Nat Commun. 2025 Aug 7;16(1):7272. doi: 10.1038/s41467-025-62214-x.

ABSTRACT

YKYY017 is a SARS-CoV-2 membrane fusion inhibitor. We report efficacy and safety of inhaled YKYY017 for COVID-19 patients with mild to moderate illness from a phase 2 trial (ChiCTR2300075467). 239 patients aged 18-75 years with mostly mild COVID-19 were randomly allocated to receive aerosol inhalation of 10 or 20 mg YKYY017 or placebo once daily. The primary endpoint is the change in SARS-CoV-2 viral load from baseline to Day 4. The mean (±SE) differences in viral load change from baseline were -0.48 ± 0.27 log10 copies/mL (95% CI, -1.01 to 0.06) for the 20 mg group and -0.27 ± 0.27 log10 copies/mL (95% CI, -0.79 to 0.26) for the 10 mg group, compared to the placebo group. Viral load changes at visits other than Day 4 did not differ significantly from placebo in either the 10 or 20 mg YKYY017 groups. The time to sustained symptom recovery was shorter in the 20 mg YKYY017 group (median 117.53, 95%CI 95.33 to 141.45 hours) than in the placebo group (median 143.00, 95%CI 139.17 to 186.87 hours; HR 1.552, 95%CI 1.089 to 2.214, p = 0.0151), whereas the 10 mg YKYY017 group showed a similar but not statistically significant trend compared to placebo (p = 0.0833). The time to sustained symptom alleviation was shorter in both the 20 and 10 mg YKYY017 groups than in the placebo group. The adverse events were mostly mild to moderate. The primary outcome was not met. Following a supplementary phase 1b trial, we are planning another phase 2/3 trial using a twice-daily 20 mg YKYY017 regimen to further assess efficacy and safety.

PMID:40775020 | DOI:10.1038/s41467-025-62214-x

Genome Res. 2025 Aug 7. doi: 10.1101/gr.280586.125. Online ahead of print.

ABSTRACT

Evolutionary rate covariation (ERC) is an established comparative genomics method that identifies sets of genes sharing patterns of sequence evolution, which suggests shared function. Whereas many functional predictions of ERC have been empirically validated, its predictive power has hitherto been limited by its inability to tackle the large numbers of species in contemporary comparative genomics data sets. This study introduces ERC2.0, an enhanced methodology for studying ERC across phylogenies with hundreds of species and tens of thousands of genes. ERC2.0 improves upon previous iterations of ERC in algorithm speed, normalizing for heteroskedasticity, and normalizing correlations via Fisher transformations. These improvements have resulted in greater statistical power to predict biological function. In exemplar yeast and mammalian data sets, we demonstrate that the predictive power of ERC2.0 is improved relative to the previous method, ERC1.0, and that further improvements are obtained by using larger yeast and mammalian phylogenies. We attribute the improvements to both the larger data sets and improved rate normalization. We demonstrate that ERC2.0 has high predictive accuracy for known annotations and can predict the functions of genes in nonmodel systems. Our findings underscore the potential for ERC2.0 to be used as a single-pass computational tool in candidate gene screening and functional predictions.

PMID:40774815 | DOI:10.1101/gr.280586.125

Biochim Biophys Acta Rev Cancer. 2025 Aug 5:189408. doi: 10.1016/j.bbcan.2025.189408. Online ahead of print.

ABSTRACT

DNA repair is involved in the cellular response to alkylating agents used for the treatment of various cancers, decreasing the damages induced by the compounds and thus limiting the efficacy of the drugs. The inhibition of DNA repair should therefore increase the cytotoxic effect of alkylating agents, and this has been suggested as a therapeutic approach to increase clinical success. In this review, we focus on proteins involved in Nucleotide Excision Repair (NER) with a particular emphasis on the heterodimer ERCC1/XPF, and give an overview of preclinical and clinical studies underlying this therapeutic approach, as well as details on studies and compounds with notable activities. We also discuss the use of computer-aided methods to develop small molecule inhibitors targeting NER-related proteins, with a focus on structure-based virtual screening, and reflect on future perspectives on this topic. Although interesting results are obtained on cell models with various molecules, we believe new efforts are needed in order to validate the proof of concept in vivo and to translate the use of NER inhibitors in cancer patients.

