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Riemerella anatipestifer (RA) is a major pathogen in waterfowl, responsible for severe septicemia and serositis, leading to significant economic losses. As antibiotic resistance becomes more widespread, there is an urgent need for effective, novel vaccine strategies. In this study, we engineered three recombinant RA antigens, PorQ, YaeT, and YiaD, onto the surface of outer membrane vesicles (OMVs) derived from a Salmonella Typhimurium mutant strain using the lipoprotein signal peptide (Lpp). The engineered OMVs were shown to induce robust humoral and cellular immune responses in ducks. Immunization with these OMVs resulted in 80% survival for ducks immunized with OMVs displaying YaeT and YiaD antigens and 70% survival for ducks immunized with OMVs displaying PorQ, following challenge with RA-SD-1 (serotype 2). Furthermore, ducks immunized with OMVs displaying YaeT and YiaD exhibited reduced pathological damage and lower bacterial loads in key organs. These findings demonstrate that OMVs displaying YaeT and YiaD provide strong protection against RA infections, suggesting the potential of OMVs as an effective vaccine platform for waterfowl across various RA serotypes. The study addresses a growing challenge in poultry health, as Riemerella anatipestifer (RA) infections continue to cause substantial losses in waterfowl farming. The development of novel vaccines is crucial due to the rise in antibiotic resistance. This study highlights the potential of using outer membrane vesicles (OMVs) as a versatile vaccine platform to display multiple RA antigens. The promising results, including high survival rates and reduced organ damage, indicate that OMVs could provide an effective means to prevent RA infection in waterfowl, paving the way for future vaccine development targeting various serotypes of RA.

This study focuses on investigating the effects of the water-to-ethanol volume ratio on the preparation of thiol-functionalized silica (SH-SiO2) particles. Using 3-mercaptopropyltrimethoxysilane (MPTMS) as the silane precursor and ammonia as the catalyst, the size, morphology, and chemical composition of the synthesized SH-SiO2 particles were systematically characterized across a gradient of water-to-ethanol volume ratios. Raman spectroscopy was utilized to quantitatively analyze the variations in the contents of thiol (-SH) and disulfide (S-S) groups within the SH-SiO2 matrix. In addition to comprehensive material characterizations, the as-prepared SH-SiO2 particles were evaluated as dual-functional platforms, which act as both adsorbents for Au3+ ions and carriers for the loading and sustained release of doxorubicin (DOX). Notably, the SH-SiO2 particles fabricated under the condition of 90% (v/v) water content demonstrated a superior DOX loading capacity and well-regulated release kinetics, highlighting the significant regulatory role of the water content in optimizing the functional performance of SH-SiO2 particles.

To investigate the geographic distribution of multiple neurodevelopmental disorders (NDDs) across different US states. Using data from 2016 to 2023 National Survey of Children's Health, we estimated the prevalence and combinations of multiple NDDs (defined as having ≥2 NDDs) at the state level among 272 598 children and adolescents aged 3-17 years. We also reported state-level prevalence estimates and combinations stratified by sociodemographic characteristics. Participant numbers ranged from 4391 in the Nevada to 11 275 in California during 2016-2023. Over half were male (51.7%), with a mean age of 10.2 years (standard deviation: 4.5). The national multiple NDDs prevalence was 8.1% (95% Confidence Interval [CI]: 7.9%-8.3%), with Kentucky reporting the highest prevalence at 10.5% (95% CI: 9.3%-11.8%) across states. Stratified analyses by period, age groups, sex, ethnicity, country of birth, household income, insurance coverage, and family education levels consistently showed the highest prevalence in southern states such as Florida, Kentucky, Louisiana, Maine, New Hampshire, and Oklahoma. Across states, the most common multiple NDDs combination was attention-deficit/hyperactivity disorder concurrent with learning disabilities (18.2%). Disparities in multiple NDDs prevalence were observed across US states. These state-level estimates can help decision-makers target programs and allocate resources to address community needs.

