BioTech (Basel). 2025 Feb 20;14(1):11. doi: 10.3390/biotech14010011.

ABSTRACT

STXBP1 syndrome is a severe early-onset epileptic encephalopathy characterized by developmental delay and intellectual disability. This review addresses key challenges in STXBP1 syndrome research, focusing on advanced therapeutic approaches and experimental models. We explore gene therapy strategies, including CRISPR-Cas9, adeno-associated viral (AAV) vectors, and RNA therapies such as antisense oligonucleotides (ASOs), aimed at correcting STXBP1 genetic dysfunctions. This review presents in vivo and in vitro models, highlighting their contributions to understanding disease mechanisms. Additionally, we provide a proposal for a detailed bioinformatic analysis of a Spanish cohort of 41 individuals with STXBP1-related disorders, offering insights into specific mutations and their biological implications. Clinical and translational perspectives are discussed, emphasizing the potential of personalized medicine approaches. Future research directions and key challenges are outlined, including the identification of STXBP1 interactors, unexplored molecular pathways, and the need for clinically useful biomarkers. This comprehensive review underscores the complexity of STXBP1-related infantile epileptic encephalopathy and opens new avenues for advancing the understanding and treatment of this heterogeneous disease.

PMID:40227275 | DOI:10.3390/biotech14010011

Antioxidants (Basel). 2025 Feb 26;14(3):268. doi: 10.3390/antiox14030268.

ABSTRACT

Metabolic syndrome (MetS) constitutes a spectrum of interconnected conditions comprising obesity, dyslipidemia, hypertension, and insulin resistance (IR). While a singular, all-encompassing treatment for MetS remains elusive, an integrative approach involving tailored lifestyle modifications and emerging functional food therapies holds promise in preventing its multifaceted manifestations. Our main objective was to scrutinize the efficacy of cranberry proanthocyanidins (PAC, 200 mg/kg/day for 12 weeks) in mitigating MetS pathophysiology in male mice subjected to standard Chow or high-fat/high-fructose (HFHF) diets while unravelling intricate mechanisms. The administration of PAC, in conjunction with an HFHF diet, significantly averted obesity, evidenced by reductions in body weight, adiposity across various fat depots, and adipocyte hypertrophy. Similarly, PAC prevented HFHF-induced hyperglycemia and hyperinsulinemia while also lessening IR. Furthermore, PAC proved effective in alleviating key risk factors associated with cardiovascular diseases by diminishing plasma saturated fatty acids, as well as levels of triglycerides, cholesterol, and non-HDL-C levels. The rise in adiponectin and drop in circulating levels of inflammatory markers showcased PAC's protective role against inflammation. To better clarify the mechanisms behind PAC actions, gut-liver axis parameters were examined, showing significant enhancements in gut microbiota composition, microbiota-derived metabolites, and marked reductions in intestinal and hepatic inflammation, liver steatosis, and key biomarkers associated with endoplasmic reticulum (ER) stress and lipid metabolism. This study enhances our understanding of the complex mechanisms underlying the development of MetS and provides valuable insights into how PAC may alleviate cardiometabolic dysfunction in HFHF mice.

PMID:40227220 | DOI:10.3390/antiox14030268

ChemistryOpen. 2025 Apr 14:e202500119. doi: 10.1002/open.202500119. Online ahead of print.

ABSTRACT

Epigenetic targeting of the Hedgehog (HH) signaling pathway has emerged as a possible strategy to combat HH pathway-driven cancers. In this study, we report on benzo[cd]indol-2(1H)-ones as downstream Hedgehog pathway inhibitors. We find that benzo[cd]indol-2(1H)-one 1 has sub-micromolar potency in a variety of Hedgehog pathway cell models, including those with constitutive activity through loss of Suppressor of Fused. Compound 1 furthermore reduces cellular and ciliary GLI levels, and, like the BET bromodomain inhibitor HPI-1, increases the cellular levels of BRD2. To directly assess the ability of compound 1 to bind to BET bromodomains in cells without the need of synthetic modifications, we develop a competition assay against degrader HPP-9, the action of which was dose-dependently outcompeted by compound 1. Indeed, compound 1 reduces the viability of GLI-driven lung cancer cells and medulloblastoma spheroids, with a potency similar to its inhibitory effect on the HH pathway. Taken together, our studies highlight the potential of the benzo[cd]indol-2(1H)-one scaffold for epigenetic targeting of the HH pathway.

