Environmental exposure patterns to 94 current-use pesticides in women of reproductive age who are preparing for pregnancy.

Current-use pesticides (CUPs), including insecticides, fungicides, and herbicides, are extensively employed in agriculture to manage pests, diseases, and weeds. Nonetheless, their widespread application raises significant concerns regarding potential impacts on human health, particularly with reproductive health. This study focuses on exploring the landscape of CUP exposure among pre-pregnancy women. Based on a cohort study comprising 354 pre-pregnancy women of reproductive age in Beijing, China, we measured the concentrations of 94 CUPs in serum and conducted an in-depth analysis of exposure profiles, health risks, and contributing factors. The results revealed that the serum of pre-pregnancy women was contaminated with CUPs, of which the median concentrations ranged from 0.114 (fenamiphos-sulfone) to 61.2 ng/L (mefenacet). Among the 94 CUPs, 54 exhibited detection rates higher than 50 %, including 26 insecticides, 14 fungicides, and 14 herbicides. The exposure concentration profile highlighted that the insecticides contributed 56 % to the total CUP concentration percentages, with organophosphate insecticides being the primary contributors within this category (63.0 %). The average daily intake (ADI) of CUPs ranged from 2.23 to 16,432.28 ng/kg, while diflubenzuron had the highest ADI. Health risk assessments showed that exposure to a combination of total insecticides or herbicides poses a moderate risk for 15.8 % and 30.2 % of women, with mefenacet being the most significant, which showed moderate hazard in 29.4 % of participants. The overlap analysis showed that methiocarb-sulfone, diflubenzuron, and mefenacet were the dominant pesticides. In addition, maternal age, annual income level, smoking, and vitamin B12 supplementation were associated with serum CUP concentrations. Our study contributes a novel and comprehensive exposure profile of CUPs in pre-pregnancy women in northern China, providing valuable insights for evaluating the potential consequences of pre-pregnancy exposure on reproductive health. SYNOPSIS: We provided a comprehensive exposure landscape, health effects, and influential factors of 94 current-use pesticides among pre-pregnancy women in China.

Construction and Preliminary Evaluation of Two 18F-Labeled Radiopharmaceuticals for Myocardial Perfusion Imaging.

AIMS: PET myocardial perfusion imaging (MPI) is the gold standard for the noninvasive diagnosis of ischemic myocardial. Construction of 18F-labeled PET MPI probe showed benefits to reduce the imaging cost, and enhance the image quality and patient-friendliness. METHODS: Two 18F-labeled MPI probes (18F-BoMPI) were developed. Detailed in vitro/vivo evaluation including photophysical properties, in vitro stability, myocardial cell uptake kinetics and mechanisms, cytotoxicity and IC50, biodistribution and plasma clearance curve were investigated. Resting and stressing myocardial perfusion PET imaging were performed in healthy and myocardial ischemic mice. RESULTS: 18F-BoMPI could be quickly labeled and easily postprocessed, and demonstrated excellent in vitro stability. Cell assays indicated that 18F-BoMPI exhibited mitochondria-targeting but potential-independent myocardial uptake. In vivo evaluation revealed the effective myocardial uptake and rapid background clearance. PET MPI confirmed effective probe accumulation in the healthy heart, but rapidly clearance in the background, making heart clearly delineated in the images. Ischemic myocardial could be clearly distinguished as the region of radioactivity sparsity in PET MPI. CONCLUSION: The 18F-labeled probes showed great potentials to reduce the practicability threshold of PET MPI.

Nitroxide radical conjugated ovalbumin theranostic nanosystem for enhanced dendritic cell-based immunotherapy and T1-magnetic resonance imaging.

