Search Results (354)

Background: Against the backdrop of the large-scale and intensive development of the livestock industry, enhancing the reproductive efficiency of cattle has become a crucial factor in industrial development. Holstein cows, as the most predominant dairy cattle breed globally, are characterized by high milk yield and excellent milk quality. However, their reproductive efficiency is comprehensively influenced by a variety of complex factors, and improving their reproductive performance faces numerous challenges. The ovary, as the core organ of the female reproductive system, plays a decisive role in embryonic development and pregnancy maintenance. It is not only the site where eggs are produced and developed but it also regulates the cow’s estrous cycle, ovulation process, and the establishment and maintenance of pregnancy by secreting various hormones. The normal functioning of the ovary is crucial for the smooth development of the embryo and the successful maintenance of pregnancy. Methods: Currently, traditional sequencing technologies have obvious limitations in deciphering ovarian function and reproductive regulatory mechanisms. To overcome the bottlenecks of traditional sequencing technologies, this study selected Holstein cows as the research subjects. Ovarian samples were collected from one pregnant and one non-pregnant Holstein cow, and single-nucleus transcriptome sequencing technology was used to conduct an in-depth study on the ovarian cells of Holstein cows. Results: By constructing a cell type-specific molecular atlas of the ovaries, nine different cell types were successfully identified. This study compared the proportions of ovarian cell types under different physiological states and found that the proportion of endothelial cells decreased during pregnancy, while the proportions of granulosa cells and luteal cells increased significantly. In terms of functional enrichment analysis, oocytes during both pregnancy and non-pregnancy play roles in the “cell cycle” and “homologous recombination” pathways. However, non-pregnant oocytes are also involved in the “progesterone-mediated oocyte maturation” pathway. Luteal cells during pregnancy mainly function in the “cortisol synthesis and secretion” and “ovarian steroidogenesis” pathways; non-pregnant luteal cells are mainly enriched in pathway processes such as the “AMPK signaling pathway”, “pyrimidine metabolism”, and “nucleotide metabolism”. Cell communication analysis reveals that there are 51 signaling pathways involved in the pregnant ovary, with endothelial cells, granulosa cells, and luteal cells serving as the core communication hubs. In the non-pregnant ovary, there are 48 pathways, and the interaction between endothelial cells and stromal cells is the dominant mode. Conclusions: This study provides new insights into the regulatory mechanisms of reproductive efficiency in Holstein cows. The differences in the proportions of ovarian cell types, functional pathways, and cell communication patterns under different physiological states, especially the increase in the proportions of granulosa cells and luteal cells during pregnancy and the specificity of related functional pathways, indicate that these cells play a crucial role in the reproductive process of cows. These findings also highlight the importance of ovarian cells in pathways such as “cell cycle”, “homologous recombination”, and “progesterone-mediated oocyte maturation”, as well as the cell communication mechanisms in regulating ovarian function and reproductive performance. Full article

Targeted radionuclide therapy (TRT) utilizes radiopharmaceuticals to deliver radiation directly to cancer cells while sparing healthy tissues. Beyond the absorbed dose of ablative radiation, TRT induces non-targeted effects (NTEs) that significantly enhance its therapeutic efficacy. These effects include radiation-induced bystander effects (RIBEs), abscopal effects (AEs), radiation-induced genomic instability (RIGI), and adaptive responses, which collectively influence the behavior of cancer cells and the tumor microenvironment (TME). TRT also modulates immune responses, promoting immune-mediated cell death and enhancing the efficacy of combination therapies, such as the use of immune checkpoint inhibitors. The molecular mechanisms underlying TRT involve DNA damage, oxidative stress, and apoptosis, with repair pathways like homologous recombination (HR) and non-homologous end joining (NHEJ) playing critical roles. However, challenges such as tumor heterogeneity, hypoxia, and radioresistance limit the effectiveness of this approach. Advances in theranostics, which integrate diagnostic imaging with TRT, have enabled personalized treatment approaches, while artificial intelligence and improved dosimetry offer potential for treatment optimization. Despite the significant survival benefits of TRT in prostate cancer and neuroendocrine tumors, 30–40% of patients remain unresponsive, which highlights the need for further research into molecular pathways, long-term effects, and combined therapies. This review outlines the dual mechanisms of TRT, direct toxicity and NTEs, and discusses strategies to enhance its efficacy and expand its use in oncology. Full article

