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

Cell Mol Gastroenterol Hepatol. 2025 Mar 24:101505. doi: 10.1016/j.jcmgh.2025.101505. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: The incidence of Barrett esophagus (BE) and Gastroesophageal Adenocarcinoma (GEAC) correlates with obesity and a diet rich in fat. Bile acids (BA) support fat digestion and undergo microbial metabolism in the gut. The farnesoid X receptor (FXR) is an important modulator of the BA homeostasis. When activated, FXR can inhibit cancer-related processes and thus, it is an appealing therapeutic target. Here, we assess the effect of diet on the microbiota-BA axis and evaluate the role of FXR in disease progression.

METHODS: L2-IL1B mice (mouse model of BE and GEAC) under different diets, and L2-IL1B-FXR KO-mice were characterized. L2-IL1B-derived organoids were exposed to different BAs and to the FXR agonist obeticholic acid, OCA. The BA profile in serum and stool of healthy controls, BE- and GEAC-patients was assessed.

RESULTS: Here we show that high fat diet accelerated tumorigenesis in L2-IL1B mice while increasing BA levels and altering the composition of the gut microbiota. While upregulated in BE, expression of FXR was downregulated in GEAC in mice and humans. In L2-IL1B mice, FXR knockout enhanced the dysplastic phenotype and increased Lgr5 progenitor cell numbers. Treatment of murine BE organoids and L2-IL1B mice with OCA notably ameliorated the phenotype.

CONCLUSION: GEAC carcinogenesis appears to be partially driven via loss or inhibition of FXR on progenitor cells at the gastroesophageal junction. Considering that the resulting aggravation in the phenotype could be reversed with OCA treatment, we suggest that FXR agonists have great potential as a preventive strategy against GEAC progression.

PMID:40139565 | DOI:10.1016/j.jcmgh.2025.101505

Stem Cells Transl Med. 2025 Mar 18;14(3):szae099. doi: 10.1093/stcltm/szae099.

ABSTRACT

Many electronic cigarettes (ECs) contain high concentrations of menthol. The effect of menthol on human embryos in pregnant women who vape is not well understood. Human embryonic stem cells (hESCs) (an epiblast model) were used to test the hypothesis that 6.4-640 nM and 19.2-192 µM menthol, which activates TRP (transient-receptor-potential) channels, alters calcium homeostasis in embryos and adversely affects processes that are critical to gastrulation. Micromolar concentrations of menthol inhibited mitochondrial reductase activity in hESCs, an effect that was blocked by TRPA1 and TRPM8 inhibitors. Pulsatile exposure to menthol elevated intracellular calcium primarily by activating TRPA1 channels at nanomolar concentrations and TRPM8 channels at µM concentrations. nM menthol significantly inhibited colony growth by activating TRPA1 channels, while both TRPA1 and TRPM8 were activated by µM menthol. Inhibition of colony growth was attributed to cell death induced by menthol activation of TRPA1 and TRPM8 channels. nM menthol altered colony phenotype by increasing the major/minor axis ratio via TRPA1 and TRPM8 channels. Both nM and µM menthol induced alterations in hESC colony motility, an effect that was blocked only by the TRPM8 inhibitor. The menthol-induced increase in intracellular calcium adversely influenced growth, death, and migration, processes that are critical in gastrulation. Menthol concentrations that reach embryos in women who vape are high enough to activate TRPA1 and TRPM8 channels and perturbed calcium homeostasis. Pregnant women who vape likely expose their embryos to menthol concentrations that are harmful. These data could help prevent birth defects or embryo/fetal death.

PMID:40139559 | DOI:10.1093/stcltm/szae099

J Dairy Sci. 2025 Mar 24:S0022-0302(25)00171-7. doi: 10.3168/jds.2024-26011. Online ahead of print.

