Microbiome. 2025 Apr 28;13(1):106. doi: 10.1186/s40168-025-02105-x.

ABSTRACT

BACKGROUND: Microbial taxonomic diversity declines with increased environmental stress. Yet, few studies have explored whether phylogenetic and functional diversities track taxonomic diversity along the stress gradient. Here, we investigated microbial communities within an aquifer in Oak Ridge, Tennessee, USA, which is characterized by a broad spectrum of stressors, including extremely high levels of nitrate, heavy metals like cadmium and chromium, radionuclides such as uranium, and extremely low pH (< 3).

RESULTS: Both taxonomic and phylogenetic α-diversities were reduced in the most impacted wells, while the decline in functional α-diversity was modest and statistically insignificant, indicating a more robust buffering capacity to environmental stress. Differences in functional gene composition (i.e., functional β-diversity) were pronounced in highly contaminated wells, while convergent functional gene composition was observed in uncontaminated wells. The relative abundances of most carbon degradation genes were decreased in contaminated wells, but genes associated with denitrification, adenylylsulfate reduction, and sulfite reduction were increased. Compared to taxonomic and phylogenetic compositions, environmental variables played a more significant role in shaping functional gene composition, suggesting that niche selection could be more closely related to microbial functionality than taxonomy.

CONCLUSIONS: Overall, we demonstrated that despite a reduced taxonomic α-diversity, microbial communities under stress maintained functionality underpinned by environmental selection. Video Abstract.

PMID:40296156 | DOI:10.1186/s40168-025-02105-x

BMC Public Health. 2025 Apr 28;25(1):1571. doi: 10.1186/s12889-025-22638-y.

ABSTRACT

BACKGROUND: The accumulation of heavy metals in surface soil raises significant environmental and public health concerns around the world. This study aimed to examine the relationship between exposure to heavy metals in surface soil and the risk of pain among residents.

METHODS: Using national data on eight heavy metals (arsenic, cadmium, chromium, copper, lead, mercury, nickel and zinc) in China's surface soil and a population cohort from 2011 to 2018, we analyzed pain occurrences in various body locations. Logistic regression models were used to assess the association between exposure to heavy metal in soil and pain, as adjusting for gender, age, education level, body mass index, living region, and lifestyle. The study included 13,178 individuals.

RESULTS: Higher exposure to soil arsenic was found to be associated with increased risk of shoulders [adjusted odds ratio (99.99% CI), 1.49 (1.01, 2.19)], wrists [1.68 (1.06, 2.64)] and ankles pain [1.58 (1.01, 2.50)]. No association was found between the remaining seven heavy metals and different types of body pain.

CONCLUSION: Our results indicate that higher soil arsenic exposure is associated with an increased risk of pain in specific body regions. This study is the first examining the associations between multiple heavy metals in surface soil and the risks of pain in different body sites. Our findings provide new insights into the health risks of soil heavy metal exposure.

PMID:40295964 | DOI:10.1186/s12889-025-22638-y

Npj Viruses. 2024 Nov 14;2(1):54. doi: 10.1038/s44298-024-00066-w.

ABSTRACT

Quasispecies theory revolutionized our understanding of viral evolution by describing viruses as dynamic populations of genetically diverse variants constantly adapting. This article explores the theory's role in virus-host interactions, including immune evasion, drug resistance, and viral emergence. We review the original model, recent advances, and key virus dynamics needing incorporation into quasispecies theory. We introduce the ultracube concept as a more realistic multidimensional sequence space to investigate virus evolutionary dynamics.

PMID:40295874 | DOI:10.1038/s44298-024-00066-w

Npj Viruses. 2024 Mar 25;2(1):16. doi: 10.1038/s44298-024-00026-4.

