Inflammasome protein scaffolds the DNA damage complex during tumor development.

Inflammasome sensors activate cellular signaling machineries to drive inflammation and cell death processes. Inflammasomes also control the development of certain diseases independently of canonical functions. Here, we show that the inflammasome protein NLR family CARD domain-containing protein 4 (NLRC4) attenuated the development of tumors in the Apcmin/+ mouse model. This response was independent of inflammasome signaling by NLRP3, NLRP6, NLR family apoptosis inhibitory proteins, absent in melanoma 2, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1 and caspase-11. NLRC4 interacted with the DNA-damage-sensing ataxia telangiectasia and Rad3-related (ATR)-ATR-interacting protein (ATRIP)-Ewing tumor-associated antigen 1 (ETAA1) complex to promote the recruitment of the checkpoint adapter protein claspin, licensing the activation of the kinase checkpoint kinase-1 (CHK1). Genotoxicity-induced activation of the NLRC4-ATR-ATRIP-ETAA1 complex drove the tumor-suppressing DNA damage response and CHK1 activation, and further attenuated the accumulation of DNA damage. These findings demonstrate a noninflammatory function of an inflammasome protein in promoting the DNA damage response and mediating protection against cancer.

Immunity against Moraxella catarrhalis requires guanylate-binding proteins and caspase-11-NLRP3 inflammasomes.

Moraxella catarrhalis is an important human respiratory pathogen and a major causative agent of otitis media and chronic obstructive pulmonary disease. Toll-like receptors contribute to, but cannot fully account for, the complexity of the immune response seen in M. catarrhalis infection. Using primary mouse bone marrow-derived macrophages to examine the host response to M. catarrhalis infection, our global transcriptomic and targeted cytokine analyses revealed activation of immune signalling pathways by both membrane-bound and cytosolic pattern-recognition receptors. We show that M. catarrhalis and its outer membrane vesicles or lipooligosaccharide (LOS) can activate the cytosolic innate immune sensor caspase-4/11, gasdermin-D-dependent pyroptosis, and the NLRP3 inflammasome in human and mouse macrophages. This pathway is initiated by type I interferon signalling and guanylate-binding proteins (GBPs). We also show that inflammasomes and GBPs, particularly GBP2, are required for the host defence against M. catarrhalis in mice. Overall, our results reveal an essential role for the interferon-inflammasome axis in cytosolic recognition and immunity against M. catarrhalis, providing new molecular targets that may be used to mitigate pathological inflammation triggered by this pathogen.

Cryo-EM structure of the zinc-activated channel (ZAC) in the Cys-loop receptor superfamily.

Cys-loop receptors are a large superfamily of pentameric ligand-gated ion channels with various physiological roles, especially in neurotransmission in the central nervous system. Among them, zinc-activated channel (ZAC) is a Zn2+-activated ion channel that is widely expressed in the human body and is conserved among eukaryotes. Due to its gating by extracellular Zn2+, ZAC has been considered a Zn2+ sensor, but it has undergone minimal structural and functional characterization since its molecular cloning. Among the families in the Cys-loop receptor superfamily, only the structure of ZAC has yet to be determined. Here, we determined the cryo-EM structure of ZAC in the apo state and performed structure-based mutation analyses. We identified a few residues in the extracellular domain whose mutations had a mild impact on Zn2+ sensitivity. The constriction site in the ion-conducting pore differs from the one in other Cys-loop receptor structures, and further mutational analysis identified a key residue that is important for ion selectivity. In summary, our work provides a structural framework for understanding the ion-conducting mechanism of ZAC.

A nanopore-based cucumber genome assembly reveals structural variations at two QTLs controlling hypocotyl elongation.