The goal of this study was to determine the effect of administering arachidonic acid (ARA) with or without the yeast Saccharomyces cerevisiae, on voluntary ethanol consumption by mice. Ethanol consumption was measured using a continuous access two-bottle choice experiment with water and 15% ethanol (vol/vol). Ethanol naïve C57BL/6J mice were orally inoculated with ARA (or acidic PBS as the control), S. cerevisiae, or both each evening for three evenings. Ethanol consumption and preference were measured on the following days. In additional experiments, male and female mice underwent chronic intermittent exposure to ethanol vapor. After a 2-week exposure protocol, these mice were given access to 15% ethanol (vol/vol) via a two-bottle choice and inoculated nightly with ARA and S. cerevisiae (or acidic PBS and mock as the control). Administration of ARA initially reduced ethanol preference and consumption by ethanol naïve female mice but the effects waned. In contrast, administration of ARA together with a fungus had a sustained effect that reduced preference and consumption. The effects of ARA and fungi were statistically significantly different from ARA alone on Day 3 of ethanol access. Chronically exposed mice that showed low initial consumption of ethanol in the two-bottle choice maintained low consumption when administered ARA and S. cerevisiae. These findings support the future development of a therapeutic regimen utilizing ARA and yeast, or targeting eicosanoids, that could be developed as a supplement to current approaches to reduce ethanol consumption.

Traditional tumor staging relies on absolute lymph node counts, making it susceptible to stage migration, particularly in young breast cancer (YBC) patients with aggressive disease. This study assessed the prognostic value of the continuous log odds of positive lymph nodes (LODDS) for breast cancer-specific survival (BCSS) and developed a predictive nomogram utilizing data from 9,989 surgically treated YBC patients (aged 20-39) sourced from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015). A multivariable Cox proportional hazards model, adjusted to account for non-proportional hazards, established continuous LODDS as an independent risk factor for poorer BCSS (hazard ratio [HR] = 1.60, 95% confidence interval [CI]: 1.45-1.77, p < 0.001), without relying on data-driven dichotomization. We constructed a nomogram that integrates continuous LODDS with clinicopathological features selected via least absolute shrinkage and selection operator (LASSO). Under a 1,000-resample bootstrap optimism-correction, the nomogram exhibited strong discriminatory power (corrected concordance index [C-index] = 0.777), surpassing the traditional tumor-node-metastasis (TNM) staging model (C-index = 0.736). Moreover, the continuous LODDS-integrated model improved 5-year mortality risk reclassification (continuous net reclassification improvement [NRI] = 0.278, integrated discrimination improvement [IDI] = 0.034; both p < 0.001). The model also demonstrated high calibration accuracy (5-year Brier score = 0.0757) and presented a greater estimated net benefit in Decision Curve Analysis (DCA). In conclusion, continuous LODDS offers critical incremental prognostic information beyond traditional staging. The proposed nomogram serves as an internally validated prediction model for risk stratification in YBC patients.

Thyroid cancer (TC), the most common endocrine malignancy, is closely linked to aging. In this study, we estimated DNA methylation (DNAm) age in TC tissues versus adjacent non-cancerous thyroid tissues using TCGA and GSE97466 datasets. We employed multi-tissue DNAm age estimators, specifically Horvath's clock and the Bayesian Neural Network (BNN) clock, to quantify epigenetic aging in TC and adjacent normal tissues from the TCGA and GSE97466 cohorts. We further integrated genomic, transcriptomic, and mutational analyses, including assessments of senescence-associated secretory phenotype (SASP), immune cell infiltration, and thyroid differentiation, to elucidate the associations between DNAm age acceleration and various cancer-related features. Our results revealed marked DNAm age acceleration in TC tissues relative to controls, with both models yielding significantly higher DNAm age estimates in tumors. Although DNAm age correlated strongly with chronological age in control tissues (R&#x2009;&#x2248;&#x2009;0.94), this association was notably diminished in TC tissues (R&#x2009;&#x2248;&#x2009;0.62). Moreover, TC tissues with accelerated DNAm age exhibited higher telomerase-associated gene expression score, heightened SASP signaling, and distinct immune profiles characterized by elevated M2 macrophages and reduced activated NK cells. Genomic analysis further showed a higher prevalence of BRAF mutations and lower thyroid differentiation scores (TDS) in the accelerated subgroup. No significant associations were detected between DNAm age and clinicopathological parameters or overall survival. Our findings provide valuable insights into the complex interplay between epigenetic regulation, immune dysfunction, and genomic instability in thyroid cancer, highlighting promising avenues for future research and therapeutic intervention.

