Organelle genome analysis reveals adaptation and conservation in endangered tree Phoebe chekiangensis.

Oxytocin beyond social bonding: Advancing neuromodulation, synaptic plasticity, and epigenetic precision in CNS disorders.

Prostate cancer is one of the most common malignancies in men and is marked by extensive clinical and molecular heterogeneity. Although genomic and transcriptomic studies have revealed recurrent alterations and lineage plasticity, these approaches lack spatial resolution and therefore cannot capture the microenvironmental context that underpins tumor progression and therapeutic resistance. Spatial omics technologies have emerged as transformative tools by integrating high-dimensional molecular profiling with preserved tissue architecture. Advances in spatial transcriptomics, proteomics, epigenomics, and metabolomics now permit the mapping of gene expression, protein signaling, chromatin accessibility, modifications, and folding, along with metabolic gradients at cellular to subcellular resolution. Spatial analysis of prostate cancer has revealed key features of disease progression, including stromal remodeling, immune evasion, lipid metabolic rewiring, and therapy-resistant niches. This review highlights recent spatial omics technologies, their emerging integrative and clinical applications in prostate cancer, and the future challenges in standardization, data integration, and clinical translation.

Abstract Introduction: Breast cancer (BC) is the most prevalent malignancy among women, and 5-10% are associated with germline pathogenic/likely pathogenic variants (PVs) in high-penetrance BC genes, mostly BRCA1/2. These genes encode proteins involved in the homologous recombination repair (HRR) pathway, whose dysfunction leads to homologous recombination deficiency (HRD). Germline PVs, somatic alterations, and/or epigenetic modifications in HRR pathway genes can induce the HRD tumor phenotype. While HRD is well-characterized in ovarian cancer and is a predictive biomarker for Parp inhibitors in this setting, data in BC remains scarce, especially in the Brazilian population. Objective: To evaluate HRD status in breast cancer samples from a Brazilian cohort. Methods: This retrospective single-center study included women with BC treated between 2020-2023 whose formalin-fixed paraffin-embedded tumor samples were available for analysis at Oncoclínicas Precision Medicine laboratory (OCPM). The laboratory database was used to identify eligible samples. All tumor samples were submitted to pathology review. HRD analysis assessed genomic scars (loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions) by sequencing 13,809 single nucleotide polymorphisms, plus mutational profiling of 15 genes involved in the HRR pathway. HRD status was defined using a validated assay by OCPM. Genomic instability score cutoff of 65 or higher. HRD profiles were described in relation to clinicopathological and molecular features. Results: Among 134 identified samples, 55 patients were consecutively selected for tumor analysis according to the study budget. Eight samples were excluded due to inadequate material for molecular analysis. Among 47 cases eligible for HRD analysis, 9 samples were excluded due to post-analytical failures. HRD profile was performed in 38 samples. The mean age of BC diagnosis was 51.4 years (range 49,8-52,2 years); 52.6% were premenopausal. Regarding molecular subtype distribution: 47.4% were Luminal B-like, 31.6% triple-negative, 15.8% Luminal A-like, and 2.6% HER2-positive. Half of the samples were from primary tumor sites and the remaining from metastatic sites. Most tumors were stage III (31.6%) at diagnosis followed by stage II (26.3%), IV (18.4%), and I (15.8%). Regarding germline status, 26.3% of patients harbored germline PVs, among these, 40% in BRCA1/2, 40% in other HRR genes, and 20% in non-HRR genes. The overall HRD prevalence was 31.6% (12/38). TNBC had a higher rate of HRD (66.7%; 8/12), followed by Luminal B-like (25%) and Luminal A-like (8.3%). None of the HER2-positive tumors had HRD phenotype. Patients with HRD tumors (n=12) were predominantly premenopausal (75%), had a younger age at BC diagnosis (mean age 49.8 years), presented more locally advanced disease (41.7% stage III), and in 75% of these cases, tumor samples were from the primary site. Thirty-three percent of patients with HRD tumors harbored germline PVs in HRR genes (2BRCA1,1BLM;1RAD51C); 60% of those were truncating variants (nonsense and frameshifts). Conclusions: This is the first Brazilian study to evaluate HRD in breast cancer, revealing a 31.6% prevalence consistent with international data. HRD was more common in aggressive tumors subtypes, younger patients, and those with germline PVs in HRR genes. The identification of alterations beyond classical BRCA1/2 mutations expands the molecular spectrum of HRD. Citation Format: A. K. Souto, F. C. Koyama, S. S. Koide, B. B. Souza, J. D. Massaro, L. J. Oliveira, L. Yamamoto, T. A. Santana, M. L. Bulcão, C. B. Fernandes, C. A. Resende, M. S. Mano, L. C. Landeiro, G. O. Bretas, C. B. Miranda, R. Dienstmann, R. L. Sandoval. Homologous Recombination Deficiency in Breast Cancer: Exploratory Analysis of a Brazilian Cohort with Germline Genetic Testing [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-05-29.