PMID:40774469 | DOI:10.1016/j.bbcan.2025.189408

Cell Syst. 2025 Aug 1:101367. doi: 10.1016/j.cels.2025.101367. Online ahead of print.

ABSTRACT

Clostridioides difficile (C. difficile) colonizes up to 40% of community-dwelling adults without causing disease but can eventually lead to infection (C. difficile infection [CDI]). There has been a lack of focus on how to prevent colonization and facilitate the successful clearance of C. difficile prior to the emergence of CDI. We show that microbial community-scale metabolic models (MCMMs) accurately predict C. difficile colonization susceptibility in vitro and in vivo, offering mechanistic insights into microbiota-specific interactions involving metabolites like succinate, trehalose, and ornithine. MCMMs reveal distinct C. difficile metabolic niches-two growth-associated and one non-growth-associated-observed across 15,204 individuals from five cohorts. We further demonstrate that MCMMs can predict personalized C. difficile growth suppression by a probiotic cocktail designed to replace fecal microbiota transplants (FMTs) for the treatment of recurrent CDI, and we identify new probiotic targets for future validation. MCMMs represent a powerful framework for predicting pathogen colonization and assessing probiotic efficacy across diverse microbiota contexts. A record of this paper's transparent peer review process is included in the supplemental information.

PMID:40774255 | DOI:10.1016/j.cels.2025.101367

Cell. 2025 Jul 29:S0092-8674(25)00803-7. doi: 10.1016/j.cell.2025.07.014. Online ahead of print.

ABSTRACT

Discrete genomic units can recombine into composite transposons that transcribe and transpose as single units, but their regulation and function are not fully understood. We report that composite transposons harbor bivalent histone marks, with activating and repressive marks in distinct regions. Genome-wide CRISPR-Cas9 screening, using a reporter driven by the hominid-specific composite transposon SVA (SINE [short interspersed nuclear element]-VNTR [variable number of tandem repeats]-Alu) in human cells, identified diverse genes that modify bivalent histone marks to regulate SVA transcription. SVA transcripts are critical for SVA's cis-regulatory function in selectively contacting and activating long-range gene expression. Remarkably, a subset of bivalent SVAs is activated during erythropoiesis to boost multiple erythroid gene expression, and knocking down these SVAs leads to deficient erythropoiesis. The RNA-dependent cis-regulatory function of SVA activates genes for myelopoiesis and can contribute to aging-associated myeloid-biased hematopoiesis. These results reveal that the cis-regulatory functions of composite transposons are bivalently regulated to control cell fate transitions in development and aging.

PMID:40774253 | DOI:10.1016/j.cell.2025.07.014

Science. 2025 Aug 7;389(6760):594-599. doi: 10.1126/science.adx4380. Epub 2025 Aug 7.

ABSTRACT

The immune system's central function is to maintain homeostasis by guarding the organism against dangerous external and internal stressors. Immunity's operational toolbox contains diverse processes, such as phagocytosis, antigen recognition, cell killing, and secretion of cytokines and antibodies. Although immune cells interact with each other, they also communicate with cells typically associated with other organ systems, including the nervous, circulatory, metabolic, musculoskeletal, endocrine, and hematopoietic. This abundant cross-talk shows that immunity transcends defense and homeostasis: It is a network that participates in many physiological processes necessary for life. By accessing the circulation and inhabiting every tissue, leukocytes sense, interpret, and regulate biological processes. In this Review, we highlight recent studies that illustrate the often bidirectional and symbiotic relationships through which the immune system regulates physiology.

PMID:40773571 | DOI:10.1126/science.adx4380

Mol Plant Pathol. 2025 Aug;26(8):e70135. doi: 10.1111/mpp.70135.

