabilized RNAPII at specific termination sites to end transcription.
Subject(s)
RNA Polymerase II , Saccharomyces cerevisiae Proteins , Humans , RNA Polymerase II/genetics , DNA , Transcription, Genetic , Exonucleases , Peptide Elongation Factors , Saccharomyces cerevisiae/genetics , RNA-Binding Proteins , Saccharomyces cerevisiae Proteins/geneticsABSTRACT
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to activate the innate immune system. Here, we report the unexpected discovery that cGAS also senses dysfunctional protein production. Purified ribosomes interact directly with cGAS and stimulate its DNA-dependent activity in vitro. Disruption of the ribosome-associated protein quality control (RQC) pathway, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and orthogonal perturbations that result in elevated levels of collided ribosomes and RQC activation cause sub-cellular re-localization of cGAS and ribosome binding in vivo as well. Thus, translation stress potently increases DNA-dependent cGAS activation. These findings have implications for the inflammatory response to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis.
Subject(s)
Cell Nucleus , Nucleotidyltransferases , Protein Biosynthesis , Ribosomes , Signal Transduction , Stress, Physiological , Active Transport, Cell Nucleus , Cell Nucleus/chemistry , Cell Nucleus/genetics , Cell Nucleus/metabolism , HEK293 Cells , Humans , Nucleotidyltransferases/chemistry , Nucleotidyltransferases/genetics , Nucleotidyltransferases/metabolism , Ribosomes/chemistry , Ribosomes/genetics , Ribosomes/metabolismABSTRACT
Translating ribosomes that slow excessively incur collisions with trailing ribosomes. Persistent collisions are detected by ZNF598, a ubiquitin ligase that ubiquitinates sites on the ribosomal 40S subunit to initiate pathways of mRNA and protein quality control. The collided ribosome complex must be disassembled to initiate downstream quality control, but the mechanistic basis of disassembly is unclear. Here, we reconstitute the disassembly of a collided polysome in a mammalian cell-free system. The widely conserved ASC-1 complex (ASCC) containing the ASCC3 helicase disassembles the leading ribosome in an ATP-dependent reaction. Disassembly, but not ribosome association, requires 40S ubiquitination by ZNF598, but not GTP-dependent factors, including the Pelo-Hbs1L ribosome rescue complex. Trailing ribosomes can elongate once the roadblock has been removed and only become targets if they subsequently stall and incur collisions. These findings define the specific role of ASCC during ribosome-associated quality control and identify the molecular target of its activity.
Subject(s)
Amino Acid Transport System y+/metabolism , Multiprotein Complexes/metabolism , Protein Biosynthesis , Ribosomes/metabolism , Amino Acid Transport System y+/genetics , Animals , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell-Free System , DNA Helicases/genetics , DNA Helicases/metabolism , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , HEK293 Cells , Humans , Multiprotein Complexes/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Peptide Termination Factors/genetics , Peptide Termination Factors/metabolism , Polyribosomes/genetics , Polyribosomes/metabolism , Rabbits , Ribosome Subunits/genetics , Ribosome Subunits/metabolism , Ribosomes/genetics , UbiquitinationABSTRACT
The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Cell Transformation, Neoplastic , Erlotinib Hydrochloride , Lung Neoplasms , Humans , Animals , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Mice , Erlotinib Hydrochloride/pharmacology , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Drug Resistance, Neoplasm/genetics , Wnt Signaling Pathway/genetics , Membrane Proteins/genetics , Membrane Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , Xenograft Model Antitumor Assays , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/metabolism , Small Cell Lung Carcinoma/pathology , Transcription, Genetic , Histocompatibility Antigens , Histone-Lysine N-MethyltransferaseABSTRACT