Abstract Rice (Oryza sativa L.) is a major staple crop worldwide, yet its productivity is severely constrained by increasing drought stress driven by climate change and water scarcity. Abscisic acid (ABA) signaling plays a central role in regulating plant responses to drought, with the PYR/PYL/RCAR family of ABA receptors acting as key molecular regulators. Among these, OsPYL9 has emerged as an important candidate gene due to its involvement in drought tolerance and circadian rhythm–associated stress regulation. This study aims to enhance drought resilience in rice through precise genome editing of OsPYL9 using CRISPR/Cas9 technology. A locally adapted, high-yielding rice variety will be subjected to targeted gene modification, followed by molecular validation, physiological screening under controlled drought stress, and comprehensive agronomic evaluation. The expected outcomes include improved water-use efficiency, enhanced antioxidant activity, optimized stomatal regulation, and stable grain yield under water-limited conditions. This research provides a sustainable and precise breeding strategy for developing climate-resilient rice varieties and offers significant potential for strengthening food security in drought-prone regions.Keywords: CRISPR/Cas9, OsPYL9, Drought tolerance, Abscisic acid signaling, Rice genomics

Lasso peptides are a class of ribosomally synthesized and post-translationally modified peptides distinguished by their lasso-like, threaded topology. Common to all lasso peptides biosynthetic gene clusters examined so far is an arrangement whereby the precursor peptide is encoded adjacent to the macrolactam synthetase and other modification genes. Here we report the cebulassopins A-D (1-4), the first example of lasso peptides synthesized by a split operon whereby multiple precursors are encoded several Mbps distant from the modification enzymes. Aside from characterizing their structures and calculating the three-dimensional topology of 1 and 2, we also find that the cebulassopins are potent antiproliferative agents with sub-μM inhibitory concentrations against human lung carcinoma cells. These results set the stage for further biological examination and exploration of other split lasso peptide gene clusters.

tRNA modification genes are associated with genomic instability, proliferative programs, and poor prognosis in breast cancer.

CRISPR/Cas9-mediated genome editing has expanded the possibilities for precise gene modifications; however, the efficiency of targeted insertion remains suboptimal. In this study, we describe a triple-reporter system in mouse embryonic stem cells that simultaneously tracks double-strand break (DSB) induction, homology-directed repair (knock-in), and end-joining-mediated targeted insertion (EJ-TI). Using both plasmid and adeno-associated virus (AAV) donor vectors, our results demonstrate that ataxia telangiectasia and Rad3-related kinase (ATR) activity is essential for knock-in regardless of the donor type, whereas ataxia telangiectasia mutated (ATM) inhibition exhibits a donor-dependent role. In cells receiving circular plasmid donors, ATM inhibition with AZD1390 markedly reduced the knock-in and EJ-TI efficiencies, consistent with its canonical role in DSB repair. In contrast, with linear AAV donors, ATM inhibition enhanced the knock-in efficiency by suppressing the overactivation of the ATM-p53-caspase 3 apoptotic pathway and partially suppressing classical non-homologous end-joining. These findings highlight the critical influence of donor DNA configuration on DNA damage response signaling and provide a strategy for optimizing genome editing efficiency by selectively modulating the ATM pathways, an approach that may have significant implications for gene therapy, cell engineering, and other applications.

