Biology Direct最新文献

Background: The recombination landscape and subsequent natural selection have vast consequences forevolution and speciation. However, most of the crossover and recombination hotspots are yet to be discovered. We previously reported the relevance of C and G trinucleotide two-repeat units (CG-TTUs) in crossovers and recombination.

Methods: On a genome-wide scale, here we mapped all combinations of A and T trinucleotide two-repeat units (AT-TTUs) in human, consisting of AATAAT, ATAATA, ATTATT, TTATTA, TATTAT, and TAATAA. We also compared a number of the colonies formed by the AT-TTUs (distance between consecutive AT-TTUs < 500 bp) in several other primates and mouse.

Results: We found that the majority of the AT-TTUs (> 96%) resided in approximately 1.4 million colonies, spread throughout the human genome. In comparison to the CG-TTU colonies, the AT-TTU colonies were significantly more abundant and larger in size. Pure units and overlapping units of the pure units were readily detectable in the same colonies, signifying that the units were the sites of unequal crossover. We discovered dynamic sharedness of several of the colonies across the primate species studied, which mainly reached maximum complexity and size in human.

Conclusions: We report novel crossover and recombination hotspots of the finest molecular resolution, massively spread and shared across the genomes of human and several other primates. With respect to crossovers and recombination, these genomes are far more dynamic than previously envisioned.

Background: Cancer-associated fibroblasts (CAFs) have been reported that can affect cancer cell proliferation, metastasis, ferroptosis, and immune escape. METTL3-mediated N6-methyladenine (m6A) modification is involved in the tumorigenesis of colorectal cancer (CRC). Herein, we investigated whether METTL3-dependent m6A in CAFs-derived exosomes (exo) affected CRC progression.

Methods: qRT-PCR and western blotting analyses detected levels of mRNAs and proteins. Cell proliferation and metastasis were evaluated using MTT, colony formation, transwell, and wound healing assays, respectively. Cell ferroptosis was assessed by detecting cell viability and the levels of Fe+, reactive oxygen species, and glutathione after erastin treatment. Exosomes were isolated from CAFs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation assay and the interaction between METTL3 and ACSL3 (acyl-CoA synthetase 3) was verified using dual-luciferase reporter assay. Animal models were established for in vivo analysis.

Results: CAFs promoted CRC cell proliferation and metastasis, and suppressed cell ferroptosis. METTL3 was enriched in CAFs and was packaged into exosomes. The m6A modification and METTL3 expression were increased in CRC samples. Knockdown of METTL3 in CAFs-exo suppressed CRC cell proliferation and metastasis, and induced cell ferroptosis. Mechanistically, METTL3 induced ACSL3 m6A modification and stabilized its expression. The anticancer effects mediated by METTL3-silenced CAFs-exo could be rescued by ACSL3 overexpression. Moreover, in vivo assay also showed that CAFs-exo with decreased METTL3 could hinder CRC growth and metastasis in mice models.

Conclusion: CAFs promoted the proliferation and metastasis, and restrained the ferroptosis in CRC by exosomal METTL3-elicited ACSL3 m6A modification.

The cell and molecular bases of arbuscular mycorrhizal (AM) symbiosis, a crucial plant-fungal interaction for nutrient acquisition, have been extensively investigated by coupling traditional RNA sequencing techniques of roots sampled in bulk, with methods to capture subsets of cells such as laser microdissection. These approaches have revealed central regulators of this complex relationship, yet the requisite level of detail to effectively untangle the intricacies of temporal and spatial development remains elusive.The recent adoption of single-cell RNA sequencing (scRNA-seq) techniques in plant research is revolutionizing our ability to dissect the intricate transcriptional profiles of plant-microbe interactions, offering unparalleled insights into the diversity and dynamics of individual cells during symbiosis. The isolation of plant cells is particularly challenging due to the presence of cell walls, leading plant researchers to widely adopt nuclei isolation methods. Despite the increased resolution that single-cell analyses offer, it also comes at the cost of spatial perspective, hence, it is necessary the integration of these approaches with spatial transcriptomics to obtain a comprehensive overview.To date, few single-cell studies on plant-microbe interactions have been published, most of which provide high-resolution cell atlases that will become crucial for fully deciphering symbiotic interactions and addressing future questions. In AM symbiosis research, key processes such as the mutual recognition of partners during arbuscule development within cortical cells, or arbuscule senescence and degeneration, remain poorly understood, and these advancements are expected to shed light on these processes and contribute to a deeper understanding of this plant-fungal interaction.