Melanoma, known for its aggressive metastatic nature, presents a formidable challenge in cancer treatment, where conventional therapies often fall short. This study introduces a pioneering approach utilizing metal-free nanosystem as tumor vaccines, spotlighting their potential in revolutionizing melanoma treatment. This work employed organic nitroxides, specifically 4-carboxy-TEMPO, in combination with chitosan (CS), to create a novel nanocomposite material - the CS-TEMPO-OVA nanovaccines. This composition not only improves biocompatibility and extends blood circulation time of TEMPO but also marks a significant departure from traditional gadolinium-based contrast agents in MRI technology, addressing safety concerns. CS-TEMPO-OVA nanovaccines demonstrate excellent biocompatibility at both the cellular and organoid level. They effectively stimulate bone marrow-derived dendritic cells (BMDCs), which in turn promote the maturation and activation of T cells. This ultimately leads to a strong production of essential cytokines. These nanovaccines serve a dual purpose as both therapeutic and preventive. By inducing an immune response, activating cytotoxic T cells, and promoting macrophage M1 polarization, they effectively inhibit melanoma growth and enhance survival in mouse models. When combined with αPD-1, the CS-TEMPO-OVA nanovaccines significantly bolster the infiltration of cytotoxic T lymphocytes (CTLs) within tumors, sparking a powerful systemic antitumor response that effectively curbs tumor metastasis. The ability of these nanovaccines to control both primary (subcutaneous) and metastatic B16-OVA tumors highlights their remarkable efficacy. Furthermore, the CS-TEMPO-OVA nanovaccine can be administered in vivo via both intravenous and intramuscular routes, both of which effectively enhance the T1 contrast of magnetic resonance imaging in tumor tissue. This study offers invaluable insights into the integrated application of these nanovaccines in both clinical diagnostics and treatment, marking a significant stride in cancer research and patient care.

Targeted codelivery of doxorubicin and oleanolic acid by reduction responsive hyaluronic acid-based prodrug nano-micelles for enhanced antitumor activity and reduced toxicity.

Chemotherapy remains one of the most commonly used strategies in cancer treatment but suffers from damages to healthy tissues and organs. How to precisely co-deliver two or more drugs with different mechanisms of action to the tumors for synergistic function is a challenge for chemotherapy. Herein, Oleanolic acid (OA)-conjugated Hyaluronic acid self-assembled nano-micelles loaded with Doxorubicin (DOX) (HSO NPs/DOX) were constructed for CD44 positive cancer targeted codelivery of DOX and OA. HSO NPs/DOX exhibited reduction triggered drug release under high concentration of glutathione, more efficient uptake by 4T1 breast cancer cells than free DOX leading to higher cytotoxicity, pro-apoptotic, and migration inhibitory activities against 4T1 cells. The ex vivo biodistribution experiment demonstrated more HSO NPs/DOX were accumulated in the tumor tissues than free DOX and less in the non-tumor tissues after injections in 4T1 tumor bearing mice. More importantly, synergistic anti-tumor effects of DOX and OA were obtained using HSO NPs/DOX in 4T1 breast tumor-bearing mice and toxicity of DOX to liver and heart were circumvented through regulating the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Silent Information Regulator 1 (Sirt1) expressions. Taken together, HSO NPs/DOX may become a promising codelivery system for chemotherapeutics in cancer therapy.

[Research on alien invasive plants in Jingzhou County, Hunan Province, China]. / æ¹–å—çœé–å·žåŽ¿å¤–æ¥å ¥ä¾µæ¤ç‰©ç ”ç©¶.

Harm from alien invasive plants is increasing in Jingzhou County, Hunan Province. Based on a one-year field investigation and available literature, we investigated species composition, origin, flora, degree of harm and distribution pattern of invasive plants in the county. The results showed that there were 34 invasive plant species from 27 genera and 16 families in this County. The dominant invasive species belonged to Asteraceae (8 species) and Amaranthaceae (6 species), which accounted for 23.5% and 17.7%, respectively. The majority of invasive plants originated from South America (45.7%) and North America (30.4%). Tropical flora showed a significantly higher representation than temperate flora, signifying robust tropical characteristics amongst the invasive plant population. Based on hazard level classification, we recognized four types as malicious invasion (Level 1): Alternanthera philoxeroides, Erigeron annuus, E. canadensis, and Xanthium chinense. In addition, five types were classified as severe invasion (Level 2), eight types as local invasion (Level 3), fifteen types as general invasion (Level 4), while two types were still under observation (Level 5). The pattern of distribution demonstrated that invasive plants in Jingzhou County mostly spread along the verges of transportation roads, in human settlements, and in a few areas of water flow. The higher levels of invasion damage were principally concentrated in the central part of Jingzhou County.

Development of a Supermolecular Radionuclide-Drug Conjugate System for Integrated Radiotheranostics for Non-small Cell Lung Cancer.