Regular physical activity is an effective non-pharmacological approach to hypertension management and maternal exercise improves offspring cardiovascular health, although mechanisms remain unclear. A-kinase anchoring protein 150 (AKAP150) targets protein kinase Cα to L-type Ca2+ channels (CaV1.2), enhancing vascular tone in arterial smooth muscle during hypertension. This study aims to uncover a novel mechanism in which epigenetic modifications of the AKAP150 gene (Akap5) mediate the beneficial effects of maternal exercise on vascular function in hypertensive offspring. Pregnant spontaneously hypertensive rats (SHRs) and smooth muscle-specific AKAP150 knock-in mice (AKAP150 smKI) were assigned to sedentary or exercise groups. Mesenteric arteries (MAs) from embryonic day 21 and 3-month-old offspring were analysed for vascular function, electrophysiology, gene expression and Akap5 promoter histone acetylation. Maternal exercise during pregnancy significantly reduced blood pressure and Cav1.2 channel function in adult male offspring of both SHR and AKAP150 smKI, but not in female SHR offspring. Maternal exercise significantly attenuated AKAP150-Cav1.2 association in mesenteric arterial myocyte from SHR offspring. Additionally, it decreased H3K9ac at the Akap5 gene promoter, with a concomitant decrease in AKAP150 protein and mRNA expressions in hypertensive offspring. Furthermore, maternal exercise activated AMPK that up-regulated silent information regulator 1 (sirtuin 1; SIRT1) in the mesenteric arteries of SHR offspring. Maternal exercise improves blood pressure and vascular function in adult male hypertensive offspring by deacetylating H3K9ac at the Akap5 promoter via AMPK/SIRT1 activation. This highlights prenatal exercise as a potential strategy to mitigate the intergenerational transmission of hypertension.

Terpenoids constitute the largest class of plant-specialized metabolites, playing essential roles throughout the plants' life cycle and having diverse applications for humans in nutrition, medicine, and flavor. 3-Hydroxy-3-methylglutaryl-CoA reductase (HMGR) is a rate-limiting enzyme of the mevalonate (MVA) pathway, producing sesquiterpenes, saponins, and other terpenoids. HMGR is post-translationally regulated by downstream MVA products through its N-terminal regulatory domain, limiting terpenoid production. To overcome this bottleneck, we employed a virus-based CRISPR/Cas9 system to genetically modify the N-terminal regulatory domain of HMGR in petunia (Petunia × hybrida) and lettuce (Lactuca sativa L.). In petunia, HMGR1-edited lines exhibited vigorous growth, larger flowers, and increased production of sesquiterpenes. Interestingly, they also showed enhanced production of phenylpropanoid volatiles, revealing a connection between these pathways. Transcript analysis revealed altered expression of genes involved in terpenoid biosynthesis, pyruvate metabolism, phenylpropanoid biosynthesis, and gibberellin- and auxin-related pathways, indicating enhanced carbon flux through these metabolic networks. In lettuce, HMGR7-edited plants displayed elevated emission of sesquiterpenes, apocarotenoids, and the phenylpropanoid benzaldehyde. Together, these results establish a transgene-free strategy to enhance the production of terpenoid and phenylpropanoid volatiles, and provide a framework for developing resilient, nutrient-enriched crops.

A Paradigm Shift in Islet Transplantation Driven by Stem Cell Technology and Gene Modification.

Systematic engineering of cell wall for improving single cell protein (SCP) production.

Acute pancreatitis (AP) is a severe inflammatory disorder in which mitochondrial dysfunction and ferroptosis critically drive acinar cell injury. Our previous work suggested a protective role for exogenous milk fat globule-epidermal growth factor 8 (MFG-E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG-E8 mitigates mitochondrial damage and ferroptosis during AP. Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding cassette subfamily E member 1 (ABCE1) in vitro. One mitophagy agonist and two ferroptosis inhibitors were used in both in vitro and in vivo experiments. Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe2+ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice. Endogenous MFG-E8 protects against AP by binding ABCE1 to sustain mitophagy flux and inhibit ferroptosis. Targeting this axis offers a promising therapeutic strategy for mitigating pancreatic injury. Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe2+ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.

Nemadectin, a milbemycin-class macrocyclic lactone antibiotic produced by Streptomyces cyaneogriseus, is a potent broad-spectrum insecticide with excellent environmental compatibility. Its derivative moxidectin, featuring a C-23 methoxime modification, demonstrates enhanced insecticidal activity and has become a commercially successful agrochemical. This study reveals ammonium regulation effectively boosts nemadectin biosynthesis in S. cyaneogriseus, with mechanistic insights gained through integrated multi-omics analysis. Transcriptomic profiling showed ammonium sulfate supplementation significantly upregulates the nemadectin biosynthetic gene cluster, including polyketide synthase (PKS) genes, backbone modification genes, and pathway-specific transcription factors, while also enhancing the expression of Avenolide-like signaling molecules and global transcription factor Afskne. Metabolomic dynamics revealed reinforced precursor biosynthesis through coordinated metabolic reprogramming: enhanced acetyl-CoA production, reinforced Embden-Meyerhof-Parnas pathway and amino acid/acyl-CoA metabolism, coupled with reduced tricarboxylic acid cycle activity. Systematic integration of physiological phenotyping, metabolite profiling, and transcriptional regulation data comprehensively elucidated the ammonium-driven overproduction mechanism, providing critical insights for developing advanced fermentation strategies and genetic engineering approaches in industrial antibiotic production.