PMID:40227130 | DOI:10.1002/open.202500119

mSphere. 2025 Apr 14:e0009825. doi: 10.1128/msphere.00098-25. Online ahead of print.

ABSTRACT

Antimicrobials are a pillar of modern medicine, yet our limited arsenal of antibiotics and antifungals is currently threatened by widespread drug resistance. Ongoing efforts are focused on developing strategies to identify compounds that enhance the efficacy of current antimicrobials and develop novel, resistance-evasive therapeutic strategies. In this study, we characterized microbial isolates from two distinct environments to identify those that exhibit antimicrobial activity alone and in combination with current antimicrobials: (i) oral isolates from domesticated animals and (ii) environmental Streptomyces spp. First, conditioned media prepared from bacterial and fungal oral isolates that were collected from Canis familiaris and Felis catus were screened for antibacterial and antifungal activity. Three supernatants from bacterial isolates exhibited antifungal activity against the human fungal pathogen Candida albicans in the presence of subinhibitory concentrations of fluconazole, the most widely deployed antifungal. Additionally, two bacterial isolates displayed antibacterial activity against Escherichia coli alone and in combination with the antibacterial ampicillin. Furthermore, 32 environmental isolates of confirmed and predicted Streptomyces spp. were screened for activity against C. albicans and E. coli. Cell-free media harvested from isolates WAC5038 and WAC5287 exhibited antifungal activity against Candida spp., while only the WAC5038-conditioned medium displayed antibacterial activity. Bioactivity-guided fractionation, coupled with UV/Vis absorbance spectra, suggested that the bioactive compound in WAC5287 has a similar absorbance spectrum to the antifungal class of polyenes, while the bioactive component of WAC5038 remains unknown. Overall, this work highlights a strategy to collect and screen environmental isolates for the identification of novel antimicrobials.

IMPORTANCE: The emergence and spread of antimicrobial resistance presents a global health challenge. As such, researchers are focused on developing pipelines to discover novel antimicrobials. In this study, we screened two distinct collections of microbes for antimicrobial activity. First, we collected bacterial and fungal isolates from the oral cavities of domesticated dogs and cats and identified these isolates using 16S (bacteria) and ITS (fungi) sequencing. Follow-up analyses confirmed that some conditioned media from bacterial isolates had antibacterial activity against Escherichia coli and antifungal activity against Candida albicans both alone and in combination with the current antimicrobial drugs. Additionally, screening 32 predicted or confirmed Streptomyces environmental isolates for antifungal and antibacterial activity identified two isolates with antifungal activity (WAC5038 and WAC5287), with only one isolate demonstrating antibacterial activity (WAC5038). Overall, this study provides a framework to identify and characterize environmental microbes with antimicrobial activity.

PMID:40227049 | DOI:10.1128/msphere.00098-25

Nucleic Acids Res. 2025 Apr 10;53(7):gkaf305. doi: 10.1093/nar/gkaf305.

ABSTRACT

Biosynthetic gene clusters (BGCs), key in synthesizing microbial secondary metabolites, are mostly hidden in microbial genomes and metagenomes. To unearth this vast potential, we present BGC-Prophet, a transformer-based language model for BGC prediction and classification. Leveraging the transformer encoder, BGC-Prophet captures location-dependent relationships between genes. As one of the pioneering ultrahigh-throughput tools, BGC-Prophet significantly surpasses existing methods in efficiency and fidelity, enabling comprehensive pan-phylogenetic and whole-metagenome BGC screening. Through the analysis of 85 203 genomes and 9428 metagenomes, BGC-Prophet has profiled an extensive array of sub-million BGCs. It highlights notable enrichment in phyla like Actinomycetota and the widespread distribution of polyketide, NRP, and RiPP BGCs across diverse lineages. It reveals enrichment patterns of BGCs following important geological events, suggesting environmental influences on BGC evolution. BGC-Prophet's capabilities in detection of BGCs and evolutionary patterns offer contributions to deeper understanding of microbial secondary metabolites and application in synthetic biology.