ABSTRACT

Asian soybean rust (ASR), caused by the obligate biotrophic fungus Phakopsora pachyrhizi, was first reported in the continental United States of America (USA) in 2004 and over the years has been of concern to soybean production in the United States. The prevailing hypothesis is that P. pachyrhizi spores were introduced into the United States via hurricanes originating from South America, particularly hurricane Ivan. To investigate the genetic diversity and global population structure of P. pachyrhizi, we employed exome-capture based sequencing on 84 field isolates collected from different geographic regions worldwide. We compared the gene-encoding regions from all these field isolates and found that four major mitochondrial haplotypes are prevalent worldwide. Here, we provide genetic evidence supporting multiple incursions that have led to the currently established P. pachyrhizi population of the United States. Phylogenetic analysis of mitochondrial genes further supports this hypothesis. We observed limited genetic diversity in P. pachyrhizi populations across different geographic regions, suggesting a clonal population structure. Additionally, this study is the first to report the F129L mutation in the Cytb gene outside South America, which is associated with strobilurin tolerance. This study provides the first comprehensive characterisation of P. pachyrhizi population structures defined by genetic evidence from populations across major soybean-growing regions.

PMID:40773485 | DOI:10.1111/mpp.70135

Proc Natl Acad Sci U S A. 2025 Aug 12;122(32):e2504578122. doi: 10.1073/pnas.2504578122. Epub 2025 Aug 7.

ABSTRACT

DNA-points accumulation for imaging in nanoscale topography (DNA-PAINT) enables nanoscale imaging with virtually unlimited multiplexing and molecular counting. Here, we address challenges, such as variable imaging performance and target accessibility, that can limit its broader applicability. Specifically, we enhance its capacity for robust single-protein imaging and molecular counting by optimizing the integration of total internal reflection fluorescence microscopy with physical sectioning, in particular, Tokuyasu cryosectioning. Our method, tomographic and kinetically enhanced DNA-PAINT (tkPAINT), achieves 3 nm localization precision across diverse samples, enhanced imager binding, and improved cellular integrity. tkPAINT can facilitate molecular counting with DNA-PAINT inside the nucleus, as demonstrated through its quantification of the in situ abundance of RNA Polymerase II in both HeLa cells as well as mouse tissues. Anticipating that tkPAINT could become a versatile tool for the exploration of biomolecular organization and interactions across cells and tissues, we also demonstrate its capacity to support multiplexing, multimodal targeting of proteins and nucleic acids, and three-dimensional (3D) imaging.

PMID:40773232 | DOI:10.1073/pnas.2504578122

Proc Natl Acad Sci U S A. 2025 Aug 12;122(32):e2502160122. doi: 10.1073/pnas.2502160122. Epub 2025 Aug 7.

ABSTRACT

Understanding the molecular mechanisms behind plant response to stress can enhance breeding strategies and help us design crop varieties with improved stress tolerance, yield, and quality. To investigate resource redistribution from growth- to defense-related processes in an essential tuber crop, potato, here we generate a large-scale compartmentalized genome-scale metabolic model (GEM), potato-GEM. Apart from a large-scale reconstruction of primary metabolism, the model includes the full known potato secondary metabolism, spanning over 566 reactions that facilitate the biosynthesis of 182 distinct potato secondary metabolites. Constraint-based modeling identifies that the activation of the largest amount of secondary (defense) pathways occurs at a decrease of the relative growth rate of potato leaf, due to the costs incurred by defense. We then obtain transcriptomics data from experiments exposing potato leaves to two biotic stress scenarios, a herbivore and a viral pathogen, and apply them as constraints to produce condition-specific models. We show that these models recapitulate experimentally observed decreases in relative growth rates under treatment as well as changes in metabolite levels between treatments, enabling us to pinpoint the metabolic rewiring underlying growth-defense trade-offs. Potato-GEM thus presents a useful resource to study and broaden our understanding of potato and general plant defense responses under stress conditions.

PMID:40773226 | DOI:10.1073/pnas.2502160122

Development. 2025 Aug 7:dev.204663. doi: 10.1242/dev.204663. Online ahead of print.

ABSTRACT

Pericellular matrix-mediated cell-cell adhesion in Xenopus gastrula tissues is characterized by a spectrum of narrow and wide cell contacts that alternate with the non-adhesive surfaces of the interstitial space. Here we show, first, that knockdown of a pericellular matrix adhesion molecule, fibronectin, diminishes contact abundance and hence cell packing density, but without reducing adhesion strength. Second, we find that cell surfaces in gastrula tissues exhibit solid-like behavior in the form of buckling and crumpling, shape modifications which are typically seen in thin elastic films. We propose that both phenomena are explained by generic properties of the pericellular matrix: its compression and consequent stiffening by the interpenetration of matrix layers during adhesive contact formation. We argue that this renders part of the cell surface non-adhesive to form interstitial gaps, and gap surfaces as well as contacts prone to buckling and crumpling in step with cell contractility fluctuations. In this elasto-capillary model of tissue cohesion, the size of the interstitial space is determined by the abundance of pericellular matrix, not by adhesion strength.