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Epigenetic modifications are heritable, reversible alterations that causally reshape chromatin architecture and thereby influence DNA repair without changing nucleotide sequence. DNA methylation, histone modifications and non-coding RNAs profoundly influence DNA repair mechanisms and genomic stability. Aberrant epigenetic patterns in cancer compromise DNA damage recognition and repair, therefore impairing homologous recombination (HR), non-homologous end joining (NHEJ), and base excision repair (BER) by suppressing key repair genes and lowering access to repair sites. Then it is dissected how loss-of-function mutations in Switch/Sucrose non-fermentable, imitation switch and CHD (Chromodomain helicase DNA-binding) chromatin-remodeling complexes impair nucleosome repositioning, preventing effective damage sensing and assembly of repair machinery. Non-coding RNAs contribute to epigenetic silencing at DNA break sites, exacerbating repair deficiencies. This review evaluates recent advances concerning epigenetic dysfunction and DNA repair impairment. It is also highlighted that nanoparticle-mediated delivery strategies are designed to overcome pharmacologic resistance. It is presented how epigenetic dysregulation of DNA repair can guide more effective and drug-resistant cancer therapies. Full article

The wolf fish Hoplias malabaricus is a Neotropical species characterized by remarkable karyotypic diversity, including seven karyomorphs (KarA-G) with distinct sex chromosome systems. This study investigated the homologous XY (KarF) and XY₁Y₂ (KarG) sex chromosome systems present in this species by integrating cytogenetics and genomics to examine sex chromosomes’ composition through characterization of repeatome (satellite DNA and transposable elements) and sex-linked markers. Our analysis indicated that both karyomorphs are little differentiated in their sex chromosomes content revealed by satDNA mapping and putative sex-linked markers. Both repeatomes were mostly composed of transposable elements, but neither intra- (male versus female) nor interspecific (KarF x KarG) variations were found. In both systems, we demonstrated the occurrence of sex-specific sequences probably located on the non-recombining region of the Y chromosome supported by the accumulation of sex-specific haplotypes of HmfSat10-28/HmgSat31-28. This investigation offered valuable insights by highlighting the composition of homologous XY and XY₁Y₂ multiple sex chromosomes. Although homologous, the large Y chromosome in KarF corresponds to two separate linkage groups (Y₁ and Y₂) in KarG implying a specific meiotic arrangement involving the X chromosome in a meiotic trivalent chain. This scenario likely influenced recombination rates and, as a result, the genomic composition of these chromosomes. Full article

Non-small cell lung cancer (NSCLC) remains a major contributor to cancer-related deaths worldwide, with therapeutic resistance presenting a critical clinical hurdle. The DNA damage response (DDR) constitutes a sophisticated cellular framework that detects, signals, and repairs genetic lesions to preserve genomic stability. While the DDR plays a crucial role in determining the efficacy of radiotherapy and chemotherapy, current research primarily focuses on direct DDR inhibitors, often overlooking the broader regulatory networks that modulate DDR activity. This review aims to comprehensively analyze the upstream and downstream pathways governing DDR in NSCLC, highlighting key molecular regulators, signaling interactions, and potential feedback mechanisms contributing to therapy resistance. By identifying novel regulatory targets and clinically relevant biomarkers, we propose innovative therapeutic strategies to enhance treatment efficacy. Our approach seeks to bridge the gap between DDR dysregulation and precision oncology, offering new perspectives on overcoming resistance and improving patient outcomes in NSCLC. Full article