PMID:40226917 | DOI:10.1093/nar/gkaf305

Nucleic Acids Res. 2025 Apr 10;53(7):gkaf280. doi: 10.1093/nar/gkaf280.

ABSTRACT

Nuclear actin mediates enhancer-dependent transcriptional regulation at compartment level, playing critical roles in 3D genome organization. In β-actin depleted cells, H3K27 acetylation is enhanced, directly affecting enhancer-dependent transcriptional regulation and gene expression changes during compartment-switching. Here, we report these mechanisms are influenced by the long non-coding RNA (lncRNA) Meg3. Bulk RNA-seq analysis and qPCR on wild-type (WT), heterozygous (HET), and β-actin knockout (KO) mouse embryonic fibroblasts (MEFs) show that β-actin depletion significantly alters expression of several lncRNAs, including Meg3. Results from ChIRP-seq, ChIRP-MS, and fRIP-qPCR revealed that in β-actin KO cells, Meg3 becomes enriched and binds to H3K27 acetylation marks within gene regulatory regions. By integrating RNA-seq, H3K27 acetylation ChIP-seq, ATAC-seq, and HiC-seq data through activity by contact (ABC) analysis, we discovered Meg3 binding disrupts promoter-enhancer interactions in β-actin KO cells. These results, combined with metabolomics in WT, HET, and β-actin KO MEFs, show Meg3 binding to regulatory regions at sites of increased H3K27 acetylation impairs the expression of genes involved in the synthesis of chondroitin, heparan, dermatan sulfate, and phospholipases. We propose that in β-actin KO cells Meg3 binds to H3K27 acetylation levels. This interferes with promoter-enhancer interactions, disrupts genome organization, and downregulates gene expression and key metabolic pathways.

PMID:40226914 | DOI:10.1093/nar/gkaf280

Pract Lab Med. 2025 Mar 21;45:e00464. doi: 10.1016/j.plabm.2025.e00464. eCollection 2025 Jul.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a significant global health challenge with complex molecular underpinnings. Recent advancements in understanding the role of non-coding RNAs (ncRNAs) and exosomes in cancer biology have opened new avenues for research into potential diagnostic and therapeutic strategies.

METHODS: This study utilized a comprehensive approach to analyze gene expression patterns and regulatory networks in HCC. We integrated RNA sequencing data gathered from both tissue samples and exosomes. The WGCNA and limma R packages were employed to construct co-expression networks and identify differentially expressed ncRNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs).

RESULTS: Our analysis demonstrated distinct expression profiles of various ncRNAs in HCC, revealing their intricate interactions with cancer-related genes. Key findings include the identification of a network of microRNAs that interact with selected lncRNAs and their potential roles as biomarkers. Moreover, exosomal RNA was shown to effectively reflect tissue-specific gene expression changes.

CONCLUSIONS: The results of this study highlight the significance of exosomal ncRNAs in the progression of liver cancer, suggesting their potential as both diagnostic biomarkers and therapeutic targets. Future research should focus on the functional implications of these ncRNAs to further elucidate their roles in HCC and explore their applications in clinical settings.

PMID:40226122 | PMC:PMC11992429 | DOI:10.1016/j.plabm.2025.e00464

Hum Mutat. 2024 Aug 29;2024:7377504. doi: 10.1155/2024/7377504. eCollection 2024.