ABSTRACT

Influenza A(H7N9) virus showed high pathogenicity in humans when it emerged in 2013. Cigarette smoke (CS) causes pulmonary diseases including bronchitis, emphysema, and lung cancer. Although habitual smoking is thought to increase the risk of severe seasonal influenza virus infection, its effect on A(H7N9) virus infection is poorly understood. Here, we employed a mouse model of long-term exposure to CS to investigate the effect of CS on the pathogenicity of A(H7N9) virus infection. Unexpectedly, body weight loss for mice exposed to CS was milder than that for mock-treated mice upon A(H7N9) virus infection. CS exposure improved the survival rate of A(H7N9) virus-infected mice even though virus titers and pathological changes in the lungs were not significantly different between CS-exposed and control mice. Microarray analysis showed that CS-exposure activates cytokine/chemokine activity, immune response, and cell cycle activities that resemble reactivities against A(H7N9) virus infection. Therefore, under conditions where cytokine and chemokine expression in the lungs is already high due to CS exposure, the enhanced expression of cytokines and chemokines caused by A(H7N9) virus infection might be less harmful to the organs compared to the rapid increase in cytokine and chemokine expression in the air-exposed mice due to the infection. CS may thus induce immunoregulatory effects that attenuate severe pulmonary disease during A(H7N9) virus infection. However, these findings do not support CS exposure due to its many other proven negative health effects.

PMID:40295873 | DOI:10.1038/s44298-024-00026-4

Npj Viruses. 2025 Apr 4;3(1):25. doi: 10.1038/s44298-025-00107-y.

ABSTRACT

Foodborne viruses are significant public health threats, capable of causing life-threatening infections and posing major risks for future pandemics. However, the development of vaccines and treatments remains limited due to gaps in understanding their biophysical properties. Among these viruses, noroviruses are currently the leading cause of viral gastroenteritis globally and are responsible for numerous foodborne outbreaks. In this review, we explore the use of biophysical methods, with a focus on atomic force microscopy (AFM), to study foodborne viruses. We demonstrate how AFM can provide crucial insights into virus-host interactions, transmission dynamics, and environmental stability. We also show that the integration of various biophysical approaches offers new opportunities for advancing our understanding of foodborne viruses, ultimately guiding the development of effective prevention strategies and antiviral therapies.

PMID:40295860 | DOI:10.1038/s44298-025-00107-y

Npj Viruses. 2024 Apr 11;2(1):12. doi: 10.1038/s44298-024-00022-8.

ABSTRACT

Ebola virus (EBOV) is able to persist and actively replicate in the reproductive tract of male disease survivors months or years after recovery from Ebola virus disease (EVD)1. Persistent EBOV infections are usually asymptomatic and can be transmitted sexually, but the host and viral factors that mediate these infections have not been characterized2,3. We investigated the interaction between host and viral factors during EBOV infection of the blood testis barrier (BTB), with a focus on Sertoli cells as a potential reservoir for viral persistence. We assessed viral replication kinetics and host responses of mouse testicular Leydig cells and Sertoli cells infected with EBOV Makona (i.e. infectious EBOV) and collected samples up to 28 days post-infection. Viral replication was apparent in both cell lines, but intracellular early viral loads were much higher in Leydig cells compared to Sertoli cells. We used RNAseq analysis to characterize transcriptomic responses of Leydig cells and Sertoli cells to EBOV infection over time. Further investigation of early interactions between host cells and EBOV was performed using virus-like particles (EBOV trVLP) and assays of phosphorylation-based cell signaling. Our findings indicate that virus-treated Sertoli cells responded more rapidly and robustly than Leydig cells, and with a particular emphasis on detection of, and response to, external stimuli. We discuss how the roles played by Sertoli cells in immune privilege and spermatogenesis may affect their initial and continued response to EBOV infection in a manner that could facilitate asymptomatic persistence.

PMID:40295798 | DOI:10.1038/s44298-024-00022-8

Light Sci Appl. 2025 Apr 28;14(1):177. doi: 10.1038/s41377-025-01866-2.