Breast cancer is the most common cause of death from cancer in women. Here, we present the case of a 43-year-old woman, who received a diagnosis of claudin-low luminal B breast cancer. The lesion revealed to be a poorly differentiated high-grade infiltrating ductal carcinoma, which was strongly estrogen receptor (ER)/progesterone receptor (PR) positive and human epidermal growth factor receptor (HER2) negative. Her tumor underwent in-depth chromosomal, mutational and gene expression analyses. We found a pathogenic protein truncating mutation in the TP53 gene, which is predicted to disrupt its transcriptional activity. The patient also harbors germline mutations in some mismatch repair (MMR) genes, and her tumor displays the presence of immune infiltrates, high tumor mutational burden (TMB) status and the apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APOBEC3) associated signatures, which, overall, are predictive for the use of immunotherapy. Here, we propose promising prognostic indicators as well as potential therapeutic strategies based on the molecular characterization of the tumor.

Background: Disulfidptosis is a newly identified mechanism of cell death triggered by disulfide stress. Thus, gaining a comprehensive understanding of the disulfidptosis signature present in gastric cancer (GC) could greatly enhance the development of personalized treatment strategies for this disease.

Methods: We employed consensus clustering to identify various subtypes of disulfidptosis and examined the distinct tumor microenvironment (TME) associated with each subtype. The Disulfidptosis (Dis) score was used to quantify the subtype of disulfidptosis in each patient. Subsequently, we assessed the predictive value of Dis score in terms of GC prognosis and immune efficacy. Finally, we conducted in vitro experiments to explore the impact of Collagen X (COL10A1) on the progression of GC.

Results: Two disulfidptosis-associated molecular subtypes (Discluster A and B) were identified, each with distinct prognosis, tumor microenvironment (TME), immune cell infiltration, and biological pathways. Discluster A, characterized by high expression of disulfidptosis genes, exhibited a high immune score but poor prognosis. Furthermore, the Dis score proved useful in predicting the prognosis and immune response in GC patients. Those in the low Dis score group showed better prognosis and increased sensitivity to immunotherapy. Finally, our experimental findings validated that downregulation of COL10A1 expression attenuates the proliferation and migration capabilities of GC cells while promoting apoptosis.

Conclusions: This study demonstrates that the disulfidptosis signature can assist in risk stratification and personalized treatment for patients with GC. The results offer valuable theoretical support for anti-tumor strategies.

It was a Lucky Strike to be working with Eraldo Antonini on hemoglobin and myoglobin when Jeffries Wyman arrived in Rome in 1961. I found myself connected with a number of creative scientists when the concept of allosteric control was conceived and gifted to the life science community. In retrospect, this was a demonstration of the skill and imagination of a few intelligent scientists that I happened to be close to. Those talents demonstrated the power of creativity as pictured by the motto "Mens agitat molem"; a celebration of humanism and intellect that paved the way to novel discoveries in the field of structure function relationships in proteins. I have presented hereby some of the events and the people as emerged from my memory over three decades of exciting scientific life.