ABSTRACT

GNE myopathy (GNEM) is a rare autosomal recessive disorder characterized by progressive skeletal muscle wasting starting in early adulthood. The prevalence of GNEM is estimated to range between one and nine cases per million individuals, but the accuracy of these estimates is limited by underdiagnosis, misdiagnosis, and bias introduced by founder allele frequencies. As GNEM is a recessive disorder, unaffected carriers of single damaging variants can be expected to be found in the healthy population, providing an alternative method for estimating prevalence. We aim to estimate the prevalence of GNEM using allele frequencies obtained from healthy population genetic databases. We performed a review to establish a complete list of all known pathogenic GNEM variants from both literature and variant databases. We then developed standardized filtering steps using in silico tools to predict the pathogenicity of unreported GNE variants of uncertain clinical significance and validated our pathogenicity inferences using Mendelian Approach to Variant Effect pRedICtion built in Keras (MAVERICK) and AlphaMissense. We calculated conservative and liberal disease prevalence estimates using allele frequencies from the Genome Aggregation Database (gnomAD) population database by employing methodologies based on the assumptions of the Hardy-Weinberg Equilibrium. We additionally calculated estimates for disease prevalence removing the contribution of unique variant combinations that either do not cause myopathy in humans or result in embryonic lethality. We present the most comprehensive list of reported pathogenic GNE variants to date, together with additional variants predicted as pathogenic by in silico methods. We provide additional pathogenicity scores for these variants using new pathogenicity prediction tools and present a set of estimates for GNEM prevalence based on the different assumptions. Our most conservative estimate suggested a prevalence of 18.46 cases per million, while our most liberal estimate places the prevalence at 95.42 cases per million. When accounting for variant severity, this range drops to 11.00-87.68 cases per million. Our findings indicate that the true global prevalence of GNEM is greater than previous predictions underscoring that this condition is considerably more widespread than previously believed.

PMID:40225917 | PMC:PMC11919241 | DOI:10.1155/2024/7377504

Bone Rep. 2025 Mar 24;25:101839. doi: 10.1016/j.bonr.2025.101839. eCollection 2025 Jun.

ABSTRACT

Genetic studies have revealed hundreds of loci associated with bone-related phenotypes, including bone mineral density (BMD) and fracture risk. However, translating discovered loci into effective new therapies remains challenging. We review success stories including PCSK9-related drugs in cardiovascular disease and evidence supporting the use of human genetics to guide drug discovery, while highlighting advances in artificial intelligence and machine learning with the potential to improve target discovery in skeletal biology. These strategies are poised to improve how we integrate diverse data types, from genetic and electronic health records data to single-cell profiles and knowledge graphs. Such emerging computational methods can position bone genomics for a future of more precise, effective treatments, ultimately improving the outcomes for patients with common and rare skeletal disorders.

PMID:40225702 | PMC:PMC11986539 | DOI:10.1016/j.bonr.2025.101839

Theranostics. 2025 Mar 21;15(10):4654-4672. doi: 10.7150/thno.111272. eCollection 2025.

ABSTRACT

Glia reactivity, neuroinflammation and excitotoxic neuronal death are central processes to ischemic stroke and neurodegenerative diseases, altogether a leading cause of death, disability, and dementia. Given the high incidence of these pathologies and the limited efficacy of current treatments, developing brain-protective therapies that target both neurons and glial cells is a priority. Truncated neurotrophin receptor TrkB-T1, a protein produced by these cell types, plays relevant roles in excitotoxicity and ischemia. We hypothesized that interactions mediated by isoform-specific TrkB-T1 sequences might contribute to neurotoxicity and/or reactive gliosis, thus representing potential therapeutic targets. Methods: We designed cell-penetrating peptides containing TrkB-T1 isoform-specific sequences to: 1) characterize peptide delivery into rat primary cortical cultures and mice brain cortex; 2) isolate and identify the isoform interactome in basal and in vitro excitotoxic conditions; 3) analyze peptide effects on neuroinflammation and neurotoxicity using primary cultures subjected to excitotoxicity or in vivo in a mouse model of ischemia. Results: We identify here the TrkB-T1-specific interactome, poorly described to date, and demonstrate that interference of these protein-protein interactions using brain-accessible TrkB-T1-derived peptides can reduce reactive gliosis and decrease excitotoxicity-induced damage in cellular and animal models of stroke, where treatment reduces the infarct volume in male and female mice. Conclusions: The crucial role of TrkB-T1 in modulating microglia and astrocyte reactivity indicates that isoform-derived peptides hold promise for the development of therapies for human stroke and other excitotoxicity-associated pathologies.

