Synaptic vesicle protein 2-targeted doxorubicin-loaded liposome for effective neuroblastoma therapy.

Neuroblastoma, a pediatric cancer originating from neural crest tissues of the sympathetic nervous system, poses significant treatment challenges due to its molecular diversity and restricted druggable targets. While chemotherapy is a common treatment, its drawbacks, including poor targeting of cancer cells and nonspecific cytotoxicity, highlight the urgent need for innovative and effective therapeutic strategies. Herein, we developed a novel drug by coupling the receptor binding domain of botulinum neurotoxin type A (Hc) fused with monomeric streptavidin (mSA) to biotin coated doxorubicin (Dox)-loaded liposome, via interaction between mSA and biotin. The resultant Hc-coated liposome (Hc-Lipo@Dox) actively targeted the recycling synaptic vesicle 2 protein (SV2) abundantly expressed on the surface of neuroblastoma cells. Our results revealed that Hc-Lipo@Dox more effectively entered the neuroblastoma SH-SY5Y cells, inducing apoptosis compared to non-targeted liposome and free Dox. Moreover, Hc-Lipo@Dox rapidly enriched Dox in the subcutaneously implanted neuroblastoma tumor in nude mice, resulting potent anti-neuroblastoma effect compared to non-targeted liposomes or free Dox. Importantly, Hc-Lipo@Dox significantly improved the survival rate of treated mice, while also exhibiting a favorable safety profile with no discernible impact on mobility or observable side effects. These findings highlight the potential of SV2-targeted Dox liposome as a promising and well-tolerated chemotherapy approach for neuroblastoma treatment. Moreover, the technology established here has broader applications for various cancer therapies by substituting the Hc moiety with other tumor-specific targeting moieties.

Remnant Cholesterol and New-onset Atrial Fibrillation: The Atherosclerosis Risk in Communities Study.

BACKGROUND: The relationship between remnant cholesterol (RC) and atrial fibrillation (AF) remains unclear. OBJECTIVE: To comprehensively explore the association between RC characteristics and new-onset AF. METHODS: Data from five follow-up visits of the ARIC study were analyzed. RC were multidimensionally evaluated in four characteristics, including baseline level, variability, cumulative exposure and trajectory. Baseline RC was obtained from the initial visit (V1), and new-onset AF was monitored in V2 to V5 (cohort 1, n=14450). RC variability, cumulative RC and RC trajectory were calculated by RC values gathered from V1 to V3, and new-onset AF was monitored in V4 and V5 (cohort 2, n=11012). Participants were divided into four groups based on quartiles or trajectories. Cox proportional hazards analyses were used to investigate the relationship between RC characteristics and AF. RESULTS: Following a median follow-up of 22.39 years in cohort 1 and 16.71 years in cohort 2, a total of 1993 AF events in cohort 1 and 1571 in cohort 2 were identified. Participants with the highest quartile exhibited an elevated risk of new-onset AF, with the multivariable-adjusted HRs of 1.35 (P=0.009) for baseline RC and 1.26 (P=0.09) for RC variability. Although the highest quartile of cumulative RC (P=0.130) and the high-increasing trajectory (P=0.322) did not demonstrate a statistically significant association with AF occurrence, they indicate a trend towards a heightened risk. CONCLUSION: Our findings reveal that higher levels of RC, particularly at baseline and in variability, are associated with an increased risk of AF.

Detection of structural variants linked to mutton flavor and odor in two closely related black goat breeds.

