MiR-125a-5p regulates the radiosensitivity of laryngeal squamous cell carcinoma via HK2 targeting through the DDR pathway.

Objective: To determine the function of miR-125a-5p in laryngeal squamous cell carcinoma (LSCC), its correlation with radiation sensitivity, and the underlying regulatory mechanism. Materials and methods: We conducted the analysis on the correlation between miR-125a-5p and head and neck squamous cell carcinoma (HNSCC) using data obtained from The Cancer Genome Atlas (TCGA). The putative gene targeted by miR-125a-5p has been identified as HK2, while the expression levels of miR-125a-5p and HK2 were measured in laryngeal cancer tissues and cells using RT-PCR. MiR-125a-5p and HK2 were introduced into the lentiviral vector and the vector was used to transfect AMC-HN-8 cells. The roles of miR-125a-5p and HK2 in LSCC and on radiosensitivity were determined by evaluating cell growth, examining colony formation, analyzing flow cytometry, and utilizing the single hit multi-target model. Western blotting was used to measure H2AX and rH2AX levels in the DNA damage response (DDR) pathway. The validation of the interaction between miR-125a-5p and HK2 was conducted through the dual-luciferase assay. To further confirm the association between miR-125a-5p and HK2, as well as its influence on radiosensitivity, rescue experiments were performed. Results: The expression of miR-125a-5p is downregulated in LSCC, while upregulating its expression could suppress cell growth, induce apoptosis, and enhance radiosensitivity. Additionally, HK2 exhibited high expression in LSCC and the biological function was opposite to miR-125a-5p. Western blotting analysis revealed that miR-125a-5p increased rH2AX levels and decreased H2AX levels, conversely, HK2 had the opposite effect on miR-125a-5p. These findings suggested that HK2 may serve as the target gene of miR-125a-5p. The double luciferase assay confirmed the binding of HK2 to miR-125a-5p, and rescue trials confirmed the role of miR-125a-5p in regulating the effects and radiation sensitivity of LSCC by targeting HK2 via the DDR pathway. Conclusion: By targeting HK2 and impacting the DDR pathway, miR-125a-5p has been found to inhibit cellular proliferation, enhance apoptosis, and heighten radiosensitivity in LSCC.

SCD2 Regulation Targeted by miR-200c-3p on Lipogenesis Alleviates Mesenchymal Stromal Cell Senescence.

The senescence of bone marrow mesenchymal stromal cells (MSCs) leads to the impairment of stemness and osteogenic differentiation capacity. In a previous study, we screened out stearoyl-CoA desaturase 2 (SCD2), the most evidently changed differential gene in lipid metabolism, using combined transcriptomic and metabolomic analyses, and verified that SCD2 could mitigate MSC senescence. However, the underlying molecular mechanism by which the rate-limiting enzyme of lipogenesis SCD2 manipulates MSC senescence has not been completely understood. In this study, we demonstrate that SCD2 over-expression alleviates MSC replicative senescence and ameliorates their osteogenic differentiation through the regulation of lipogenesis. Furthermore, SCD2 expression is reduced, whereas miR-200c-3p expression is elevated in replicative senescent MSCs. SCD2 is the direct target gene of miR-200c-3p, which can bind to the 3'-UTR of SCD2. MiR-200c-3p replenishment in young MSCs is able to diminish SCD2 expression levels due to epigenetic modulation. In addition, SCD2-rescued MSC senescence and enhanced osteogenic differentiation can be attenuated by miR-200c-3p repletion via suppressing lipogenesis. Taken together, we reveal the potential mechanism of SCD2 influencing MSC senescence from the perspective of lipid metabolism and epigenetics, which provides both an experimental basis for elucidating the mechanism of stem cell senescence and a novel target for delaying stem cell senescence.

Transcriptomics integrated with metabolomics reveals partial molecular mechanisms of nutritional risk and neurodevelopment in children with congenital heart disease.