PMID:40225562 | PMC:PMC11984388 | DOI:10.7150/thno.111272

NAR Mol Med. 2025 Mar 28;2(2):ugaf010. doi: 10.1093/narmme/ugaf010. eCollection 2025 Apr.

ABSTRACT

Understanding how exercise improves whole-body insulin sensitivity (Si) involves complex molecular signaling. This study examines skeletal muscle gene expression changes related to Si, considering sex differences, exercise amount, and intensity to identify pharmacologic targets mimicking exercise benefits. Fifty-three participants from STRRIDE (Studies of Targeted Risk Reduction Interventions through Defined Exercise) I and II completed eight months of aerobic training. Gene expression was assessed via Affymetrix and Illumina technologies, and Si was measured using intravenous glucose tolerance tests. A novel discovery protocol integrating literature-derived and data-driven modeling identified causal pathways and direct transcriptional targets. In women, exercise amount primarily influenced transcription factor targets, which were generally inhibitory, while in men, exercise intensity drove activating targets. Common transcription factors included ATF1, CEBPA, BACH2, and STAT1. Si-related transcriptional targets included TACR3 and TMC7 for intensity-driven effects, and GRIN3B and EIF3B for amount-driven effects. Two key pathways mediating Si improvements were identified: estrogen signaling and protein kinase C (PKC) signaling, both converging on the epidermal growth factor receptor (EGFR) and other relevant targets. The molecular pathways underlying Si improvements varied by sex and exercise parameters, highlighting potential skeletal muscle-specific drug targets such as EGFR to replicate the metabolic benefits of exercise.

PMID:40225320 | PMC:PMC11992681 | DOI:10.1093/narmme/ugaf010

Life Metab. 2025 Feb 8;4(2):loaf004. doi: 10.1093/lifemeta/loaf004. eCollection 2025 Apr.

ABSTRACT

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.

PMID:40225300 | PMC:PMC11992618 | DOI:10.1093/lifemeta/loaf004

Iran J Biotechnol. 2024 Oct 1;22(4):e3927. doi: 10.30498/ijb.2024.459448.3927. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Human leukocyte antigens (HLAs) play a pivotal role in orchestrating the host's immune response, offering a promising avenue with reduced adverse effects compared to conventional treatments. Cancer immunotherapies use HLA class I molecules for T cells to recognize tumor antigens, emphasizing the importance of identifying peptides that bind effectively to HLAs. Computer modeling of HLA-peptide binding speeds up the search for immunogenic epitopes, which enhances the prospect of personalized medicine and targeted therapies. The Immune Epitope Database (IEDB) is a vital repository, housing curated immune epitope data and prediction tools for HLA-peptide binding. It can be challenging for immunologists to choose the best tool from the IEDB for predicting HLA-peptide binding. This has led to the creation of consensus-based methods that combine the results of several predictors. One of the major challenges in these methods is how to effectively integrate the results from multiple predictors.

OBJECTIVES: Previous consensus-based methods integrate at most three tools by relying on simple strategies, such as selecting prediction methods based on their proximity to HLA in training data. In this study, we introduce HLAPepBinder, a novel consensus approach using ensemble machine learning methods to predict HLA-peptide binding, addressing the challenges biologists face in model selection.

MATERIALS AND METHODS: The key contribution is the development of an automatic pipeline named HLAPepBinder that integrates the predictions of multiple models using a random forest approach. Unlike previous approaches, HLAPepBinder seamlessly integrates results from all nine predictors, providing a comprehensive and accurate predictive framework. By combining the strengths of these models, HLAPepBinder eliminates the need for manual model selection, providing a streamlined and reliable solution for biologists.