The Xishuangbanna (XIS) cucumber (Cucumis sativus var. xishuangbannanesis) is a semiwild variety that has many distinct agronomic traits. Here, long reads generated by Nanopore sequencing technology helped assembling a high-quality genome (contig N50 = 8.7 Mb) of landrace XIS49. A total of 10,036 structural/sequence variations (SVs) were identified when comparing with Chinese Long (CL), and known SVs controlling spines, tubercles, and carpel number were confirmed in XIS49 genome. Two QTLs of hypocotyl elongation under low light, SH3.1 and SH6.1, were fine-mapped using introgression lines (donor parent, XIS49; recurrent parent, CL). SH3.1 encodes a red-light receptor Phytochrome B (PhyB, CsaV3_3G015190). A ∼4 kb region with large deletion and highly divergent regions (HDRs) were identified in the promoter of the PhyB gene in XIS49. Loss of function of this PhyB caused a super-long hypocotyl phenotype. SH6.1 encodes a CCCH-type zinc finger protein FRIGIDA-ESSENTIAL LIKE (FEL, CsaV3_6G050300). FEL negatively regulated hypocotyl elongation but it was transcriptionally suppressed by long terminal repeats retrotransposon insertion in CL cucumber. Mechanistically, FEL physically binds to the promoter of CONSTITUTIVE PHOTOMORPHOGENIC 1a (COP1a), regulating the expression of COP1a and the downstream hypocotyl elongation. These above results demonstrate the genetic mechanism of cucumber hypocotyl elongation under low light.

Clostridium perfringens virulence factors are nonredundant activators of the NLRP3 inflammasome.

Inflammasome signaling is a central pillar of innate immunity triggering inflammation and cell death in response to microbes and danger signals. Here, we show that two virulence factors from the human bacterial pathogen Clostridium perfringens are nonredundant activators of the NLRP3 inflammasome in mice and humans. C. perfringens lecithinase (also known as phospolipase C) and C. perfringens perfringolysin O induce distinct mechanisms of activation. Lecithinase enters LAMP1+ vesicular structures and induces lysosomal membrane destabilization. Furthermore, lecithinase induces the release of the inflammasome-dependent cytokines IL-1ß and IL-18, and the induction of cell death independently of the pore-forming proteins gasdermin D, MLKL and the cell death effector protein ninjurin-1 or NINJ1. We also show that lecithinase triggers inflammation via the NLRP3 inflammasome in vivo and that pharmacological blockade of NLRP3 using MCC950 partially prevents lecithinase-induced lethality. Together, these findings reveal that lecithinase activates an alternative pathway to induce inflammation during C. perfringens infection and that this mode of action can be similarly exploited for sensing by a single inflammasome.

Integrated morphological, physiological and transcriptomic analyses reveal the responses of Toona sinensis seedlings to low-nitrogen stress.

Nitrogen is one of the most essential elements for plant growth and development. In this study, the growth, physiology, and transcriptome of Toona sinensis (A. Juss) Roem seedlings were compared between low-nitrogen (LN) and normal-nitrogen (NN) conditions. These results indicate that LN stress adversely influences T. sinensis seedling growth. The activities of key enzymes related to nitrogen assimilation and phytohormone contents were altered by LN stress. A total of 2828 differentially expressed genes (DEGs) in roots and 1547 in leaves were identified between the LN and NN treatments. A differential enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways indicated that nitrogen and sugar metabolism, flavonoid biosynthesis, plant hormone signal transduction, and ABC transporters, were strongly affected by LN stress. In summary, this research provides information for further understanding the response of T. sinensis to LN stress.

Increased Apolipoprotein A1 Expression Correlates with Tumor-Associated Neutrophils and T Lymphocytes in Upper Tract Urothelial Carcinoma.

An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.

Generation of anti-idiotypic antibodies mimicking Cry2Aa toxin from an immunized mouse phage display library as potential insecticidal agents against Plutella xylostella.