Cases of new COVID-19 infection, which manifested in 2019 and caused a global socioeconomic crisis, still continue to be registered worldwide. The high mutational activity of SARS-CoV-2 leads to the emergence of new antigenic variants of the virus, which significantly reduces the effectiveness of COVID-19 vaccines, as well as the sensitivity of diagnostic test systems based on variable viral antigens. These problems may be solved by focusing on highly conserved coronavirus antigens, for example nucleocapsid (N) protein, which is actively expressed by coronavirus-infected cells and serves as a target for the production of virus-specific antibodies and T cell responses. It is known that anti-N antibodies are non-neutralizing, but their protective potential and functional activity are not sufficiently studied. Here, the protective effect of anti-N antibodies was studied in Syrian hamsters passively immunized with polyclonal sera raised to N(B.1) recombinant protein. The animals were infected with 10⁵ or 10⁴ TCID₅₀ of SARS-CoV-2 (B.1, Wuhan or BA.2.86.1.1.18, Omicron) 6 h after serum passive transfer, and protection was assessed by weight loss, clinical manifestation of disease, viral titers in the respiratory tract, as well as by the histopathological evaluation of lung tissues. The functional activity of anti-N(B.1) antibodies was evaluated by complement-dependent cytotoxicity (CDC) and antibody-dependent cytotoxicity (ADCC) assays. The protection of anti-N antibodies was evident only against a lower dose of SARS-CoV-2 (B.1) challenge, whereas almost no protection was revealed against BA.2.86.1.1.18 variant. Anti-N(B.1) monoclonal antibodies were able to stimulate both CDC and ADCC. Thus, anti-N(B.1) antibodies possess protective activity against homologous challenge infection, which is possibly mediated by innate Fc-mediated immune reactions. These data may be informative for the development of N-based broadly protective COVID-19 vaccines. Full article

Background: Defective DNA repair systems result in the accumulation of mutations, loss of genomic integrity, and eventually cancer. Following initial malignant transformation due to specific DNA damage and defective DNA repair, cancer cells become reliant upon other DNA repair pathways for their survival. The co-occurrence of specific repair deficiencies brings catastrophic outcomes such as cell death for cancer cells and thus holds promise as a potential therapeutic strategy. Exploring the co-occurrence and mutual exclusivity of mutational signatures provides valuable knowledge regarding combinations of defective repair pathways that are cooperative and confer selective advantage to cancer cells and those that are detrimental and cannot be tolerated by them. Methods: Taking advantage of mutational signature profiling, we analyzed whole-genome sequences of 1014 breast cancers to reveal the underlying mutational processes and their interrelationships. Results: We found an inverse relationship between deficiencies of homologous recombination (HRd) and non-homologous end joining (NHEJd) with reactive oxygen species (ROS). Moreover, HRd and NHEJd co-occurred with APOBEC but were mutually exclusive with mismatch repair deficiency (MMRd) and ROS. Our analysis revealed that SBS8 and SBS39 signatures of currently unknown etiology correlate with NHEJd. ID1 and ID2 signatures co-occur with ROS and have mutual exclusivity with HRd, SBS8, SBS39 and NHEJd. The ID4 signature, with currently unknown etiology, has mutual exclusivity with HRd and NHEJd and co-occurred with ROS. On the other hand, the ID15 signature, with currently unknown etiology, co-occurred with SBS8, SBS39, HRd, NHEJd and DBS2, while having an inverse relationship with MMRd and ROS. Comparing the mutational signatures of HRd and non-HRd TNBC genomes reveals the unique presence of ROS signatures in non-HRd tumors and the lack of ROS signature in HRd tumors. Conclusion: Taken together, these analyses indicate the possible application of mutation signatures and their interactions in advancing patient stratification and suggest appropriate therapies targeting the make-up of individual tumors’ mutational processes. Ultimately, this information provides the opportunity to discover promising synthetic lethal candidates targeting DNA repair systems. Full article

The Reverse Transcriptase of the Human Immunodeficiency Virus (HIV) is distinguished by its high rate of homologous recombination. A less-studied consequence of this phenomenon is the increased occurrence of non-homologous recombination, which results in length polymorphism. While most of these genome-wide variations are sporadic, some provide a replication advantage to variant strains, such as those in the Long Terminal Repeat (LTR) and p6-Gag regions. By analyzing sequences from these two regions in the HIV-1 databases, we categorize all types of non-homologous recombination into four groups based on the presence or absence of two molecular features. Additionally, drawing on established models of homologous recombination, we propose a model that describes the process of sequence duplication. This model can also be applied to explain non-homologous recombination in different types of HIV and other viruses. Full article