BACKGROUND: Mutton quality is closely related to genetic variants and gene expression alterations during growth and development, resulting in differences in nutritional values, flavor, and odor. RESULTS: We first evaluated and compared the composition of crude protein, crude fat, cholesterol, amino acid (AA), and fatty acid (FA) in the longissimus dorsi muscle of Guizhou black goats (GZB, n = 5) and Yunshang black goats (YBG, n = 6). The contents of cholesterol and FA related to odor in GZB were significantly lower than that in YBG, while the concentrations of umami amino acids and intramuscular fat were significantly higher in GZB. Furthermore, structural variants (SVs) in the genomes of GZB (n = 30) and YBG (n = 11) were explored. It was found that some regions in Chr 10/12/18 were densely involved with a large number of SVs in the genomes of GZB and YBG. By setting FST ≥ 0.25, we got 837 stratified SVs, of which 25 SVs (involved in 12 genes, e.g., CORO1A, CLIC6, PCSK2, and TMEM9) were limited in GZB. Functional enrichment analysis of 14 protein-coding genes (e.g., ENPEP, LIPC, ABCA5, and SLC6A15) revealed multiple terms and pathways related with metabolisms of AA, FA, and cholesterol. The SVs (n = 10) obtained by the whole genome resequencing were confirmed in percentages of 36.67 to 86.67% (n = 96) by PCR method. The SVa and SVd polymorphisms indicated a moderate negative correlation with HMGCS1 activity (n = 17). CONCLUSION: This study is the first to comprehensively reveal potential SVs related to mutton nutritional values, flavor, and odor based on genomic compare between two black goat breeds with closely genetic relationship. The SVs generated in this study provide a data resource for deeper studies to understand the genomic characteristics and possible evolutionary outcomes with better nutritional values, flavor and extremely light odor.

Novel platform for engineering stable and effective vaccines against botulinum neurotoxins A, B and E.

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is the most toxic protein known, capable of causing severe paralysis and posing a significant bioterrorism threat due to its extreme lethality even in minute quantities. Despite this, there are currently no FDA-approved vaccines for widespread public use. To address this urgent need, we have developed an innovative vaccine platform by fusing the neuronal binding domain of BoNT/E (Hc/E) with core-streptavidin (CS), resulting in a stable CS-Hc/E vaccine. Mice vaccinated with CS-Hc/E exhibited superior antibody titers compared to those receiving Hc/E alone. To develop a trivalent vaccine against BoNT/A, BoNT/B, and BoNT/E- key contributors to the vast majority of human botulism-we conjugated CS-Hc/E with a biotinylated atoxic chimeric protein incorporating neutralizing epitopes from BoNT/A and BoNT/B. This chimeric protein includes the binding domain of BoNT/A, along with the protease-inactive light chain and translocation domains of BoNT/B. The interaction between CS and biotin formed a stable tetrameric antigen, EBA. Vaccination with EBA in mice elicited robust antibody responses and provided complete protection against lethal doses of BoNT/A, BoNT/B, and BoNT/E. Our findings highlight EBA's potential as a stable and effective broad-spectrum vaccine against BoNT. Moreover, our technology offers a versatile platform for developing multivalent, stable vaccines targeting various biological threats by substituting the BoNT domain(s) with neutralizing epitopes from other life-threatening pathogens, thereby enhancing public health preparedness and biodefense strategies.

Knockdown of LncRNA-HAGLR restrains the viability and motility of pancreatic cancer via miR-625-5p/TAF15 axis in vitro and in vivo.

Dysregulation of long non-coding RNAs (lncRNAs) has been strongly involved to the development of pancreatic cancer (PC). However, the potential mechanisms by which lncRNA regulate PC development still need to be further explored. We attempted to elucidate the functional role and regulatory mechanism of lncRNA HAGLR on PC progression in vitro and vivo. RT-qPCR, Western blot, RNA pull-down, luciferase reporter assay, RNA immunoprecipitation assay, CCK-8 assay, EdU assay, flow cytometry, transwell assay and xenograft tumor experiment were performed in this study. We found that the expressions of HAGLR and TAF15 were increased in PC tissues and cells. HAGLR silencing restrained the PC cell growth and invasion, but induced cell apoptosis. Moreover, HAGLR targeted miR-625-5p to modulate the expression of TAF15. HAGLR overexpression partially eliminated the suppressive effect of TAF15 depletion on PC cell growth and the stimulative effect on apoptosis. In vivo assays showed that HAGLR knockdown inhibited PC cell growth by regulating the TAF15 expression. These findings suggest HAGLR could facilitate PC cell malignant behaviors through regulating the TAF15 expression, demonstrating that HAGLR might be a valuable target for the PC treatment.