Intracellular plant immune receptors, termed NLRs (Nucleotide-binding Leucine-rich repeat Receptors), confer effector-triggered immunity. Sensor NLRs are responsible for pathogen effector recognition. Helper NLRs function downstream of sensor NLRs to transduce signaling and induce cell death and immunity. Activation of sensor NLRs that contain TIR (Toll/interleukin-1receptor) domains generates small molecules that induce an association between a downstream heterodimer signalosome of EDS1 (EnhancedDisease Susceptibility 1)/SAG101 (Senescence-AssociatedGene 101) and the helper NLR of NRG1 (NRequired Gene 1). Autoactive NRG1s oligomerize and form calcium signaling channels largely localized at the plasma membrane (PM). The molecular mechanisms of helper NLR PM association and effector-induced NRG1 oligomerization are not well characterized. We demonstrate that helper NLRs require positively charged residues in their N-terminal domains for phospholipid binding and PM association before and after activation, despite oligomerization and conformational changes that accompany activation. We demonstrate that effector activation of a TIR-containing sensor NLR induces NRG1 oligomerization at the PM and that the cytoplasmic pool of EDS1/SAG101 is critical for cell death function. EDS1/SAG101 cannot be detected in the oligomerized NRG1 resistosome, suggesting that additional unknown triggers might be required to induce the dissociation of EDS1/SAG101 from the previously described NRG1/EDS1/SAG101 heterotrimer before subsequent NRG1 oligomerization. Alternatively, the conformational changes resulting from NRG1 oligomerization abrogate the interface for EDS1/SAG101 association. Our data provide observations regarding dynamic PM association during helper NLR activation and underpin an updated model for effector-induced NRG1 resistosome formation.
Subject(s)
Arabidopsis Proteins , Arabidopsis , Arabidopsis Proteins/metabolism , Arabidopsis/genetics , NLR Proteins/genetics , Plant Immunity/genetics , Plants/metabolism , Receptors, Immunologic/metabolism , Cell Membrane/metabolism , Plant Diseases , Carboxylic Ester Hydrolases/geneticsABSTRACT
Cellular eukaryotic replication initiation helicases are first loaded as head-to-head double hexamers on double-stranded (ds) DNA origins and then initiate S-phase DNA melting during licensed (once per cell cycle) replication. Merkel cell polyomavirus (MCV) large T (LT) helicase oncoprotein similarly binds and melts its own 98-bp origin but replicates multiple times in a single cell cycle. To examine the actions of this unlicensed viral helicase, we quantitated multimerization of MCV LT molecules as they assembled on MCV DNA origins using real-time single-molecule microscopy. MCV LT formed highly stable double hexamers having 17-fold longer mean lifetime (τ, >1,500 s) on DNA than single hexamers. Unexpectedly, partial MCV LT assembly without double-hexamer formation was sufficient to melt origin dsDNA as measured by RAD51, RPA70, or S1 nuclease cobinding. DNA melting also occurred with truncated MCV LT proteins lacking the helicase domain, but was lost from a protein without the multimerization domain that could bind only as a monomer to DNA. SV40 polyomavirus LT also multimerized to the MCV origin without forming a functional hexamer but still melted origin DNA. MCV origin melting did not require ATP hydrolysis and occurred for both MCV and SV40 LT proteins using the nonhydrolyzable ATP analog, adenylyl-imidodiphosphate (AMP-PNP). LT double hexamers formed in AMP-PNP, and melted DNA, consistent with direct LT hexamer assembly around single-stranded (ss) DNA without the energy-dependent dsDNA-to-ssDNA melting and remodeling steps used by cellular helicases. These results indicate that LT multimerization rather than helicase activity is required for origin DNA melting during unlicensed virus replication.
