JMIR Med Inform. 2025 Mar 27;13:e67591. doi: 10.2196/67591.

ABSTRACT

BACKGROUND: Integrated clinical databases from national biobanks have advanced the capacity for disease research. Data quality and completeness filters are used when building clinical cohorts to address limitations of data missingness. However, these filters may unintentionally introduce systemic biases when they are correlated with race and ethnicity.

OBJECTIVE: In this study, we examined the race and ethnicity biases introduced by applying common filters to 4 clinical records databases. Specifically, we evaluated whether these filters introduce biases that disproportionately exclude minoritized groups.

METHODS: We applied 19 commonly used data filters to electronic health record datasets from 4 geographically varied locations comprising close to 12 million patients to understand how using these filters introduces sample bias along racial and ethnic groupings. These filters covered a range of information, including demographics, medication records, visit details, and observation periods. We observed the variation in sample drop-off between self-reported ethnic and racial groups for each site as we applied each filter individually.

RESULTS: Applying the observation period filter substantially reduced data availability across all races and ethnicities in all 4 datasets. However, among those examined, the availability of data in the white group remained consistently higher compared to other racial groups after applying each filter. Conversely, the Black or African American group was the most impacted by each filter on these 3 datasets: Cedars-Sinai dataset, UK Biobank, and Columbia University dataset. Among the 4 distinct datasets, only applying the filters to the All of Us dataset resulted in minimal deviation from the baseline, with most racial and ethnic groups following a similar pattern.

CONCLUSIONS: Our findings underscore the importance of using only necessary filters, as they might disproportionally affect data availability of minoritized racial and ethnic populations. Researchers must consider these unintentional biases when performing data-driven research and explore techniques to minimize the impact of these filters, such as probabilistic methods or adjusted cohort selection methods. Additionally, we recommend disclosing sample sizes for racial and ethnic groups both before and after data filters are applied to aid the reader in understanding the generalizability of the results. Future work should focus on exploring the effects of filters on downstream analyses.

PMID:40146917 | DOI:10.2196/67591

Science. 2025 Mar 28;387(6741):1362. doi: 10.1126/science.ads8799. Epub 2025 Mar 27.

NO ABSTRACT

PMID:40146823 | DOI:10.1126/science.ads8799

Appl Environ Microbiol. 2025 Mar 27:e0249124. doi: 10.1128/aem.02491-24. Online ahead of print.

ABSTRACT

Traditional directed evolution is limited by labor-intensive iterative steps and low-throughput selection and screening. To address these challenges, we developed a growth-coupled continuous directed evolution (GCCDE) approach, enabling automated and efficient enzyme engineering. By linking enzyme activity to bacterial growth and utilizing the MutaT7 system, GCCDE combines in vivo mutagenesis and high-throughput selection of superior enzyme variants in a single process. To validate this approach, we evolved the thermostable enzyme CelB from Pyrococcus furiosus to enhance its β-galactosidase activity at lower temperatures while maintaining thermal stability. CelB activity was coupled to the growth of E. coli, allowing variants with improved activity to utilize lactose more efficiently and promote faster growth in a minimal medium. Using a continuous culture system, we achieved automated high-throughput mutagenesis and simultaneous real-time selection of over 10⁹ variants per culture. Integrating in vitro and in vivo mutagenesis further increased genetic diversity, yielding CelB variants with significantly enhanced low-temperature activity compared to the wild type while preserving thermostability. DNA sequencing identified key mutations likely responsible for improved substrate binding and catalytic turnover. This GCCDE approach is broadly applicable for optimizing diverse enzymes, demonstrating the potential of automated continuous evolution for industrial and research applications.

IMPORTANCE: Enzyme engineering aims to develop enzymes with improved or novel traits, but traditional methods are slow and require repetitive manual steps. This study presents a faster, automated protein engineering approach. We utilized an in vivo mutagenesis technique, MutaT7 tools, to induce mutations in living bacteria and established a direct link between enzyme activity and bacterial growth. A continuous culture setup enables automated mutagenesis and growth-coupled selection of better-performing variants in real time. Bacteria with improved enzymes grew faster, selecting superior variants without manual intervention. Using this method, we engineered CelB with better performance at lower temperatures while maintaining thermal stability. By combining high-throughput mutagenesis and selection in a single process, this system bypasses iterative cycles of error-prone PCR, transformation, and screening. Our approach is adaptable to various enzymes, providing a faster and more efficient solution for enzyme engineering.