Radionuclide-drug conjugates (RDCs) designed from small molecule or nanoplatform shows complementary characteristics. We constructed a new RDC system with integrated merits of small molecule and nanoplatform-based RDCs. Erlotinib was labeled with 131I to construct the bulk of RDC (131I-ER). Floxuridine was mixed with 131I-ER to develop a hydrogen bond-driving supermolecular RDC system (131I-ER-Fu NPs). The carrier-free 131I-ER-Fu NPs supermolecule not only demonstrated integrated merits of small molecule and nanoplatform-based RDC, including clear structure definition, stable quality control, prolonged circulation lifetime, enhanced tumor specificity and retention, and rapidly nontarget clearance, but also exhibited low biological toxicity and stronger antitumor effects. In vivo imaging also revealed its application for tumor localization of nonsmall cell lung cancer (NSCLC) and screening of patients suitable for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. We considered that 131I-ER-Fu NPs showed potentials as an integrated platform for the radiotheranostics of NSCLC.

Alkali and alkaline earth elements in follicular fluid and the likelihood of diminished ovarian reserve in reproductive-aged women: a case‒control study.

BACKGROUND: Imbalances in alkali elements (AEs) and alkaline earth elements (AEEs) cause reproductive disorders. However, it remains unclear whether AEs/AEEs in follicular fluid have a relationship with the serious reproductive disorder known as diminished ovarian reserve (DOR). METHODS: A nested case‒control study was carried out in China. Follicular fluid samples from 154 DOR patients and 154 controls were collected and assessed for nine AEs/AEE levels. Both the mixed and single effects of the elements on DOR were estimated with a Bayesian kernel machine (BKMR) and logistic regressions. RESULTS: The DOR group had higher median concentrations of Li, Na, and K in follicular fluid (all P values < 0.05). The logistic regression showed that compared with their lowest tertile, the high tertiles of K [OR:2.45 (1.67-4.43)], Li [OR: 1.89 (1.06-3.42)], and Cs [OR: 1.97 (1.10-3.54)] were significantly associated with the odds of DOR. The BKMR model reported that the DOR likelihood increased linearly across the 25th through 75th percentiles of the nine-AE/AEE mixture, while the AE group contributed more to the overall effect. CONCLUSION: This study revealed an association in which the likelihood of DOR increased with higher overall concentrations of AE/AEEs in follicular fluid. Among the nine detected elements, K, Li, and Cs exhibited significant individual associations with DOR. We provide new clues for the environmental factors on female fertility decline. TRIAL REGISTRATION: Retrospectively registered.

Bacterial community analysis of the skin microbiota of cultured Chinese giant salamander infected with Ranavirus.

Skin microorganisms are an important component of host innate immunity and serve as the first line of defense against pathogenic infections. The relative abundance of bacterial species, microbial community assembly, and secretion of specific bacterial metabolites are closely associated with host health. In this study, we investigated the association between the skin microbiome and Ranavirus, and compared the bacterial community assemblage, alpha and beta diversity, and functional predictions of the skin bacterial assemblage in cultured healthy Chinese giant salamanders (Andrias davidianus) and individuals infected with Chinese giant salamander iridovirus (GSIV or ADRV). To achieve this, we employed 16S rRNA amplicon sequencing. The results identified Proteobacteria, Firmicutes, Bacteroidota, and Actinobacteriota as the dominant phyla in the diseased and healthy groups. Alpha diversity analysis indicated that the skin bacterial community in the diseased group exhibited no significant differences in bacterial species diversity and lower species richness compared to the healthy group. Beta diversity suggested that the two group bacterial community was quite different. Kyoto encyclopedia of genes and genomes (KEGG) pathway analyze and clusters of orthologous groups of proteins (COG) function predictions revealed that changes and variations occurred in the metabolic pathways and function distribution of skin bacterial communities in two groups.

Rotational Load Fatigue Performance of a One-Size Implant- Abutment Connection System.