This study tried to generate anti-idiotypic antibodies (Ab2s) which mimic Cry2Aa toxin using a phage-display antibody library (2.8 × 107 CFU/mL). The latter was constructed from a mouse immunized with F (ab')2 fragments digested from anti-Cry2Aa polyclonal antibodies. The F (ab')2 fragments and Plutella xylostella (P. xylostella) brush border membrane vesicles (BBMV) were utilized as targets for selection. Eight mouse phage-display single-chain variable fragments (scFvs) were isolated and identified by enzyme-linked immunoassay (ELISA), PCR and DNA sequencing after four rounds of biopanning. Among them, M3 exhibited the highest binding affinity with F (ab')2, while M4 bound the best with the toxin binding region of cadherin of P. xylostella (PxCad-TBR). Both of these two fragments were chosen for prokaryotic expression. The expressed M3 and M4 proteins with molecular weights of 30 kDa were purified. The M4 showed a binding affinity of 29.9 ± 2.4 nM with the PxCad-TBR and resulted in 27.8 ± 4.3 % larvae mortality against P. xylostella. Computer-assisted molecular modeling and docking analysis showed that mouse scFv M4 mimicked some Cry2Aa toxin binding sites when interacting with PxCad-TBR. Therefore, anti-idiotypic antibodies generated by BBMV-based screening could be useful for the development of new bio-insecticides as an alternative to Cry2Aa toxin for pest control.

Assessing small molecule conformational sampling methods in molecular docking.

Small molecule conformational sampling plays a pivotal role in molecular docking. Recent advancements have led to the emergence of various conformational sampling methods, each employing distinct algorithms. This study investigates the impact of different small molecule conformational sampling methods in molecular docking using UCSF DOCK 3.7. Specifically, six traditional sampling methods (Omega, BCL::Conf, CCDC Conformer Generator, ConfGenX, Conformator, RDKit ETKDGv3) and a deep learning-based model (Torsional Diffusion) for generating conformational ensembles are evaluated. These ensembles are subsequently docked against the Platinum Diverse Dataset, the PoseBusters dataset and the DUDE-Z dataset to assess binding pose reproducibility and screening power. Notably, different sampling methods exhibit varying performance due to their unique preferences, such as dihedral angle sampling ranges on rotatable bonds. Combining complementary methods may lead to further improvements in docking performance.

Dirac spectroscopy of strongly correlated phases in twisted trilayer graphene.

Magic-angle twisted trilayer graphene (MATTG) hosts flat electronic bands, and exhibits correlated quantum phases with electrical tunability. In this work, we demonstrate a spectroscopy technique that allows for dissociation of intertwined bands and quantification of the energy gaps and Chern numbers C of the correlated states in MATTG by driving band crossings between Dirac cone Landau levels and energy gaps in the flat bands. We uncover hard correlated gaps with C = 0 at integer moiré unit cell fillings of ν = 2 and 3 and reveal charge density wave states originating from van Hove singularities at fractional fillings ν = 5/3 and 11/3. In addition, we demonstrate displacement-field-driven first-order phase transitions at charge neutrality and ν = 2, which are consistent with a theoretical strong-coupling analysis, implying C2T symmetry breaking. Overall, these properties establish a diverse electrically tunable phase diagram of MATTG and provide an avenue for investigating other related systems hosting both steep and flat bands.

Collagen degradation assessment with an in vitro rotator cuff tendinopathy model using multiparametric ultrashort-TE magnetization transfer (UTE-MT) imaging.