Hydrogels that adhere to biological tissues and resist fibrosis are required to provide both optimal functionality and appropriate stiffness on diverse soft tissues to achieve therapeutic efficacy and biocompatibility. However, their performance is often limited by an intrinsic trade-off between functionality and stiffness. Through the incorporation of polymer brush coatings, we develop a modular hydrogel system to enable independent control of functionality and stiffness. By tailoring coating chemistry, coating thickness, and hydrogel network topology, we obtain consistent bioadhesion (~100 joules per square meter) and fibrosis suppression across the full stiffness range of soft tissues (1 kilopascal to 1 megapascal). Using this approach, we design a hydrogel that can maintain stable adhesion in vivo on a beating mouse heart and a hydrogel with no fibrotic capsule in immunocompetent mice over 40 days. This modular system offers a customizable approach for designing functional implants with tailored mechanical properties.

We investigated the real-world criteria and thresholds physicians use to classify patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence as high risk, and how these align with guidelines. Descriptive analyses were conducted using data abstracted from an independent, retrospective, cross-sectional survey completed by urologists and radiation oncologists in the USA between April and November 2023. Physicians provided their perspectives and extracted chart data for the last 6-8&#xa0;patients they diagnosed with high-risk biochemical recurrence. The cohort included 87 physicians (79% urologist, 21% radiation oncologist), who reported data for 460 patients. Physicians believed in using multiple factors for risk stratification, notably prostate-specific antigen doubling time (94%), absolute prostate-specific antigen rise following definitive therapy (89%), and Gleason score (87%). Over half named prostate-specific antigen doubling time as the most important factor. Physicians used a median (interquartile range) prostate-specific antigen doubling time threshold of 6.0 (6.0-9.0) months when identifying patients with high-risk biochemical recurrence. At the patient level, prostate-specific antigen doubling time (58%), Gleason score (44%), and absolute prostate-specific antigen rise following definitive therapy (43%) were the most frequently reported factors used for determining high-risk biochemical recurrence in the real world. Physicians use multiple clinical factors to identify high-risk biochemical recurrence. These factors generally align with guidelines. However, physicians generally used a more restrictive prostate-specific antigen doubling time threshold than many guidelines recommend. Discrepancies present an opportunity for further education, potentially expanding the pool of patients with high-risk biochemical recurrence who may benefit from recent advances in management.

By phytochemically profiling the methanolic extract of Actinidia polygama gall fruits, we isolated six iridoid glycosides, comprising five new derivatives named actinidiosides A-E (1, 3-6), and one known analogue, actinidin A (2). Their planar structures were established by comprehensive 1D/2D NMR and high-resolution mass spectrometry analyses, while stereochemical assignments were achieved through electronic circular dichroism spectroscopy, and GIAO/DP4+ NMR chemical shift calculations. The isolated compounds were screened for cytotoxicity and inhibition of NO production in RAW264.7 macrophage cells. An MTT assay demonstrated no cytotoxicity at concentrations up to 100&#xa0;&#xb5;M. However, none of the isolates inhibited lipopolysaccharide-induced nitric oxide production under the evaluated conditions. This work expands the secondary metabolite profile of A. polygama and provides fully characterized iridoid scaffolds for future chemical and pharmacological investigations.