ABSTRACT

Improving calf health on dairy farms contributes to animal welfare and business productivity gains. In recent years, traditional genetic evaluations have broadened to include cow health traits that have economic importance. Calf health is a new frontier to explore but new traits require sufficient data to be effectively evaluated. Researchers who work in countries without obligatory record keeping systems, commonly promote the need to significantly improve record keeping practices to enable research, benchmarking, and genetic evaluation, as is the case in Australia. The aim of this study was to estimate variance components for novel calf traits using a data set that was co-designed with farmers and included calf identity, calving ease, health records and genotypes. Almost 20,000 calf records from over 50 farms located throughout Australia were collected between 2020 and 2023. In Holstein calves, the mean ± SE prevalence of preweaning mortality (PWM) and scours, were 0.020 ± 0.001 and 0.059 ± 0.002, respectively. A newly defined and subjectively scored trait called Calf Vitality (vitality) was co-developed with farmers, where 21% of calves were classed in the top category of ripper/vigorous, while 54% were good or average, 6% were duds and 19% of scored calves died. Univariate linear models that included a genomic relationship matrix were used to estimate variance components for diseases and vitality, where heritability values were between 1% and 11% in Holsteins depending on the trait. The models included herd-year-season (HYS), sex, parity group and calving ease (Holstein only) as fixed effects and these were found to be significant (P < 0.05 to 0.001) for most breed and trait combinations. The estimated reliability of EBVs ranged between 0.2 and 0.3. In Australia, Holsteins are more numerous than the Jersey breed, and so despite efforts to compile an appropriate data set, the disease prevalence and record numbers were too low to report genetic variance for calf health traits in the Jersey breed. Approximate genetic correlations with other calf health traits such as stillbirth (SB) and PWM were modest but favorable. There were few significant correlations with lactating cow traits (such as survival, somatic cell count and likeability) and national selection indexes that are routinely evaluated in Australia and those that were significant were in a favorable direction.

PMID:40139346 | DOI:10.3168/jds.2024-26011

Food Chem. 2025 Mar 19;480:143966. doi: 10.1016/j.foodchem.2025.143966. Online ahead of print.

ABSTRACT

Consumers' interest in healthy and sustainable food of superior organoleptic quality has contributed to an increased market of mildly processed chilled NFC orange juices, preserved by methods such as high pressure processing (HPP) and pulsed electric fields (PEF). To protect consumers from food fraud, analytical methods to differentiate such juices from thermally pasteurized juices are required. To screen for appropriate candidate markers, we applied a complementary non-targeted volatilomics and sensomics approach resulting in a total of 58 candidate markers, among which 20 were quantitated and nine were statistically confirmed. Extension of the quantitations to stored and doubly-treated juices finally resulted in (S)-carvone and vanillin as promising candidate markers. In combination, the two compounds allowed to distinguish the HPP-treated juice from thermally treated juices and even was able to identify an HPP-treated juice that had received an additional thermal pasteurization.

PMID:40138831 | DOI:10.1016/j.foodchem.2025.143966

Sci Adv. 2025 Mar 28;11(13):eads6021. doi: 10.1126/sciadv.ads6021. Epub 2025 Mar 26.

ABSTRACT

Emerging evidence has shown that epigenetic regulation plays a fundamental role in cancer metastasis, the major cause of cancer-related deaths. Here, we conducted an in vivo screen for vulnerabilities of brain metastasis and identified N-acetyltransferase 10 (NAT10) as a driver of brain metastasis. Knockdown of NAT10 restrains cancer cell proliferation and migration in vitro and tumor growth and brain metastasis in vivo. The poorly characterized RNA helicase domain of NAT10 is critical for cell growth in vitro, while both RNA helicase and NAT domains are essential for primary tumor growth and brain metastasis in vivo. Mechanically, NAT10 promotes the expression of 3-phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1), two enzymes for serine biosynthesis implicated in brain metastasis. Silencing PHGDH or PSAT1 in metastatic breast cancer cells inhibits their growth in the serine/glycine-limited condition, phenocopying the effects of NAT10 depletion. These findings establish NAT10 as a key regulator of brain metastasis and nominate NAT10 as a target for treating metastasis.

PMID:40138393 | DOI:10.1126/sciadv.ads6021

STAR Protoc. 2025 Mar 24;6(2):103714. doi: 10.1016/j.xpro.2025.103714. Online ahead of print.