RESULTS: HLAPepBinder offers a practical and high-performing alternative for HLA-peptide binding predictions, outperforming both traditional methods and complex deep learning models. Compared to the recently introduced transformer-based model, TranspHLA, which requires substantial computational resources, HLAPepBinder demonstrates superior performance in both prediction accuracy and resource efficiency. Notably, it operates effectively in limited computational environments, making it accessible to researchers with minimal resources. The codes are available online at https://github.com/CBRC-lab/HLAPepBinder.

CONCLUSION: Our study introduces a novel ensemble-learning model designed to enhance the accuracy and efficiency of HLA-peptide binding predictions. Due to the lack of reliable negative data and the typical assumption of unknown interactions being negative, we focus on analyzing the unknown HLA-peptide bindings in the test set that our model predicts with 100% certainty as positive bindings. Using HLAPepBinder, we identify 26 HLA-peptide pairs with absolute prediction confidence. These predictions are validated through a multi-step pipeline involving literature review, BLAST sequence similarity analysis, and molecular docking studies. This comprehensive validation process highlights HLAPepBinder's ability to make accurate and reliable predictions, contributing significantly to advancements in immunotherapy and vaccine development.

PMID:40225296 | PMC:PMC11993240 | DOI:10.30498/ijb.2024.459448.3927

Iran J Biotechnol. 2024 Oct 1;22(4):e3817. doi: 10.30498/ijb.2024.421319.3817. eCollection 2024 Oct.

ABSTRACT

BACKGROUND: Clear cell renal cell carcinoma (ccRCC, KIRC) is the most prevalent subtype of RCC, and even with different available therapies, the average progression-free survival is worse. Therefore, the identification of new molecular targets could be helpful for its therapeutic purposes.

MATERIALS AND METHODS: We used the Cancer Genome Atlas to perform bioinformatic analyses for genes with possible tumor suppressor roles in KIRC.

OBJECTIVE: This research aims to identify new prognostic biomarkers and potential therapeutic targets for this type of cancer.

RESULTS: We identified 14 down-regulated genes in KIRC that had not previously been studied or poorly studied, with the majority of them impacted by increased promoter methylation. Eight genes showed shorter overall survival and worse prognosis, indicating their function as tumor suppressors, and six genes revealed good prognosis. From the 8 genes, C7ORF41 and CTXN3 revealed only downregulation in most cancers, proposing them as highly potential tumor suppressors. Among these 8 genes, the function of CTXN3 in cancers is unknown. Moreover, we identified the CWH43 gene as the major signature of KIRC. In addition, we found different genes as signatures of KIRC tumor stages and grades.

CONCLUSIONS: Our results may shed light on identifying KIRC pathogenesis and developing effective therapeutic targets for renal cancers, mainly KIRC.

PMID:40225292 | PMC:PMC11993239 | DOI:10.30498/ijb.2024.421319.3817

Front Plant Sci. 2025 Mar 28;16:1543168. doi: 10.3389/fpls.2025.1543168. eCollection 2025.