The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving METTL5 depletion-caused cancer regression by sustaining mitochondrial respiration. The methyltransferase METTL5 is upregulated in non-small cell lung cancer (NSCLC) and associated with advanced tumor grade and poor prognosis. Depletion of METTL5 impairs NSCLC cell proliferation and migration in vitro and in vivo, with p53-null cells displaying enhanced sensitivity. While METTL5-depletion inhibits cytoplasmic translation in both p53-WT and p53-null cells, only cells lacking p53 exhibit severe tumor regression due to defective mitochondrial protein synthesis and consequent respiratory dysfunction. Mechanistically, p53 binds 5'UTR of TOMM40, the crucial gatekeeper of mitochondrial protein import, to enforce its exclusion from translation. METTL5 loss promotes p53 nuclear retention via inhibiting MDM2-mediated p53 ubiquitination, alleviating its translational suppression of TOMM40, and supporting oxidative phosphorylation. Remarkably, the combination targeting of p53 and METTL5 synergistically attenuates the proliferation and migration in p53-WT cancer cells. Our study elucidates the essential role of p53 in supporting tumor viability upon METTL5 deficiency by maintaining mitochondrial respiration. Meanwhile, it provides a molecular foundation for developing therapeutic strategies regarding cancers with WT p53.

Surveys have indicated that patients and clinicians can overestimate the efficacy and safety of drugs approved by the US Food and Drug Administration (FDA). In recent years, only approximately half of new drug approvals have been based on 2 or more adequate and well-controlled trials; furthermore, regulations do not limit how many trials can be conducted or provide clear guidance on how the FDA should consider a drug with conflicting evidence of benefit from multiple trials. To understand how the FDA evaluated a single investigational drug with positive and negative preapproval trials. The case of gepirone extended release (ER), approved for major depressive disorder, was reviewed. The FDA based its efficacy evaluation of gepirone ER on 13 trials: 12 acute treatment trials and 1 maintenance or relapse prevention trial. The FDA judged 2 acute treatment trials as positive. In the others, gepirone ER did not demonstrate superiority to placebo; and for 3, the FDA found evidence of statistical inferiority to an active comparator. Concerned that the positive trials might have occurred by chance and the amount of countervailing evidence, the FDA rejected the New Drug Application from the sponsor 4 times (Organon in 1999, 2002, and 2004, and Fabre-Kramer Pharmaceuticals, Inc in 2007). In 2014, the sponsor filed a dispute resolution request, leading to intervention by senior FDA leaders. In 2015, an FDA Advisory Committee voted that drug efficacy had not been demonstrated. Nevertheless, FDA leaders came to agree with the sponsor's arguments that the 2 positive trials had not occurred by chance and that the drug satisfied the FDA statutory standard for efficacy, and the drug was approved. The case of gepirone shows how the FDA evaluated an investigational drug with conflicting evidence. The FDA sometimes exercises "regulatory flexibility" and focuses on statistical (as opposed to clinical) significance in a few trials, allowing the approval of drugs with scant benefits. Product labeling should transparently report on all adequate and well-controlled trials relating to an FDA-approved indication, not just those with positive outcomes, so that clinicians can make better-informed prescribing decisions.

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To assess the prevalence and trends of developmental disabilities among U.S. children and adolescents aged 3-17 years from 2016 to 2024. Using data from the National Health Interview Survey (NHIS, 2021-2024) and the National Survey of Children's Health (NSCH, 2016-2023). Only NHIS contributed 2024 data, with NSCH through 2023. We calculated the weighted prevalence with 95% confidence intervals for attention-deficit/hyperactivity disorder, learning disability, autism spectrum disorder, intellectual disability, and other developmental delays and examined trends from 2016 to 2024. Prevalence increased significantly for attention-deficit/hyperactivity disorder, learning disability, and autism spectrum disorder but remained stable for intellectual disability and other developmental delays. Age-specific analyses revealed distinct distributions: attention-deficit/hyperactivity disorder, learning disability were most common in school-age children, whereas autism spectrum disorder was higher among preschool-aged children compared with older groups. The prevalence of developmental disabilities among U.S. children has risen substantially. This persistent upward trend underscores a growing public health challenge, necessitating enhanced early identification, service delivery, and research into the multifactorial drivers behind these increases.