PMID:40145755 | DOI:10.1128/aem.02491-24

Development. 2025 Mar 27:dev.204506. doi: 10.1242/dev.204506. Online ahead of print.

ABSTRACT

A crucial step in early embryogenesis is the establishment of spatial patterns of signaling activity. Tools to perturb morphogen signals with high resolution in space and time can help reveal how embryonic cells decode these signals to make appropriate fate decisions. Here, we present new optogenetic reagents and an experimental pipeline for creating designer Nodal signaling patterns in live zebrafish embryos. Nodal receptors were fused to the light-sensitive heterodimerizing pair Cry2/CIB1N, and the Type II receptor was sequestered to the cytosol. The improved optoNodal2 reagents eliminate dark activity and improve response kinetics, without sacrificing dynamic range. We adapted an ultra-widefield microscopy platform for parallel light patterning in up to 36 embryos and demonstrated precise spatial control over Nodal signaling activity and downstream gene expression. Patterned Nodal activation drove precisely controlled internalization of endodermal precursors. Further, we used patterned illumination to generate synthetic signaling patterns in Nodal signaling mutants, rescuing several characteristic developmental defects. This study establishes an experimental toolkit for systematic exploration of Nodal signaling patterns in live embryos.

PMID:40145591 | DOI:10.1242/dev.204506

Front Immunol. 2025 Mar 12;16:1534615. doi: 10.3389/fimmu.2025.1534615. eCollection 2025.

ABSTRACT

Tuberculosis (TB) is one of the leading causes of death due to infectious disease. The sole established vaccine against TB is the Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine. However, owing to the lack of durable immunity with the BCG vaccine and its risk of infection, safer vaccines that can also be used as boosters are needed. Here, we examined whether membrane vesicles (MVs) from BCG (BCG-MVs) isolated from BCG statically cultured in nutrient-restricted Sauton's medium (s-MVs) and from BCG planktonically cultured in nutrient-rich medium commonly used in the laboratory (p-MVs) could be used as novel TB vaccines. MVs are extracellular vesicles produced by various bacteria, including mycobacteria. Differences in the culture conditions affected the morphology, contents, immunostimulatory activity and immunogenicity of BCG-MVs. s-MVs presented greater immunostimulatory activity than p-MVs via the induction of TLR2 signaling. Mouse immunization experiments revealed that s-MVs, but not p-MVs, induced mycobacterial humoral and mucosal immunity, especially when administered in combination with adjuvants. In a BCG challenge experiment using BCG Tokyo type I carrying pMV361-Km, subcutaneous vaccination with s-MVs reduced the bacterial burden in the mouse lung to a level similar to that after intradermal vaccination with live BCG. Furthermore, the administration of s-MVs induced a significant lipopolysaccharide-induced proinflammatory response in macrophages in vitro. These results indicate that BCG-MVs obtained from static culture in Sauton's medium induce not only humoral immunity against mycobacteria but also trained immunity, which can allow the clearance of infectious agents other than mycobacteria. Together, these findings highlight the immunological properties of BCG-MVs and the availability of acellular TB vaccines that confer broad protection against various infectious diseases.

PMID:40145097 | PMC:PMC11937015 | DOI:10.3389/fimmu.2025.1534615

J Allergy Clin Immunol Glob. 2025 Feb 18;4(2):100443. doi: 10.1016/j.jacig.2025.100443. eCollection 2025 May.

ABSTRACT

BACKGROUND: Orchiectomy, which results in hypogonadism, may increase the risk of asthma due to androgen deficiency.

OBJECTIVES: We aimed to investigate the association between orchiectomy and asthma risk.

METHODS: Men aged 18 years or older between 1999 and 2016 were identified from the national real-world database IBM-Explorys. We used multivariable logistic regression adjusted for age and body mass index to determine the risk of asthma among individuals who had and had not undergone orchiectomy. To reproduce our findings, we selected men aged 18 years or older with or without a history of orchiectomy who were enrolled in the globally federated TriNetX database as of May 2024.

