Communications Biology最新文献

The pig is an important animal model increasingly used for biomedical research, particularly in transplantation strategies involving xenotransplantation or the development of human organs in pig for exotransplantation. Pigs, however, are less characterized than other animal models. In this study, we produced wildtype (WT) pig embryos via somatic cell nuclear transfer (SCNT) technology and compared them to skeletal muscle null embryos (lacking MYF5/MYOD/MYF6) at embryonic day 41, 62, and 90, critical stages of porcine myogenesis. Magnetic resonance imaging (MRI) and histological analyses revealed progressive development of skeletal muscle in WT embryos but not in null embryos whereas development of viscera progressed equally in both groups. Molecular analyses highlighted dynamic changes in myogenic gene expression and myofiber formation, demonstrating an organized progression of myogenesis in WT embryos. Morphologically, the null embryos exhibited abnormalities, including marked edema and underdeveloped limbs. MRI revealed severe skeletal abnormalities, including the absence of ribs, sternum, and associated vertebral malformations. In addition, histological analysis confirmed the complete lack of myofiber formation. Immunohistochemical analysis revealed the absence of myogenic stem cells and muscle differentiation, and RNA sequencing demonstrated that the skeletal muscle development process was entirely disrupted in null embryos. Additionally, analysis of neuromuscular junctions (NMJs) in the null embryos revealed that functional NMJ formation was absent, consistent with the lack of skeletal muscle formation. Importantly, these defects culminated in embryonic lethality after day 62 in the null embryos. We determined that the myogenic regulatory gene cascade is crucial for porcine embryo development and viability. The deletion of skeletal muscle is essential for the creating a vacant niche to allow for complementation of null porcine embryos with human induced pluripotent stem cells. Characterization of this skeletal muscle null pig model provide an important platform for engineering humanized muscle in gene-edited pigs.

The regulatory mechanism between N6-methyladenosine (m⁶A) RNA methylation and histone modification in endometrial receptivity remains poorly understood. In this study, we depict that RIF induced m⁶A and Mettl3 level restrain, affecting H3K27me3 modification and chromatin accessibility. We show that Mettl3 deletion in the endometrium alters mRNA m⁶A methylation via Eed interaction. This reduces m⁶A recognized by Ythdc1, which recruits Eed to suppress H3K27me3 modification co-transcriptionally. The reduction of H3K27me3 disrupts chromatin accessibility and impairs transcription of genes critical for endometrial receptivity. Collectively, these results shed light on a Mettl3-Eed-m⁶A-Ythdc1 axis that links m⁶A and histone modification in regulating local chromatin state and gene expression, advancing our understanding of the epigenetic crosstalk between RNA and DNA modification in infertility disease.

Hypoxic postconditioning (HPC) was reported to stabilize nuclear β-catenin by inhibiting lysine (K)-specific demethylase 2 A (KDM2A) in hippocampal CA1 against transient global cerebral ischemia (tGCI). Herein we investigate how HPC inhibits the K48-linked poly-ubiquitination (K48-Ub)-related degradation of nuclear β-catenin in CA1 after tGCI. We confirmed that SCF^KDM2A complex targets nuclear β-catenin for degradation via ubiquitin proteasome pathway in vitro. HPC reduced SCF^KDM2A complex and the K48-Ub of β-catenin, and increased ubiquitin-specific peptidase 22 (USP22) in nucleus after tGCI. Furthermore, KDM2A knockdown decreased the K48-Ub of nuclear β-catenin and nuclear β-catenin-SCF^KDM2A complex interaction after tGCI. Moreover, β-catenin knockdown suppressed nuclear survivin expression and attenuated neuroprotection induced by HPC. In contrast, the overexpression of USP22 promoted nuclear β-catenin deubiquitination and enhanced the neuroprotective effects offered by HPC. Taken together, this study supports that HPC downregulated the K48-Ub of nuclear β-catenin through suppressing SCF^KDM2A and increasing USP22, thereby inducing cerebral ischemic tolerance.

The environmental pollutant Benzo[a]pyrene (BaP) is commonly found in the environment, with microplastics (MPs) acting as the primary carriers of BaP into living organisms, increasing its availability in the body. However, the specific pathways and mechanisms through which MPs carrying pollutants cause kidney damage are not fully understood. This study aimed to investigate the routes and mechanisms of kidney injury in mice to low concentrations of both MPs and BaP. The combination of polystyrene (PS) and BaP disrupted lipid metabolism in the kidneys, leading to a form of cell death known as ferroptosis. However, this effect was not observed in HK-2 cells in vitro, indicating a cell-specific response. Interestingly, in HIEC-6 cells, both PS and BaP directly induced ferroptosis. These findings confirm that exposure to both PS and BaP can disrupt metabolic homeostasis in the kidneys, contributing to kidney dysfunction and cell death.

Understanding the environmental and microbial processes involved in DNA degradation from archaeological remains is a fundamental part of managing bone specimens. We investigated the state of DNA preservation in 33 archaeozoological caribou (Rangifer tarandus) ribs excavated from the same excavation trench at a former Inuit hunting camp in West Greenland, separated by 43 years: 1978 and 2021. Our findings show that DNA is better preserved in the most recently excavated samples, indicating a detrimental effect of museum storage on DNA integrity. Additionally, our data reveals a diverse microbiome in these bones, encoding genes relevant for bone degradation, such as enzymatic families relating to collagenases, peptidases and glycosidases. Microbes associated with bone degradation were present in both new and historical samples, with museum-stored bones showing significantly more DNA damage. Overall, our research sheds light on the nuanced dynamics governing the preservation of genomic material in archaeological contexts, underscoring the vital importance of careful considerations in museum curation practices for the sustainable conservation of invaluable skeletal records in museum repositories and in situ.