ABSTRACT

This review examines imaging-based nanophotonic biosensing and interferometric label-free imaging, with a particular focus on vesicle detection. It specifically compares dielectric and plasmonic metasurfaces for label-free protein and extracellular vesicle detection, highlighting their respective advantages and limitations. Key topics include: (i) refractometric sensing principles using resonant dielectric and plasmonic surfaces; (ii) state-of-the-art developments in both plasmonic and dielectric nanostructured resonant surfaces; (iii) a detailed comparison of resonance characteristics, including amplitude, quality factor, and evanescent field enhancement; and (iv) the relationship between sensitivity, near-field enhancement, and analyte overlap in different sensing platforms. The review provides insights into the fundamental differences between plasmonic and dielectric platforms, discussing their fabrication, integration potential, and suitability for various analyte sizes. It aims to offer a unified, application-oriented perspective on the potential of these resonant surfaces for biosensing and imaging, aiming at addressing topics of interest for both photonics experts and potential users of these technologies.

PMID:40295495 | DOI:10.1038/s41377-025-01866-2

Ann Bot. 2025 Apr 29:mcaf078. doi: 10.1093/aob/mcaf078. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Flowering phenology has been suggested as an important factor to explain invasions of non-native plant species. Invasive species success may be enhanced by flowering at different times (the vacant niche hypothesis) or flowering for longer periods (the niche breath hypothesis) than native species. However, comprehensive regional assessments of the flowering phenology of invasive and native floras are lacking in the literature. In this study, we evaluated the flowering phenology of invasive and native plant species pools to test the above-mentioned hypotheses within a biogeographically meaningful region.

METHODS: We investigated the start, end, and length of flowering between the invasive and native floras that occur at the same elevation range in the Cantabrian Mixed Forests ecoregion (NW Iberian Peninsula), a biogeographical hotspot for invasive plants in SW Europe. We also accounted for species habitat preferences and climatic and biogeographic origin of the invasive species.

KEY RESULTS: We found a mismatch in flowering time between the ecoregional invasive and native floras. Invasive species had a delayed and longer flowering phenology compared to native species. These differences in flowering time were more pronounced in man-made habitats and in invaders from temperate and tropical regions.

CONCLUSIONS: Our results are consistent with the vacant niche hypothesis; the asynchrony in flowering time could allow invaders to exploit a temporally empty niche. Our results are also consistent with the niche breath hypothesis, suggesting that invasive species exhibit a longer flowering period than natives, which may allow them to have prolonged access to resources. Future studies should explore the phenological patterns of invasive and native species across biogeographically relevant regions to enhance our understanding of large-scale invasion events.

PMID:40295227 | DOI:10.1093/aob/mcaf078

Exp Neurol. 2025 Apr 26:115271. doi: 10.1016/j.expneurol.2025.115271. Online ahead of print.

ABSTRACT

Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) are known to ameliorate Alzheimer's disease (AD)-like pathology and cognitive decline through distinct mechanisms. In this study, we investigated how these antidiabetic drugs elevate ketone levels and subsequently reduce amyloid-β (Aβ) and tau pathology via the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in microglia, using a type 2 diabetes (T2D)-AD mouse model. Male C57BL/6 mice were fed a high-fat diet and injected with low doses of streptozotocin to establish a T2D-AD model. The mice were then treated with either SGLT2-i or DPP4-i. Our results revealed that both the inhibitors markedly enhanced brain ketone metabolism by upregulating key metabolic enzymes and transporters. They also reduced neuroinflammation by suppressing the expression of pro-inflammatory cytokines, such as IL-1β, and increasing the expression of the anti-inflammatory cytokine IL-4. A critical mechanism for this anti-inflammatory effect involved the inhibition of the expression of the NLRP3 inflammasome, a key driver of neuroinflammation. Notably, SGLT2-i appeared to inhibit NLRP3 inflammasome expression by disrupting the pTau-CX3C1 interaction, whereas DPP4-i exerted its effects through the Aβ-TLR4-NF-κB pathway. Moreover, our results showed that both the inhibitors promoted a shift in microglial activation from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, as indicated by the changes in CD206 and CD86 expression. These findings suggest that SGLT2-i and DPP4-i provide neuroprotective benefits through multiple mechanisms, including enhanced ketone metabolism, reduced neuroinflammation, and modulation of microglial activity in T2D-AD mouse model. This research offers a scientific basis for considering these inhibitors as potential therapeutic agents for neurodegenerative diseases, particularly in cognitive impairment patients with metabolic dysfunction.