Epidermal stem cells (EPSCs) are essential for maintaining skin homeostasis and ensuring a proper wound healing. During in vitro cultivations, EPSCs give rise to transient amplifying progenitors and differentiated cells, finally forming a stratified epithelium that can be grafted onto patients. Epithelial grafts have been used in clinics to cure burned patients or patients affected by genetic diseases. The long-term success of these advanced therapies relies on the presence of a correct amount of EPSCs that guarantees long-term epithelial regeneration. For this reason, a deeper understanding of self-renewal and differentiation is fundamental to fostering their clinical applications.The coordination between energetic metabolism (e.g., glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and amino acid synthesis pathways), molecular signalling pathways (e.g., p63, YAP, FOXM1, AMPK/mTOR), and epigenetic modifications controls fundamental biological processes as proliferation, self-renewal, and differentiation. This review explores how these signalling and metabolic pathways are interconnected in the epithelial cells, highlighting the distinct metabolic demands and regulatory mechanisms involved in skin physiology.

Background: High glucose levels are key factors and key contributors to several cardiovascular diseases associated with cardiomyocyte injury. Ferroptosis, which was identified in recent years, is a mode of cell death caused by the iron-mediated accumulation of lipid peroxides. Neuregulin-4 (Nrg4) is an adipokine that has protective effects against metabolic disorders and insulin resistance. Our previous study revealed that Nrg4 has a protective effect against diabetic myocardial injury, and the aim of this study was to investigate whether Nrg4 could attenuate the occurrence of high glucose-induced ferroptosis in cardiomyocytes.

Methods: We constructed an in vivo diabetic myocardial injury model in which primary cardiomyocytes were cultured in vitro and treated with Nrg4. Changes in ferroptosis-related protein levels and ferroptosis-related indices in cardiomyocytes were observed. In addition, we performed back-validation and explored signalling pathways that regulate ferroptosis in primary cardiomyocytes.

Results: Nrg4 attenuated cardiomyocyte ferroptosis both in vivo and in vitro. Additionally, the AMPK/NRF2 signalling pathway was activated during this process, and when the AMPK/NRF2 pathway was inhibited, the beneficial effects of Nrg4 were attenuated.

Conclusion: Nrg4 antagonizes high glucose-induced ferroptosis in cardiomyocytes via the AMPK/NRF2 signalling pathway.

Myofibroblast buildup and prostatic fibrosis play a crucial role in the development of benign prostatic hyperplasia (BPH). Treatments specifically targeting myofibroblasts could be a promising approach for treating BPH. Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, holds the potential to intervene in this biological process. This study employs prostatic stromal fibroblasts to induce myofibroblast differentiation through TGFβ1 stimulation. As a result, tadalafil significantly inhibited prostatic stromal fibroblast proliferation and fibrosis process, compared to the control group. Furthermore, our transcriptome sequencing results revealed that tadalafil inhibited FGF9 secretion and simultaneously improved miR-3126-3p expression via TGFβ1 suppression. Overall, TGFβ1 can trigger pro-fibrotic signaling through miR-3126-3p in the prostatic stroma, and the use of tadalafil can inhibit this process.

Retrotransposition is one of the main factors responsible for gene duplication and thus genome evolution. However, the sequences that undergo this process are not only an excellent source of biological diversity, but in certain cases also pose a threat to the integrity of the DNA. One of the mechanisms that protects against the incorporation of mobile elements is the HUSH complex, which is responsible for silencing long, intronless, transcriptionally active transposed sequences that are rich in adenine on the sense strand. In this study, broad sets of human and porcine retrocopies were analysed with respect to the above factors, taking into account evolution of these molecules. Analysis of expression pattern, genomic structure, transcript length, and nucleotide substitution frequency showed the strong relationship between the expression level and exon length as well as the protective nature of introns. The results of the studies also showed that there is no direct correlation between the expression level and adenine content. However, protein-coding retrocopies, which have a lower adenine content, have a significantly higher expression level than the adenine-rich non-coding but expressed retrocopies. Therefore, although the mechanism of HUSH silencing may be an important part of the regulation of retrocopy expression, it is one component of a more complex molecular network that remains to be elucidated.