ER/PR+HER2- breast tumours are the most predominant subtype of breast cancer worldwide, including India. Unlike TNBCs, these tumours can be treated with anti-estrogens or aromatase inhibitors. Despite the success of endocrine therapy, a fraction of patients with ER/PR+ breast tumours do not respond to hormone-receptor-specific treatment and encounter disease recurrence contributing to their poor survival. The genomic underpinnings of therapy resistance in ER/PR+HER2- breast tumours are incompletely understood. We have performed whole genome sequencing (WGS) from tumour and normal tissue samples from endocrine-therapy resistant ER/PR+HER2- breast cancer patients who have relapsed on endocrine therapy and have conducted a comparative analysis of WGS data generated from tissues of endocrine therapy sensitive patients who remained free of disease during a minimum 5-year follow-up. Our analysis shows (a) a three-gene (PIK3CA-ESR1-TP53) resistance signature, and (b) impaired DNA double-strand break repair and homologous recombination pathways, were significantly associated with endocrine-therapy resistance and disease recurrence in ER/PR+HER2- tumours. Genome instability, contributing to high burden of copy-number, structural alterations and telomere-shortening identified as major markers of endocrine treatment resistance. Early prediction of endocrine-therapy resistance from the genomic landscape of breast tumours will aid therapeutics. Our finding also opens up the possibility of repurposing PARP inhibitors in treating endocrine therapy-resistant breast cancer patients.

Quantifying emesis in Suncus murinus (S. murinus) has traditionally relied on direct observation or reviewing recorded behaviour, which are laborious, time-consuming processes that are susceptible to operator error. With rapid advancements in deep learning, automated animal behaviour quantification tools with high accuracy have emerged. In this study, we pioneere the use of both three-dimensional convolutional neural networks and self-attention mechanisms to develop the Automatic Emesis Detection (AED) tool for the quantification of emesis in S. murinus, achieving an overall accuracy of 98.92%. Specifically, we use motion-induced emesis videos as training datasets, with validation results demonstrating an accuracy of 99.42% for motion-induced emesis. In our model generalisation and application studies, we assess the AED tool using various emetics, including resiniferatoxin, nicotine, copper sulphate, naloxone, U46619, cyclophosphamide, exendin-4, and cisplatin. The prediction accuracies for these emetics are 97.10%, 100%, 100%, 97.10%, 98.97%, 96.93%, 98.91%, and 98.41%, respectively. In conclusion, employing deep learning-based automatic analysis improves efficiency and accuracy and mitigates human bias and errors. Our study provides valuable insights into the development of deep learning neural network models aimed at automating the analysis of various behaviours in S. murinus, with potential applications in preclinical research and drug development.

Binding of hexokinase HKI to mitochondrial voltage-dependent anion channels (VDACs) has far-reaching physiological implications. However, the structural basis of this interaction is unclear. Combining computer simulations with experiments in cells, we here show that complex assembly relies on intimate contacts between the N-terminal α-helix of HKI and a charged membrane-buried glutamate on the outer wall of VDAC1 and VDAC2. Protonation of this residue blocks complex formation in silico while acidification of the cytosol causes a reversable release of HKI from mitochondria. Membrane insertion of HKI occurs adjacent to the bilayer-facing glutamate where a pair of polar channel residues mediates a marked thinning of the cytosolic leaflet. Disrupting the membrane thinning capacity of VDAC1 dramatically impairs its ability to bind HKI in silico and in cells. Our data reveal key topological and mechanistic insights into HKI-VDAC complex assembly that may benefit the development of therapeutics to counter pathogenic imbalances in this process.

Fatty acid composition (FA) is an important indicator of meat quality in beef cattle. We investigated potential functional candidate genes for FA in beef cattle by integrating genomic and transcriptomic dataset through multiple strategies. In this study, we observed 65 SNPs overlapping with five candidate genes (CCDC57, FASN, HDAC11, ALG14, and ZMAT4) using two steps association based on the imputed sequencing variants. Using multiple traits GWAS, we further identified three significant SNPs located in the upstream of FASN and one SNP (chr19:50779529) was embedded in FASN. Of those, two SNPs were further identified as the cis-eQTL based on transcriptomic analysis of muscle tissues. Moreover, the knockdown of FASN yielded a significant reduction in intracellular triglyceride content in preadipocytes and impeded lipid droplet accumulation in adipocytes. RNA-seq analysis of preadipocytes with FASN interference revealed that the differentially expressed genes were enriched in cell differentiation and lipid metabolic pathway. Our study underscored the indispensable role of FASN in orchestrating adipocyte differentiation, and fatty acid metabolism. The integrative analysis with multiple strategies may contribute to the understanding of the genetic architecture of FA in farm animals.

The opioid receptor family, particularly the µ opioid receptor, are the main drug targets in the management of severe pain. However, their pain-relieving effects are often accompanied by severe adverse effects, underlining the necessity for extensive research on this receptor family. Opioids, the agonists targeting these receptors, differ in their chemical structure and also in their mode of action in different aspects of signaling. Here we introduce novel tools that facilitate the analysis of this receptor family, by the development of FRET- and BRET-based receptor conformation sensors. With these sensors we were able to characterize especially the µ opioid receptor in more detail and reveal a strongly agonist-dependent activation kinetics for this receptor. Moreover, our sensors offer an assay independent from other signaling pathways, thereby minimizing the potential for interfering influences or biases within the system.