ABSTRACT

A reproducible study system is essential for understanding the role of microbes in human skin health and disease. We present a protocol for constructing a synthetic microbial community (SkinCom) of nine strains dominant to native human skin microbiome. We describe steps for computing growth metrics, constructing communities, and extracting DNA and library preparation for shotgun sequencing. We detail steps for data preprocessing and analysis of community samples. We illustrate SkinCom's application with an epicutaneous murine model and downstream multiomic analysis. For complete details on the use and execution of this protocol, please refer to Lekbua et al.1.

PMID:40138316 | DOI:10.1016/j.xpro.2025.103714

PLoS One. 2025 Mar 26;20(3):e0320377. doi: 10.1371/journal.pone.0320377. eCollection 2025.

ABSTRACT

Decisions where an individual lays their eggs are important, as the choice may affect their offspring's survival and lifetime reproductive success. Information produced by conspecifics can potentially be useful in making decisions as this "social information" may provide an energetically cheaper means of assessing oviposition site suitability rather than acquiring it personally. However, as not all public information may be equally beneficial, cues produced by kin may be especially valuable as they might signal suitable microenvironments, and are associated with other fitness advantages resulting from improved foraging success and/or a decreased risk of competition/cannibalism compared to sites where unrelated conspecifics are located. Using the fruit fly, Drosophila melanogaster, we explored whether public information use is associated with kin-based egg-laying decisions. Kinship is potentially recognized in several ways, including environmentally-associated proxy cues, so we explored whether there were biases in how focal females interacted with cues from conspecifics that differed in both genetic relatedness, and environmental "familiarity." In a series of inter-connected assays, we examined the behaviour of focal females that interacted with a choice of potential egg-laying substrates that differed in the manner of their prior conspecific exposure, and counted the offspring that eclosed from these different substrates. Sites that had exhibited cues produced by conspecific demonstrators were visited more, and yielded more focal offspring compared to unexposed substrates. Furthermore, patterns of bias in offspring production were consistent with ovipositing females exhibiting sensitivity to the kinship status of the prior substrate's occupants. The basis of the kinship categorization by ovipositing females appears to be based on phenotypes that reflect true genetic relatedness, but the nature of the social information can be affected by other factors. These results further highlight the potential usefulness of D. melanogaster as a model to understand the evolution of social behaviour in the expression of decision-making.

PMID:40138267 | DOI:10.1371/journal.pone.0320377

Acta Neurol Belg. 2025 Mar 26. doi: 10.1007/s13760-025-02770-7. Online ahead of print.

NO ABSTRACT

PMID:40138160 | DOI:10.1007/s13760-025-02770-7

Cell Tissue Res. 2025 Mar 26. doi: 10.1007/s00441-025-03965-3. Online ahead of print.

ABSTRACT

The Na,K-ATPase is a vital transmembrane enzyme, which is important for maintaining cell membrane potentials and the general functionality of animal cells. The enzyme's minimal functional unit consists of one α and one β-subunit, whereas the number of existing paralogs varies in different insect species. The functional roles of different β-subunits, which can account for their diversity within a single species, are so far only partially explained. The emphasis of this study was to specifically elucidate the involvement in septate junctions of the four β-subunits of the new model system Oncopeltus fasciatus. Septate junctions function as a paracellular barrier controlling the flow of solutes across epithelia. So far, studies in Drosophila revealed that nervana2, the β2 homolog of Drosophila, is involved in septate junction formation. In O. fasciatus, we demonstrate that most of the Na,K-ATPase subunits colocalize with septate junction proteins. This agrees with our previous findings implying a role of β2 in the control of tracheal tube size in O. fasciatus, which according to the findings in Drosophila appears to be dependent on a stable formation of septate junctions. Finally, our data suggest a connection between the septate junction protein coracle and the enigmatic, N-terminally strongly truncated βx, which has no obvious homologs in other insects. Our study proposes that the four β-subunits form functional units with septate junction proteins, either allowing tissue-adjusted formation of cell-cell contacts or other yet unknown functions.

PMID:40137937 | DOI:10.1007/s00441-025-03965-3

Pathogens. 2025 Mar 14;14(3):279. doi: 10.3390/pathogens14030279.