Purpose: To explore molecular mechanisms affecting nutritional risk and neurodevelopment in children with congenital heart disease (CHD) by combining transcriptome and metabolome analysis. Methods: A total of 26 blood and serum samples from 3 groups of children with CHD low nutritional risk combined with normal neurodevelopment (group A), low nutritional risk combined with neurodevelopmental disorders (group B) and high nutritional risk combined with normal neurodevelopment (group C) were analyzed by transcriptome and metabolomics to search for differentially expressed genes (DEGs) and metabolites (DEMs). Functional analysis was conducted for DEGs and DEMs. Further, the joint pathway analysis and correlation analysis of DEGs and DEMs were performed. Results: A total of 362 and 1,351 DEGs were detected in group B and C compared to A, respectively. A total of 6 and 7 DEMs were detected in group B and C compared to A in positive mode, respectively. There were 39 and 31 DEMs in group B and C compared to A in negative mode. Transcriptomic analysis indicated that neurodevelopment may be regulated by some genes such as NSUN7, SLC6A8, CXCL1 and LCN8, nutritional risk may be regulated by SLC1A3 and LCN8. Metabolome analysis and joint pathway analysis showed that tryptophan metabolism, linoleic and metabolism and glycerophospholipid metabolism may be related to neurodevelopment, and glycerophospholipid metabolism pathway may be related to nutritional risk. Conclusion: By integrating transcriptome and metabolome analyses, this study revealed key genes and metabolites associated with nutritional risk and neurodevelopment in children with CHD, as well as significantly altered pathways. It has important clinical translational significance.

A Degradable Bioelectronic Scaffold for Localized Cell Transfection toward Enhancing Wound Healing in a 3D Space.

Large skin wounds, with extensive surface area and deep vertical full-thickness involvement, can pose significant challenges in clinical settings. Traditional routes for repairing skin wounds encompass three hallmarks: 1) scab formation for hemostasis; 2) proliferation and migration of epidermal cells for wound closure; 3) proliferation, migration, and functionalization of fibroblasts and endothelial cells for dermal remodeling. However, this route face remarkable challenges to healing large wounds, usually leading to disordered structures and loss of functions in the regenerated skin, due to limited control on the transition among the three stages. In this work, an implantable bioelectronics is developed that enables the synchronization of the three stages, offering accelerated and high-quality healing of large skin wounds. The system efficiently electro-transfect local cells near the wounds, forcing cellular proliferation, while providing a 3D porous environments for synchronized migration of epidermal and dermal cells. In vivo experiments demonstrated that the system achieved synchronous progression of multiple layers within the wounds, leading to the reconstruction of a complete skin structure similar to healthy skin, which presents a new avenue for the clinical translation of large wound healing.

Exploration of Response Mechanisms in the Gills of Pacific Oyster (Crassostrea gigas) to Cadmium Exposure through Integrative Metabolomic and Transcriptomic Analyses.

Marine mollusks, including oysters, are highly tolerant to high levels of cadmium (Cd), but the molecular mechanisms underlying their molecular response to acute Cd exposure remain unclear. In this study, the Pacific oyster Crassostrea gigas was used as a biological model, exposed to acute Cd stress for 96 h. Transcriptomic analyses of their gills were performed, and metabolomic analyses further validated these results. In our study, a total of 111 differentially expressed metabolites (DEMs) and 2108 differentially expressed genes (DEGs) were identified under acute Cd exposure. Further analyses revealed alterations in key genes and metabolic pathways associated with heavy metal stress response. Cd exposure triggered physiological and metabolic responses in oysters, including enhanced oxidative stress and disturbances in energy metabolism, and these changes revealed the biological response of oysters to acute Cd stress. Moreover, oysters could effectively enhance the tolerance and detoxification ability to acute Cd exposure through activating ABC transporters, enhancing glutathione metabolism and sulfur relay system in gill cells, and regulating energy metabolism. This study reveals the molecular mechanism of acute Cd stress in oysters and explores the molecular mechanism of high tolerance to Cd in oysters by using combined metabolomics and transcriptome analysis.