PURPOSE: This study aims to assess ultrashort-TE magnetization transfer (UTE-MT) imaging of collagen degradation using an in vitro model of rotator cuff tendinopathy. METHODS: Thirty-six supraspinatus tendon specimens were divided into three groups and treated with 600 U collagenase (Group 1), 150 U collagenase (Group 2), and phosphate buffer saline (Group 3). UTE-MT imaging was performed to assess changes in macromolecular fraction (MMF), macromolecule transverse relaxation time (T2m), water longitudinal relaxation rate constant (R1m), the magnetization exchange rate from the macromolecular to water pool (Rm0 w) and from water to the macromolecular pool (Rm0 m), and magnetization transfer ratio (MTR) at baseline and following digestion and their differences between groups. Biochemical and histological studies were conducted to determine the extent of collagen degradation. Correlation analyses were performed with MMF, T2m, R1m, Rm0 w, Rm0 m, and MTR, respectively. Univariate and multivariate linear regression analyses were performed to evaluate combinations of UTE-MT parameters to predict collagen degradation. RESULTS: MMF, T2m, R1m, Rm0 m, and MTR decreased after digestion. MMF (r = -0.842, p < 0.001), MTR (r = -0.78, p < 0.001), and Rm0 m (r = -0.662, p < 0.001) were strongly negatively correlated with collagen degradation. The linear regression model of differences in MMF and Rm0 m before and after digestion explained 68.9% of collagen degradation variation in the tendon. The model of postdigestion in MMF and T2m and the model of MTR explained 54.2% and 52.3% of collagen degradation variation, respectively. CONCLUSION: This study highlighted the potential of UTE-MT parameters for evaluation of supraspinatus tendinopathy.

Interdependence between myocardial deformation and perfusion in patients with T2DM and HFpEF: a feature-tracking and stress perfusion CMR study.

BACKGROUND: Patients with diabetes have an increased risk of developing heart failure with preserved ejection fraction (HFpEF). This study aimed to compare indices of myocardial deformation and perfusion between patients with type 2 diabetes mellitus (T2DM) with and without HFpEF and to investigate the relationship between myocardial strain and perfusion reserve. METHODS: This study included 156 patients with T2DM without obstructive coronary artery disease (CAD) and 50 healthy volunteers who underwent cardiac magnetic resonance (CMR) examination at our center. Patients with T2DM were subdivided into the T2DM-HFpEF (n = 74) and the T2DM-non-HFpEF (n = 82) groups. The parameters of left ventricular (LV) and left atrial (LA) strain as well as stress myocardial perfusion were compared. The correlation between myocardial deformation and perfusion parameters was also assessed. Mediation analyses were used to evaluate the direct and indirect effects of T2DM on LA strain. RESULTS: Patients with T2DM and HFpEF had reduced LV radial peak systolic strain rate (PSSR), LV circumferential peak diastolic strain rate (PDSR), LA reservoir strain, global myocardial perfusion reserve index (MPRI), and increased LA booster strain compared to patients with T2DM without HFpEF (all P < 0.05). Furthermore, LV longitudinal PSSR, LA reservoir, and LA conduit strain were notably impaired in patients with T2DM without HFpEF compared to controls (all P < 0.05), but LV torsion, LV radial PSSR, and LA booster strain compensated for these alterations (all P < 0.05). Multivariate linear regression analysis demonstrated that LA reservoir and LA booster strain were independently associated with global MPRI (ß = 0.259, P < 0.001; ß = - 0.326, P < 0.001, respectively). Further, the difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI. Global stress PI, LA booster, global rest PI, and global MPRI showed high accuracy in diagnosing HFpEF among patients with T2DM (areas under the curve [AUC]: 0.803, 0.790, 0.740, 0.740, respectively). CONCLUSIONS: Patients with T2DM and HFpEF exhibited significant LV systolic and diastolic deformation, decreased LA reservoir strain, severe impairment of myocardial perfusion, and elevated LA booster strain that is a compensatory response in HFpEF. Global MPRI was identified as an independent influencing factor on LA reservoir and LA booster strain. The difference in LA reservoir and LA booster strain between patients with T2DM with and without HFpEF was totally mediated by global MPRI, suggesting a possible mechanistic link between microcirculation impairment and cardiac dysfunction in diabetes. Myocardial perfusion and LA strain may prove valuable for diagnosing and managing HFpEF in the future.

Nomogram predicting early urinary incontinence after radical prostatectomy.