PURPOSE: One-size implant-abutment (OSIA) connection systems have been developed for simplicity of clinical use and for a range of implant diameters. The aim of this in vitro study was to investigate the rotational load fatigue performance of different implant diameters and abutment platforms of an OSIA connection system. METHODOLOGY: Narrow, regular and wide diameter implants were tested with Regular Base (RB/WB) abutments of an OSIA system (Straumann. BLX). Wide diameter implants were also tested with Wide Base (WB) abutments. This resulted in 4 test groups (n=5): N-RB/WB (Narrow, 3.5mm, RB/WB abutment), R-RB/WB (Regular, 4.0mm, RB/WB abutment), W-RB/WB (Wide, 5.0mm, RB/WB abutment) and W-WB (Wide, 5.0mm, WB abutment). A rotational load fatigue machine applied a sinusoidally varying stress at an angle of 45o, producing an effective bending moment of 35Ncm at a frequency of 10 Hz in air at 20 oC. The number of cycles to failure was recorded. Results were evaluated using ANOVA. Failed specimens were examined with SEM to evaluate the failure mode. Pristine specimens were sectioned to examine the implant-abutment connection. RESULTS: All specimens in the 3 test groups with RB/WB abutments failed within the range of 558,750 cycles to 4,497,619 cycles, while the W-WB test group reached the upper limit of 5 million cycles without failure. Significant difference was found between abutment platforms (P < .001). There were no significant differences found for implant diameters (P =.857). However, with increasing implant diameter, implant fracture was less common and the location of failure was more coronal and consistently at the level of the implant platform for the abutment, and at the screw neck. CONCLUSIONS: For wide diameter implants, WB abutments exhibited a superior fatigue performance than RB/WB abutments, and would be preferred in situations of high mechanical risk. Increasing implant diameter, when used with RB/WB abutments, did not improve fatigue performance due to the one-size prosthetic connection, but failures were less catastrophic, and coronally located, which may be advantageous in managing failures.

Exposure to heavy metallic and trace essential elements and risk of diminished ovarian reserve in reproductive age women: A case-control study.

The associations between metallic elements and ovarian reserve function have remained uncertain yet. In this case-control study, we involved 149 women with diminished ovarian reserve (DOR) and 151 women with normal ovarian reserve, and assessed the levels of six heavy metallic (Cr, Cd, As, Hg, Pb, and Mn) and seven trace essential (Se, Fe, Zn, Co, Mo, Cu, I) elements in their follicular fluid with inductively coupled plasma mass spectrometry. Associations were examined with logistic regressions and Bayesian kernel machine regression (BKMR). As a result, we found that the medium and the highest tertiles of Pb were significantly associated with an increased likelihood of DOR compared to the lowest tertile, while the medium or/an the highest tertiles of Cu, I, and Fe showed significantly lower likelihoods of DOR compared to the lowest tertiles. Cu and Pb showed significantly non-linear associations with ovarian reserve markers such as follicle-stimulating, anti-mullerian hormone levels, and antral follicle count. With the rising overall concentrations of heavy metals, the likelihood of DOR increased although not significant. There was a trend of a "U-shaped" association across the whole concentration range of trace essential elements and the likelihood of DOR. Our study revealed that avoiding heavy metallic elements and properly supplementing trace essential elements are conducive to ovarian function.

Federated attention consistent learning models for prostate cancer diagnosis and Gleason grading.

Artificial intelligence (AI) holds significant promise in transforming medical imaging, enhancing diagnostics, and refining treatment strategies. However, the reliance on extensive multicenter datasets for training AI models poses challenges due to privacy concerns. Federated learning provides a solution by facilitating collaborative model training across multiple centers without sharing raw data. This study introduces a federated attention-consistent learning (FACL) framework to address challenges associated with large-scale pathological images and data heterogeneity. FACL enhances model generalization by maximizing attention consistency between local clients and the server model. To ensure privacy and validate robustness, we incorporated differential privacy by introducing noise during parameter transfer. We assessed the effectiveness of FACL in cancer diagnosis and Gleason grading tasks using 19,461 whole-slide images of prostate cancer from multiple centers. In the diagnosis task, FACL achieved an area under the curve (AUC) of 0.9718, outperforming seven centers with an average AUC of 0.9499 when categories are relatively balanced. For the Gleason grading task, FACL attained a Kappa score of 0.8463, surpassing the average Kappa score of 0.7379 from six centers. In conclusion, FACL offers a robust, accurate, and cost-effective AI training model for prostate cancer pathology while maintaining effective data safeguards.

Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy.

The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with self-stimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

Rapid identification of SARS-CoV-2 variants using stable high-frequency mutation sites.