Revealing Cellular Heterogeneity and Key Regulatory Factors of Triple-Negative Breast Cancer through Single-Cell RNA Sequencing.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). TNBC has a poor prognosis due to high intratumoral heterogeneity and metastasis, pointing to the need to explore distinct molecular subtypes and gene regulatory networks. METHODS: The scRNA-seq data of five primary BC samples were downloaded from the Gene Expression Omnibus (GEO) database. Clustering was performed based on filtered and normalized data using the Seurat R package to identify marker genes, which were subsequently annotated to each subset using the CellMarker database. AUCell R package was applied to calculate the hallmark score for each epithelial cell. Marker genes of each subset were screened with FindAllMarkers and their biological functions were analyzed using the Database for Annotation Visualization and Integrated Discovery (DAVID) database. Next, cell-cell communication was performed with the CellChat R package. To identify the key regulatory genes, single-cell regulatory network inference and clustering (SCENIC) analysis was conducted. Finally, the expression and potential biological functions of the key regulatory factors were verified through cellular experiments. RESULTS: A total of 29,101 cells were classified into nine cell subsets, namely, Fibroblasts, Fibroepithelial cells, Epithelial cells 1, Epithelial cells 2, Epithelial cells 3, Endothelial cells, T cells, Plasma B cells and Macrophages. Particularly, the epithelial cells had a higher proportion and higher transforming growth factor-ß (TGF-ß) activity in the TNBC pathotype as compared to the non-TNBC pathotype. Furthermore, four epithelial cell subsets (marked as Stearoyl-CoA Desaturase (SCD1), marker of proliferation Ki67 (MKI67), Annexin A3 (ANXA3) and aquaporin 5 (AQP5)) were identified as having the greatest impact on the TNBC pathotype. Cell-cell interaction analysis revealed that ANXA3-epithelial cell subset suppressed the T cell function through different mechanisms. C-fos gene (FOS) and X-box binding protein 1 (XBP1) were considered critical regulons involved in TNBC progression. Notably, cellular experiments demonstrated that silencing XBP1 and overexpressing FOS inhibited cancer cell invasion. CONCLUSION: The four epithelial cell subsets and two critical regulons identified based on the scRNA-seq data could help explore the underlying intratumoral heterogeneity molecular mechanism and develop effective therapies for TNBC.

Chromosome-level genome assembly of a deep-sea Venus flytrap sea anemone sheds light upon adaptations to an extremely oligotrophic environment.

The Venus flytrap sea anemone Actinoscyphia liui inhabits the nutrient-limited deep ocean in the tropical western Pacific. Compared with most other sea anemones, it has undergone a distinct modification of body shape similar to that of the botanic flytrap. However, the molecular mechanism by which such a peculiar sea anemone adapts to a deep-sea oligotrophic environment is unknown. Here, we report the chromosomal-level genome of A. liui constructed from PacBio and Hi-C data. The assembled genome is 522 Mb in size and exhibits a continuous scaffold N50 of 58.4 Mb. Different from most other sea anemones, which typically possess 14-18 chromosomes per haplotype, A. liui has only 11. The reduced number of chromosomes is associated with chromosome fusion, which likely represents an adaptive strategy to economize energy in oligotrophic deep-sea environments. Comparative analysis with other deep-sea sea anemones revealed adaptive evolution in genes related to cellular autophagy (TMBIM6, SESN1, SCOCB and RPTOR) and mitochondrial energy metabolism (MDH1B and KAD2), which may aid in A. liui coping with severe food scarcity. Meanwhile, the genome has undergone at least two rounds of expansion in gene families associated with fast synaptic transmission, facilitating rapid responses to water currents and prey. Positive selection was detected on putative phosphorylation sites of muscle contraction-related proteins, possibly further improving feeding efficiency. Overall, the present study provides insights into the molecular adaptation to deep-sea oligotrophic environments and sheds light upon potential effects of a novel morphology on the evolution of Cnidaria.

Regulation of Hippo/YAP axis in colon cancer progression by the deubiquitinase JOSD1.