PMID:40294740 | DOI:10.1016/j.expneurol.2025.115271

J Biol Chem. 2025 Apr 26:108553. doi: 10.1016/j.jbc.2025.108553. Online ahead of print.

ABSTRACT

FabZ, a β-hydroxyacyl-ACP dehydratase in the Type II fatty acid synthesis pathway, is essential for the viability of Pseudomonas aeruginosa by ensuring proper fatty acid elongation and membrane stability. However, the precise genetic interactions between fabZ and lipid A biosynthesis genes, such as lpxA and lpxC, as well as the potential existence of other suppressor genes of fabZ in P. aeruginosa, remain unclear. To explore these genetic interactions and identify potential suppressor genes, we constructed a conditional fabZ mutant, ΔfabZ(p_ts-fabZ), by deleting the chromosomal fabZ gene and complementing it with a temperature-sensitive plasmid-borne copy. The ΔfabZ(p_ts-fabZ) mutant exhibited lethality and cell morphology defects at a restrictive temperature, confirming its essentiality. Genetic interaction analyses revealed that deletion of lpxA or lpxC failed to rescue ΔfabZ(p_ts-fabZ) lethality at restrictive temperature. Through suppressor screening, we isolated a mutant strain capable of rescuing ΔfabZ lethality and identified lpxH as the suppressor gene using genome resequencing. Further analysis revealed that the fabZ and lpxH double mutant (ΔfabZΔlpxH) produced odd-chain fatty acids, identified as pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) through fatty acid methyl ester (FAME) analysis coupled with gas chromatography-mass spectrometry (GC-MS), and supplementation with these fatty acids restored the growth and morphology of ΔfabZ(p_ts-fabZ) and ΔlpxH(p_ts-lpxH) mutants at restrictive temperature, suggesting their critical role in membrane stability. These results indicate that deletion of lpxH serves as a genetic suppressor of ΔfabZ lethality, highlighting a previously unrecognized compensatory mechanism involving odd-chain fatty acid synthesis essential for membrane stability in P. aeruginosa.

PMID:40294648 | DOI:10.1016/j.jbc.2025.108553

Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2410092122. doi: 10.1073/pnas.2410092122. Epub 2025 Apr 28.

ABSTRACT

Plasmacytoid Dendritic cells (pDCs) are the most potent producers of interferons, which are critical antiviral cytokines. pDC development is, however, compromised following a viral infection, and this phenomenon, as well as its relationship to conventional (c)DC development is still incompletely understood. By using lymphocytic choriomeningitis virus (LCMV) infection in mice as a model system, we observed that DC progenitors skewed away from pDC and toward cDC development during in vivo viral infection. Subsequent characterization of the transcriptional and epigenetic landscape of fms-like tyrosine kinase 3+ (Flt3+) DC progenitors and follow-up studies revealed increased apoptosis and reduced proliferation in different individual DC-progenitors as well as a profound type I interferon (IFN-I)-dependent ablation of pre-pDCs, but not pre-DC precursors, after both acute and chronic LCMV infections. In addition, integrated genomic analysis identified altered activity of 34 transcription factors in Flt3+ DC progenitors from infected mice, including two regulators of Glucocorticoid (GC) responses. Subsequent studies demonstrated that addition of GCs to DC progenitors led to downregulated pDC-primed-genes while upregulating cDC-primed-genes, and that endogenous GCs selectively decreased pDC, but not cDC, numbers upon in vivo LCMV infection. These findings demonstrate a significant ablation of pre-pDCs in infected mice and identify GCs as suppressors of pDC generation from early progenitors. This provides a potential explanation for the impaired pDC development following viral infection and links pDC numbers to the hypothalamic-pituitary-adrenal axis.