ABSTRACT

Helicobacter pylori (H. pylori) possess an arsenal of virulence genes that makes them the main etiological factor in gastric diseases. In this study, 120 southern Moroccan patients who were dyspeptic were profiled to investigate the potential association between disease severity and the combination of multiple virulence genes. Gastric biopsies were taken from patients, followed by histopathological evaluation and genotyping of H. pylori using PCR. H. pylori was detected in 58.3% of cases, and genotypes were distributed as follows: oipA (94.3%), cagA (62.9%), virB11 (60%), babA (55.7%), dupA (54.3%), cagE (51.4%), iceA1 (31.4%), iceA2 (45.7%), vacA s2m2 (47.1%), vacA s1m1 (30%), and vacA s1m2 (7.1%). Statistically significant associations with males were observed for the cagA, cagE, and virB11 genes and multiple strain infections. Multivariate analysis revealed an association between cagE and heightened neutrophil activity, with an odds ratio (OR) of 4.99 (p = 0.03). The gene combination [cagA (+), cagE (+), virB11 (+), vacA s1m1, and babA (+)] emerged as a predictive factor for gastric cancer (OR = 11.10, p = 0.046), while the combination [cagA (-), cagE (-), virB11 (-), vacA s2m2, babA (+)] was associated with gastric atrophy (OR = 10.25, p = 0.016). Age (≤40 years) (OR = 5.87, p = 0.013) and moderate to severe bacterial density (OR = 15.38, p = 0.017) were identified as predictive factors for follicular gastritis. These findings underscore the significance of multigene profiling as a prognostic marker and emphasize the importance of age and sex in preventing adverse outcomes in severe gastric diseases.

PMID:40137764 | DOI:10.3390/pathogens14030279

Pathogens. 2025 Feb 27;14(3):234. doi: 10.3390/pathogens14030234.

ABSTRACT

Mitochondrial genomes serve as essential tools in evolutionary biology, phylogenetics, and population genetics due to their maternal inheritance, lack of recombination, and conserved structure. Traditional morphological methods for identifying nematodes are often insufficient for distinguishing cryptic species complexes. This study highlights recent advancements in nematode mitochondrial genome research, particularly the impact of long-read sequencing technologies such as Oxford Nanopore. These technologies have facilitated the assembly of mitochondrial genomes from mixed soil samples, overcoming challenges associated with designing specific primers for long PCR amplification across different groups of parasitic nematodes. In this study, we successfully recovered and assembled eleven nematode mitochondrial genomes using long-read sequencing, including those of two plant-parasitic nematode species. Notably, we detected Heterodera cruciferae in Victoria, expanding its known geographic range within Australia. Additionally, short-read sequencing data from a previous draft genome study revealed the presence of the mitochondrial genome of Heterodera filipjevi. Comparative analyses of Heterodera mitogenomes revealed conserved protein-coding genes essential for oxidative phosphorylation, as well as gene rearrangements and variations in transfer RNA placement, which may reflect adaptations to parasitic lifestyles. The consistently high A+T content and strand asymmetry observed across species align with trends reported in related genera. This study demonstrates the utility of long-read sequencing for identifying coexisting nematode species in agricultural fields, providing a rapid, accurate, and comprehensive alternative to traditional diagnostic methods. By incorporating non-target endemic species into public databases, this approach enhances biodiversity records and informs biosecurity strategies. These findings reinforce the potential of mitochondrial genomics to strengthen Australia's as well as the global biosecurity framework against plant-parasitic nematode threats.

PMID:40137719 | DOI:10.3390/pathogens14030234

Adv Healthc Mater. 2025 Mar 26:e2500681. doi: 10.1002/adhm.202500681. Online ahead of print.

ABSTRACT

The extracellular matrix (ECM) plays a pivotal role in immunomodulation, providing structural and biochemical cues that shape immune cell function. In pathological conditions like cancer and chronic inflammation, dysregulated remodeling often results in altered ECM composition and architecture, with fibrillar alignment being a hallmark linked to disease progression. Here, how ECM alignment influences dendritic cell (DC) behavior using 3D biomimetic collagen matrices with controlled fibril anisotropy is investigated. This results show that immature DCs in aligned matrices exhibited increased expression of CD86 and HLA-DR with elevated secretion of CXCL8 and CCL2 chemokines, which may enhance immune cell recruitment. However, transcriptomic and metabolomic analysis revealed significant downregulation of oxidative phosphorylation and an insufficient compensatory shift toward glycolysis, resulting in reduced ATP production. This metabolic constraint correlated with impaired/reduced DC migratory speed and distance. In contrast, mature DCs displayed minimal sensitivity to ECM alignment, maintaining uniform differentiation and functional profiles across matrix conditions. T-cell coculture experiments revealed that ECM alignment dampens T-cell activation and proliferation, likely through direct modulation of T-cell behavior. These findings highlight the stage-specific effects of ECM alignment on DC function, highlighting its role in DC immunomodulation, with implications for therapeutic development in cancer and other pathological contexts.