Colon cancer is a prevalent malignancy, while recent studies revealed the dys-regulation of Hippo signaling as the important driver for colon cancer progression. Several studies have indicated that post-translational modifications on YAP play crucial roles in both Hippo signaling activity and cancer progression. This raises a puzzling question about why YAP/TAZ, an auto-inhibitory pathway, is frequently over-activated in colon cancer, despite the suppressive cascade of Hippo signaling remaining operational. The protein stability of YAP is subject to a tiny balance between ubiquitination and deubiquitination processes. Through correlation analysis of DUBs (deubiquitinases) expression and Hippo target gene signature in colon cancer samples, we found JOSD1 as a critical deubiquitinase for Hippo signaling and colon cancer progression. JOSD1 could facilitate colon cancer progression and in colon cancer, inhibition of JOSD1 via shRNA has been demonstrated to impede tumorigenesis. Furthermore, molecular mechanism studies have elucidated that JOSD1 enhances the formation of the Hippo/YAP transcriptome by impeding K48-linked polyubiquitination on YAP. ChIP assays have shown that YAP binds to JOSD1's promoter region, promoting its gene transcription. These results suggest that JOSD1 is involved in both activating and being targeted by the Hippo signaling pathway in colon cancer. Consequently, a positive regulatory loop between JOSD1 and Hippo signaling has been identified, underscoring their interdependence during colon cancer progression. Thus, targeting JOSD1 may represent a promising therapeutic approach for managing colon cancer.

Molecular regulation of DNA damage and repair in female infertility: a systematic review.

DNA damage is a key factor affecting gametogenesis and embryo development. The integrity and stability of DNA are fundamental to a woman's successful conception, embryonic development, pregnancy and the production of healthy offspring. Aging, reactive oxygen species, radiation therapy, and chemotherapy often induce oocyte DNA damage, diminished ovarian reserve, and infertility in women. With the increase of infertility population, there is an increasing need to study the relationship between infertility related diseases and DNA damage and repair. Researchers have tried various methods to reduce DNA damage in oocytes and enhance their DNA repair capabilities in an attempt to protect oocytes. In this review, we summarize recent advances in the DNA damage response mechanisms in infertility diseases such as PCOS, endometriosis, diminished ovarian reserve and hydrosalpinx, which has important implications for fertility preservation.

Loss of clear cell characteristics in aggressive clear cell odontogenic carcinoma: a case report.

BACKGROUND: Clear cell odontogenic carcinoma (CCOC) is an odontogenic carcinoma characterized by sheets and islands of vacuolated and clear cells. The diagnosis of atypical CCOC can pose a challenge when tumor cells deviate from their characteristic clear morphology, even with the aid of genetic profiling for CCOC identification. CASE PRESENTATION: In this manuscript, we detailed the inaugural instance of a recurrently recurring clear cell odontogenic carcinoma (CCOC) with pronounced squamous differentiation in a 64-year-old male. The primary tumor in this individual initially displayed a biphasic clear cell phenotype. However, subsequent to the third recurrence, the clear tumor cells were entirely supplanted by epidermoid cells characterized by eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. Notable aggressive attributes such as necrosis, conspicuous cytological malignancy, perineural dissemination, and vascular invasion were noted. Additionally, the tumor progressed to manifest lung metastases. The tumor cells exhibited positive immunoreactivity for AE1/AE3, KRT19, Pan-CK, EMA, P40, P63, CK34ßE12, and P53, while they tested negative for CK35ßH11, KRT7, S-100, and neuroendocrine markers. The Ki-67 proliferation index was calculated at an average of 15%. Furthermore, FISH analysis unveiled the presence of the EWSR1::ATF1 gene fusion. CONCLUSIONS: This case illustrated a rare and aggressive case of CCOC characterized by significant squamous differentiation upon recurrence of the tumor.

Meaningful nomograms based on systemic immune inflammation index predicted survival in metastatic pancreatic cancer patients receiving chemotherapy.

OBJECTIVE: The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. METHODS: This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut-off value. The Kaplan-Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). RESULTS: The best cut-off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional-hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. CONCLUSION: We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.

Methylobacterium amylolyticum sp. nov. and Methylobacterium ligniniphilum sp. nov., isolated from soil.