PMID:40294270 | DOI:10.1073/pnas.2410092122

Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2411446122. doi: 10.1073/pnas.2411446122. Epub 2025 Apr 28.

ABSTRACT

Transposable elements (TEs) make up the bulk of eukaryotic genomes and examples abound of TE-derived sequences repurposed for organismal function. The process by which TEs become coopted remains obscure because most cases involve ancient, transpositionally inactive elements. Reports of active TEs serving beneficial functions are scarce and often contentious due to difficulties in manipulating repetitive sequences. Here, we show that recently active TEs in zebrafish encode products critical for embryonic development. Knockdown and rescue experiments demonstrate that the endogenous retrovirus family BHIKHARI-1 (Bik-1) encodes a Gag protein essential for mesoderm development. Mechanistically, Bik-1 Gag associates with the cell membrane, and its ectopic expression in chicken embryos alters cell migration. Similarly, depletion of BHIKHARI-2 Gag, a relative of Bik-1, causes defects in neural crest development in zebrafish. We propose an "addiction" model to explain how active TEs can be integrated into conserved developmental processes.

PMID:40294259 | DOI:10.1073/pnas.2411446122

Cancer Res Commun. 2025 Apr 1;5(4):706-718. doi: 10.1158/2767-9764.CRC-25-0030.

ABSTRACT

This study presents a novel approach that integrates LLMs with real-time biomedical literature to uncover drug-gene relationships, transforming how cancer researchers identify therapeutic targets, repurpose drugs, and interpret complex molecular interactions. GeneRxGPT, our user-friendly tool, enables researchers to leverage this approach without requiring computational expertise.

PMID:40293950 | DOI:10.1158/2767-9764.CRC-25-0030

J Med Internet Res. 2025 Apr 28;27:e66231. doi: 10.2196/66231.

ABSTRACT

BACKGROUND: A substantially lower proportion of female individuals participate in sufficient daily activity compared to male individuals despite the known health benefits of exercise. Investment in female sports and exercise medicine research may help close this gap; however, female individuals are underrepresented in this research. Hesitancy to include female participants is partly due to assumptions that biological rhythms driven by menstrual cycles and occurring on the timescale of approximately 28 days increase intraindividual biological variability and weaken statistical power. An analysis of continuous skin temperature data measured using a commercial wearable device found that temperature cycles indicative of menstrual cycles did not substantially increase variability in female individuals' skin temperature. In this study, we explore physical activity (PA) data as a variable more related to behavior, whereas temperature is more reflective of physiological changes.

OBJECTIVE: We aimed to determine whether intraindividual variability of PA is affected by biological sex, and if so, whether having menstrual cycles (as indicated by temperature rhythms) contributes to increased female intraindividual PA variability. We then sought to compare the effect of sex and menstrual cycles on PA variability to the effect of PA rhythms on the timescales of days and weeks and to the effect of nonrhythmic temporal structure in PA on the timescale of decades of life (age).

METHODS: We used minute-level metabolic equivalent of task data collected using a wearable device across a 206-day study period for each of 596 individuals as an index of PA to assess the magnitudes of variability in PA accounted for by biological sex and temporal structure on different timescales. Intraindividual variability in PA was represented by the consecutive disparity index.