A Wide-Bandwidth Inexpensive Current Sensor Based on the Signal Fusion of Tunneling Magnetoresistance and a Current Transformer.

In technology and industrial production, many applications require wide-bandwidth current measurements. In this paper, a signal fusion scheme for a current sensor comprising tunneling magnetoresistance and a current transformer is proposed, achieving a flat frequency response in the DC to MHz range. The measurement principles in different cases of the scheme are introduced, and the total transfer function of the entire scheme is derived by analyzing each section separately. Furthermore, the feasibility and selected parameters of the scheme are verified through a systematic simulation utilizing the MATLAB software. Based on the proposed scheme, a group of principal prototypes are built to experimentally evaluate the bandwidth, amplitude and phase flatness, accuracy, sensitivity, and impulse response. The relative amplitude variation in the passband of the fusion sensor is less than 4%, and the estimated bandwidth of the fusion sensor is close to 17 MHz. The accuracy is better than 0.6%, even when measuring the current at 1 MHz, and the relative standard deviation is 5% when measuring the impulse signal. The sensors developed using this scheme, with a low financial cost, have advantages in many wide-bandwidth current measuring scenarios.

Effects of adipose tissues on the relationship between type 2 diabetes mellitus and reduced heart rate variability: mediation analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with decreased heart rate variability (HRV) with an unclear intermediate mechanism. This study aimed to conduct mediation analysis to explore the impact of various adipose tissues on the relationship between T2DM and HRV. METHODS: A total of 380 participants were enrolled for analysis, including 249 patients with T2DM and 131 non-diabetic controls. The thicknesses of four adipose tissues (subcutaneous, extraperitoneal, intraperitoneal, and epicardial) were measured by abdominal ultrasound or echocardiography respectively. HRV was assessed by 24-hour Holter for monitoring both frequency domain indices (LF, HF, and LF/HF) and time domain indices (SDNN, SDANN, SDNN index, rMSSD and pNN50). Mediation analysis was used toexamine whether adipose tissues mediated the relationship between T2DM and each index of HRV. Then, a latent variable - HRV burden - was constructed by structural equation model with selected HRV indices to comprehensively assess the whole HRV. RESULTS: Compared to non-diabetic controls, patients with T2DM exhibited a significant reduction in indices of HRV, and a remarkable increase in the thicknesses of extraperitoneal, intraperitoneal, and epicardial adipose tissues. Mediation analysis found significant indirect effects of T2DM on six indices of HRV, including HF, SDNN, SDANN, SDNN index, rMSSD, and pNN50, which was mediated by epicardial adipose tissue rather than other adipose tissues, with the mediation proportions of 64.21%, 16.38%, 68.33%, 24.34%, 24.10% and 30.51%, respectively. Additionally, epicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV burden (24.26%), which composed by SDNN, SDNN index, rMSSD, and pNN50. CONCLUSION: Epicardial adipose tissue partially mediated the relationship between T2DM and reduced HRV, which reinforces the value of targeting heart-specific visceral fat to prevent cardiac autonomic neuropathy in diabetes.

Perirenal Fat Thickness Is Associated With Contrast-Induced Nephropathy in Type 2 Diabetic Patients Undergoing Coronary Catheterization.