PMID:40134371 | DOI:10.1002/adhm.202500681

Nat Med. 2025 Mar 25. doi: 10.1038/s41591-025-03526-9. Online ahead of print.

ABSTRACT

The 2022 global mpox epidemic was caused by transmission of MPXV clade IIb, lineage B.1 through sexual contact networks, with New York City (NYC) experiencing the first and largest outbreak in the United States. By performing phylogeographic analysis of MPXV genomes sampled from 757 individuals in NYC between April 2022 and April 2023, and 3,287 MPXV genomes sampled around the world, we identify over 200 introductions of MPXV into NYC with at least 84 leading to onward transmission. These infections primarily occurred among men who have sex with men, transgender women and nonbinary individuals. Through a comparative analysis with HIV in NYC, we find that both MPXV and HIV genomic cluster sizes are best fit by scale-free distributions, and that people in MPXV clusters are more likely to have previously received an HIV diagnosis and be a member of a recently growing HIV transmission cluster. We model MPXV transmission through sexual contact networks and show that highly connected individuals would be disproportionately infected at the start of an epidemic, which would likely result in the exhaustion of the most densely connected parts of the network, and, therefore, explain the rapid expansion and decline of the NYC outbreak. By coupling the genomic epidemiology of MPXV and HIV with epidemic modeling, we demonstrate that the transmission dynamics of MPXV in NYC can be understood by general principles of sexually transmitted pathogens.

PMID:40133528 | DOI:10.1038/s41591-025-03526-9

Sci Rep. 2025 Mar 25;15(1):10296. doi: 10.1038/s41598-025-88571-7.

ABSTRACT

Lignin is composed of phenylpropanoid monomers linked by ether and carbon-carbon bonds to form a complex heterogeneous structure. Bond-specific studies of lignin-modifying enzymes (LMEs; e.g., laccases and peroxidases) are limited by the polymerization of model lignin substrates and repolymerization of cleavage products. Here we present a high throughput platform to screen LME activities on four tagged model lignin compounds that represent the β-O-4', β-β', 5-5', and 4-O-5' linkages in lignin. We utilized nanostructure-initiator mass spectrometry (NIMS) and model lignin compounds with tags containing perfluorinated and cationic moieties, which effectively limit polymerization and condensation of the substrates and their degrading products. Sub-microliter sample droplets were printed on the NIMS chip with a novel robotics method. This rapid platform enabled characterization of LMEs across a range of pH 3-10 and relative quantification of modified (typically oxidized), cleaved, and polymerized products. All tested enzymes oxidized the four substrates and cleaved the β-O-4' and β-β' substrates to monomeric products. We discovered that the active pH range depended on both the substrate and the enzyme type. This has important applications for biomass conversion to biofuels and bioproducts, where the relative percentages of different bond types in lignin varies depending on feedstock and chemical pretreatment methods.

PMID:40133407 | DOI:10.1038/s41598-025-88571-7

Cell Discov. 2025 Mar 25;11(1):31. doi: 10.1038/s41421-025-00771-7.

ABSTRACT

An outbreak of mpox has triggered concerns regarding the adequacy of intervention strategies. Passive immunity conferred by neutralizing antibodies exhibits potential in the prophylaxis and treatment of orthopoxvirus infections. Despite this, the investigations of effective antibody therapeutics have been hindered by the varied nature of orthopoxvirus envelope proteins and the intricate mechanisms underpinning viral invasion. Our study involves the production of six mpox virus (MPXV) envelope proteins, which are relatively conservative and considered to play a role in the neutralization process. We employed a synthetic nanobody (Nb) library to derive a broad array of specific Nbs against these viral proteins. We identified a cross-reactive Nb, termed M1R-01, which targets the M1R protein and effectively neutralizes both vaccinia virus (VACV) and MPXV. Notably, the M1R-01-based antibody strategy provided optimal protection against a lethal VACV challenge in mice. Additionally, we determined the crystal structure of the M1R-Nb complex, uncovering novel binding attributes of M1R-01 and detailed conformational epitope information. This work provides a promising candidate for the therapy and prophylaxis of orthopoxvirus infections.