RESULTS: In the IBM-Explorys database, the orchiectomy group had a 2-fold increase in the odds of having asthma (adjusted odds ratio = 2.03 [95% CI = 1.91-2.16]; P < .001). Similarly, in the TriNetX database, the risk of asthma was higher in the orchiectomy group than in the nonorchiectomy group (adjusted odds ratio =1.61 [95% CI = 1.42-1.82]; P < .001).

CONCLUSION: Patients who have undergone an orchiectomy are at increased risk of developing asthma. More research is needed to determine the mechanisms underlying the relationship between asthma diagnosis and orchiectomy.

PMID:40144019 | PMC:PMC11938140 | DOI:10.1016/j.jacig.2025.100443

Viruses. 2025 Feb 26;17(3):318. doi: 10.3390/v17030318.

ABSTRACT

The journal Viruses retracts the article "PERK Is Critical for Alphavirus Nonstructural Protein Translation" [...].

PMID:40143380 | DOI:10.3390/v17030318

Viruses. 2025 Feb 28;17(3):355. doi: 10.3390/v17030355.

ABSTRACT

Viruses are ubiquitous across all kingdoms of cellular life, posing a significant threat to human health, and analyzing viral communities is challenging due to their genetic diversity and lack of a single, universally conserved marker gene. To address this challenge, we developed the AliMarko pipeline, a tool designed to streamline virus identification in metagenomic data. Our pipeline uses a dual approach, combining mapping reads with reference genomes and a de novo assembly-based approach involving an HMM-based homology search and phylogenetic analysis, to enable comprehensive detection of viral sequences, including low-coverage and divergent sequences. We applied our pipeline to total RNA sequencing of bat feces and identified a range of viruses, quickly validating viral sequences and assessing their phylogenetic relationships. We hope that the AliMarko pipeline will be a useful resource for the scientific community, facilitating the interpretation of viral communities and advancing our understanding of viral diversity and its impact on human health.

PMID:40143285 | DOI:10.3390/v17030355

Pharmaceutics. 2025 Feb 24;17(3):296. doi: 10.3390/pharmaceutics17030296.

ABSTRACT

Melanoma, a highly aggressive form of skin cancer, poses a major therapeutic challenge due to its metastatic potential, resistance to conventional therapies, and the complexity of the tumor microenvironment (TME). Materials science and nanotechnology advances have led to using nanocarriers such as liposomes, dendrimers, polymeric nanoparticles, and metallic nanoparticles as transformative solutions for precision melanoma therapy. This review summarizes findings from Web of Science, PubMed, EMBASE, Scopus, and Google Scholar and highlights the role of nanotechnology in overcoming melanoma treatment barriers. Nanoparticles facilitate passive and active targeting through mechanisms such as the enhanced permeability and retention (EPR) effect and functionalization with tumor-specific ligands, thereby improving the accuracy of drug delivery and reducing systemic toxicity. Stimuli-responsive systems and multi-stage targeting further improve therapeutic precision and overcome challenges such as poor tumor penetration and drug resistance. Emerging therapeutic platforms combine diagnostic imaging with therapeutic delivery, paving the way for personalized medicine. However, there are still issues with scalability, biocompatibility, and regulatory compliance. This comprehensive review highlights the potential of integrating nanotechnology with advances in genetics and proteomics, scalable, and patient-specific therapies. These interdisciplinary innovations promise to redefine the treatment of melanoma and provide safer, more effective, and more accessible treatments. Continued research is essential to bridge the gap between evidence-based scientific advances and clinical applications.

PMID:40142960 | DOI:10.3390/pharmaceutics17030296

J Clin Med. 2025 Mar 17;14(6):2040. doi: 10.3390/jcm14062040.

ABSTRACT

Oncologists increasingly recognize the microbiome as an important facilitator of health as well as a contributor to disease, including, specifically, cancer. Our knowledge of the etiologies, mechanisms, and modulation of microbiome states that ameliorate or promote cancer continues to evolve. The progressive refinement and adoption of "omic" technologies (genomics, transcriptomics, proteomics, and metabolomics) and utilization of advanced computational methods accelerate this evolution. The academic cancer center network, with its immediate access to extensive, multidisciplinary expertise and scientific resources, has the potential to catalyze microbiome research. Here, we review our current understanding of the role of the gut microbiome in cancer prevention, predisposition, and response to therapy. We underscore the promise of operationalizing the academic cancer center network to uncover the structure and function of the gut microbiome; we highlight the unique microbiome-related expert resources available at the City of Hope of Comprehensive Cancer Center as an example of the potential of team science to achieve novel scientific and clinical discovery.