Background: Deposition of adipose tissue may have a promoting role in the development of diabetic complications. This study is aimed at investigating the relationship between adipose tissue thickness and risk of contrast-induced nephropathy (CIN) in patients with Type 2 diabetes mellitus (T2DM). Methods: A total of 603 T2DM patients undergoing percutaneous coronary angiography or angioplasty with suspicious or confirmed stable coronary artery disease were enrolled in this study. The thicknesses of perirenal fat (PRF), subcutaneous fat (SCF), intraperitoneal fat (IPF), and epicardial fat (ECF) were measured by color Doppler ultrasound, respectively. The association of various adipose tissues with CIN was analyzed. Results: Seventy-seven patients (12.8%) developed CIN in this cohort. Patients who developed CIN had significantly thicker PRF (13.7 ± 4.0 mm vs. 8.9 ± 3.6 mm, p < 0.001), slightly thicker IPF (p = 0.046), and similar thicknesses of SCF (p = 0.782) and ECF (p = 0.749) compared to those who did not develop CIN. Correlation analysis showed that only PRF was positively associated with postoperation maximal serum creatinine (sCr) (r = 0.18, p = 0.012), maximal absolute change in sCr (r = 0.33, p < 0.001), and maximal percentage of change in sCr (r = 0.36, p < 0.001). In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) of PRF (0.809) for CIN was significantly higher than those of SCF (0.490), IPF (0.594), and ECF (0.512). Multivariate logistic regression analysis further confirmed that thickness of PRF, rather than other adipose tissues, was independently associated with the development of CIN after adjusted for confounding factors (odds ratio (OR) = 1.53, 95% CI: 1.38-1.71, p < 0.001). Conclusions: PRF is independently associated with the development of CIN in T2DM patients undergoing coronary catheterization.

Genome-wide identification of copy number variations in wrinkled skin cases of Xiang pigs.

Copy number variation (CNV) tends to occur in genetically enriched regions and is likely associated with a number of complex diseases such as skin aging. In this study, we investigated the genome-wide CNVs in 20 wrinkled skin cases (WSC) of Xiang pigs and 63 controls, and identified 7893 copy number variable regions (CNVRs). We estimated the F-statistic (Fst) at each locus and identified that 93 case-controls stratified CNVRs (Fst > = 0.15) overlapped with 87 known genes. Functional enrichment analysis showed that most of these genes were predominantly enriched in pathways and terms related to the extracellular matrix. Finally, we found that some CNVs were predicted to have high effects on genes such as VCAN, TIMP1 and FOXO1 through transcriptional amplification, transcript ablation and so on. Most of the genes overlapped with those CNVRs have been reported to be related to aging in human or animals. The copy numbers presented the positive correlations with the transcript level of the genes in skins between the cases and controls. Our results suggested that those 22 CNVRs, including 19 CNV losses and 3 CNV gains, were putatively associated with the skin wrinkle of Xiang pigs.

Genome-wide characterization of structure variations in the Xiang pig for genetic resistance to African swine fever.

African swine fever (ASF) is a rapidly fatal viral haemorrhagic fever in Chinese domestic pigs. Although very high mortality is observed in pig farms after an ASF outbreak, clinically healthy and antibody-positive pigs are found in those farms, and viral detection is rare from these pigs. The ability of pigs to resist ASF viral infection may be modulated by host genetic variations. However, the genetic basis of the resistance of domestic pigs against ASF remains unclear. We generated a comprehensive set of structural variations (SVs) in a Chinese indigenous Xiang pig with ASF-resistant (Xiang-R) and ASF-susceptible (Xiang-S) phenotypes using whole-genome resequencing method. A total of 53,589 nonredundant SVs were identified, with an average of 25,656 SVs per individual in the Xiang pig genome, including insertion, deletion, inversion and duplication variations. The Xiang-R group harboured more SVs than the Xiang-S group. The F-statistics (FST) was carried out to reveal genetic differences between two populations using the resequencing data at each SV locus. We identified 2,414 population-stratified SVs and annotated 1,152 Ensembl genes (including 986 protein-coding genes), in which 1,326 SVs might disturb the structure and expression of the Ensembl genes. Those protein-coding genes were mainly enriched in the Wnt, Hippo, and calcium signalling pathways. Other important pathways associated with the ASF viral infection were also identified, such as the endocytosis, apoptosis, focal adhesion, Fc gamma R-mediated phagocytosis, junction, NOD-like receptor, PI3K-Akt, and c-type lectin receptor signalling pathways. Finally, we identified 135 candidate adaptive genes overlapping 166 SVs that were involved in the virus entry and virus-host cell interactions. The fact that some of population-stratified SVs regions detected as selective sweep signals gave another support for the genetic variations affecting pig resistance against ASF. The research indicates that SVs play an important role in the evolutionary processes of Xiang pig adaptation to ASF infection.