Subject(s)
Antigens, Polyomavirus Transforming , Simian virus 40 , Antigens, Polyomavirus Transforming/genetics , Antigens, Polyomavirus Transforming/metabolism , Simian virus 40/genetics , Simian virus 40/metabolism , Nucleic Acid Denaturation , Adenylyl Imidodiphosphate , DNA Replication , DNA/genetics , DNA/metabolism , DNA Helicases/genetics , DNA Helicases/metabolism , DNA, Single-Stranded , DNA, Viral/genetics , DNA, Viral/metabolismABSTRACT
Epilepsy is a chronic neurological disorder featuring recurrent, unprovoked seizures, which affect more than 65 million people worldwide. Here, we discover that the PKHD1L1, which is encoded by polycystic kidney and hepatic disease1-like 1 (Pkhd1l1), wildly distributes in neurons in the central nervous system (CNS) of mice. Disruption of PKHD1L1 in the dentate gyrus region of the hippocampus leads to increased susceptibility to pentylenetetrazol-induced seizures in mice. The disturbance of PKHD1L1 leads to the overactivation of the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK)-Calpain pathway, which is accompanied by remarkable degradation of cytoplasmic potassium chloride co-transporter 2 (KCC2) level together with the impaired expression and function of membrane KCC2. However, the reduction of membrane KCC2 is associated with the damaged inhibitory ability of the vital GABA receptors, which ultimately leads to the significantly increased susceptibility to epileptic seizures. Our data, thus, indicate for the first time that Pkhd1l1, a newly discovered polycystic kidney disease (PKD) association gene, is required in neurons to maintain neuronal excitability by regulation of KCC2 expression in CNS. A new mechanism of the clinical association between genetic PKD and seizures has been built, which could be a potential therapeutic target for treating PKD-related seizures.
Subject(s)
Epilepsy , Symporters , Mice , Animals , Seizures/genetics , Seizures/metabolism , Epilepsy/metabolism , Hippocampus/metabolism , Symporters/genetics , Dentate Gyrus/metabolismABSTRACT
Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.
Subject(s)
Pemphigoid, Bullous , Humans , Mice , Animals , Matrix Metalloproteinase 9 , Chemokine CCL24 , Immunoglobulin E , Chemokine CCL11 , Receptors, CCR3 , Non-Fibrillar Collagens , Autoantigens , Immunoglobulin G , Autoantibodies , Receptors, IgEABSTRACT
Rechargeable sodium-ion batteries (SIBs) have emerged as an advanced electrochemical energy storage technology with potential to alleviate the dependence on lithium resources. Similar to Li-ion batteries, the cathode materials play a decisive role in the cost and energy output of SIBs. Among various cathode materials, Na layered transition-metal (TM) oxides have become an appealing choice owing to their facile synthesis, high Na storage capacity/voltage that are suitable for use in high-energy SIBs, and high adaptivity to the large-scale manufacture of Li layered oxide analogues. However, going from the lab to the market, the practical use of Na layered oxide cathodes is limited by the ambiguous understanding of the fundamental structure-performance correlation of cathode materials and lack of customized material design strategies to meet the diverse demands in practical storage applications. In this review, we attempt to clarify the fundamental misunderstandings by elaborating the correlations between the electron configuration of the critical capacity-contributing elements (e.g., TM cations and oxygen anion) in oxides and their influence on the Na (de)intercalation (electro)chemistry and storage properties of the cathode. Subsequently, we discuss the issues that hinder the practical use of layered oxide cathodes, their origins and the corresponding strategies to address their issues and accelerate the target-oriented research and development of cathode materials. Finally, we discuss several new Na layered cathode materials that show prospects for next-generation SIBs, including layered oxides with anion redox and high entropy and highlight the use of layered oxides as cathodes for solid-state SIBs with higher energy and safety. In summary, we aim to offer insights into the rational design of high-performance Na layered oxide cathode materials towards the practical realization of sustainable electrochemical energy storage at a low cost.
ABSTRACT
HIV-1 Vif is known to counteract the antiviral activity of human apolipoprotein B mRNA-editing catalytic polypeptide-like (A3), a cytidine deaminase, in various ways. However, the precise mechanism behind this interaction has remained elusive. Within infected cells, Vif forms a complex called VßBCC, comprising CBFß and the components of E3 ubiquitin ligase, Elongin B, Elongin C, and Cullin5. Together with the ubiquitin-conjugating enzyme, VßBCC induces ubiquitination-mediated proteasomal degradation of A3. However, Vif exhibits additional counteractive effects. In this study, we elucidate that VßBCC inhibits deamination by A3G, A3F, and A3B independently of proteasomal degradation. Surprisingly, we discovered that this inhibition for A3G is directly attributed to the interaction between VßBCC and the C-terminal domain of A3G. Previously, it was believed that Vif did not interact with the C-terminal domain. Our findings suggest that inhibiting the interaction between VßBCC and the C-terminal domain, as well as the N-terminal domain known to be targeted for ubiquitination, of A3G may be needed to prevent counteraction by Vif.