PMID:40133273 | DOI:10.1038/s41421-025-00771-7

Nat Commun. 2025 Mar 25;16(1):2923. doi: 10.1038/s41467-025-58035-7.

ABSTRACT

Macroautophagy/autophagy is a key catabolic-recycling pathway that can selectively target damaged organelles or invading pathogens for degradation. The selective autophagic degradation of the endoplasmic reticulum (hereafter referred to as ER-phagy) is a homeostatic mechanism, controlling ER size, the removal of misfolded protein aggregates, and organelle damage. ER-phagy can also be stimulated by pathogen infection. However, the link between ER-phagy and bacterial infection remains poorly understood, as are the mechanisms evolved by pathogens to escape the effects of ER-phagy. Here, we show that Salmonella enterica serovar Typhimurium inhibits ER-phagy by targeting the ER-phagy receptor FAM134B, leading to a pronounced increase in Salmonella burden after invasion. Salmonella prevents FAM134B oligomerization, which is required for efficient ER-phagy. FAM134B knock-out raises intracellular Salmonella number, while FAM134B activation reduces Salmonella burden. Additionally, we found that Salmonella targets FAM134B through the bacterial effector SopF to enhance intracellular survival through ER-phagy inhibition. Furthermore, FAM134B knock-out mice infected with Salmonella presented severe intestinal damage and increased bacterial burden. These results provide mechanistic insight into the interplay between ER-phagy and bacterial infection, highlighting a key role for FAM134B in innate immunity.

PMID:40133256 | DOI:10.1038/s41467-025-58035-7

J Pers Med. 2025 Mar 5;15(3):103. doi: 10.3390/jpm15030103.

ABSTRACT

Background: In the United States, approximately 1 in 5 children experience comorbidities with mental illness, including depression and anxiety, which lead to poor general health outcomes. Adolescents with substance use disorders exhibit high rates of co-occurring mental illness, with over 60% meeting diagnostic criteria for another psychiatric condition in community-based treatment programs. Comorbidities are influenced by both genetic (DNA antecedents) and environmental (epigenetic) factors. Given the significant impact of psychiatric comorbidities on individuals' lives, this study aims to uncover common mechanisms through a Genome-Wide Association Study (GWAS) meta-meta-analysis. Methods: GWAS datasets were obtained for each comorbid phenotype, followed by a GWAS meta-meta-analysis using a significance threshold of p < 5E-8 to validate the rationale behind combining all GWAS phenotypes. The combined and refined dataset was subjected to bioinformatic analyses, including Protein-Protein Interactions and Systems Biology. Pharmacogenomics (PGx) annotations for all potential genes with at least one PGx were tested, and the genes identified were combined with the Genetic Addiction Risk Severity (GARS) test, which included 10 genes and eleven Single Nucleotide Polymorphisms (SNPs). The STRING-MODEL was employed to discover novel networks and Protein-Drug interactions. Results: Autism Spectrum Disorder (ASD) was identified as the top manifestation derived from the known comorbid interaction of anxiety, depression, and attention deficit hyperactivity disorder (ADHD). The STRING-MODEL and Protein-Drug interaction analysis revealed a novel network associated with these psychiatric comorbidities. The findings suggest that these interactions are linked to the need to induce "dopamine homeostasis" as a therapeutic outcome. Conclusions: This study provides a reliable genetic and epigenetic map that could assist healthcare professionals in the therapeutic care of patients presenting with multiple psychiatric manifestations, including anxiety, depression, and ADHD. The results highlight the importance of targeting dopamine homeostasis in managing ASD linked to these comorbidities. These insights may guide future pharmacogenomic interventions to improve clinical outcomes in affected individuals.

PMID:40137419 | DOI:10.3390/jpm15030103