BNP facilitates NMB-encoded histaminergic itch via NPRC-NMBR crosstalk

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded b

Caspase polymorphisms and prognosis of hepatocellular carcinoma

The aim of our study was to determine the impact of genetic polymorphisms in the caspase (CASP) genes on prognosis of hepatocellular carcinoma (HCC). We genotyped 7 potentially functional polymorphisms in CASP3, CASP7, CASP8, CASP9, CASP10 genes in 362 HCC patients of receiving surgical resection of HCC tumor. The associations of genotype and haplotype with overall survival (OS) and disease free survival (DFS) were analyzed by using the Cox proportional hazards model. We found that the CASP9 rs4645981 C allele was significantly associated with positive effect on DFS (P = 0.011 and 0.016 for CT+CC vs. TT in univariate and multivariate analysis, respectively), CT genotype was associated with a better OS of HCC than the TT genotype both in univariate and multivariate analysis (P = 0.048 and 0.041, respectively). Moreover, the CASP3 rs2705897 GT genotype showed marginally significant association with decreased OS and DFS, compared with the GG genotype. One haplotype TT/TG in CASP3 (constructed by rs12108497 T>C and rs2705897 T>G) was significantly associated with decreased OS and DFS, compared to the common haplotype TT/TT both in univariate analysis (P = 0.021 and 0.026, respectively) and multivariate analysis (P = 0.025 and 0.030, respectively). The haplotype GT/GT in CASP9 (constructed by rs4645978 A>G and rs4645981 C>T) was significantly associated with decreased DFS both in univariate and multivariate analysis (P = 0.012 and 0.010, respectively). In conclusion, the CASP9 rs4645981 polymorphism, CASP3 and CASP9 haplotypes may be useful prognosis markers for HCC patients with surgical resection of tumor

Mapping and functional characterization of structural variation in 1060 pig genomes

BACKGROUND: Structural variations (SVs) have significant impacts on complex phenotypes by rearranging large amounts of DNA sequence.RESULTS: We present a comprehensive SV catalog based on the whole-genome sequence of 1060 pigs (Sus scrofa) representing 101 breeds, covering 9.6% of the pig genome. This catalog includes 42,487 deletions, 37,913 mobile element insertions, 3308 duplications, 1664 inversions, and 45,184 break ends. Estimates of breed ancestry and hybridization using genotyped SVs align well with those from single nucleotide polymorphisms. Geographically stratified deletions are observed, along with known duplications of the KIT gene, responsible for white coat color in European pigs. Additionally, we identify a recent SINE element insertion in MYO5A transcripts of European pigs, potentially influencing alternative splicing patterns and coat color alterations. Furthermore, a Yorkshire-specific copy number gain within ABCG2 is found, impacting chromatin interactions and gene expression across multiple tissues over a stretch of genomic region of ~200 kb. Preliminary investigations into SV's impact on gene expression and traits using the Pig Genotype-Tissue Expression (PigGTEx) data reveal SV associations with regulatory variants and gene-trait pairs. For instance, a 51-bp deletion is linked to the lead eQTL of the lipid metabolism regulating gene FADS3, whose expression in embryo may affect loin muscle area, as revealed by our transcriptome-wide association studies.CONCLUSIONS: This SV catalog serves as a valuable resource for studying diversity, evolutionary history, and functional shaping of the pig genome by processes like domestication, trait-based breeding, and adaptive evolution.</p

Differential Regulation of H3K9/H3K14 Acetylation by Small Molecules Drives Neuron-Fate-Induction of Glioma Cell

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells

Network disruption based on multi-modal EEG-MRI in α-synucleinopathies

BackgroundBrain network dysfunction has been characterized by resting-state electroencephalography (EEG) and magnetic resonance imaging (MRI) in the prodromal stage. This study aimed to identify multi-modal electrophysiological and neuroimaging biomarkers for differential diagnosis in synucleinopathies and phenoconversion in isolated rapid eye movement sleep behavior disorder (iRBD).MethodsWe enrolled 35 patients with multiple system atrophy (MSA), 32 with Parkinson's disease (PD), 30 with iRBD and 30 matched healthy controls (HC). Power spectral density (PSD) was calculated in different frequency bands. EEG functional connectivity (FC) was calculated using the weighted Phase Lag Index (wPLI) after source localization. Significant network disruptions were further confirmed by MRI FC analysis.ResultsQuantitative EEG analysis demonstrated that delta and theta power spectral density significantly differed among MSA, PD and HC. The increased PSD was correlated with cognitive decline and olfactory dysfunction in PD. Band-specific FC profiles were observed in theta, alpha, and gamma bands. The hypoconnected alpha network significantly correlated with motor dysfunction, while the gamma FC distinguished PD from MSA. By integrating EEG and MRI network analyses, we found that FC between the olfactory cortex and dorsolateral prefrontal cortex was significantly different between MSA and PD. A multimodal discriminative model for MSA and PD, integrating spectral and FC attributes of EEG and MRI, yielded an area under the receiver operating characteristic curve of 0.900. Simultaneously, we found the FC abnormalities were more prominent than spectral features in iRBD indicating prodromal dysfunction. The decreased FC between the angular gyrus and striatum was identified in α-synucleinopathies. This hypoconnectivity was associated with dopaminergic degeneration in iRBD examined by dopamine transporter imaging.DiscussionOur study demonstrated EEG spectral and functional profiles in prodromal and clinical-defined synucleinopathies. Multimodal EEG and MRI provided a novel approach to discriminate MSA and PD, and monitor neurodegenerative progression in the preclinical phase

A compendium of genetic regulatory effects across pig tissues

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.</p