PMID:40142848 | DOI:10.3390/jcm14062040

Int J Mol Sci. 2025 Mar 20;26(6):2823. doi: 10.3390/ijms26062823.

ABSTRACT

This study investigates the proteomic dynamics in tomato cultivars with differing resistance to potato cyst nematodes (PCNs). Cyst-forming nematodes, significant agricultural pests, induce complex molecular responses in host plants, forming syncytia in roots for their nutrition. This research employs mass spectrometry to analyze the proteomes of infected and uninfected roots from susceptible (Moneymaker) and resistant (LA1792 and L10) tomato lines. Over 2800 high-confidence protein hits were identified, revealing significant differences in abundance between susceptible and resistant lines. Notably, resistant lines exhibited a higher number of newly expressed proteins compared to susceptible lines; however, the proportion of induced and suppressed proteins was strongly genotype-dependent. Gene ontology (GO) analysis highlighted that nematode infection in susceptible line significantly regulates many defense-related proteins, particularly those involved in oxidative stress, with a similar number being upregulated and downregulated. Some GO terms enriched among nematode-regulated proteins also indicate the involvement of programmed cell death (PCD)-related processes. The susceptible line exhibited a prevalence of downregulated proteins, among which defense associated GO terms were significantly overrepresented. Four proteins (APY2, NIA2, GABA-T, and AATP1) potentially crucial for nematode parasitism were identified and their Arabidopsis orthologs were studied. Mutant Arabidopsis lines showed altered nematode resistance, supporting the involvement of these proteins in plant defense. This study highlights the complexity of host-nematode interactions and emphasizes the importance of proteomic analyses in identifying key factors and understanding plant defense mechanisms.

PMID:40141466 | DOI:10.3390/ijms26062823

Int J Mol Sci. 2025 Mar 11;26(6):2483. doi: 10.3390/ijms26062483.

ABSTRACT

Clinacanthus nutans is a valuable traditional medicinal plant that contains enriched active compounds such as triterpenoids and flavonoids. Understanding the accuulation process of these secondary metabolites in C. nutans requires exploring gene expression regulation under abiotic stresses and hormonal stimuli. qRT-PCR is a powerful method for gene expression analysis, with the selection of suitable reference genes being paramount. However, reports on stably expressed reference genes in C. nutans and even across the entire family Acanthaceae are limited. In this study, we evaluated the expression stability of 12 candidate reference genes (CnUBQ, CnRPL, CnRPS, CnPTB1, CnTIP41, CnACT, CnUBC, CnGAPDH, Cn18S, CnCYP, CnEF1α, and CnTUB) in C. nutans across different tissues and under abiotic stresses and MeJA treatment using three programs (geNorm, NormFinder, and BestKeeper). The integrated ranking results indicated that CnUBC, CnRPL, and CnCYP were the most stably expressed genes across different tissues. Under abiotic stress conditions, CnUBC, CnRPL, and CnEF1α were the most stable, while under MeJA treatment, CnRPL, CnEF1α, and CnGAPDH exhibited the highest stability. Additionally, CnRPL, CnUBC, and CnEF1α were the most stable reference genes across all tested samples, whereas CnGAPDH was the least stable. CnRPL, consistently ranking among the top three most stable genes, may therefore serve as an ideal reference gene for qRT-PCR analysis in C. nutans. To further validate the selected reference genes, we assessed the expression of two key biosynthetic genes, CnPAL and CnHMGR. The results confirmed that using the most stable reference genes yielded expression patterns consistent with biological expectations, while using unstable reference genes led to significant deviations. These findings offer valuable insights for accurately quantifying target genes via qRT-PCR in C. nutans, facilitating investigations into the mechanisms underlying active compound accumulation.

PMID:40141128 | DOI:10.3390/ijms26062483

Nat Microbiol. 2025 Mar 26. doi: 10.1038/s41564-025-01959-z. Online ahead of print.