Subject(s)
HIV-1 , vif Gene Products, Human Immunodeficiency Virus , Humans , Cytosine Deaminase/metabolism , HIV-1/metabolism , Protein Binding , ProteolysisABSTRACT
BACKGROUND: Aortic dissection (AD) is a fatal cardiovascular disorder without effective medications due to unclear pathogenic mechanisms. Bestrophin3 (Best3), the predominant isoform of bestrophin family in vessels, has emerged as critical for vascular pathological processes. However, the contribution of Best3 to vascular diseases remains elusive. METHODS: Smooth muscle cell-specific and endothelial cell-specific Best3 knockout mice (Best3SMKO and Best3ECKO, respectively) were engineered to investigate the role of Best3 in vascular pathophysiology. Functional studies, single-cell RNA sequencing, proteomics analysis, and coimmunoprecipitation coupled with mass spectrometry were performed to evaluate the function of Best3 in vessels. RESULTS: Best3 expression in aortas of human AD samples and mouse AD models was decreased. Best3SMKO but not Best3ECKO mice spontaneously developed AD with age, and the incidence reached 48% at 72 weeks of age. Reanalysis of single-cell transcriptome data revealed that reduction of fibromyocytes, a fibroblast-like smooth muscle cell cluster, was a typical feature of human ascending AD and aneurysm. Consistently, Best3 deficiency in smooth muscle cells decreased the number of fibromyocytes. Mechanistically, Best3 interacted with both MEKK2 and MEKK3, and this interaction inhibited phosphorylation of MEKK2 at serine153 and MEKK3 at serine61. Best3 deficiency induced phosphorylation-dependent inhibition of ubiquitination and protein turnover of MEKK2/3, thereby activating the downstream mitogen-activated protein kinase signaling cascade. Furthermore, restoration of Best3 or inhibition of MEKK2/3 prevented AD progression in angiotensin II-infused Best3SMKO and ApoE-/- mice. CONCLUSIONS: These findings unveil a critical role of Best3 in regulating smooth muscle cell phenotypic switch and aortic structural integrity through controlling MEKK2/3 degradation. Best3-MEKK2/3 signaling represents a novel therapeutic target for AD.
Subject(s)
Aortic Dissection , Muscle, Smooth, Vascular , Animals , Humans , Mice , Aortic Dissection/genetics , MAP Kinase Signaling System , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , PhosphorylationABSTRACT
Insights into the formation mechanisms of two-dimensional covalent organic frameworks (2D COFs) at both the in-plane and interlayer levels are essential for improving material quality and synthetic methodology. Here, we report the controllable preparation of 2D COF films via on-surface synthesis and investigate the growth mechanism using atomic force microscopy. Monolayer, bilayer, and layer-plus-island multilayer COF films were successfully constructed on hexagonal boron nitride in a controlled manner. The porphyrin-based COF films grow in the Stranski-Krastanov mode, i.e., a uniform bilayer COF film can be formed through layer-by-layer growth in the initial stage followed by island growth starting from the third layer. Furthermore, fluorescence quenching caused by π-π stacking interactions between 2D COF neighboring layers was revealed. These results provide new perspectives on the synthesis of high-quality 2D COF films with controllable thickness and morphology, paving the way for a diverse range of applications.