ABSTRACT

In plant cell walls, lignin, cellulose, and the hemicelluloses form intricate three-dimensional structures. Owing to its complexity, lignin often acts as a bottleneck for the efficient utilization of polysaccharide components as biochemicals and functional materials. A promising approach to mitigate and/or overcome lignin recalcitrance is the qualitative and quantitative modification of lignin by genetic engineering. Feruloyl-CoA 6'-hydroxylase (F6'H1) is a 2-oxoglutarate-dependent dioxygenase that catalyzes the conversion of feruloyl-CoA, one of the intermediates of the lignin biosynthetic pathway, into 6'-hydroxyferuloyl-CoA, the precursor of scopoletin (7-hydroxy-6-methoxycoumarin). In a previous study with Arabidopsis thaliana, we demonstrated that overexpression of F6'H1 under a xylem-preferential promoter led to scopoletin incorporation into the cell wall. This altered the chemical structure of lignin without affecting lignin content or saccharification efficiency. In the present study, the same F6'H1 construct was introduced into hybrid aspen (Populus tremula × tremuloides T89), a model woody plant, and its effects on plant morphology, lignin chemical structure, global gene expression, and phenolic metabolism were examined. The transgenic plants successfully overproduced scopoletin while exhibiting severe growth retardation, a phenotype not previously observed in Arabidopsis. Scopoletin accumulation was most pronounced in the secondary walls of tracheary elements and the compound middle lamella, with low levels in the fiber cell walls. Overexpression of F6'H1 also affected the metabolism of aromatics, including lignin precursors. Heteronuclear single-quantum coherence (HSQC) NMR spectroscopy revealed that scopoletin in cell walls was bound to lignin, leading to a reduction in lignin content and changes in its monomeric composition and molar mass distribution. Furthermore, the enzymatic saccharification efficiency of the transgenic cell walls was more than three times higher than that of the wild-type plants, even without pretreatment. Although addressing growth inhibition remains a priority, incorporating scopoletin into lignin demonstrates significant potential for improving woody biomass utilization.

PMID:40225026 | PMC:PMC11985793 | DOI:10.3389/fpls.2025.1543168

Indian J Hematol Blood Transfus. 2025 Apr;41(2):383-387. doi: 10.1007/s12288-024-01826-7. Epub 2024 Jul 30.

ABSTRACT

BACKGROUND: Acute erythroid leukemia (AEL) accounts for 3% to 5% of AML patients. We present a case of AEL with whole exome sequencing (WES) data.

CASE REPORT: A 25-year-old male presented with easy fatiguability and fever on & off for 6 months. Complete blood counts revealed anemia, leukocytosis and thrombocytopenia. Peripheral blood smear showed numerous nucleated RBCs ~600nRBCs/ 100WBCs and no blastsBone marrow aspirate smears were markedly hemodiluted. Bone marrow biopsy was hypercellular for age with marked erythroid hyperplasia and predominance of early erythroid precursors. On immunohistochemistry, Glycophorin was diffusely positive, E-cadherin highlighted the early erythroid precursors and CD34 was negative. Possibility of AEL was considered.Total 77 AEL associated genes were taken out for functional association studies. Mutations already described in literature for AEL noted in this case were EPOR, JAK2, TP53, GATA 2, NPM1 and WT1. Novel mutations found in this case were ERCC6L2, PYGO1 and MYH9The patient left the hospital against medical advice and expired within a month of diagnosis.

CONCLUSION: This case is interesting as AEL presented in a young male and PBS showed 600nRBCs/ 100 WBCs. Targeted sequencing can help to confirm the diagnosis of AEL especially in dilute marrows.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12288-024-01826-7.

PMID:40224680 | PMC:PMC11992317 | DOI:10.1007/s12288-024-01826-7

Neuropsychopharmacology. 2025 Apr 13. doi: 10.1038/s41386-025-02092-5. Online ahead of print.

ABSTRACT

Refining previous learning when environmental contingencies change is a critical adaptive function. Studies have shown that systemic noradrenaline (NA) manipulations, as well as optogenetic manipulations of the locus coeruleus (LC), the primary source of forebrain NA, can improve long-term retention of appetitive extinction. To determine whether the contribution of NA is specific to extinction or extends to other forms of learning where reward is less than expected, we suppressed LC activity with clonidine, an α2A-adrenergic receptor agonist, in two tasks: compound extinction, where two previously rewarded cues are presented together and no longer rewarded, and overexpectation, where animals are presented with two previously rewarded cues but receive a single reward rather than the expected two. In compound extinction, we found no differences between groups in training, extinction, or a spontaneous recovery test. However, animals that received clonidine reacquired responding to the previously extinguished cue significantly faster than saline-treated animals, suggesting weakened extinction learning. In overexpectation testing, the saline group responded significantly less to a stimulus that had undergone overexpectation relative to a control stimulus, indicating that they had recalibrated their estimation of reward magnitude following training where reward was less than expected. In contrast, clonidine-treated animals did not differ in responding to the overexpectation versus control stimuli, suggesting that clonidine impaired learning resulting from overexpectation. These results demonstrate that activity of the LC is important for learning to reduce responding in both extinction and overexpectation paradigms.