As an important class of microorganisms, filamentous fungi have crucial roles in protein secretion, secondary metabolite production and environmental pollution control. However, characteristics such as apical growth, heterokaryon, low homologous recombination (HR) efficiency and the scarcity of genetic markers mean that the application of traditional gene editing technology in filamentous fungi faces great challenges. The introduction of the RNA-mediated CRISPR/Cas (clustered regularly interspaced short palindromic repeat/CRlSPR-associated protein) system in filamentous fungi in recent years has revolutionized gene editing in filamentous fungi. In addition, the continuously expressed CRISPR system has significantly improved the editing efficiency, while the optimized sgRNA design and reduced cas9 concentration have effectively reduced the off-target effect, further enhancing the safety and reliability of the technology. In this review, we systematically analyze the molecular mechanism and regulatory factors of CRISPR/Cas9, focus on the optimization of its expression system and the improvement of the transformation efficiency in filamentous fungi, and reveal the core regulatory roles of HR and non-homologous end-joining (NHEJ) pathways in gene editing. Based on the analysis of various filamentous fungi applications, this review reveals the outstanding advantages of CRISPR/Cas9 in the enhancement of protein secretion, addresses the reconstruction of secondary metabolic pathways and pollutant degradation in the past decade, and provides a theoretical basis and practical guidance for the optimization of the technology and engineering applications. Full article

DNA damage has emerged as a critical factor in fuelling the development and progression of cancer. DNA damage response (DDR) pathways lie at the crux of cell fate decisions following DNA damage induction, which can either trigger the repair of detrimental DNA lesions to protect cancer cells or induce the cell death machinery to eliminate damaged cells. Cytoskeletal dynamics have a critical role to play and influence the proper function of DDR pathways. Microfilaments, intermediate filaments, microtubules, and their associated proteins are well involved in the DDR. For instance, they are not only implicated in the recruitment of specific DDR molecules to the sites of DNA damage but also in the regulation of the mobility of the damaged DNA to repair sites in the periphery of the nucleus. The exquisite roles that these cytoskeletal proteins play in different DDR pathways, such as non-homologous end joining (NHEJ), homologous recombination (HR), base excision repair (BER), and nucleotide excision repair (NER), in cancer cells are extensively discussed in this review. Many cancer treatments are reliant upon inducing DNA damage in cancer cells to eliminate them; thus, it is important to shed light on factors that could affect their efficacy. Although the cytoskeleton is intricately involved in the DDR process, this has often been overlooked in cancer research and has not been exploited in developing DDR-targeting cancer therapy. Understanding the interplay between the cytoskeleton and the DDR in cancer will then provide insights into improving the development of cancer therapies that can leverage the synergistic action of DDR inhibitors and cytoskeleton-targeting agents. Full article

The canonical model of vertebrate sex chromosome evolution predicts a one-way trend toward degradation. However, most sex chromosomes in lower vertebrates are homomorphic. Recent progress in studies of sex determination has resulted in the discovery of more than 30 master sex determination (MSD) genes, most of which are from teleost fish. An analysis of MSD gene acquisition, recombination suppression, and sex chromosome-specific sequences revealed correlations in the modes of MSD gene acquisition and the evolution of sex chromosomes. Sex chromosomes remain homomorphic with MSD genes acquired by simple mutations, gene duplications, allelic variations, or neofunctionalization; in contrast, they become heteromorphic with MSD genes acquired by chromosomal inversion, fusion, and fission. There is no recombination suppression with sex chromosomes carrying MSD genes gained through simple mutations. In contrast, there is extensive recombination suppression with sex chromosomes carrying MSD genes gained through chromosome inversion. There is limited recombination suppression with sex chromosomes carrying MSD genes gained through transposition or translocation. We propose a cause–effect model that predicts sex chromosome evolution as a consequence of the acquisition modes of MSD genes, which explains the evolution of sex chromosomes in various vertebrates. A key factor determining the trend of sex chromosome evolution is whether non-homologous regions are created during the acquisition of MSD genes. Chromosome inversion creates inversely homologous but directly non-homologous sequences, which lead to recombination suppression but retain recombination potential. Over time, recurrent recombination in the inverted regions leads to the formation of strata and may cause the degradation of sex chromosomes. Depending on the nature of deletions in the inverted regions, sex chromosomes may evolve with dosage compensation, or the selective retention of haplo-insufficient genes may be used as an alternative strategy. Full article