Respiratory infectious viruses, including SARS-CoV-2, undergo rapid genetic evolution, resulting in diverse subtypes with complex mutations. Detecting and differentiating these subtypes pose significant challenges in respiratory virus surveillance. To address these challenges, we integrated ARMS-PCR with molecular beacon probes, allowing selective amplification and discrimination of subtypes based on adjacent mutation sites. The method exhibited high specificity and sensitivity, detecting as low as 104 copies/mL via direct fluorescence analysis and ~106 copies/mL using real-time PCR. Our robust detection approach offers a reliable and efficient solution for monitoring evolving respiratory infections, aiding early diagnosis and control measures. Further research could extend its application to other respiratory viruses and optimize its implementation in clinical settings.

A Sustainable Retinal Drug Co-Delivery for Boosting Therapeutic Efficacy in wAMD: Unveiling Multifaceted Evidence and Synergistic Mechanisms.

Sustainable retinal codelivery poses significant challenges technically, although it is imperative for synergistic treatment of wet age-related macular degeneration (wAMD). Here, a microemulsion-doped hydrogel (Bor/PT-M@TRG) is engineered as an intravitreal depot composing of temperature-responsive hydrogel (TRG) and borneol-decorated paeoniflorin (PF) & tetramethylpyrazine (TMP)-coloaded microemulsions (Bor/PT-M). Bor/PT-M@TRG, functioning as the "ammunition depot", resides in the vitreous and continuously releases Bor/PT-M as the therapeutic "bullet", enabling deep penetration into the retina for 21 days. A single intravitreal injection of Bor/PT-M@TRG yields substantial reductions in choroidal neovascularization (CNV, a hallmark feature of wAMD) progression and mitigates oxidative stress-induced damage in vivo. Combinational PF&TMP regulates the "reactive oxygen species/nuclear factor erythroid-2-related factor 2/heme oxygenase-1" pathway and blocks the "hypoxia inducible factor-1α/vascular endothelial growth factor" signaling in retina, synergistically cutting off the loop of CNV formation. Utilizing fluorescence resonance energy transfer and liquid chromatography-mass spectrometry techniques, they present compelling multifaceted evidence of sustainable retinal codelivery spanning formulations, ARPE-19 cells, in vivo eye balls, and ex vivo section/retina-choroid complex cell levels. Such codelivery approach is elucidated as the key driving force behind the exceptional therapeutic outcomes of Bor/PT-M@TRG. These findings highlight the significance of sustainable retinal drug codelivery and rational combination for effective treatment of wAMD.

Sensing and regulation of long-chain polyunsaturated fatty acids pool in marine mollusks: Characterization of UBXD8 from the razor clam Sinonovacula constricta.

The razor clam Sinonovacula constricta is known for its richness in long-chain polyunsaturated fatty acids (LC-PUFA, C ≥ 20). Previously, we demonstrated that it possesses a complete LC-PUFA biosynthetic pathway. However, the mechanisms by which it senses the LC-PUFA pool to regulate their biosynthesis remain unclear. Here, we presented the LC-PUFA sensor UBXD8 as a critical molecule in this intriguing process. The S. constricta UBXD8 (ScUBXD8) shared all characteristic features of its mammalian counterpart and exhibited high mRNA levels in digestive tissues, suggesting its functional role in this bivalve species. By purification of ScUBXD8 protein in vitro, we discovered its ability to sense unsaturated fatty acids (UFA, C ≥ 14) but not saturated ones, as evidenced by polymerization detection. Furthermore, the intensity of ScUBXD8 polymerization increased progressively with longer acyl chain lengths, greater unsaturation degrees, and higher UFA concentrations. Exceptionally, for those located at the same node in LC-PUFA biosynthetic pathway, ScUBXD8 displayed a stronger sensitivity to n-6 UFA compared to n-3 UFA. These results suggested a critical role for ScUBXD8 in balancing fatty acids composition and ratio of n-6/n-3 UFA in S. constricta. Moreover, the UAS domain was confirmed essential for ScUBXD8 polymerization. Through knockdown of ScUbxd8 gene in vivo, there were significant shifts in expression patterns of genes related to LC-PUFA biosynthesis, concurrently influencing fatty acids compositions. These results suggested that ScUBXD8 likely plays a regulatory role in LC-PUFA biosynthesis, possibly through the INSIG-SREBP pathway. Collectively, this study proposed that S. constricta might maintain LC-PUFA homeostasis through UBXD8 to regulate their biosynthesis.

Cell-free DNA testing for early hepatocellular carcinoma surveillance.