Biomass-derived carbon quantum dots (BCDs) have attracted considerable research attention as a novel category of sustainable fluorescent nanomaterials, attributed to their adjustable photoluminescence, superior biocompatibility, and eco-friendly synthesis methods. BCDs are made from renewable biomass sources like plants, algae, animal byproducts, and microorganisms, following the principles of green chemistry. This makes them much better for the environment and cheaper to make than carbon dots made in the traditional way. The field still has three big problems, though: the luminescence mechanism is still not well understood, with different pathways like carbon-core and surface-state emissions not having a single theoretical framework; optical modulation strategies are still not well developed, with quantum yields often falling below 30% and poor batch-to-batch consistency making it hard to standardize applications; and not enough is known about in vivo metabolic pathways and long-term toxicity to allow for systematic toxicological evaluation and clinical translation. The complex luminescence mechanisms, including carbon-core-state, surface-state, molecular-state, and cross-linked enhanced emission (CEE), are thoroughly examined to clarify the structure-property relationships that dictate their optical behavior. By using controlled synthesis and surface modification techniques, BCDs can be made to emit light in the visible to near-infrared (NIR) range. This makes them perfect for use in different types of multimodal imaging, such as single-photon, multi-photon, and photoacoustic bioimaging. Their natural ability to emit light, along with their low toxicity to cells and high stability in light, makes it possible to see cells and tissues in high detail. We talk more about the problems we are having right now with standardizing synthesis and controlling optical properties with precision. Future research should concentrate on refining reaction conditions and clarifying luminescence mechanisms to promote the clinical application of BCDs as next-generation, sustainable imaging agents.

Marmoritis complanata (Dunn) A. L. Budantzev, a Tibetan medicinal plant endemic to alpine regions, is traditionally used for its anti-inflammatory properties. A novel sesquiterpenoid, marmoritiolide (1), featuring a novel 14-nor-5, 6-seco-eudesmane-type carbon skeleton with an isopropyl migration from C-7 to C-8, was isolated together with four known sesquiterpenoids (2-5). The structure of 1 was determined by HRESIMS and 1D/2D NMR. A plausible biogenetic pathway is proposed. In an H2O2-induced oxidative stress zebrafish model, compound 1 dose-dependently (12.5-50&#xa0;&#xb5;M) reduced intracellular ROS levels, achieving 36.9% inhibition at 50&#xa0;&#xb5;M (vs. the model group), comparable to the positive control (38.2%). Superoxide dismutase (SOD) activity was restored from 58.0% (model) to 82.8% of control levels at 50&#xa0;&#xb5;M. qPCR analysis showed that 1 upregulated the mRNA expression of Nrf2 (1.3-fold), Mn-SOD (1.6-fold), Cu/Zn-SOD (2.6-fold), and NQO1 (2.1-fold) at 50&#xa0;&#xb5;M. suggesting modulation of the Nrf2 pathway. Covalent docking further indicated that compound 1 can covalently modify Keap1 at Cys151, providing a mechanistic basis for Nrf2 activation. These findings highlight M. complanata as a source of structurally unique sesquiterpenoids with potent antioxidant activity.

In flowering plants, the shoot apical meristem (SAM) is maintained through cross-talk between the stem cell identity gene WUSCHEL (WUS) and several phytohormone-signaling pathways. However, whether the well-known sterol phytohormone brassinosteroid (BR) signaling directly regulates SAM activity remains mysterious. Here, we showed that BR signaling maintains SAM homeostasis through both enhancing WUS expression and modulating WUS activity in organizing center. Plants with compromised BR signaling exhibited reduced SAM size, prematurely terminated SAM, and decreased total flower numbers. BRs synergize with cytokinin (CK) to activate WUS expression via a protein complex formed by the BR transcription factor brassinazole-resistant 1 (BZR1) and the CK-responsive factor Arabidopsis response regulator 1 (ARR1). In addition, BR promotes nuclear accumulation of BZR1-WUS protein complex, which binds E-box (CANNTG) motifs genome-wide and represses type A ARRs and FRUITFUL, thereby sustaining CK output and delaying SAM arrest. This BZR1-WUS module under BR signaling is conserved in tomatoes, revealing a general regulatory mechanism of SAM maintenance by BR signaling.