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests that BRCA1 is an essential driver of all phases of the cell cycle, thereby maintaining orderly steps during cell cycle progression. Specifically, loss of BRCA1 activity causes the S-phase, G₂/M, spindle checkpoints, and centrosome duplication to be dysregulated, thereby blocking cell proliferation and inducing apoptosis. In vertebrates, loss of HR genes such as BRCA1 and/or BRCA2 is lethal, since HR is a prerequisite for genome integrity. Thus, cancer cells utilize alternative DNA repair pathways such as non-homologous end joining (NHEJ) to cope with the loss of BRCA1 function. In this review, we attempt to update and discuss how these novel components are crucial for regulating DNA damage repair (DDR) in BRCA1-deficient cancers. Full article

Lycopene is a natural carotenoid with antioxidation properties. The objective of the present study was to investigate the roles of glutamate and proline in lycopene biosynthesis in a newly isolated purple non-sulfur bacterium Cereibacter sphaeroides DT.1, under aerobic conditions. This strain contained a distinct CrtI₄ capable of converting phytoene to lycopene via four-step desaturation. In order to enhance lycopene production, a crtC knockout mutant was constructed via homologous recombination. Supplementation with glutamate or proline to fermentative medium significantly enhanced intracellular lycopene accumulation in wildtype strain by a respective 99.40 ± 0.54% and 101.70 ± 0.49% and in a ΔcrtC mutant strain by 38.13 ± 0.15% and 39.83 ± 0.27%, respectively. Differential transcriptomic and metabolomic analyses showed that these promoting effects were associated with downregulation of the expression of the acyclic carotenoid 1,2-hydratase gene, and increased accumulation of lycopene precursors such as pyruvate and acetyl-CoA. The fermentation conditions for lycopene production were optimized through shake flask experiments. Feasibility for lycopene production was confirmed in a fed-batch cultivation process and a high yield of 151.10 ± 0.13 mg/L was achieved. This ΔcrtC mutant strain exhibited advantages, such as relatively lower oxygen demand and no need for illumination, making it a potentially useful strain for lycopene production under aerobic conditions. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) is the most common type of cancer, with lung adenocarcinoma (LUAD) as the predominant subtype. Despite advancements in targeted therapies, many NSCLC patients still experience poor outcomes due to treatment resistance and disease progression. Genomic instability (GI), a hallmark of cancer, defined as the increased tendency of DNA mutations and alterations, is closely linked to cancer initiation, progression, and resistance to therapy. Emerging evidence suggests that long non-coding RNAs (lncRNAs)—molecules longer than 200 nucleotides that do not encode proteins but regulate gene expression—play critical roles in cancer biology and are associated with GI. However, the relationship between GI and lncRNA expression in LUAD remains poorly understood. Methods: In this study, we analyzed the transcript profiles of lncRNAs and mRNAs from LUAD samples in The Cancer Genome Atlas (TCGA) database and classified them based on their Homologous Recombination Deficiency (HRD) score. The HRD score is an unweighted sum of three independent DNA-based measures of genomic instability: loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions. We then performed a differential gene expression analysis to identify lncRNAs and mRNAs that were either upregulated or downregulated in samples with high HRD scores compared to those with low HRD scores. Following this, we conducted a correlation analysis to assess the significance of the association between HRD scores and the expression of both lncRNAs and mRNAs. Results: We identified 30 differentially expressed lncRNAs and 200 mRNAs associated with genomic instability. Using an RNA interactome database from sequencing experiments, we found evidence of interactions between GI-associated lncRNAs (GI-lncRNAs) and GI-associated mRNAs (GI-mRNAs). Further investigation showed that some GI-lncRNAs play regulatory and functional roles in LUAD and other diseases. We also found that GI-lncRNAs have potential as prognostic biomarkers, particularly when integrated with HRD stratification. The expression of specific GI-lncRNAs was associated with primary therapy response and immune infiltration in LUAD. Additionally, we identified existing drugs that could modulate GI-lncRNAs, offering potential therapeutic strategies to address GI in LUAD. Conclusions: Our findings suggest that GI-associated lncRNAs could serve as valuable biomarkers for LUAD prognosis and therapeutic response. Furthermore, modulating these lncRNAs presents potential treatment avenues to address genomic instability in LUAD. Full article