BACKGROUND: Liver cirrhosis (LC) is the highest risk factor for hepatocellular carcinoma (HCC) development worldwide. The efficacy of the guideline-recommended surveillance methods for patients with LC remains unpromising. METHODS: A total of 4367 LCs not previously known to have HCC and 510 HCCs from 16 hospitals across 11 provinces of China were recruited in this multi-center, large-scale, cross-sectional study. Participants were divided into Stage Ⅰ cohort (510 HCCs and 2074 LCs) and Stage Ⅱ cohort (2293 LCs) according to their enrollment time and underwent Tri-phasic CT/enhanced MRI, US, AFP, and cell-free DNA (cfDNA). A screening model called PreCar Score was established based on five features of cfDNA using Stage Ⅰ cohort. Surveillance performance of PreCar Score alone or in combination with US/AFP was evaluated in Stage Ⅱ cohort. FINDINGS: PreCar Score showed a significantly higher sensitivity for the detection of early/very early HCC (Barcelona stage A/0) in contrast to US (sensitivity of 51.32% [95% CI: 39.66%-62.84%] at 95.53% [95% CI: 94.62%-96.38%] specificity for PreCar Score; sensitivity of 23.68% [95% CI: 14.99%-35.07%] at 99.37% [95% CI: 98.91%-99.64%] specificity for US) (P < 0.01, Fisher's exact test). PreCar Score plus US further achieved a higher sensitivity of 60.53% at 95.08% specificity for early/very early HCC screening. INTERPRETATION: Our study developed and validated a cfDNA-based screening tool (PreCar Score) for HCC in cohorts at high risk. The combination of PreCar Score and US can serve as a promising and practical strategy for routine HCC care. FUNDING: A full list of funding bodies that contributed to this study can be found in Acknowledgments section.

Lipid-based nanoparticles to address the limitations of GBM therapy by overcoming the blood-brain barrier, targeting glioblastoma stem cells, and counteracting the immunosuppressive tumor microenvironment.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, characterized by high heterogeneity, strong invasiveness, poor prognosis, and a low survival rate. A broad range of nanoparticles have been recently developed as drug delivery systems for GBM therapy owing to their inherent size effect and ability to cross the blood-brain barrier (BBB). Lipid-based nanoparticles (LBNPs), such as liposomes, solid lipid NPs (SLNs), and nano-structured lipid carriers (NLCs), have emerged as the most promising drug delivery system for the treatment of GBM because of their unique size, surface modification possibilities, and proven bio-safety. In this review, the main challenges of the current clinical treatment of GBM and the strategies on how novel LBNPs overcome them were explored. The application and progress of LBNP-based drug delivery systems in GBM chemotherapy, immunotherapy, and gene therapy in recent years were systematically reviewed, and the prospect of LBNPs for GBM treatment was discussed.

Eyeless razor clam Sinonovacula constricta discriminates light spectra through opsins to guide Ca2+ and cAMP signaling pathways.

Phototransduction is based on opsins that drive distinct types of Gα cascades. Although nonvisual photosensitivity has long been known in marine bivalves, the underlying molecular basis and phototransduction mechanism are poorly understood. Here, we introduced the eyeless razor clam Sinonovacula constricta as a model to clarify this issue. First, we showed that S. constricta was highly diverse in opsin family members, with a significant expansion in xenopsins. Second, the expression of putative S. constricta opsins was highly temporal-spatio specific, indicating their potential roles in S. constricta development and its peripheral photosensitivity. Third, by cloning four S. constricta opsins with relatively higher expression (Sc_opsin1, 5, 7, and 12), we found that they exhibited different expression levels in response to different light environments. Moreover, we demonstrated that these opsins (excluding Sc_opsin7) couple with Gαq and Gαi cascades to mediate the light-dependent Ca2+ (Sc_opsin1 and 5) and cAMP (Sc_opsin12) signaling pathways. The results indicated that Sc_opsin1 and 5 belonged to Gq-opsins, Sc_opsin12 belonged to Gi-opsins, while Sc_opsin7 might act as a photo-isomerase. Furthermore, we found that the phototransduction function of S. constricta Gq-opsins was dependent on the lysine at the seventh transmembrane domain, and greatly influenced by the external light spectra in a complementary way. Thus, a synergistic photosensitive system mediated by opsins might exist in S. constricta to rapidly respond to the transient or subtle changes of the external light environment. Collectively, our findings provide valuable insights into the evolution of opsins in marine bivalves and their potential functions in nonvisual photosensitivity.