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Heterologous expression of the G231L variant of VioA into 16 strains of marine-derived Streptomyces, combined with bioactivity tracking, leads to the activation of seven antibiotic streptogramins (1–7) in Streptomyces sp. OUC20-O. Among these, compound 1, named linstreptogramin, is a new compound with an unusual linear streptogramin skeleton. The planar structure and stereochemistry of compound 1 were established based on extensive MS and NMR spectroscopic analyses, together with ECD calculations. In the antibacterial activity evaluation, compounds 1–4 showed significant growth inhibition against the multidrug-resistant Enterococcus faecium CCARM 5203 with MIC values of 0.2–1.6 µg/mL, which are comparable to the positive control vancomycin.

Acute kidney injury (AKI) severely impairs renal function. In early AKI, tubular cells release damage-associated molecular patterns (DAMPs) that induce neutrophil recruitment. Infiltrating neutrophils can exacerbate kidney injury through degranulation or formation of neutrophil extracellular traps (NETs), but the specific DAMPs mediating early neutrophil chemotaxis remain unclear. We integrated single-cell and spatial transcriptomic data from early AKI kidneys to identify signaling pathways underlying crosstalk between injured tubular cells and neutrophils. A murine unilateral ischemia-reperfusion injury (uIRI) model was then established, with intraperitoneal administration of the anti-inflammatory drug mesalazine (5-aminosalicylic acid, 5-ASA) during the perioperative period, followed by assessment of renal histopathology and function. In vitro, polymorphonuclear neutrophils (PMNs) were isolated from mouse peripheral blood and co-cultured with renal tubular cells in a Transwell migration system under hypoxia/reoxygenation (H/R), with 5-ASA treatment or Spp1 knockdown to evaluate effects on PMN migration. Integrated single-cell and spatial transcriptomic analyses revealed that injured tubular cells upregulate Spp1, which interacts with Cd44 on neutrophils. In vivo and in vitro, injured tubular cells released Spp1 in a paracrine manner, enhancing Cd44 neutrophil migration, impairing tubular regeneration, and aggravating AKI progression. 5-ASA attenuated this process by suppressing Spp1 expression and paracrine signaling, thereby reducing early Cd44 neutrophil infiltration, promoting tubular cell proliferation, and improving renal function. This study provides the first evidence that tubular cell-derived Spp1 functions as a key DAMP mediating the early recruitment of Cd44 neutrophils in AKI. By inhibiting paracrine Spp1, 5-ASA limits neutrophil migration and ameliorates renal injury, supporting its therapeutic potential in AKI. Targeting Spp1 may represent a promising new strategy for AKI treatment.

Ride-hailing or Transportation Network Companies (TNCs) such as Uber, Lyft and Didi Chuxing are gaining increasing market share and importance in many transportation markets. To estimate the efficiency of these systems and to help them meet the needs of riders, big data technologies and algorithms should be used to process the massive amounts of data available to improve service reliability. The model developed predicts the gap between rider demands and driver supply in a given time period and specific geographic area using data from Didi Chuxing, the dominant ride-hailing company in China. The data provided includes car sharing orders, point of interest (POI), traffic, and weather information. A passenger calls a ride (makes a request) by entering the place of origin and destination and clicking \"Request Pickup\" on the Didi phone based application. A driver answers the request by taking the order. Our training data set contains three consecutive weeks of data in 2016, for large Chinese city which is referred to as City M. Though the training set is relatively small when compared to the whole of Didi's ride sharing market, it is large enough so that patterns can be discovered and generalized. These data were made available to researchers and entrepreneurs by Didi after removal of some identifying information.

Dynamic change of mitochondrial morphology and distribution along neuronal branches are essential for neural circuitry formation and synaptic efficacy. However, the underlying mechanism remains elusive. We show here that Pink1 knockout (KO) mice display defective dendritic spine maturation, reduced axonal synaptic vesicles, abnormal synaptic connection, and attenuated long-term synaptic potentiation (LTP). Drp1 activation via S616 phosphorylation rescues deficits of spine maturation in Pink1 KO neurons. Notably, mice harboring a knockin (KI) phosphor-null Drp1 S616A recapitulate spine immaturity and synaptic abnormality identified in Pink1 KO mice. Chemical LTP (cLTP) induces Drp1 S616 phosphorylation in a PINK1-dependent manner. Moreover, phosphor-mimetic Drp1 S616D restores reduced dendritic spine localization of mitochondria in Pink1 KO neurons. Together, this study provides the first in vivo evidence of functional regulation of Drp1 by phosphorylation and suggests that PINK1-Drp1 S616 phosphorylation coupling is essential for convergence between mitochondrial dynamics and neural circuitry formation and refinement.