ABSTRACT
Ni-rich cathodes are some of the most promising candidates for advanced lithium-ion batteries, but their available capacities have been stagnant due to the intrinsic Li+ storage sites. Extending the voltage window down can induce the phase transition from O3 to 1T of LiNiO2-derived cathodes to accommodate excess Li+ and dramatically increase the capacity. By setting the discharge cutoff voltage of LiNi0.6Co0.2Mn0.2O2 to 1.4 V, we can reach an extremely high capacity of 393 mAh g-1 and an energy density of 1070 Wh kg-1 here. However, the phase transition causes fast capacity decay and related structural evolution is rarely understood, hindering the utilization of this feature. We find that the overlithiated phase transition is self-limiting, which will transform into solid-solution reaction with cycling and make the cathode degradation slow down. This is attributed to the migration of abundant transition metal ions into lithium layers induced by the overlithiation, allowing the intercalation of overstoichiometric Li+ into the crystal without the O3 framework change. Based on this, the wide-potential cycling stability is further improved via a facile charge-discharge protocol. This work provides deep insight into the overstoichiometric Li+ storage behaviors in conventional layered cathodes and opens a new avenue toward high-energy batteries.
ABSTRACT
Cross-coupling reactions represent an indispensable tool in chemical synthesis. An intriguing challenge in this field is to achieve selective cross-coupling between two precursors with similar reactivity or, to the limit, the identical molecules. Here we report an unexpected dehydrobrominative cross-coupling between 1,3,5-tris(2-bromophenyl)benzene molecules on silver surfaces. Using scanning tunneling microscopy, we examine the reaction process at the single-molecular level, quantify the selectivity of the dehydrobrominative cross-coupling, and reveal the modulation of selectivity by substrate lattice-related catalytic activity or molecular assembly effect. Theoretical calculations indicate that the dehydrobrominative cross-coupling proceeds via regioselective C-H bond activation of debrominated TBPB and subsequent highly selective C-C coupling of the radical-based intermediates. The reaction kinetics plays an important role in the selectivity for the cross-coupling. This work not only expands the toolbox for chemical synthesis but also provides important mechanistic insights into the selectivity of coupling reactions on the surface.
ABSTRACT
Polysomnography (PSG) is the gold standard for clinical sleep monitoring, but its cost, discomfort, and limited suitability for continuous use present challenges. The flexible electrode sleep patch (FESP) emerges as an economically viable and patient-friendly solution, offering lightweight, simple operation, and self-applicable. Nevertheless, its utilization in young individuals remains uncertain. The objective of this study was to compare sleep data obtained by FESP and PSG in healthy young individuals and analyze agreement for sleep parameters and structure classification. Overnight monitoring with FESP and PSG recordings in 48 participants (mean age: 23 yr) was done. Correlation analysis, Bland-Altman plots, and Cohen's kappa coefficient assessed consistency. Sensitivity, specificity, and predictive values compared classification against PSG. FESP showed strong correlation and consistency with PSG for sleep monitoring. Bland-Altman plots indicated small errors and high consistency. Kappa values (0.70-0.84) suggested substantial agreement for sleep stage classification. Pearson correlation coefficient values for sleep stages (0.75-0.88) and sleep parameters (0.80-0.96) confirm that FESP has a strong application. Intraclass correlation coefficient yielded values between 0.65 and 0.97. In addition, FESP demonstrated an impressive accuracy range of 84.12-93.47% for sleep stage classification. The FESP also features a wearable self-test program with an error rate of no more than 8% for both deep sleep and wake. In young adults, FESP demonstrated reliable monitoring capabilities comparable to PSG. With its low cost and user-friendly design, FESP is a potential alternative for portable sleep assessment in clinical and research applications. Further studies involving larger populations are needed to validate its diagnostic potential.NEW & NOTEWORTHY By comparison with PSG, this study confirmed the reliability of an efficient, objective, low-cost, and noninvasive portable automatic sleep-monitoring device FESP, which provides effective information for long-term family sleep disorder diagnosis and sleep quality monitoring.