PMID:40772725 | DOI:10.1242/dev.204663

Mol Ecol. 2025 Aug 7:e70061. doi: 10.1111/mec.70061. Online ahead of print.

ABSTRACT

Sex-specific genomic differentiation is a crucial yet frequently overlooked factor in population genetics. In this opinion piece, we leverage the substantial genomic resources available for the great tit (Parus major), including population-scale data sets from many European populations, to investigate genomic differentiation between males and females. Unlike in some other species, where high-quality genome assemblies exist but broad population sampling is lacking, the great tit offers a unique opportunity to study sex-based differentiation at both the genomic and population level. We identify significant differentiation at an autosomal locus on chromosome 5, which we hypothesise originates from sex-linked variation present on the sex chromosomes (Z and potentially W). By referencing genomic data from other songbirds with well-assembled sex chromosomes, we illustrate how autosomal loci may exhibit high sequence similarity to sex-linked regions. Our analyses demonstrate that uneven sex ratios in sampled populations can substantially bias differentiation metrics (e.g., FST), potentially resulting in false-positive interpretations of adaptive differentiation. To mitigate such issues, we stress the importance of sex-aware study designs, including balanced sex sampling and explicitly incorporating sex as a covariate. Furthermore, while optimal study designs would include high-quality reference genomes from both sexes, we recommend, as a pragmatic and cost-effective alternative for labs with limited resources, generating a reference genome from the heterogametic sex (females in birds) to ensure both sex chromosomes are represented in mapping and analysis. Finally, we emphasise the need for rigorous validation of candidate loci to ensure accurate and biologically meaningful outcomes in evolutionary genomic studies.

PMID:40772596 | DOI:10.1111/mec.70061

Front Pharmacol. 2025 Jul 23;16:1542159. doi: 10.3389/fphar.2025.1542159. eCollection 2025.

ABSTRACT

BACKGROUD: Papillary thyroid carcinoma (PTC) represents a malignant epithelial tumor characterized with a preference for younger individuals. Despite its generally favorable prognosis, PTC still poses considerable challenges, particularly in regards to the propensity for distant metastasis. As a key enzyme in the glycolytic pathway, phosphoglycerate kinase 1 (PGK1) has been linked to the progression of various cancer types. However, its role in PTC remains to be elucidated. This study aimed to investigate the association between PGK1 expression in thyroid cancer tissues and clinicopathological features, postoperative recurrence, and prognosis to provide clinical assessment and intervention reference.

METHODS: We investigated the correlation between PGK1 expression and the clinicopathological characteristics, recurrence, and prognosis in 97 PTC patients who underwent surgical treatments between 1 January 2020, and 31 December 2020 in Zhengzhou University First Affiliated Hospital. Besides, we also analysed the correlation of PGK1 expression with the 10-year survival rate of patients with thyroid carcinoma (THCA) in UALCAN database.

RESULTS: PGK1 expression was higher in cancerous tissues than that in adjacent non-cancerous tissues. Further analysis of PGK1 expression across clinicopathological characteristics revealed that patients with poorly differentiated tumors, TNM stages III-IV, lymph node metastasis, and tumor diameter ≥1.0 cm exhibited higher PGK1 expression levels in cancerous tissues. A subsequent 3-year postoperative follow-up was conducted to evaluate the correlation between PGK1 expression and recurrence. During this period, 31.96% of patients experienced recurrence, with higher PGK1 expression correlating with increased recurrence rates. Moreover, patients with higher PGK1 expression in cancerous tissue exhibited a significantly lower survival rate of 79.20% compared to the PGK1-low/medium group. Lastly, age, lymph node metastasis, differentiation degree, TNM stage, and tumor diameter were identified as risk factors for poor prognosis in patients with PTC analyzed by Cox regression.

CONCLUSION: Our study demonstrated that PGK1 expression may serve as a potential prognostic biomarker of PTC.

PMID:40771921 | PMC:PMC12325314 | DOI:10.3389/fphar.2025.1542159

Front Nutr. 2025 Jul 23;12:1640407. doi: 10.3389/fnut.2025.1640407. eCollection 2025.