Cerebral small vessel disease is an age-related condition that severely affects the quality of life of older adults; however, there are currently no definitive treatments or preventive measures. Cells from both the peripheral and central immune systems significantly impact the development of cerebral small vessel disease. By analyzing the effects of different immune cells on brain dysfunction associated with this disease, we aim to explore the various mechanisms through which autoimmune and acquired immune cells in peripheral circulation and the central nervous system contribute to disease development. Additionally, we seek to identify potential therapeutic modalities targeting these immune cells. In innate immunity, treatment targeting different monocyte loci includes four main modalities: cytokines (CSF1R, MIF, P2X7, CX3CR1, and CCL2), signaling pathways (DAP12/TREM, PI3K/AKT, and Wnt/β-catenin), tissue engineering (mitochondrial transplantation and exosomes), and traditional Chinese medicines. Treatment targeting different dendritic cell loci encompasses two modalities: signaling pathway (cGAS/STING/NF-κB) and tissue engineering (tolerogenic dendritic cells and engineered probiotics). For natural killer cells, treatment targeting different loci includes two modalities: tissue engineering (natural killer cell-based immunotherapies) and traditional Chinese medicines (Tongxinluo capsule). In adaptive immunity, treatment targeting different T cell loci includes four modalities: cytokines (S1PR and RXR), signaling pathway (Nrf2/GPX4 and Notch-ITGB1), tissue engineering (elimination of senescent T cells, monoclonal antibodies targeting amyloid-beta protofibrils, nanovaccines, and nanomedicines), and traditional Chinese medicines (traditional herbal remedies and microneedle therapy). Treatment targeting different B cell loci includes three modalities: monoclonal antibodies (targeting CD49d and CD20), purine glycoside analogs (Cladribine), and plasma exchange. This review explores the relationship between nerve regeneration, immune cells, and cerebral small vessel disease. The disease is characterized by the crucial role played by signaling and interactions between immune cells and components of the neurovascular unit, which is a functional complex composed of neurons, glial cells, and microvessels that regulate inflammatory responses and tissue repair. The central nervous system lacks intrinsic regenerative capacity, and currently, there is no effective method to fully restore its function. The primary focus of current research is on utilizing tissue engineering and regenerative medicine to create environments that facilitate cell proliferation and tissue regeneration. Hydrogels, induced pluripotent stem cells, exosomes, regulatory T cell transplants, and gene modification are key areas of focus in neural regeneration research. In the future, immune rejuvenation and other emerging therapies may offer potential treatment strategies for cerebral small vessel disease. This review analyzes the functions of various immune cells in cerebral small vessel disease, explores the relationship between nerve regeneration and these immune cells, and discusses potential therapeutic avenues that target immune cells for future treatments and neural regeneration related to cerebral small vessel disease.

ABSTRACT Legumes play a vital role in agriculture, nutrition, and the economy, but their production faces significant threats. Among these, drought and its unpredictability will be the most damaging constraint in the coming decades. Enhancing drought tolerance is essential for resilient and sustainable legume cultivation, and genetic engineering through gene modification or editing offers promising solutions. Long‐term drought tolerance involves regulating molecular pathways, such as the ABA‐dependent or independent mechanisms, which control the expression of stress‐related genes, making them ideal targets for genetic optimization. However, many legume crop genotypes are difficult to transform due to low transformation or regeneration efficiency. Recent research has therefore focused on both identifying key genes for modification and improving transformation and regeneration techniques. This review examines recent advancements in legume transformation methods and the genetic modifications aimed at increasing drought resilience in legume crops.