PURPOSE: One of the most frequent side effects of radical prostatectomy (RP) is urinary incontinence. The primary cause of urine incontinence is usually thought to be impaired urethral sphincter function; nevertheless, the pathophysiology and recovery process of urine incontinence remains unclear. This study aimed to identify potential risk variables, build a risk prediction tool that considers preoperative urodynamic findings, and direct doctors to take necessary action to reduce the likelihood of developing early urinary incontinence. METHODS: We retrospectively screened patients who underwent radical prostatectomy between January 1, 2020 and December 31, 2023 at the First People 's Hospital of Nantong, China. According to nomogram results, patients who developed incontinence within three months were classified as having early incontinence. The training group's general characteristics were first screened using univariate logistic analysis, and the LASSO method was applied for the best prediction. Multivariate logistic regression analysis was carried out to determine independent risk factors for early postoperative urine incontinence in the training group and to create nomograms that predict the likelihood of developing early urinary incontinence. The model was internally validated by computing the performance of the validation cohort. The nomogram discrimination, correction, and clinical usefulness were assessed using the c-index, receiver operating characteristic curve, correction plot, and clinical decision curve. RESULTS: The study involved 142 patients in all. Multivariate logistic regression analysis following RP found seven independent risk variables for early urinary incontinence. A nomogram was constructed based on these independent risk factors. The training and validation groups' c-indices showed that the model had high accuracy and stability. The calibration curve demonstrates that the corrective effect of the training and verification groups is perfect, and the area under the receiver operating characteristic curve indicates great identification capacity. Using a nomogram, the clinical net benefit was maximised within a probability threshold of 0.01-1, according to decision curve analysis (DCA). CONCLUSION: The nomogram model created in this study can offer a clear, personalised analysis of the risk of early urine incontinence following RP. It is highly discriminatory and accurate, and it can help create efficient preventative measures and identify high-risk populations.

Microbe-derived Antioxidants Enhance Lipid Synthesis by Regulating the Hepatic AMPKα-SREBP1c Pathway in Weanling Piglets.

BACKGROUND: Weaning usually causes low feed intake and weight loss in piglets, which mobilizes lipid to energize. The microbe-derived antioxidants (MAs) exhibit great potential in antioxidation, anti-inflammation, and metabolic regulation. OBJECTIVES: We aimed to investigate the changes of lipid metabolism postweaning and effects of MA on growth performance and hepatic lipid metabolism in weanling piglets. METHODS: In the first experiment, piglets weaned at 21 d of age were slaughtered on weaning day (d0), 4 (d4), and 14 (d14) postweaning (6 piglets per day). In the second experiment, piglets were divided into 2 groups, receiving MA (MA) and saline gavage (CON), respectively. All piglets were weaned at 21 d of age and 6 piglets from each group were slaughtered at 25 d of age. RESULTS: In experiment 1, the serum triglyceride, total cholesterol (TC), and LDL cholesterol on d4 and d14 declined significantly compared with d0 (P < 0.05). The serum leptin on d0 was higher than that on d4 and d14 (P < 0.05). The serum ghrelin kept increasing from d0 to d14 (P < 0.05). The hepatic hormone-sensitive lipase and adipose triglyceride lipase first increased from d0 to d4 and then decreased from d4 to d14 (P < 0.05). In experiment 2, the average daily gain and average daily feed intake from 21 to 25 d of age increased in the MA group compared with the CON group (P < 0.05). The serum TC, hepatic TC, and glucose of MA group showed a significant increase than that of the CON group (P < 0.05). The expression of SCD1, ACAT2, and PPARγ were upregulated in the MA group (P < 0.05). Contrary to the decreased expression of phosphorylation of adenosine 5'-monophosphate-activated protein kinase alfa subunit (Thr172), the nuclear sterol regulatory element-binding protein 1c, fatty acid synthase, and peroxisome proliferator-activated receptor gamma of MA group increased than that of CON group (P < 0.05). CONCLUSIONS: Weaning promoted hepatic lipolysis and MA could enhance lipid synthesis by regulating adenosine 5'-monophosphate-activated protein kinase alfa subunit-sterol regulatory element-binding protein 1c pathway, thus improving growth performance of weanling piglets.