ABSTRACT

BACKGROUND AND AIMS: The bioelectrical impedance vector analysis (BIVA) requires population-specific references to correctly classify individuals based on body composition properties. The aim of this study was: (i) to develop new references specific to the older adult population; (ii) to evaluate vector patterns based on age and appendicular lean soft mass (ALMS); (iii) to compare the new references with others already existing in the literature.

METHODS: The present study included 835 older adults [472 women (mean age 73.9 ± 7.4 years, BMI 27.2 ± 5.4 kg/m2) and 363 men (mean age 73.1 ± 7.2 years, BMI 27.0 ± 4.4 kg/m2)]. Bioimpedance analysis was conducted using a phase-sensitive foot-to-hand technology at 50 kHz. Bioelectrical properties were analyzed among participants grouped by age categories and ALSM tertiles. New bivariate tolerance ellipses for resistance (R) and reactance (Xc), standardized by participants' height (H), were compared with data from adult populations and the original BIVA references proposed by Piccoli in 1995 (ages 15-85).

RESULTS: New reference values for older adults were established. Significant differences (p < 0.001) in R/H and phase angle were observed when older adults were grouped by age categories, while R/H, Xc/H, and phase angle showed significant differences among ALSM/H2 tertiles. The mean bioelectrical vector for older adults differed from the references in the literature, showing a moderate magnitude relative to Piccoli's original BIVA references (men: D2 = 0.6; women: D2 = 0.5) and a larger magnitude compared to the adult standards (men: D2 = 1.7; women: D2 = 1.8).

CONCLUSION: This study provides BIVA references for older adults. Aging was associated with increased R/H and decreased phase angle, whereas older individuals with higher ALSM exhibited a greater phase angle and lower R/H, and Xc/H. The original BIVA references proposed in 1995 lack specificity and are no longer recommended for future use, as age-specific bioelectrical references are now available.

PMID:40771207 | PMC:PMC12325078 | DOI:10.3389/fnut.2025.1640407

Front Aging Neurosci. 2025 Jul 23;17:1591796. doi: 10.3389/fnagi.2025.1591796. eCollection 2025.

ABSTRACT

Alzheimer's disease (AD) is a growing global challenge, representing the most common neurodegenerative disorder and affecting millions of lives. As life expectancy continues to rise and populations expand, the number of individuals coping with the cognitive declines caused by AD is projected to double in the coming years. By 2050, we may see over 115 million people diagnosed with this devastating condition. Unfortunately, while we currently lack effective cures, there are preventative measures that can slow disease progression in symptomatic patients. Thus, research has shifted toward early detection and intervention for AD in recent years. With technological advances, we are now harnessing large datasets and more efficient, minimally invasive methods for diagnosis and treatment. This review highlights critical demographic insights, health conditions that increase the risk of developing AD, and lifestyle factors in midlife that can potentially trigger its onset. Additionally, we delve into the promising role of plant-based metabolites and their sources, which may help delay the disease's progression. The innovative multi-omics research is transforming our understanding of AD. This approach enables comprehensive data analysis from diverse cell types and biological processes, offering possible biomarkers of this disease's mechanisms. We present the latest advancements in genomics, transcriptomics, Epigenomics, proteomics, and metabolomics, including significant progress in gene editing technologies. When combined with machine learning and artificial intelligence, multi-omics analysis becomes a powerful tool for uncovering the complexities of AD pathogenesis. We also explore current trends in the application of radiomics and machine learning, emphasizing how integrating multi-omics data can transform our approach to AD research and treatment. Together, these pioneering advancements promise to develop more effective preventive and therapeutic strategies soon.

PMID:40771197 | PMC:PMC12325291 | DOI:10.3389/fnagi.2025.1591796

J Cell Mol Med. 2025 Aug;29(15):e70725. doi: 10.1111/jcmm.70725.