BackgroundThyroglobulin measurement in fine-needle aspiration (FNA-Tg) is an additional diagnostic tool of lymph node metastasis (LNM) in papillary thyroid carcinoma (PTC). However, its performance as a preoperative indicator of lateral neck LNM in PTC is unclear. We evaluated the use of FNA cytology and FNA-Tg to detect neck LNM presurgery using a simple methodology, and established a cut-off value for diagnosing LNM in PTC.MethodsWe performed a retrospective cohort study based on hospital records, including 299 FNA-Tg measurements from 228 patients with PTC. The cut-off value for FNA-Tg was obtained through a receiver operating characteristic (ROC) curve analysis. The relationships between various parameters and FNA-Tg were analyzed using Spearman’s correlation.ResultsOf 299 lymph nodes (LNs) from 228 patients following surgery, 151 were malignant and 148 were benign. The median FNA-Tg levels were 414.40 ng/mL and 6.36 ng/mL in the metastatic and benign LNs, respectively. An FNA-Tg cut-off value of 28.3 ng/mL had the best diagnostic performance (93.38% sensitivity, 70.27% specificity, area under the ROC curve [AUC] 0.868) in the whole cohort. The diagnostic value performed better in the lateral neck group (level II–V, n = 163) than in the central neck group (level VI, n = 136); in the lateral neck group, the sensitivity and specificity of the FNA-Tg cut-off (16.8 ng/mL) were 96.25% and 96.36%, respectively.ConclusionsFNA-Tg is a useful technique for the diagnosis of LNM before surgery, especially in lateral neck dissection.Clinical trial registration numberChiCTR1900028547.

Background Promoting diabetic wound healing is still a challenge, and angiogenesis is believed to be essential for diabetic wound healing. Vermiculite is a natural clay material that is very easy to obtain and exhibits excellent properties of releasing bioactive ions, buffering pH, adsorption, and heat insulation. However, there are still many unsolved difficulties in obtaining two-dimensional vermiculite and using it in the biomedical field in a suitable form. Results In this study, we present a versatile organic–inorganic composite scaffold, which was constructed by embedding two-dimensional vermiculite nanosheets in polycaprolactone electrospun fibers, for enhancing angiogenesis through activation of the HIF-1α signaling pathway and promoting diabetic wound healing both in vitro and in vivo. Conclusions Together, the rational-designed polycaprolactone electrospun fibers-based composite scaffolds integrated with two-dimensional vermiculite nanosheets could significantly improve neo-vascularization, re-epithelialization, and collagen formation in the diabetic wound bed, thus promoting diabetic wound healing. This study provides a new strategy for constructing bioactive materials for highly efficient diabetic wound healing. Graphical Abstract

Background CD26 (DPP4) is shown in literature to be implicated in multiple tumors and antitumor immunity, yet its pan-cancer and context-dependent roles remain imprecisely defined. This study comprehensively characterizes the clinical relevance of CD26 and its association with invasion-related features and immunotherapy-relevant immune infiltration and response-associated biomarkers, and to validate key findings in breast cancer cells. Methods The integrated pan-cancer analysis of CD26 was performed using public databases, assessing its expression patterns, associations with cancer staging and prognostic value. Co-expression and protein-interaction data were used for GO/KEGG enrichment to infer potential biological pathways. Correlations between CD26 and immune cell infiltration, cancer-associated fibroblasts (CAFs), immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigen load were systematically evaluated. R software and online bioinformatics tools were employed. Additionally, qPCR, western blot and other in-vitro experiments compared CD26 expression in MCF-7 breast cancer cells and MCF-10A normal breast epithelial cells, and examined the effects of pharmacologic CD26 inhibition (alogliptin) on proliferation, invasion, and MMP9 expression in vitro. Results CD26 exhibited broad but low tissue specificity and was significantly upregulated in multiple malignancies compared with normal tissues, particularly in highly aggressive tumors ( P  < 0.01). Higher CD26 expression was associated with advanced pathological stage and adverse prognosis in several tumor types ( p  < 0.01), including breast cancer, while exhibiting a favorable prognostic association in a subset of tumors, indicating context-dependent relationships. Functional enrichment suggested involvement of CD26-related networks in chemokine signaling and EMT-related processes. CD26 expression correlated with estimated immune infiltration in 34 of 38 tumor types, including CD4 + and CD8 + T cells and CAFs, and was associated with multiple immune checkpoints, as well as TMB, MSI and neoantigens in selected cancers. In vitro, CD26 was elevated in MCF-7 versus MCF-10A cells ( p  < 0.05), and alogliptin treatment reduced MCF-7 cell proliferation and invasion ( p  < 0.05), accompanied by decreased MMP9 expression ( p  < 0.05). Conclusions This study presents an integrative pan-cancer framework linking CD26 expression to immune infiltration, together with in vitro observations in breast cancer cells, offering a comprehensive pan-cancer and experimental characterization of CD26. CD26 might be a novel prognostic biomarker candidate and therapeutic target to counteract tumor development in highly aggressive cancer.