RESULTS: Female individuals (regardless of whether they had menstrual cycles) demonstrated lower intraindividual variability in PA than male individuals (Kruskal-Wallis H=29.51; P<.001). Furthermore, individuals with menstrual cycles did not have greater intraindividual variability than those without menstrual cycles (Kruskal-Wallis H=0.54; P=.46). PA rhythms differed at the weekly timescale: individuals with increased or decreased PA on weekends had larger intraindividual variability (Kruskal-Wallis H=10.13; P=.001). In addition, intraindividual variability differed by decade of life, with older age groups tending to have less variability in PA (Kruskal-Wallis H=40.55; P<.001; Bonferroni-corrected significance threshold for 15 comparisons: P=.003). A generalized additive model predicting the consecutive disparity index of 24-hour metabolic equivalent of task sums (intraindividual variability of PA) showed that sex, age, and weekly rhythm accounted for only 11% of the population variability in intraindividual PA variability.

CONCLUSIONS: The exclusion of people from PA research based on their biological sex, age, the presence of menstrual cycles, or the presence of weekly rhythms in PA is not supported by our analysis.

PMID:40293784 | DOI:10.2196/66231

Synth Syst Biotechnol. 2025 Apr 8;10(3):827-834. doi: 10.1016/j.synbio.2025.03.011. eCollection 2025 Sep.

ABSTRACT

Synthetic RNA-based switches provide distinctive merits in modulating gene expression. Simple and flexible RNA-based switches are crucial for advancing the field of gene regulation, paving the way for innovative tools that can sense and manipulate cellular processes. In this research, we have developed programmable ribozymes that are capable of suppressing gene expression in response to specific, endogenously expressed trigger RNAs. We engineer ribozymes by introducing upstream antisense sequences (anti-ribozymes) to inhibit the self-cleaving activity of the hammerhead ribozyme and open the expression of the target gene. The trigger RNA is designed to recognize and bind to complementary sequences within the anti-ribozymes, thereby inhibiting their ability to direct protein synthesis. The anti-ribozyme performance is optimized by regulating the essential sequence modules that play a crucial role in determining the specificity and efficiency of the anti-ribozyme's interaction with its trigger RNA. By applying this switch mechanism to various ribozyme designs, we have shown that it is possible to achieve control over gene expression across a wide range of trigger RNAs. By exploiting these programmable anti-ribozymes, we aim to create a powerful tool for controlling gene expression in mammalian cells, which could have important implications for basic research, disease diagnosis, and therapeutic interventions.

PMID:40291978 | PMC:PMC12033390 | DOI:10.1016/j.synbio.2025.03.011

F1000Res. 2024 Sep 5;13:792. doi: 10.12688/f1000research.153244.2. eCollection 2024.

ABSTRACT

Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-coupled protein receptor that induces crucial biological processes when bound by sphingosine 1-phosphate. Here, we have characterized nine S1PR1 commercial antibodies for western blot, immunoprecipitation, and immunofluorescence using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.

PMID:40291769 | PMC:PMC12022542 | DOI:10.12688/f1000research.153244.2

ACS Omega. 2025 Apr 8;10(15):15204-15218. doi: 10.1021/acsomega.4c10939. eCollection 2025 Apr 22.

ABSTRACT

Selective serotonin reuptake inhibitors (SSRIs) are known to have anticancer activity against different types of cancer. In this study, an integrative informatics approach was applied to identify compound and genetic perturbations that produce similar effects to SSRIs to formulate systems biology hypotheses and identify biological pathways involved in the putative anticancer effects of SSRIs in prostate cancer. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay assessed the antiproliferative effects of SSRIs and drug combinations. Cell death mechanisms were studied using annexin V-FITC/PI staining, and the cell cycle analysis was carried out by counterstaining with propidium iodide. Relative gene expression was assessed using a real-time polymerase chain reaction (PCR). Computational results hypothesized that SSRIs could potentially exert anticancer effects in prostate cancer cell lines by modulating apoptotic and tumorigenesis pathways and significantly inhibiting the growth of prostate cancer cells in a time and concentration-dependent manner. The combination of SSRIs with cisplatin, 5-fluorouracil, and raloxifene resulted in either synergistic or additive effects. SSRIs resulted in a significant increase in the early and late apoptotic activity in PC3 cells. Dapoxetine, paroxetine, and sertraline resulted in cell cycle arrest at the G0/G1 phase. Treatment with either dapoxetine or paroxetine decreases the expression of Bcl-2, CASP8, DR5, and VEGF. At the same time, sertraline decreases the expression of Bcl-2 and VEGF and increases the expression of CASP8 and DR5. Results revealed that SSRIs can potentially act as antiproliferative agents against prostate cancer cells, and their activity is mediated through different signaling pathways.