ABSTRACT

Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.

PMID:40140706 | DOI:10.1038/s41564-025-01959-z

Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08795-5. Online ahead of print.

ABSTRACT

Regulatory T (Treg) cells, which specifically express the master transcription factor FOXP3, have a pivotal role in maintaining immunological tolerance and homeostasis and have the potential to revolutionize cell therapies for autoimmune diseases1-3. Although stimulation of naive CD4+ T cells in the presence of TGFβ and IL-2 can induce FOXP3+ Treg cells in vitro (iTreg cells), the resulting cells are often unstable and have thus far hampered translational efforts4-6. A systematic approach towards understanding the regulatory networks that dictate Treg differentiation could lead to more effective iTreg cell-based therapies. Here we performed a genome-wide CRISPR loss-of-function screen to catalogue gene regulatory determinants of FOXP3 induction in primary human T cells and characterized their effects at single-cell resolution using Perturb-icCITE-seq. We identify the RBPJ-NCOR repressor complex as a novel, context-specific negative regulator of FOXP3 expression. RBPJ-targeted knockout enhanced iTreg differentiation and function, independent of canonical Notch signalling. Repeated cytokine and T cell receptor signalling stimulation in vitro revealed that RBPJ-deficient iTreg cells exhibit increased phenotypic stability compared with control cells through DNA demethylation of the FOXP3 enhancer CNS2, reinforcing FOXP3 expression. Conversely, overexpression of RBPJ potently suppressed FOXP3 induction through direct modulation of FOXP3 histone acetylation by HDAC3. Finally, RBPJ-ablated human iTreg cells more effectively suppressed xenogeneic graft-versus-host disease than control iTreg cells in a humanized mouse model. Together, our findings reveal novel regulators of FOXP3 and point towards new avenues to improve the efficacy of adoptive cell therapy for autoimmune disease.

PMID:40140585 | DOI:10.1038/s41586-025-08795-5

Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08676-x. Online ahead of print.

ABSTRACT

Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

PMID:40140573 | DOI:10.1038/s41586-025-08676-x

Cell Death Differ. 2025 Mar 27. doi: 10.1038/s41418-025-01479-7. Online ahead of print.

ABSTRACT

Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

PMID:40140561 | DOI:10.1038/s41418-025-01479-7

Nat Plants. 2025 Mar 26. doi: 10.1038/s41477-025-01938-6. Online ahead of print.

ABSTRACT

During secondary growth, the vascular cambium produces conductive xylem and phloem cells, while the phellogen (cork cambium) deposits phellem (cork) as the outermost protective barrier. Although most of the secondary tissues are made up of parenchyma cells, which are also produced by both cambia, their diversity and function are poorly understood. Here we combined single-cell RNA sequencing analysis with lineage tracing to recreate developmental trajectories of the cell types in the Arabidopsis root undergoing secondary growth. By analysing 93 reporter lines, we were able to identify 20 different cell types or cell states, many of which have not been described before. We additionally observed distinct transcriptome signatures of parenchyma cells depending on their maturation state and proximity to the conductive cell types. Our data show that both xylem and phloem parenchyma tissues are required for normal formation of conductive tissue cell types. Furthermore, we show that mature phloem parenchyma gradually obtains periderm identity, and this transformation can be accelerated by jasmonate treatment or wounding. Our study thus reveals the diversity of parenchyma cells and their capacity to undergo considerable identity changes during secondary growth.

PMID:40140531 | DOI:10.1038/s41477-025-01938-6

Nat Plants. 2025 Mar 26. doi: 10.1038/s41477-025-01944-8. Online ahead of print.

ABSTRACT

Differential growth between tissues generates mechanical conflicts influencing organogenesis in plants. Here we use the anther, the male floral reproductive organ, as a model system to understand how cell dynamics and tissue-scale mechanics control 3D morphogenesis of a complex shape. Combining deep live-cell imaging, growth analysis, osmotic treatments, genetics and mechanical modelling, we show that localized expansion of internal cells actively drives anther lobe outgrowth, while the epidermis stretches in response. At later stages, mechanical load is transferred to the sub-epidermal layer (endothecium), contributing to proper organ shape. We propose the concept of 'inflation potential', encapsulating mechanical and anatomical features causing differential growth. Our data emphasize the active mechanical role of inner tissue in controlling both organ shape acquisition and cell dynamics in outer layers.