Guidelines recommend stopping breastfeeding before radioactive iodine (131I) therapy, yet the optimal timing for safe resumption remains unclear. We report a detailed dosimetric case study of a 29-year-old woman treated with 3700 MBq 131I for papillary thyroid carcinoma who wished to resume breastfeeding. Weekly breast milk samples were analyzed using calibrated gamma counting until radioactivity fell below a conservative safety threshold. Results showed substantial iodine excretion in milk (&#x223c;15% of administered activity) with biphasic clearance. Estimated infant radiation exposure varied dramatically depending on resumption timing, ranging from 0.62 to 688 mSv. A strict activity-based threshold suggested delaying breastfeeding for 51 days, whereas a dosimetric approach limiting infant exposure to 1 mSv supported resumption as early as 9-10 days post-therapy. These findings highlight the limitations of fixed recommendations and support an individualized, measurement-based strategy to optimize mother and child safety.

Hepatocellular carcinoma (HCC) is a common, aggressive, and potentially fatal malignancy. Ginger possesses a wide range of beneficial biological effects on different body organs. The present study investigated the therapeutic effects of ginger extract (GE) and ginger nanoparticles (GNPs) against HCC induced by diethylnitrosamine (DEN) and carbon tetrachloride (CCl&#x2084;). Treatment was initiated 15 weeks after HCC induction and continued for six consecutive weeks. Forty rats were equally divided into four groups. Group 1 (normal control): rats received saline; Group 2 (DEN/CCl&#x2084;): HCC-induced rats; Group 3 (HCC&#x2009;+&#x2009;GE): HCC-induced rats treated with ginger extract (300&#xa0;mg/kg body weight/day); and Group 4 (HCC&#x2009;+&#x2009;GNPs): HCC-induced rats treated with ginger nanoparticles (50&#xa0;mg/kg body weight/day). Liver function enzymes and gene expression levels were assessed in blood and tissue samples. The HCC-induced group showed a significant elevation in liver marker enzymes, global DNA hypermethylation, upregulation of HAT1 and HDAC4, and downregulation of miRNA-34a expression. In contrast, treatment with GE or GNPs resulted in significant global DNA hypomethylation, downregulation of HAT1 and HDAC4, and upregulation of hepatic miRNA-34a expression. The findings suggest that GE and GNPs suppress hepatocarcinogenesis, potentially through activation of the miRNA-34a pathway involved in apoptosis regulation.

Hyperplasia of mammary glands (HMG) is a common benign disease of the female breast. This study aimed to observe the clinical efficacy and safety of Honghua Xiaoyao pills in the treatment of liver depression and haemostasis-type HMG, as well as their impact on menstruation. Sixty patients diagnosed with liver depression and haemostasis-type HMG in the breast disease department of our hospital were selected as the study participants. The treatment involved oral administration of Honghua Xiaoyao pills: four pills per dose, three times a day, for a duration of 3&#x2009;months without interruption during menstruation. Hormones, Western painkillers and similar Chinese herbal medicines were prohibited during the trial. Changes in breast pain, breast masses, menstrual volume and safety indicators were observed. Three patients were lost to follow-up after 2&#x2009;months of treatment, and four patients voluntarily withdrew from the study. The changes in breast pain scores, breast mass size scores and breast mass texture scores relative to baseline and their respective change rates showed statistically significant differences (p < 0.0001). Changes in lower abdominal distension, breast distension, menstrual blood clots, chest tightness/discomfort and emotional scores relative to baseline were also statistically significant (p < 0.0001). Honghua Xiaoyao pills are effective in reducing breast pain, shrinking breast masses and improving lower abdominal distension, breast distension, menstrual blood clots, chest tightness/discomfort and emotional symptoms in patients with liver depression and haemostasis-type HMG. International Traditional Medicine Clinical Trial Registry: ITMCTR2024000165.