PMID:40223132 | DOI:10.1038/s41386-025-02092-5

Cell Res. 2025 Apr 14. doi: 10.1038/s41422-025-01115-6. Online ahead of print.

NO ABSTRACT

PMID:40223018 | DOI:10.1038/s41422-025-01115-6

Biotechnol Adv. 2025 Apr 11:108579. doi: 10.1016/j.biotechadv.2025.108579. Online ahead of print.

ABSTRACT

Synthetic biology offers transformative opportunities to optimise Fusarium species as efficient platforms for the sustainable production of diverse bioproducts. Advanced engineering techniques, including CRISPR/Cas9, RNA interference and synthetic promoters, have enhanced the manipulation of metabolic pathways, enabling higher yields of industrially relevant compounds. Recent insights from next-generation sequencing and omics technologies have significantly expanded our understanding of Fusarium's metabolic networks, leading to more precise strain engineering. Despite these advances, challenges such as metabolic bottlenecks, regulatory complexities and strain stability remain significant barriers to industrial-scale applications. The development of efficient genetic tools, together with the expansion of our knowledge of Fusarium physiology and genetics thanks to systems biology approaches, holds promise to unlock Fusarium's full potential as a sustainable cell factory. This review focuses on the genetic and metabolic tools available to enhance Fusarium's capacity to produce biofuels, pharmaceuticals, enzymes and other valuable compounds. It also highlights key innovations and discusses future directions for leveraging Fusarium as an environmentally friendly bioproduction system.

PMID:40222460 | DOI:10.1016/j.biotechadv.2025.108579

Stem Cell Res Ther. 2025 Apr 12;16(1):174. doi: 10.1186/s13287-025-04282-w.

ABSTRACT

BACKGROUND: The kidney's endocrine function is essential for maintaining body homeostasis. Erythropoietin (EPO) is one of the key endocrine factors produced by the kidney, and kidney disease patients frequently experience anemia due to impaired EPO production. In the present study we explored the potential of human induced pluripotent stem cell (iPSC)-derived kidney organoids to restore EPO production.

METHODS: EPO secretion by kidney organoids was examined under 1% and 20% oxygen levels. To increase the EPO secreting capacity of kidney organoids, iPSC were genetically engineered with a non-integrating scaffold/matrix attachment region (S/MAR) DNA vector containing the EPO gene and generated EPO-overexpressing (EPO+) kidney organoids. To assess the physiological effects of EPO + organoids, 2-8 organoids were implanted subcutaneously in immunodeficient mice.

RESULTS: Kidney organoids produced low amounts of EPO under 1% oxygen. EPO S/MAR DNA vectors persisted and continued to robustly express EPO during iPSC expansion and kidney organoid differentiation without interfering with cellular proliferation. EPO + iPSC demonstrated efficient differentiation into kidney organoids. One-month post-implantation, EPO + organoids displayed continuously elevated EPO mRNA levels and significantly increased endothelial cell numbers compared to control organoids. Hematocrit levels were notably elevated in mice implanted with EPO + organoids in an organoid number-dependent manner. EPO + organoids furthermore influenced bone homeostasis in their hosts, evidenced by a change in trabecular bone composition.

CONCLUSION: Kidney organoids modified by EPO S/MAR DNA vector allow stable long-term delivery of EPO. The observed physiological effects following the implantation of EPO + organoids underscore the potential of gene-edited kidney organoids for endocrine restoration therapy.

PMID:40221815 | DOI:10.1186/s13287-025-04282-w