Background Carotenoids have been shown to have multiple health benefits, including antioxidant and anti-inflammatory. The data for the effect of dietary specific carotenoids on biological aging is limited. Our study aims to examine the association between dietary carotenoid intake levels and biological aging. Methods This cross-sectional study was performed among 27,338 adults from NHANES 1999–2018. Dietary intake was assessed through two 24-hour dietary recall interviews. Biological aging indices included allostatic load (AL), homeostatic dysregulation (HD), Klemera-Doubal method (KDM), and phenoAge (PA). Multiple linear regression, weighted quantile sum (WQS) regression and quantile g-computation (QG-comp) were used to explore the associations of single carotenoid and mixed carotenoids with biological aging. Results Associations between dietary carotenoid intake levels and biological aging indices were significant among adults across the United States. Multiple linear regression showed that most carotenoids were significantly negatively correlated with AL (β = -0.017 - -0.011), HD (β = -0.045 - -0.032), KDM (β = -0.984 - -0.471), and PA (β = -0.975 - -0.539). Subgroup analysis indicated that male, older individuals, smokers, alcohol drinkers, and less physically active individuals are particularly sensitive populations. Meanwhile, WQS regression and QG-comp analyses consistently indicated a negative association between mixed carotenoids exposure and four biological aging indices, highlighting that lutein/zeaxanthin and β-carotene were responsible for the outcomes. Conclusions Increased dietary intakes of various carotenoids were associated with lower biological aging indices, which was possibly and mainly driven by lutein/zeaxanthin and β-carotene.

Repairing bone defects with implants is an important topic in the field of regenerative medicine, but bacterial infection presents a significant barrier in clinical practice. Therefore, bone implants with antibacterial functionality are currently in high demand. Fresh seaweed-derived exosomes (EXOs) exhibited promising antibacterial activity against bacteria, indicating their potential as natural antimicrobial agents. Moreover, equipping the exosomal lipid bilayer with bacteria-targeting aptamers (Apt), termed EXOs-Apt, enabled precise bacterial killing, thereby promoting more effective antibacterial functions. In our design, porous polyetheretherketone (PEEK) scaffolds were 3D-printed using the melt deposition manufacturing process. Subsequently, the scaffold surfaces were modified via dopamine self-polymerization, resulting in the formation of a polydopamine (PDA) coating. Then, EXOs-Apt was applied to functionalize PEEK scaffolds with antibacterial activity. Given that EXOs display bactericidal effects while Apt facilitates bacterial capture, we engineered a surface coating platform that incorporates both components to produce a multifunctional scaffold with synergistic antibacterial activity. The results showed that modifying EXOs-Apt on PEEK scaffolds significantly improved their antibacterial performance against Escherichia coli and Staphylococcus aureus. To our knowledge, this is the first study to use EXOs-Apt as antibacterial coatings modified on PEEK scaffolds. This study provides new strategies and ideas for the development of antibacterial PEEK orthopedic implants with promising clinical value for infection-resistant repair of bone defects.

The Wnt signaling pathway deeply participates in multiple physiological and pathological processes. Its activity is intricately regulated by a diverse network of modulators, reflecting the pathway's structural and functional complexity. Dysregulation of Wnt signaling leads to cellular dysfunction and is associated with a wide spectrum of diseases, among which tissue fibrosis represents a major pathological outcome, characterized by activation of myofibroblasts and subsequent excessive deposition of extracellular matrix in response to injury. Wnt signaling is a central driver of fibrotic progression across multiple tissues and organs; however, effective therapeutic strategies directly targeting Wnt signaling in fibrosis remain scarce. In this review, we provide a comprehensive overview of Wnt pathway components, regulatory mechanisms, and therapeutic approaches. We systematically examine how Wnt signaling governs both developmental processes and pathological conditions, with particular emphasis on its role in fibrosis while also extending discussion to other diseases. Special attention is devoted to the secreted frizzled‐related proteins (SFRPs) family, soluble regulators with biphasic, context‐dependent effects that are especially relevant in fibrosis. Finally, we summarize insights from preclinical and clinical studies, review advances and challenges in the development of small‐molecule compounds targeting Wnt components, highlighting the vital role of SFRPs as promising targets for antifibrotic intervention. The Wnt signaling pathway is essential for development and tissue homeostasis, while its dysregulation drives diverse diseases. This review systematically outlines its components, functions, regulators, and preclinical models, highlighting secreted frizzled‐related proteins (SFRPs) as context‐dependent, biphasic modulators. Their dual roles in tissue fibrosis underscore both the complexity of Wnt regulation and the therapeutic potential of SFRPs.