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Ropinirole Functions Through a Dopamine Receptor D2-Independent Mechanism to Ameliorate Amyotrophic Lateral Sclerosis Phenotypes in TARDBP-Mutant iPSC-Derived Motor Neurons.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by motor neuron (MN) degeneration. Ropinirole h … onal hyperexcitation, independently of DRD2. Further analyses revealed that ROPI corrected aberrant RNA splicing and restored the mRNA expression of mitochondrial proteins in a DRD2-independent manner. Our findings suggest that ROPI not only functions as a canonical DRD2 agonist but also has pleiotropic DRD2-independent effects, offering a novel avenue for tre …

IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms.

Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1α and IRE1β, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1α and IRE1β in IECs using mice using intestine-specific deletion of Ire1α or germline Ire1β deletion, and subsequently with double deleted Ire1α, Ire1β mice. At baseline, intestine-specific Ire1α deleted mice and mice with germline Ire1β deletion exhibited no morphologic changes in small intestine or colon, but double deleted Ire1α -/- Ire1β -/- mice developed progressive intestina

Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF).

AIMS: Heart failure with preserved ejection fraction (HFpEF) is prevalent, deadly, and difficult to treat. Risk factors such as obesity and hypertension contribute to cardiac inflammation, metabolic defects, and pathological remodelling that impair ventricular filling in diastole. Titin based stiffness is a main determinant of diastolic function and can be adjusted by the splicing regulator RNA binding motif protein 20 (RBM20). Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms, which reduce stiffness. However, dose finding and documentin

Erythroid-predominant myelodysplastic neoplasms exhibit a distinct genomic landscape with poor outcomes after venetoclax-based therapy.

Erythroid differentiation confers BCL-XL dependence and venetoclax resistance in acute myeloid leukemia (AML). However, whether myelodysplastic neoplasms (MDS) with erythroid predominance (EP), defined by ≥50% erythroid bone marrow elements, have distinct biology and drug sensitivities remains unknown. To study this, we evaluated an MDS patient cohort (n = 371) and showed that EP MDS (n = 67, 18%) are characterized by higher TP53 (multihit TP53: 36% vs 17%, p = 0.004), BCOR and WT1 and lower ASXL1 and SRSF2 mutation frequencies compared to non-EP (NEP) MDS (n = 304, 82%). TP53-mutant variant a

Proteome analysis of preserved formalin-fixed and paraffin-embedded specimens to explore the pathogenesis of infantile hypertrophic pyloric stenosis.

PURPOSE: This study aimed to explore the mechanisms underlying the development of infantile hypertrophic pyloric stenosis (IHPS) using forma … to the extracellular matrix were more prevalent in the IHPS group, whereas proteins associated with RNA splicing were less frequent. CONCLUSION: Proteomic analysis of FFPE samples may provide a new avenue for elucidating the pathophysiology of IHPS. Future collaborative studies should increase the sample size, allowing for a more detailed understanding of the …

PTBP2 promotes cell survival and autophagy in chronic myeloid leukemia by stabilizing BNIP3.

Polypyrimidine tract binding protein 2 (PTBP2) regulates alternative splicing in neuronal, muscle, and Sertoli cells. PTBP2 and its paralog, PTBP1, which plays a role in B-cell development, was found to be expressed aberrantly in myeloid leukemia. Genetic ablation of Ptbp2 in the cells resulted in decreased cellular proliferation and repopulating ability, decreased reactive oxygen species (ROS), and altered mitochondrial morphology. RNA immunoprecipitation followed by sequencing (RIP-seq) and functional assays confirmed that PTBP2 binds to Bcl-2 Interacting Protein 3 (Bnip3)-3'UTR and stabiliz

Pregnancy induces extensive changes of transcript usage in the goat brain.

Gestation induces strong anatomical, histological and transcriptomic changes in the pregnant female brain. Our study aimed to characterize the RNA transcripts expressed in the goat brain and their main structural, transcriptional, and functional features, while also exploring whether 2-mo (57 d) pregnancy affects transcript usage in the brain. Twelve brain tissue samples from three 2-mo pregnant and 4 nonpregnant Murciano-Granadina goats were sequenced. A total of 62,185 transcripts from 29,043 genes (averaging ∼2.14 transcripts per gene) were detected, and ∼60% of them were novel transcripts

The Emerging Role of METTL3 in Lung Diseases.

N6-methyladenosine (m6A) represents the most abundant and tightly controlled modification within eukaryotic mRNA, critically influencing RNA metabolism and function. The m6A methyltransferase Like-3 (METTL3), responsible for the complex's catalytic function, has emerged as a central epitranscriptomic regulator governing mRNA stability, alternative splicing, nuclear export, and the efficiency of mRNA translation. Converging research shows that METTL3 is involved in the pathogenesis of numerous disorders via m6A-dependent, post-transcriptional regulation of gene programs controlling cell growth,

Comparing the effects and mechanisms of exposure to polystyrene nanoplastics with different functional groups on the male reproductive system.

After aging in the environment, some nanoplastics will carry different charges and functional groups, thereby altering their toxicological e … on the differentially expressed proteins, and found they were mainly enriched in protein transport, RNA splicing and mTOR signaling. We confirmed that the PI3K-AKT-mTOR pathway is over activated, which may lead to reduction of spermatogonia stem cells by over differentiation. Strikingly, PS-NPs with functional group modifications are more toxic than those of u …

R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.