Two pink-pigmented bacteria, designated strains NEAU-140T and NEAU-KT, were isolated from field soil collected from Linyi, Shandong Province, PR China. Both isolates were aerobic, Gram-stain-negative, rod-shaped, and facultatively methylotrophic. 16S rRNA gene sequences analysis showed that these two strains belong to the genus Methylobacterium. Strain NEAU-140T exhibited high 16S rRNA gene sequence similarities to Methylobacterium radiotolerans NBRC 15690T (97.43 %) and Methylobacterium phyllostachyos NBRC 105206T (97.36 %). Strain NEAU-KT exhibited high 16S rRNA gene sequence similarities to M. phyllostachyos NBRC 105206T (99.00 %) and Methylobacterium longum DSM 23933T (98.72 %). A phylogenetic tree based on 16S rRNA gene sequences showed that strain NEAU-140T formed a clade with Methylobacterium aerolatum (95.94 %), Methylobacterium persicinum (95.66 %) and Methylobacterium komagatae (96.87 %), and strain NEAU-KT formed a cluster with M. phyllostachyos and M. longum. The predominant fatty acid in both strains was C18 : 1 ω7c. Both strains contained ubiquinone Q-10 as the only respiratory quinone. The polar lipid profiles of both strains contained diphosphatidylglycerol, phosphatidylethanolamine, and phosphatidylcholine. Whole-genome phylogeny showed that strains NEAU-140T and NEAU-KT formed a phyletic line with M. aerolatum, M. persicinum, Methylobacterium radiotolerans, Methylobacterium fujisawaense, Methylobacterium oryzae, Methylobacterium tardum, M. longum and M. phyllostachyos. The orthologous average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain NEAU-140T and its closely related strains were lower than 82.62 and 25.90  %, respectively. The ANI and dDDH values between strain NEAU-KT and its closely related strains were lower than 86.29 and 31.7 %, respectively. The genomic DNA G+C contents were 71.63 mol% for strain NEAU-140T and 69.08 mol% for strain NEAU-KT. On the basis of their phenotypic and phylogenetic distinctiveness and the results of dDDH and ANI hybridization, these two isolates represent two novel species within the genus Methylobacterium, for which the names Methylobacterium amylolyticum sp. nov. (type strain NEAU-140T=MCCC 1K08801T=DSM 110568T) and Methylobacterium ligniniphilum sp. nov. (type strain NEAU-KT=MCCC 1K08800T=DSM 110567T) are proposed.

YAP represses the TEAD-NF-κB complex and inhibits the growth of clear cell renal cell carcinoma.

The Hippo pathway is generally understood to inhibit tumor growth by phosphorylating the transcriptional cofactor YAP to sequester it to the cytoplasm and reduce the formation of YAP-TEAD transcriptional complexes. Aberrant activation of YAP occurs in various cancers. However, we found a tumor-suppressive function of YAP in clear cell renal cell carcinoma (ccRCC). Using cell cultures, xenografts, and patient-derived explant models, we found that the inhibition of upstream Hippo-pathway kinases MST1 and MST2 or expression of a constitutively active YAP mutant impeded ccRCC proliferation and decreased gene expression mediated by the transcription factor NF-κB. Mechanistically, the NF-κB subunit p65 bound to the transcriptional cofactor TEAD to facilitate NF-κB-target gene expression that promoted cell proliferation. However, by competing for TEAD, YAP disrupted its interaction with NF-κB and prompted the dissociation of p65 from target gene promoters, thereby inhibiting NF-κB transcriptional programs. This cross-talk between the Hippo and NF-κB pathways in ccRCC suggests that targeting the Hippo-YAP axis in an atypical manner-that is, by activating YAP-may be a strategy for slowing tumor growth in patients.

Pilose antler extracts promotes hair growth in androgenetic alopecia mice by activating hair follicle stem cells via the AKT and Wnt pathways.