ABSTRACT

Abdominal aortic aneurysm (AAA) is the most prevalent and lethal form of arterial aneurysm, frequently manifesting asymptomatically until a catastrophic rupture occurs. While various diagnostic imaging tools and several potential biomarkers have been explored for the purpose of early AAA screening, the usage of liquid biopsy such as extracellular vesicles (EVs)-carried protein for the early diagnosis of AAA is still being overlooked. In this study, we enrolled 18 AAA patients and nine healthy normal controls, including data from the National Drug Clinical Trial Organisation-Vascular Surgery (NDCTO) (in-house cohort) and the Second Clinical Medical College, Jinan University (Shenzhen People's Hospital) (external cohort). We employed Olink's proximity extension assay (PEA) technology based on the plasma EV proteins and first comprehensively characterised the proteomics landscape in circulating EV underlying AAA disease development. A complex profile of differential EV proteins and EV protein-protein interactions network in AAA patients was identified. The differentially expressed EV proteins in AAA patients were found to be significantly associated with several enriched pathways, including the cellular response to cytokine stimuli, inflammatory response, and the regulation of the glucocorticoid receptor (GR) pathway. Moreover, five hub proteins were identified as being of particular significance: these were Interleukin-4, Interleukin-6, MCP-1, Neurturin, and Oncostatin-M. The Olink proteomics technique was utilised in order to identify these proteins. The significance of these proteins was further validated through Western blotting and enzyme-linked immunosorbent assay (ELISA) in the external cohort. The five EV proteins displayed reliable performance and robustness for distinguishing AAA from healthy people, revealing high accuracy with AUC values of 0.760, 0.840, 0.800, 0.840, and 0.900, respectively. The present study has revealed the plasma EV proteins landscape within AAA and further uncovered their potential roles in the pathogenesis of the disease. This presents a new direction for clinical diagnosis and management of AAA. Consequently, these five EV proteins have the potential to serve as useful biomarkers for the diagnosis and prediction of AAA. Further research is warranted to explore their potential as therapeutic targets.

PMID:40770945 | DOI:10.1111/jcmm.70725

Nat Genet. 2025 Aug 6. doi: 10.1038/s41588-025-02284-1. Online ahead of print.

ABSTRACT

Cell atlas projects have revealed that common cell types often comprise distinct, recurrent transcriptional states, but the function and regulation of these states remain poorly understood. Here, we show that systematic activation of transcription factors can recreate such states in vitro, providing tractable models for mechanistic and functional studies. Using a scalable CRISPR activation (CRISPRa) Perturb-seq platform, we activated 1,836 transcription factors in two cell types. CRISPRa induced gene expression within physiological ranges, with chromatin features predicting responsiveness. Comparisons with atlas datasets showed that transcription factor perturbations recapitulated key fibroblast states and identified their regulators, including KLF2 and KLF4 for a universal state present in many tissues, and PLAGL1 for a disease-associated inflammatory state. Inducing the universal state suppressed the inflammatory state, suggesting therapeutic potential. These findings position CRISPRa as a nuanced tool for perturbing differentiated cells and establish a general strategy for studying clinically relevant transcriptional states ex vivo.

PMID:40770575 | DOI:10.1038/s41588-025-02284-1

Nat Neurosci. 2025 Aug 6. doi: 10.1038/s41593-025-02010-4. Online ahead of print.

ABSTRACT

Parkinson's disease (PD) is characterized by inclusions of α-synuclein (α-syn) and mitochondrial dysfunction in dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc). Patients with PD anecdotally experience symptom improvement at high altitude; chronic hypoxia prevents the development of Leigh-like brain disease in mice with mitochondrial complex I deficiency. Here we report that intrastriatal injection of α-syn preformed fibrils (PFFs) in mice resulted in neurodegeneration and movement disorder, which were prevented by continuous exposure to 11% oxygen. Specifically, PFF-induced α-syn aggregation resulted in brain tissue hyperoxia, lipid peroxidation and DA neurodegeneration in the SNpc of mice breathing 21% oxygen, but not in those breathing 11% oxygen. This neuroprotective effect of hypoxia was also observed in Caenorhabditis elegans. Moreover, initiating hypoxia 6 weeks after PFF injection reversed motor dysfunction and halted further DA neurodegeneration. These results suggest that hypoxia may have neuroprotective effects downstream of α-syn aggregation in PD, even after symptom onset and neuropathological changes.

PMID:40770507 | DOI:10.1038/s41593-025-02010-4

Sci Rep. 2025 Aug 7;15(1):28852. doi: 10.1038/s41598-025-13635-7.