Rational design and application of broad-spectrum antibodies for Bt Cry toxins determination.

Using the amino acid sequences and analysis of selected known structures of Bt Cry toxins, Cry1Ab, Cry1Ac, Cry1Ah, Cry1B, Cry1C and Cry1F we specifically designed immunogens. After antibodies selection, broad-spectrum polyclonal antibodies (pAbs) and monoclonal antibody (namely 1A0-mAb) were obtained from rabbit and mouse, respectively. The produced pAbs displayed broad spectrum activity by recognizing Cry1 toxin, Cry2Aa, Cry2Ab and Cry3Aa with half maximal inhibitory concentration (IC50) values of 0.12-9.86 µg/mL. Similarly, 1A0-mAb showed broad spectrum activity, recognizing all of the above Cry protein (IC50 values of 4.66-20.46 µg/mL) with the exception of Cry2Aa. Using optimizations studies, 1A10-mAb was used as a capture antibody and pAbs as detection antibody. Double antibody sandwich enzyme-linked immunosorbent assays (DAS-ELISAs) were established for Cry1 toxin, Cry2Ab and Cry3Aa with the limit of detection (LOD) values of 2.36-36.37 ng/mL, respectively. The present DAS-ELISAs had good accuracy and precisions for the determination of Cry toxin spiked tap water, corn, rice, soybeans and soil samples. In conclusion, the present study has successfully obtained broad-spectrum pAbs and mAb. Furthermore, the generated pAbs- and mAb-based DAS-ELISAs protocol can potentially be used for the broad-spectrum monitoring of eight common subtypes of Bt Cry toxins residues in food and environmental samples.

Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

Transcriptomic analysis reveals molecular characterization and immune landscape of PANoptosis-related genes in atherosclerosis.

BACKGROUND: Atherosclerosis is a chronic inflammatory disease characterized by abnormal lipid deposition in the arteries. Programmed cell death is involved in the inflammatory response of atherosclerosis, but PANoptosis, as a new form of programmed cell death, is still unclear in atherosclerosis. This study explored the key PANoptosis-related genes involved in atherosclerosis and their potential mechanisms through bioinformatics analysis. METHODS: We evaluated differentially expressed genes (DEGs) and immune infiltration landscape in atherosclerosis using microarray datasets and bioinformatics analysis. By intersecting PANoptosis-related genes from the GeneCards database with DEGs, we obtained a set of PANoptosis-related genes in atherosclerosis (PANoDEGs). Functional enrichment analysis of PANoDEGs was performed and protein-protein interaction (PPI) network of PANoDEGs was established. The machine learning algorithms were used to identify the key PANoDEGs closely linked to atherosclerosis. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic potency of key PANoDEGs. CIBERSORT was used to analyze the immune infiltration patterns in atherosclerosis, and the Spearman method was used to study the relationship between key PANoDEGs and immune infiltration abundance. The single gene enrichment analysis of key PANoDEGs was investigated by GSEA. The transcription factors and target miRNAs of key PANoDEGs were predicted by Cytoscape and online database, respectively. The expression of key PANoDEGs was validated through animal and cell experiments. RESULTS: PANoDEGs in atherosclerosis were significantly enriched in apoptotic process, pyroptosis, necroptosis, cytosolic DNA-sensing pathway, NOD-like receptor signaling pathway, lipid and atherosclerosis. Four key PANoDEGs (ZBP1, SNHG6, DNM1L, and AIM2) were found to be closely related to atherosclerosis. The ROC curve analysis demonstrated that the key PANoDEGs had a strong diagnostic potential in distinguishing atherosclerotic samples from control samples. Immune cell infiltration analysis revealed that the proportion of initial B cells, plasma cells, CD4 memory resting T cells, and M1 macrophages was significantly higher in atherosclerotic tissues compared to normal tissues. Spearman analysis showed that key PANoDEGs showed strong correlations with immune cells such as T cells, macrophages, plasma cells, and mast cells. The regulatory networks of the four key PANoDEGs were established. The expression of key PANoDEGs was verified in further cell and animal experiments. CONCLUSIONS: This study evaluated the expression changes of PANoptosis-related genes in atherosclerosis, providing a reference direction for the study of PANoptosis in atherosclerosis and offering potential new avenues for further understanding the pathogenesis and treatment strategies of atherosclerosis.