Sugarcane (Saccharum spp.) is an important cash crop that provides about 90% of sugar and 40% of bioethanol in China. Due to its large genome and complicated genetic background, conventional breeding is difficult to achieve efficient genetic improvement of sugarcane. Genome editing is a disruptive technology in life sciences, enabling precise and efficient modification of target genes. From zinc-finger nucleases (ZFNs) to transcription activator-like effector nucleases (TALENs), the CRISPR/Cas system and the derived base editing and prime editing, these technologies have greatly advanced genetic research and upgraded biological breeding. With the decoding of the sugarcane genome, genome editing has provided a new technical means for the genetic improvement of polyploid sugarcane. This article provides a comprehensive review of the trajectory of genome editing in plants, the optimization of the CRISPR/Cas system, the genetic transformation status of sugarcane, the development of sugarcane genomics, and the application of genome editing in sugarcane. It focuses on exploring the application prospects of genome editing in breeding lodging-resistant sugarcane varieties. This review aims to provide valuable references for promoting the use of genome editing in sugarcane breeding.

Targeted identification of new phaterpenes and elucidation of the relevant biosynthetic pathway in Streptomyces phaeochromogenes OSK-123

Acute lung injury/Acute respiratory distress syndrome (ALI/ARDS) is a life-threatening inflammatory lung disorder characterized by high mortality rates and a lack of effective treatment options. Although mesenchymal stem cell (MSC)-based therapies have emerged as a promising approach for ARDS management, optimizing their therapeutic efficacy remains a significant challenge. Recent advances in gene modification techniques have opened new avenues for enhancing MSC functionality. Among these, Fibronectin type III domain-containing protein 5 (Fndc5)/irisin has attracted considerable attention due to its ability to improve endothelial function. This study aims to evaluate the therapeutic potential of Fndc5-modified MSCs in sepsis-induced ALI/ARDS and to elucidate the underlying molecular mechanisms driving their protective effects. To comprehensively evaluate the therapeutic potential of Fndc5-modified MSCs (MSCs-Fndc5) in ARDS, we employed both in vivo and in vitro experimental models. In vivo, a mouse model of sepsis-induced ALI was established through intraperitoneal injection of lipopolysaccharide (LPS), and the protective effects of MSCs-Fndc5 were systematically assessed by analyzing lung histopathology, inflammatory cytokine levels, vascular endothelial integrity, lung wet-to-dry weight ratio, and MSC retention in lung tissue. In parallel, in vitro studies were conducted to investigate the role of MSCs-Fndc5 in mitigating LPS-induced endothelial cell (EC) injury, with a focus on EC proliferation, angiogenesis, barrier permeability, apoptosis, and the regulation of key signaling pathways. Fndc5 modification significantly increased the retention rate of MSCs in sepsis-induced ALI murine model while augmenting their in vitro proliferation and migration potential. In vivo, treatment with Fndc5-modified MSCs markedly attenuated lung inflammation, as evidenced by reduced levels of pro-inflammatory cytokines, decreased neutrophil infiltration, and improved lung histopathology. Additionally, MSCs-Fndc5 alleviated pulmonary edema, reduced fibrosis, lowered the lung wet-to-dry weight ratio, and preserved vascular endothelial integrity. In vitro, MSCs-Fndc5 significantly enhanced cell proliferation, migration, angiogenesis, endothelial barrier function, apoptosis inhibition, likely via PI3K/AKT pathway activation. Fndc5 overexpression in MSCs augments their therapeutic efficacy in sepsis-induced ALI/ARDS, which may be achieved by activating the endothelial PI3K/AKT pathway and improving MSCs retention in vivo. These findings propose MSCs-Fndc5 as a promising therapeutic strategy for sepsis-induced ALI/ARDS by enhancing endothelial repair, curbing inflammation, and modulating pivotal signaling pathways. Further investigation is warranted to explore the clinical applicability of MSCs-Fndc5 therapy for ARDS.

Mitochondrial retrograde signaling plays crucial roles in maintaining metabolic homeostasis via regulating genome modification and oxidative responsive gene expression. In this study, we identified GCN5L1, a protein localized in both mitochondria and cytoplasm, and demonstrated its specific translocation from mitochondria to cytoplasm during lipid overload and high-fat diet feeding. Using transcriptome and proteome analyses, we identified that cytoplasmic GCN5L1 binds to and promotes the acetylation of PPARγ at lysine 289 (K289). This acetylation protected PPARγ from ubiquitination-mediated degradation by proteasome. GCN5L1 translocation enhanced protein stability of PPARγ and subsequently promoted lipid accumulation in both cultured cells and murine models. Our study further reveals that PPARγ-K289 mutation reduces the ubiquitination of PPARγ and exacerbates liver steatosis in mice. These findings unveil a mitochondrial retrograde signaling during lipid overload, which regulates the crucial lipogenic transcriptional factor. This discovery elucidates an unrecognized mitochondrial function and mechanism underlying hepatic lipid synthesis.