PMID:40290959 | PMC:PMC12019733 | DOI:10.1021/acsomega.4c10939

JHEP Rep. 2025 Jan 30;7(5):101340. doi: 10.1016/j.jhepr.2025.101340. eCollection 2025 May.

ABSTRACT

BACKGROUND & AIMS: Actionable candidates of hepatocarcinogenesis remain elusive, and tools for early detection are suboptimal. Our aim was to demonstrate that serum metabolome profiles reflect the initiation of hepatocellular carcinoma (HCC) and enable the identification of biomarkers for early HCC detection and actionable candidates for chemoprevention.

METHODS: This global cohort study included 654 patients and 801 biospecimens. Following serum metabolome profiling across the spectrum of hepatocarcinogenesis, we conducted a phase II biomarker case-control study for early HCC detection. Findings were independently validated through in silico analysis, mRNA sequencing, and proteome profiling of primary HCC and non-tumoral tissue, and in vitro experiments.

RESULTS: Aspartic acid, glutamic acid, taurine, and hypoxanthine were differentially abundant in the serum across chronic liver disease, cirrhosis, initial HCC, and progressed HCC, independent of sex, age, and etiology. In a phase II biomarker case-control study, a blood-based metabolite signature yielded an AUC of 94% to discriminate between patients with early-stage HCC and controls with cirrhosis, including independent validation. Unsupervised biclustering (MoSBi), lipid network analysis (LINEX2), and pathway enrichment analysis confirmed alterations in amino acid-, lipid-, and nucleotide-related pathways. In tumor tissue, these pathways were significantly deregulated regarding gene and protein expression in two independent datasets, including actionable targets RRM2, GMPS, BCAT1, PYCR2, and NEU1. In vitro knockdown confirmed a functional role in proliferation and migration, as exemplified for PYCR2.

CONCLUSIONS: These findings demonstrate that serum metabolome profiling indicates deregulated metabolites and pathways during hepatocarcinogenesis. Our liquid biopsy approach accurately detects early-stage HCC outperforming currently recommended surveillance tools and facilitates identification of actionable candidates for chemoprevention.

IMPACT AND IMPLICATIONS: Deregulated cellular metabolism is a hallmark of cancer. In smaller studies, circulating metabolite profiles have been associated with HCC, although mainly in the context of fatty liver disease. Translation strategies for primary prevention or early detection are lacking. In this global study, we present an unsupervised landscape of the altered serum metabolome profile during hepatocarcinogenesis, independent of age, sex, and etiology. We provide a blood-based metabolite signature that accurately identifies early-stage HCC in a phase II biomarker study including independent validation. Further RRM2, GMPS, BCAT1, PYCR2, and NEU1 are identified in tumor tissue as actionable candidates for prevention. Our data provide the rationale for clinical trials testing liquid biopsy metabolome-based signatures for early HCC detection and the development of chemoprevention strategies.

PMID:40290517 | PMC:PMC12023797 | DOI:10.1016/j.jhepr.2025.101340

BMC Microbiol. 2025 Apr 27;25(1):253. doi: 10.1186/s12866-025-03968-8.

ABSTRACT

BACKGROUND: Research has established links between the gut microbiome (GM) and both obesity and type 2 diabetes (T2D), which is much discussed, but underexplored. This study employed body mass index (BMI) as the measurement of obesity to delve deeper into the correlations from a genetic perspective.