A robust amphiphilic ionic covalent organic framework intercalated into functionalized graphene oxide hybrid membranes for ultrafast extraction uranium from wastewater.

The efficient capture of uranium from wastewater is crucial for environmental remediation and the sustainable development of nuclear energy, yet it poses considerable challenges. In this study, amphiphilic ionic covalent organic framework intercalated into graphene oxide (GO) nanosheets functionalized with polyethyleneimine (PEI) were used to construct hybrid membranes with ultrafast uranium adsorption. These hybrid membranes achieved equilibrium in just 10 min and the adsorption capacity was as high as 358.8 mg g-1 at pH = 6. X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) analyses revealed that the strong interaction between sulfonic acid groups and uranyl ions was the primary reason for the high adsorption capacity and selectivity. The extended transition state and natural orbitals for chemical valence (ETS-NOCV) analysis revealed that the interaction between the 7 s and 5f orbitals of uranyl and the 2p orbitals of S and O in the sulfonate was the primary reason for the strong interaction between the sulfonate and the uranyl ion. This research presents an effective method for the rapid extraction of uranium from wastewater.

Tris (2-chloroisopropyl) phosphate and Tris (nonylphenyl) phosphite Promote Human Renal Cell Apoptosis through the ERK/CEPBA/Long Non-Coding RNA Cytoskeleton Regulator Axis.

Organophosphorus compounds (OPs) are widely used and have the potential to be harmful environmental toxicants to humans. Long non-coding RNA (lncRNA) plays a crucial regulatory role in cytotoxicity. This study aimed to investigate the effects of OPs on the expression of lncRNAs in cells. The effects of the industrial OPs TNPP and TCPP on both CYTOR and cellular viability were examined in the following human renal cell lines: HEK293T and HK-2. Both TCPP and TNPP downregulated CYTOR expression, increased reactive oxygen species levels, and induced apoptosis; the upregulated expression of CYTOR resulted in a reduction in apoptosis. The results of the luciferase reporter assay and the knock-down assay indicate that CEBPA binds to the upstream promoter region of CYTOR and regulates its transcription. Furthermore, TCPP and TNPP were found to downregulate the phosphorylation of ERK in the signaling pathway that is upstream of CEBPA. These results indicate that TCPP and TNPP can decrease the level of CEBPA by reducing ERK phosphorylation; this leads to a decrease in CYTOR expression, which further promotes cellular reactive oxygen species and apoptosis. Therefore, the ERK/CEBPA/CYTOR axis is one of the pathways by which organophosphates produce cytotoxicity, leading to renal cell injury. This study presents evidence for both the abnormal expression of lncRNA that is caused by organophosphates and the regulatory function of lncRNA regarding downstream cellular viability.

Multifunctional integrated metamaterials for radar-infrared-visible compatible multispectral stealth.

Metamaterials offer exciting opportunities for developing multispectral stealth due to their unique electromagnetic properties. However, currently transparent radar-infrared-visible compatible stealth metamaterials typically involve complex hierarchical designs, leading to thickness and transparency limitations. Here, we propose an integrated metamaterial for multispectral stealth with high transparency. Our design features an ITO/dielectric/ITO sandwich structure, with the upper-layer ITO acting as a resonator for broadband microwave absorption while maintaining a high filling ratio to suppress infrared (IR) radiation. Experimental results demonstrate excellent performance, with over 90% microwave absorption in 8-18 GHz, an IR emissivity of approximately 0.36 in 3-14 µm, an average optical transmittance of 74.1% in 380-800 nm, and a thickness of only 2.4 mm. With its multispectral compatibility, the proposed metamaterial has potential applications in stealth and camouflage fields.

Multi-spectral compatible metasurface with low infrared emissivity, independent microwave complex-amplitude control, and high visible transparency.