Subject(s)
Actigraphy , Spiperone/analogs & derivatives , Wearable Electronic Devices , Humans , Young Adult , Adult , Polysomnography , Reproducibility of Results , Sleep , ElectrodesABSTRACT
The quantum battery (QB) makes use of quantum effects to store and supply energy, which may outperform its classical counterpart. However, there are two challenges in this field. One is that the environment-induced decoherence causes the energy loss and aging of the QB, the other is that the decreasing of the charger-QB coupling strength with increasing their distance makes the charging of the QB become inefficient. Here, we propose a QB scheme to realize a remote charging via coupling the QB and the charger to a rectangular hollow metal waveguide. It is found that an ideal charging is realized as long as two bound states are formed in the energy spectrum of the total system consisting of the QB, the charger, and the electromagnetic environment in the waveguide. Using the constructive role of the decoherence, our QB is immune to the aging. Additionally, without resorting to the direct charger-QB interaction, our scheme works in a way of long-range and wireless-like charging. Effectively overcoming the two challenges, our result supplies an insightful guideline to the practical realization of the QB by reservoir engineering.
ABSTRACT
BACKGROUND: Although there is a strong correlation between the novel cholesterol-to-lymphocyte ratio (CLR) and tumor survival, its prognostic significance in breast cancer (BC) is unknown. After analyzing the relationship between CLR and the overall survival (OS) of patients with BC, we created a predictive model. METHODS: Following retrospective enrollment, 1316 patients with BC were randomized into two cohorts: validation (n = 392) and training (n = 924). Distinct factors within the training dataset were identified for OS by univariate and multivariate Cox analyses; two-tailed P-value < 0.05 were considered to indicate statistical significance. On this premise, we developed novel signals for survival prediction and utilized the calibration curve, receiver operating characteristic curves, and concordance index (C-index) to validate their efficacy across both datasets. RESULTS: Patients with BC were categorized into two categories with differing prognoses based on the CLR score [hazard ratio = 0.492; 95% confidence interval (CI): 0.286-0.846, P = 0.009]. A prediction nomogram was created based on multivariate analysis, which showed that N stage, postoperative pathological categorization, and CLR score were all independently correlated with OS. In the training [C-index = 0.831 (95% CI: 0.788-0.874)] and validation [C-index = 0.775 (95% CI: 0.694-0.856)] cohorts, the nomogram demonstrated favorable performance in predicting OS. In both the training and validation cohorts, it outperformed the traditional staging system [C-index = 0.702 (95% CI: 0.623-0.782)] and [C-index = 0.709 (95% CI: 0.570-0.847)]. The accurate prediction by the signature was further demonstrated by the time-dependent receiver operating characteristic curves. CONCLUSIONS: The novel immunonutritional marker CLR could function as a simplified, cost-effective, easily accessible, non-invasive, and readily promotive prognostic indicator for patients with early-stage BC and demonstrates superior predictive power than the traditional staging system.
Subject(s)
Breast Neoplasms , Cholesterol , Lymphocytes , Nomograms , Humans , Female , Breast Neoplasms/pathology , Breast Neoplasms/blood , Breast Neoplasms/immunology , Breast Neoplasms/mortality , Prognosis , Middle Aged , Cholesterol/blood , Retrospective Studies , Adult , Aged , ROC Curve , Biomarkers, Tumor/blood , Lymphocyte Count , Neoplasm StagingABSTRACT
Ethylene response factors have been shown to be involved in the effects of plant developmental processes and to regulate stress tolerance. The aim of this study was to recognize the regulatory mechanisms of ethylene response factors on tobacco plant height. In this study, a gene-edited mutant (ERF10-KO) and wild type (WT) were utilized as experimental materials. Transcriptome and metabolome analyses were used to investigate the regulatory mechanism of NtERF10 gene editing on plant height in tobacco. Here, through the analysis of differentially expressed genes (DEGs), 2051 genes were upregulated and 1965 genes were downregulated. We characterized the different ERF10-KO and WT plant heights and identified key genes for photosynthesis, the plant hormone signal transduction pathway and the terpene biosynthesis pathway. NtERF10 was found to affect the growth and development of tobacco by regulating the expression levels of the PSAA, PSBA, GLY17 and GGP3 genes. Amino acid metabolism was analyzed by combining analyses of differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs). In addition, we found that members of the bHLH, NAC, MYB, and WRKY transcription factor families have vital roles in regulating plant height. This study not only provides important insights into the positive regulation of the ethylene response factor NtERF10 on plant height during plant growth and development but also provides new research ideas for tobacco molecular breeding.