PMID:40140530 | DOI:10.1038/s41477-025-01944-8

Transl Psychiatry. 2025 Mar 26;15(1):97. doi: 10.1038/s41398-025-03321-7.

ABSTRACT

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence disease progression. Still, the molecular mechanisms caused by different mutations of AD are not understood. We have performed a multidisciplinary study to investigate and compare the early stages of the pathology in two transgenic AD mouse models: P301S and 5xFAD. Using SNOTRAP-based mass spectrometry, we assessed changes in S-nitrosylation, a nitric oxide-mediated post-translational modification, of proteins in both models during their juvenile age. The increased levels of 3-nitrotyrosine confirmed nitrosative stress in the mutant mice. Systems biology analysis revealed shared processes between the models, particularly in the γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission processes. In the P301S model, we identified 273 S-nitrosylated (SNOed) proteins in the cortex, with 244 proteins uniquely SNOed in the diseased mice. In the 5xFAD model, 309 SNOed proteins were identified. We have found altered proteins expression of different glutamate/GABA-related markers in the cortex and hippocampus of both AD mouse models. Additionally, the phosphorylation levels of the mTOR signaling components revealed hyperactivation of this pathway in P301S mice. Conversely, 5xFAD mice showed no significant changes in mTOR signaling except for elevated phosphorylation of the ribosomal protein S6 in the cortex. Our findings revealed key molecular mechanisms in the two AD mouse models during their early stages. These mechanisms could serve as potential biomarkers and therapeutic targets for early-stage AD.

PMID:40140365 | DOI:10.1038/s41398-025-03321-7

Environ Sci Pollut Res Int. 2025 Mar 26. doi: 10.1007/s11356-025-36286-7. Online ahead of print.

ABSTRACT

Nanotechnology has been utilized in diverse domains, encompassing sustainable agriculture. However, the ecotoxicity and environmental safety of nanoparticles need to be evaluated before their large-scale use. This study synthesizes and characterizes magnesium (Mg) and zinc (Zn) co-doped aluminum (Al) oxide (MgZnAl2O4) NPs and elucidates its potential growth-promoting or genotoxic performance on barley (Hordeum vulgare L.). XRD, EDX, TEM, SEM, and XPS were used to characterize the MgZnAl2O4 NPs. After characterization, the seedlings were grown in a hydroponic solution containing 0, 50, 100, 200, and 400 mg L-1 NPs for 3 weeks. The germination, growth indices, photosynthetic parameters, and nutrient absorption properties were determined. Confocal microscopy, TEM, and SEM were utilized to follow the path and reveal the structural and morphological effects of NPs. The potential genotoxic effect was evaluated using the RAPD-PCR method. Elemental composition analysis of plant parts confirmed that synthesized MgZnAl2O4 NPs, sized at 21.8 nm, were up-taken by the plant roots, leading to increased Mg, Zn, and Al contents of leaves. In addition, compared with the untreated control, the abundance of Ca, K, B, Fe, Mn, and Cu were increased by the NPs treatment. In addition, physiological indices like germination rate (~ 11%), root and leaf growth (15-29%), chlorophyll, and carotenoids (~ 39%) pigments were significantly raised by the NPs inclusion. It can be concluded that low concentrations (< 200 mg L-1) of MgZnAl2O4 NPs enhance growth parameters effectively and are safe for plant growth. On the other hand, a phytotoxic and genotoxic impact was observed at high concentrations (100-400 mg L-1). However, considerable amounts of NPs were found to be adsorbed on roots, disrupting root morphology and cell membrane integrity, thus nutrient trafficking and transport. Therefore, it is recommended that MgZnAl2O4 NPs can be used in barley breeding programs at low concentrations. Adding micro- or macroelements required by plants to the NP composition is a promising way to compensate for plant nutrition. However, the negative effects of MgZnAl2O4 NPs on the environment and other living beings due to their genotoxic effects at high doses must be carefully considered.

PMID:40140202 | DOI:10.1007/s11356-025-36286-7