Background: Angrogenetic alopecia (AGA) is one of the most prevalent hair loss disorders worldwide. The hair follicle stem cell (HFSC) is closely related to the formation of hair follicle (HF) structure and HF self-renewal. The activation of HFSC in AGA is critical for hair growth. Pilose antler has been reported to have hair growth-promoting activity, but the mechanism of action on AGA and HFSC has not been reported. Methods: We previously extracted an active component from the pilose antler known as PAEs. In this study, we conducted experiments using AGA mice and HFSC. The effects of PAEs on hair growth in AGA mice were firstly detected, and then the mechanisms of PAEs for AGA were predicted by integrating network pharmacology and de novo transcriptomics data of pilose antler. Finally, biological experiments were used to validate the molecular mechanism of PAEs in treating AGA both in vivo and in vitro. Results: It was found that PAEs promoted hair regrowth by accelerating the activation of anagen, delaying the anagen-catagen transition. It also alleviated the morphological changes, such as hair shortening, thinning, miniaturization, and HF number reduction, and regulated the hair regeneration process of four subtypes of hair. We further found that PAEs could promote the proliferation of HFSC, outer root sheath (ORS) cells, and hair bulb cells in AGA mice. We then integrated network pharmacology and pilose antler transcriptomics data to predict that the mechanism of PAEs treatment in AGA mice is closely related to the PI3K-AKT/Wnt-ß-Catenin pathways. Subsequently, it was also verified that PAEs could activate both pathways in the skin of AGA mice. In addition, we found that PAEs perhaps increased the number of blood vessels around dermal papilla (DP) in experiments in vivo. Meanwhile, the PAEs stimulated the HFSC proliferation in vitro and activated the AKT and Wnt pathways. However, the proliferative activity of HFSC was inhibited after blocking the Wnt pathway and AKT activity. Conclusion: This study suggests that the hair growth-promoting effect of PAEs in AGA mice may be closely related to the stimulation of the AKT and Wnt pathways, which in turn activates the proliferation of HFSC.

MiR-34a-HK1 signal axis retards bone marrow mesenchymal stem cell senescence via ameliorating glycolytic metabolism.

BACKGROUND: Mesenchymal stem cells (MSCs) are one of the most widely studied adult stem cells, while MSC replicative senescence occurs with serial expansion in vitro. We determined whether miR-34a can regulate MSC senescence by directly targeting glycolytic key enzymes to influence glycolysis. METHODS: Detected the effects of miR-34a on MSC senescence and glycolytic metabolism through gene manipulation. Bioinformatics prediction and luciferase reporter assay were applied to confirm that HK1 is a direct target of miR-34a. The underlying regulatory mechanism of miR-34a targeting HK1 in MSC senescence was further explored by a cellular function recovery experiment. RESULTS: In the current study, we revealed that miR-34a over-expression exacerbated senescence-associated characteristics and impaired glycolytic metabolism. Then we identified hexokinase1 (HK1) as a direct target gene of miR-34a. And HK1 replenishment reversed MSC senescence and reinforced glycolysis. In addition, miR-34a-mediated MSC senescence and lower glycolytic levels were evidently rescued following the co-treatment with HK1 over-expression. CONCLUSION: The miR-34a-HK1 signal axis can alleviate MSC senescence via enhancing glycolytic metabolism, which possibly provides a novel mechanism for MSC senescence and opens up new possibilities for delaying and suppressing the occurrence and development of aging and age-related diseases.

Residual distribution and risk assessment of neonicotinoids in urban green space soils of the pearl river delta, South China: A socioeconomic analysis.

Urban green spaces are the soil component in cities that interacts most closely with humans. This study investigated the residues of seven neonicotinoids (NEOs) in soils from urban green spaces within the Pearl River Delta (PRD) region and analyzed the correlation between the residue characteristics and the region's economic development. Notably, we introduced the Nemerow Index method, a comprehensive approach, to quantify the overall pollution level of NEOs in the soil of urban park green spaces and utilized this to assess the cumulative exposure probability risks for different populations in this scenario. We found that: (1) The soil of urban park green spaces exhibited varying degrees of NEOs contamination (Σ7NEOs: N.D.-137.31; 6.25 µg/kg), with imidacloprid and clothianidin constituting the highest proportions (89.46 % and 83.60 %); (2) The residual levels of NEOs in Children's Park were significantly higher than those in community parks within Guangzhou, with an average value of 13.30 µg/kg compared to 3.30 µg/kg; (3) The residual characteristics of NEOs exhibited a positive correlation with regional economic development; specifically, the per capita GDP well correlated with IMIRPF, a summation of seven NEOs in imidacloprid equivalents via relative potency factors (R2 =0.86). Regions with higher economic development typically exhibited elevated IMIRPF levels; (4) The fitted cumulative probability distributions for average daily exposure doses revealed that children's exposure was an order of magnitude higher than adults'. Despite this, the exposure risks for both groups remained within acceptable limits.