UNLABELLED: RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop…

The Liver-Protective Effects of the Essential Oil from Amomum villosum in Tilapia (Oreochromis niloticus): Antioxidant, Transcriptomic, and Metabolomic Modulations.

This study investigates the effects of the essential oil from Amomum villosum (EOA) on liver-protective effects in Nile tilapia (Oreochromis … The transcriptomic analysis revealed significant alterations in gene expression profiles related to RNA splicing, metabolism, and disease pathways. The identification of differential genes and disease databases identified key target genes associated with the primary component of EOA for its anti-hepatobiliary disease effects. Furthermore, a molecular docking a …

Split intein-mediated protein trans-splicing to express large dystrophins.

Gene replacement using adeno-associated virus (AAV) vectors is a promising therapeutic approach for many diseases1,2. However, this therapeutic modality is challenged by the packaging capacity of AAVs (approximately 4.7 kilobases)3, limiting its application for disorders involving large coding sequences, such as Duchenne muscular dystrophy, with a 14 kilobase messenger RNA. Here we developed a new method for expressing large dystrophins by utilizing the protein trans-splicing mechanism mediated by split inteins. We identified several split intein pairs that efficiently join two or three fragme

Trypanosoma cruzi infection induces DNA double-strand breaks and activates DNA damage response pathway in host epithelial cells.

Trypanosoma cruzi, the etiological agent of Chagas disease, invades many cell types affecting numerous host-signalling pathways. During the T. cruzi infection, we demonstrated modulations in the host RNA polymerase II activity with the downregulation of ribonucleoproteins affecting host transcription and splicing machinery. These alterations could be a result of the initial damage to the host DNA caused by the presence of the parasite, however, the mechanisms are not well understood. Herein, we examined whether infection by T. cruzi coincided with enhanced DNA damage in the host cell. We studi

Updated mutational spectrum and genotype-phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants.

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequen

Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex.

To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)+ RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3'-end processing defect

Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases.

During the aging of the global population, the prevalence of neurodegenerative diseases will be continuously growing. Although each disorder … bar muscular atrophy (SBMA). Underlying mechanisms include the regulation of gene transcription and RNA splicing, as well as their implication in various signaling pathways related to oxidative stress responses, apoptosis, neuroinflammation, vacuole degeneration, abnormal protein accumulation and neurotransmission. The targeting of PRMTs is a therapeutic appro …

AAGGG repeat expansions trigger RFC1-independent synaptic dysregulation in human CANVAS Neurons.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a late onset, recessively inherited neurodegenerative disorder caused by biallelic, non-reference pentameric AAGGG(CCCTT) repeat expansions within the second intron of replication factor complex subunit 1 (RFC1). To investigate how these repeats cause disease, we generated CANVAS patient induced pluripotent stem cell (iPSC) derived neurons (iNeurons) and utilized calcium imaging and transcriptomic analysis to define repeat-elicited gain-of-function and loss-of-function contributions to neuronal toxicity. AAGGG repe

Молекулярная основа для человеческой митохондриальной модификации tRNA m3C с помощью альтернативной разбрызгивания METTL8.

METTL8 недавно был определен как катализатор метилпереносазы 3-methylcytidine Биогенез на месте 32 (м3С32) митохондриальных tRNA. METTL8 также потенциально участвует в мRNA метилации и R-loop Biogenesis. Как METTL8 играет многообразную роль в разных камерах, и митохондриальное образование митохондриала tRNA m3C остается неясным. Здесь мы обнаружили, что альтернативное скрещивание mRNA вызвало несколько изоформ METTL8. One (изоформ)METTL8-Iso1) был направлен на митохондрию через N-терминальную предпоследнюю последовательность, в то время как другой one (В тыс.METTL8-Iso4) в основном локализован

Совпадение в аннотации оригинала
METTL8 has recently been identified as the methyltransferase catalyzing 3-methylcytidine biogenesis at position 32 (m3C32) of mitochondrial … nd catalyzes mitochondrial tRNA m3C formation remain unclear. Here, we discovered that alternative mRNA splicing generated several isoforms of METTL8. One isoform (METTL8-Iso1) was targeted to mitochondria via an N-terminal pre-sequence, while another one (METTL8-Iso4) mainly localized to the nucleolus. METTL8-Iso1-mediated m3C32 modification of human mitochon …

A High-Fat Diet Modifies Brain Neurotransmitter Profile and Hippocampal Proteome and Morphology in an IUGR Pig Model.

Intrauterine Growth Restriction (IUGR) hinders the correct growth of the fetus during pregnancy due to the lack of oxygen or nutrients. The … xidative phosphorylation and the extracellular matrix, whereas LBW animals presented differences in RNA splicing, anterograde and retrograde transport and the mTOR pathway.

Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice.

Recurrent mutations in RNA splicing proteins and epigenetic regulators contribute to the development of myelodysplastic syndrome (MDS) and related myeloid neoplasms. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations occur in ~50% of patients and TET2 mutations in ~60%. Clonal analysis indicates that either mutation can arise as the founder lesion. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly in hematopoietic stem cells. At 20-24 weeks post mutation induction, we observed subtle differences in the Srsf2…