METHODS: We performed the Mendelian randomization (MR) analysis to examine the causal effects of GM on T2D and BMI, and vice versa. Genome-wide association study (GWAS) summary datasets were utilized for the analysis, including T2D (N = 933,970), BMI (N = 806,834), and two GM datasets from the international consortium MiBioGen (211 taxa, N = 18,340) and the Dutch Microbiome Project (DMP) (207 taxa, N = 7,738). These datasets mainly cover European populations, with additional cohorts from Asia and other regions. To further explore the potential mediating role of GM in the connections between BMI and T2D, their interaction patterns were summarized into a network.

RESULTS: MR analysis identified 9 taxa that showed protective properties against T2D. Seven species were within the Firmicutes and Bacteroidales phyla in the DMP, and two were from the MiBioGen (Odds Ratio (OR): 0.94-0.95). Conversely, genetic components contributing to the abundance of 12 taxa were associated with increased risks of T2D (OR: 1.04-1.12). Furthermore, T2D may elevate the abundance of seven taxa (OR: 1.03-1.08) and reduce the abundance of six taxa (OR: 0.93-0.97). In the analysis of the influence of the genetic component of BMI on GM composition, BMI affected 52 bacterial taxa, with 28 decreasing (OR: 0.75-0.92) and 24 increasing (OR: 1.08-1.27). Besides, abundances of 25 taxa were negatively correlated with BMI (OR: 0.95-0.99), while positive correlations were detected for 14 taxa (OR: 1.01-1.05). Notably, we uncovered 11 taxa genetically associated with both BMI and T2D, which formed an interactive network.

CONCLUSIONS: Our findings provide evidence for the GM-mediated links between obesity and T2D. The identification of relevant GM taxa offers valuable insights into the potential role of the microbiome in these diseases.

PMID:40289103 | DOI:10.1186/s12866-025-03968-8

BMC Biol. 2025 Apr 28;23(1):112. doi: 10.1186/s12915-025-02216-9.

ABSTRACT

BACKGROUND: Plant growth and morphogenesis is a mechanical process controlled by genetic and molecular networks. Measuring mechanical properties at various scales is necessary to understand how these processes interact. However, obtaining a device to perform the measurements on plant samples of choice poses technical challenges and is often limited by high cost and availability of specialized components, the adequacy of which needs to be verified. Developing software to control and integrate the different pieces of equipment can be a complex task.

RESULTS: To overcome these challenges, we have developed a computer automated micro-extensometer combined with low-cost optical tracking (Camelot) that facilitates measurements of elasticity, creep, and yield stress. It consists of three primary components: a force sensor with a sample attachment point, an actuator with a second attachment point, and a camera. To monitor force, we use a parallel beam sensor, commonly used in digital weighing scales. To stretch the sample, we use a stepper motor with a screw mechanism moving a stage along linear rail. To monitor sample deformation, a compact digital microscope or a microscope camera is used. The system is controlled by MorphoRobotX, an integrated open-source software environment for mechanical experimentation. We first tested the basic Camelot setup, equipped with a digital microscope to track landmarks on the sample surface. We demonstrate that the system has sufficient accuracy to measure the stiffness in delicate plant samples, the etiolated hypocotyls of Arabidopsis, and were able to measure stiffness differences between wild type and a xyloglucan-deficient mutant. Next, we placed Camelot on an inverted microscope and used a C-mount microscope camera to track displacement of cell junctions. We stretched onion epidermal peels in longitudinal and transverse directions and obtained results similar to those previously published. Finally, we used the setup coupled with an upright confocal microscope and measured anisotropic deformation of individual epidermal cells during stretching of an Arabidopsis leaf.

CONCLUSIONS: The portability and suitability of Camelot for high-resolution optical tracking under a microscope make it an ideal tool for researchers in resource-limited settings or those pursuing exploratory biomechanics work.

PMID:40289087 | DOI:10.1186/s12915-025-02216-9