PGC-1α agonism induces fetal hemoglobin and exerts antisickling effects in sickle cell disease.

Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. Additional pharmacologic agents to induce sufficient fetal hemoglobin to diminish clinical severity is an unmet medical need. We recently found that up-regulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecule, SR-18292, increases PGC-1α leading to enhanced fetal hemoglobin expression in human erythroid cells, ß-globin yeast artificial chromosome mice, and sickle cell disease mice. In SR-18292-treated sickle mice, sickled red blood cells are significantly reduced, and disease complications are alleviated. SR-18292, or agents in its class, could be a promising additional therapeutic for sickle cell disease.

Programmable Chemical Evolution with Natural/non-natural Building Blocks.

Non-natural building blocks (BBs) present a vast reservoir of chemical diversity for molecular recognition and drug discovery. However, leveraging evolutionary principles to efficiently generate bioactive molecules with a larger number of diverse BBs poses challenges within current laboratory evolution systems. Here, we introduce programmable chemical evolution (PCEvo) by integrating chemoinformatic classification and high-throughput array synthesis/screening. PCEvo initiates evolution by constructing a diversely combinatorial library to create ancestral molecules, streamlines the molecular evolution process and identifies high-affinity binders within 2-4 cycles. By employing PCEvo with 108 BBs and exploring >10^17 chemical space, we identify bicyclic peptidomimetic binders against targets SAR-CoV-2 RBD and Claudin18.2, achieving nanomolar affinity. Remarkably, Claudin18.2 binders selectively stain gastric adenocarcinoma cell lines and patient samples. PCEvo achieves expedited evolution in a few rounds, marking a significant advance in utilizing non-natural building blocks for rapid chemical evolution applicable to targets with or without prior structural information and ligand preference.

Prevalence, antibiotic susceptibility, and genomic analysis of Vibrio alginolyticus isolated from seafood and freshwater products in China.

Introduction: This study characterized Vibrio alginolyticus isolated from seafood and freshwater products in China (2020). Methods and Results: In total, 122 (95.31%) V. alginolyticus isolates were resistant to at least 1 antibiotic category, and 2 (1.56%) isolates were resistant to at least 3 antibiotic categories and belong to multi-drug resistance (MDR) isolates. A high prevalence rate was observed to be blaCARB (98.04%) encoding beta-lactam resistance, followed by tet (97.06%) encoding tetracycline resistance and fos (4.90%) encoding resistance to fosfomycin. Among the 57 V. alginolyticus isolates, the commonest virulence genes were type III secretion system translocated gene vopD, vopB, and vcrH (54.4%, 31/57), type III secretion system regulated gene tyeA (54.39%), followed by vscI and vscF (50.88%) encoded type III secretion system inner rod protein and needle protein, respectively. Multilocus sequence typing (MLST) showed considerable genetic diversity, with 34 distinct sequence types (STs) identified among 55 isolates. ST421 (n = 5), ST166 (n = 4), ST523 (n = 3), ST516 (n = 3), and ST507 (n = 3) were dominant STs among 55 V. alginolyticus isolates. Discussion: These findings highlight the widespread occurrence of V. alginolyticus in both freshwater and seafood products, underscoring the critical need for vigilant monitoring of these bacteria. Such measures are essential for ensuring effective food safety management and safeguarding public health.

Identification of the New GmJAG1 Transcription Factor Binding Motifs Using DAP-Seq.

Interaction between transcription factors (TFs) and motifs is essential for gene regulation and the subsequent phenotype formation. Soybean (Glycine max) JAGGEED 1 (GmJAG1) is a key TF that controls leaf shape, seed number and flower size. To understand the GmJAG1 binding motifs, in this study, we performed the GmJAG1 DNA affinity purification sequencing (DAP-seq) experiment, which is a powerful tool for the de novo motif prediction method. Two new significant GmJAG1 binding motifs were predicted and the EMSA experiments further verified the ability of GmJAG1 bound to these motifs. The potential binding sites in the downstream gene promoter were identified through motif scanning and a potential regulatory network mediated by GmJAG1 was constructed. These results served as important genomic resources for further understanding the regulatory mechanism of GmJAG1.