With the rapid development of communication technology and detection technology, it is difficult for devices operating in a single spectrum to meet the application requirements of device integration and miniaturization, resulting in the exploration of multi-spectrum compatible devices. However, the functional design of different spectra is often contradictory and difficult to be compatible. In this work, a transparent slit circular metasurface with a high filling ratio is proposed to achieve the compatibility of microwave, infrared and visible light. In the microwave, based on the Pancharatnam-Berry phase theory, the continuous amplitude and binary phase can be customized only by rotating the slit angle to achieve an Airy beam function at 8-12 GHz. In the infrared, the mean infrared emissivity is reduced to 0.3 at 3-14 µm by maintaining high conductive filling ratio, and in visible light, based on the transparency of materials, the mean transmittance can achieve 50% at 400-800 nm. All the results can verify the multi-spectral compatibility performance, which can also verify the validity of our design method. Importantly, the multi-spectral compatible metasurface contributes an option for multifunctional integration, which can be further applied in communication, camouflage, and other fields.

Enantioselective bioaccumulation, biotransformation and spatial distribution of chiral fungicide difenoconazole in earthworms (Eisenia fetida).

The enantioselective environmental behavior of difenoconazole, a widely utilized triazole fungicide commonly detected in agricultural soils, has yet to be comprehensively explored within the earthworm-soil system. To address this research gap, we investigated the bioaccumulation and elimination kinetics, degradation pathways, biotransformation mechanisms, spatial distribution, and toxicity of chiral difenoconazole. The four stereoisomers of difenoconazole were baseline separated and analyzed using SFC-MS/MS. Pronounced enantioselectivity was observed during the uptake phase, with earthworms exhibiting a preference for (2R,4R)-difenoconazole and (2R,4S)-difenoconazole. A total of five transformation products (TPs) were detected and identified using UHPLC-QTOF/MS in the earthworm-soil system. Four of the TPs were detected in both earthworm and soil, and one TP was produced only in eaerthwroms. Hydrolysis and hydroxylation were the primary transformation pathways of difenoconazole in both earthworms and soil. Furthermore, a chiral TP, 3-chloro, 4-hydroxy difenoconazole, was generated with significant enantioselectivity, and molecular docking results indicate the greater catalytic bioactivity of (2R,4R)- and (2R,4S)-difenoconazole, leading to the preferential formation of their corresponding hydroxylated TPs. Furthermore, Mass Spectrometry Imaging (MSI) was applied for the first time to explore the spatial distribution of difenoconazole and the TPs in earthworms, and the "secretory zone" was found to be the dominant region to uptake and biodegrade difenoconazole. ECOSAR predictions highlighted the potentially hazardous impact of most difenoconazole TPs on aquatic ecosystems. These findings are important for understanding the environmental fate of difenoconazole, evaluating environmental risks, and offering valuable insights for guiding scientific bioremediation efforts.

Applying the Wake-Up-like Effect to Enhance the Capabilities of Two-Dimensional Ferroelectric Field-Effect Transistors.

For traditional ferroelectric field-effect transistors (FeFETs), enhancing the polarization domain of bulk ferroelectric materials is essential to improve device performance. However, there has been limited investigation into the enhancement of polarization field in two-dimensional (2D) ferroelectric material such as CuInP2S6 (CIPS). In this study, similar to bulk ferroelectric materials, CIPS exhibited enhanced polarization field upon application of external cyclic voltage. Moreover, unlike traditional ferroelectric materials, the polarization enhancement of CIPS is not due to redistribution of the defect but rather originates from a mechanism: the long-distance migration of Cu ions. We termed this mechanism the "wake-up-like effect". After incorporating the wake-up-like effect into the graphene/CIPS/WSe2 FeFET device, we successfully increased the hysteresis window and enhanced the current on/off ratio by 4 orders of magnitude. Moreover, the FeFET yielded remarkable achievements, such as multilevel nonvolatile memory with 21 distinct conductance levels, a high on/off ratio exceeding 106, a long retention time exceeding 103 s, and neuromorphic computing with 93% accuracy at recognizing handwritten digits. Introducing the wake-up-like effect to 2D CIPS may pave the way for innovative approaches to achieve advanced multilevel nonvolatile memory and neuromorphic computing capabilities for next-generation micro-nanoelectronic devices.