Brønsted Acid-Catalyzed Intramolecular Tandem Double Cyclization of γ-Hydroxy Acetylenic Ketones with Alkynes into Naphtho[1,2-b]furan-3-ones.

A metal-free and atom-economic route for the synthesis of naphtho[1,2-b]furan-3-ones has been realized via p-TsOH·H2O-catalyzed intramolecular tandem double cyclization of γ-hydroxy acetylenic ketones with alkynes in formic acid. The benzene-linked furanonyl-ynes are the key intermediates obtained by the scission/recombination of C-O double bonds. Further, the structural modifications of the representative product were implemented by reduction, demethylation, substitution, and [5 + 2]-cycloaddition.

A longitudinal study of the effect of visuomotor learning on functional brain connectivity.

Neural adaptation in the frontoparietal and motor cortex-sensorimotor circuits is crucial for acquiring visuomotor skills. However, the specific nature of highly dynamic neural connectivity in these circuits during the acquisition of visuomotor skills remains unclear. To achieve a more comprehensive understanding of the relationship between acquisition of visuomotor skills and neural connectivity, we used electroencephalographic coherence to capture highly dynamic nature of neural connectivity. We recruited 60 male novices who were randomly assigned to either the experimental group (EG) or the control group (CG). Participants in EG were asked to engage in repeated putting practice, but CG did not engage in golf practice. In addition, we analyzed the connectivity by using 8-13 Hz imaginary inter-site phase coherence in the frontoparietal networks (Fz-P3 and Fz-P4) and the motor cortex-sensorimotor networks (Cz-C3 and Cz-C4) during a golf putting task. To gain a deeper understanding of the dynamic nature of learning trajectories, we compared data at three time points: baseline (T1), 50% improvement from baseline (T2), and 100% improvement from baseline (T3). The results primarily focused on EG, an inverted U-shaped coherence curve was observed in the connectivity of the left motor cortex-sensorimotor circuit, whereas an increase in the connectivity of the right frontoparietal circuit from T2 to T3 was revealed. These results imply that the dynamics of cortico-cortical communication, particularly involving the left motor cortex-sensorimotor and frontal-left parietal circuits. In addition, our findings partially support Hikosaka et al.'s model and provide additional insight into the specific role of these circuits in visuomotor learning.

A High-Quality Data Set of Protein-Ligand Binding Interactions Via Comparative Complex Structure Modeling.

High-quality protein-ligand complex structures provide the basis for understanding the nature of noncovalent binding interactions at the atomic level and enable structure-based drug design. However, experimentally determined complex structures are scarce compared with the vast chemical space. In this study, we addressed this issue by constructing the BindingNet data set via comparative complex structure modeling, which contains 69,816 modeled high-quality protein-ligand complex structures with experimental binding affinity data. BindingNet provides valuable insights into investigating protein-ligand interactions, allowing visual inspection and interpretation of structural analogues' structure-activity relationships. It can also be used for evaluating machine-learning-based scoring functions. Our results indicate that machine learning models trained on BindingNet could reduce the bias caused by buried solvent-accessible surface area, as we previously found for models trained on the PDBbind data set. We also discussed strategies to improve BindingNet and its potential utilization for benchmarking the molecular docking methods and ligand binding free energy calculation approaches. The BindingNet complements PDBbind in constructing a sufficient and unbiased protein-ligand binding data set and is freely available at http://bindingnet.huanglab.org.cn.