ABSTRACT

The gastrointestinal epithelium relies on activation of the hypoxia-inducible factor (HIF) to promote cell survival and maintain bioenergetic homeostasis during hypoxia. While many pathogens can activate HIF, the effects of enteric protozoa on HIF activation in gastrointestinal epithelial cells remain unclear. Giardia duodenalis, a prevalent protozoan enteropathogen, causes intestinal barrier dysfunction characterized by epithelial malabsorption, mucus depletion, altered mucin glycosylation, and microbiota dysbiosis. Findings from the present study reveal an epithelial hypoxic signature upon Giardia infection. Human intestinal epithelial cells were exposed to vehicle or Giardia duodenalis isolate GS/M under normoxic (21% O2) or hypoxic (1% O2) conditions. In normoxia, infected cells displayed a time-dependent increase in HIF-1α protein expression, the oxygen-dependent subunit of HIF-1. In normoxia, Giardia infection upregulated HIF-1 target genes involved in cellular stress (i.e., VEGFA, ANKRD37, GADD45A) and glycolysis (i.e., HK2, LDHA). This was accompanied by changes in the abundance of glycolytic intermediates (i.e., glucose-6-phosphate, pyruvate, lactate). Although infection in hypoxia failed to augment the hypoxia-induced HIF-1α stabilization, HIF-1 target genes were still upregulated, albeit to a lesser degree. These findings indicate that Giardia induces a transient epithelial hypoxic response in normoxic conditions, revealing a hitherto unrecognized epithelial rescue response to this intestinal parasite.

PMID:40770382 | DOI:10.1038/s41598-025-13635-7

bioRxiv [Preprint]. 2025 Aug 2:2025.07.31.667803. doi: 10.1101/2025.07.31.667803.

ABSTRACT

A major goal in agriculture is to engineer crops that can maintain yield with less nitrogen (N) fertilizer input. Major orchestrators of plant responses to N include members of the HRS1 HOMOLOG (HHO) family of transcription factors (TFs). However, HHO TFs have been difficult targets for functional studies in planta due to their redundancy. Here, we highlight a unique role for a phylogenetically diverged HHO TF, HHO5, whose expression is regulated in an N-dose dependent fashion and is specifically expressed in phloem. We found that an HHO5 single mutant displays significant misregulation of N-dose dependent genes and plant growth rates. HHO5 is also unique as it displays a dual activator/repressor activity on N-dose dependent gene regulation. HHO5 specifically acts as a direct gene repressor when binding DNA targets. In contrast, genes activated by HHO5 include indirect targets regulated by TFs downstream of HHO5 (TF2s). To validate the influence of HHO5 via its direct TF2s, we used validated TF2 data to build a gene regulatory network that links HHO5-TF2 targets to ~70% of the N-dose genes regulated by HHO5 in planta. By these means, we define HHO5 as a novel dual activator/repressor of plant N-dose signaling.

PMID:40766722 | PMC:PMC12324496 | DOI:10.1101/2025.07.31.667803

Environ Microbiol Rep. 2025 Aug;17(4):e70170. doi: 10.1111/1758-2229.70170.

ABSTRACT

Biogeochemical cycles in the ocean are strongly influenced by microbial activity, which affects nutrient and organic matter cycling. These processes, influenced by factors such as temperature, salinity, density and inorganic nutrients, drive the vertical stratification of microbial communities, which subsequently influence the chemistry at different depth layers. Sequencing technology has expanded our understanding of oceanic prokaryotic communities' taxonomic and functional potential. However, there is limited information on how these communities vary across gradients. In this study, we conducted metagenomic analyses on samples from the eastern North Pacific, collected across a longitudinal transect around 45°N and throughout the entire water column. We assessed taxonomic and functional classification, focusing on the roles of prokaryotic communities in biogeochemical cycling. Our results revealed that the surface community was dominated by the SAR11 clade, followed by Flavobacterales and Rhodobacterales. The deep layers harboured a more diverse community, where Thaumarchaeota accounted for the most significant proportion. This clear taxonomic stratification led to variations in the communities' functional capabilities across different depth layers. Photosynthesis and heterotrophy dominated the surface layers, whereas the deeper layers exhibited a mix of metabolic features, allowing organisms to potentially utilise both inorganic and organic carbon sources.

PMID:40769940 | DOI:10.1111/1758-2229.70170