Coronary Sinus Metabolite 12,13-diHOME Is a Novel Biomarker for Left Atrial Remodeling in Patients With Atrial Fibrillation.

BACKGROUND: 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) has shown potential in protecting against heart disease, but its relationship with atrial fibrillation (AF) remains unknown. METHODS: Coronary sinus (CS) and femoral vein blood samplings were synchronously collected from AF and non-AF subjects (paroxysmal supraventricular tachycardia or idiopathic premature ventricular complexes) who underwent catheter ablation. First, untargeted metabolomic profiling was performed in a discovery cohort (including 12 AF and 12 non-AF subjects) to identify the most promising CS or femoral vein metabolite. Then, the selected metabolite was further measured in a validation cohort (including 119 AF and 103 non-AF subjects) to confirm its relationship with left atrium remodeling and 1-year postablation recurrence of AF. Finally, the biological function of the selected metabolite was validated in a rapid-paced cultured HL-1 atrial cardiomyocytes model. RESULTS: Metabolomic analysis identified CS 12,13-diHOME as the most pronounced change metabolite correlated with left atrium remodeling in the discovery cohort. In the validation cohort, CS 12,13-diHOME was significantly lower in patients with AF than non-AF controls (84.32±20.13 versus 96.24±23.56 pg/mL; P<0.01), and associated with worse structural, functional, and electrical remodeling of left atrium. Multivariable regression analyses further demonstrated that decreased CS 12,13-diHOME was an independent predictor of 1-year postablation recurrence of AF (odds ratio, 0.754 [95% CI, 0.648-0.920]; P=0.005). Biological function validations showed that 12,13-diHOME treatment significantly protect the cell viability, improved the expression of MHC (myosin heavy chain) and Cav1.2 (L-type calcium channel α1c), and attenuated mitochondrial damage in the rapid-paced cultured HL-1 cardiomyocytes model. CONCLUSIONS: CS metabolite 12,13-diHOME is decreased in patients with AF and can serve as a novel biomarker for left atrium remodeling.

GPR39-mediated ERK1/2 signaling reduces permethrin-induced proliferation of estrogen receptor α-negative cells.

Certain insecticides are known to have estrogenic effects by activating estrogen receptors through genomic transcription. This has led researchers to associate specific insecticide use with an increased breast cancer risk. However, it is unclear if estrogen receptor-dependent pathways are the only way in which these compounds induce carcinogenic effects. The objective of this study was to determine the impact of the pyrethroid insecticide permethrin on the growth of estrogen receptor negative breast cancer cells MDA-MB-231. Using tandem mass spectrometric techniques, the effect of permethrin on cellular protein expression was investigated, and gene ontology and pathway function enrichment analyses were performed on the deregulated proteins. Finally, molecular docking simulations of permethrin with the candidate target protein was performed and the functionality of the protein was confirmed through gene knockdown experiments. Our findings demonstrate that exposure to 10-40 µM permethrin for 48 h enhanced cell proliferation and cell cycle progression in MDA-MB-231. We observed deregulated expression in 83 upregulated proteins and 34 downregulated proteins due to permethrin exposure. These deregulated proteins are primarily linked to transmembrane signaling and chemical carcinogenesis. Molecular docking simulations revealed that the overexpressed transmembrane signaling protein, G protein-coupled receptor 39 (GPR39), has the potential to bind to permethrin. Knockdown of GPR39 partially impeded permethrin-induced cellular proliferation and altered the expression of proliferation marker protein PCNA and cell cycle-associated protein cyclin D1 via the ERK1/2 signaling pathway. These findings offer novel evidence for permethrin as an environmental breast cancer risk factor, displaying its potential to impact breast cancer cell proliferation via an estrogen receptor-independent pathway.