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Molecular cloning and functional characterization of two forms of Pax8 in the rainbow trout, Oncorhynchus mykiss.

We have identified two distinct Pax8 (a and b) mRNAs from the thyroid gland of the rainbow trout (Oncorhynchus mykiss), which seemed to be generated by alternative splicing. Both Pax8a and Pax8b proteins were predicted to possess the paired domain, octapeptide, and partial homeodomain, while Pax8b lacked the carboxy-terminal portion due to an insertion in the coding region of the mRNA. RT-PCR analysis showed each of Pax8a and Pax8b mRNAs to be abundantly expressed in the thyroid and kidney. In situ hybridization histochemistry further detected the expression of Pax8 mRNA in the epithelial cell

Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis.

Sympathetic neuronal death induced by nerve growth factor (NGF) deprivation requires the macromolecular synthesis-dependent translocation of BAX from the cytosol to mitochondria and its subsequent integration into the mitochondrial outer membrane, followed by BAX-mediated cytochrome c (cyt c) release. The gene products triggering this process remain unknown. Here, we report that BIM, a member of the BH3-only proapoptotic subfamily of the BCL-2 protein family, is one such molecule. NGF withdrawal induced expression of BIM(EL), an integral mitochondrial membrane protein that functions upstream o

Long QT and Brugada syndrome gene mutations in New Zealand.

BACKGROUND: Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service. OBJECTIVE: This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand. METHODS: Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, K

Axonal defects in mouse models of motoneuron disease.

Human motoneuron disease is characterized by loss of motor endplates, axonal degeneration, and cell death of motoneurons. The identification of the underlying gene defects for familial ALS, spinal muscular atrophy (SMA), and spinal muscular atrophy with respiratory distress (SMARD) has pointed to distinct pathophysiological mechanisms that are responsible for the various forms of the disease. Accumulating evidence from mouse models suggests that enhanced vulnerability and sensitivity to proapoptotic stimuli is only responsible for some but not all forms of motoneuron disease. Mechanisms that m

FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells.

In this study, we describe human FDF03, a novel member of the Ig superfamily expressed as a monomeric 44-kDa transmembrane glycoprotein and containing a single extracellular V-set Ig-like domain. Two potential secreted isoforms were also identified. The gene encoding FDF03 mapped to chromosome 7q22. FDF03 was mostly detected in hemopoietic tissues and was expressed by monocytes, macrophages, and granulocytes, but not by lymphocytes (B, T, and NK cells), indicating an expression restricted to cells of the myelomonocytic lineage. FDF03 was also strongly expressed by monocyte-derived dendritic ce

Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma.

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A Rare and Fatal Case of Hemophagocytic Lymphohistiocytosis Associated with Sarcoidosis.

BACKGROUND Sarcoidosis is a systemic inflammatory disorder characterized by a classic pathologic feature of non-caseating granulomas involving any organ system. Hemophagocytic lymphohistiocytosis (HLH) is a catastrophic cytokine surge characterized by dysregulation of the macrophage response, which can be rapidly fatal. Recognition of HLH has been increasing over the past decade. HLH can present with features of sepsis that can make the diagnosis challenging and requires high clinical suspicion. CASE REPORT We report a case of a 48-year-old African American male with a past medical history of

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers.

Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical cancer. This aberra

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… occurred at the intron–exon junctions, resulting in RNA splicing defects. 21 , 22 The actual percentage is most likely much higher as defined enhancer and repressor sequences were not analyzed. … Oncogenes and RNA splicing of human tumor viruses. Emerg Microb Infect. 2014;3(9):e63. doi: 10.1038/emi.2014.62. 105. Wieland U, Kreuter A. Merkel cell polyomavirus infection and Merkel cell carcinoma in HIV-positive individuals. …

Изучение роли микроРНК и ассоциированных протеинов в многоразовом склерозе.

ВВЕДЕНИЕ: Множественный склероз (MS) представляет собой хроническое аутоиммунное заболевание, затрагивающее центральную нервную систему (КНС). Диагностика и последующая деятельность в области НР сопряжены с трудностями из-за его сложного патогенеза и отсутствия конкретных биомаркеров. Целью этого исследования является внедрение соответствующих микроРНК (миРНК) и связанных с ними белков с MS. МЕТОДЫ: СВОДНЫЕ ДАННЫЕ МИРНА 4 периферийные профили крови пациентов, которые вновь излучают кровоизлияние, и 8 Из базы данных ГЭП были взяты данные о здоровых видах контроля. Их родственные белки анализиро

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… These proteins involve various cellular processes relevant to MS pathogenesis, such as RNA splicing, transcription, inflammation, and apoptosis. Therefore, we propose a new biomarker panel consisting of PTBP1, STAT3, and TLR4, as well as SNRNP70, YBX1, PTB1, and PI3K as candidate drug targets. …

Lost in transcription: molecular mechanisms that control HIV latency.

Highly active antiretroviral therapy (HAART) has limited the replication and spread of the human immunodeficiency virus (HIV). However, despite treatment, HIV infection persists in latently infected reservoirs, and once therapy is interrupted, viral replication rebounds quickly. Extensive efforts are being directed at eliminating these cell reservoirs. This feat can be achieved by reactivating latent HIV while administering drugs that prevent new rounds of infection and allow the immune system to clear the virus. However, current approaches to HIV eradication have not been effective. Moreover,

Circular RNA as a Novel Biomarker for Diagnosis and Prognosis and Potential Therapeutic Targets in Multiple Myeloma.

Circular RNAs (circRNAs) are a novel type of covalently closed RNAs involved in several physiological and pathological processes. They display tissue-specific expression and are constant, abundant, and highly conserved, making them perfect markers for diagnosis and prognosis. Several studies have proposed that circRNAs are also differentially produced in malignancies where they have oncogenic effects. Furthermore, circRNAs affecting microRNAs modify the expression profile of several transcription factors which play essential roles in tumors. CircRNAs within the hematopoietic compartment were i

PRMT inhibitor promotes SMN2 exon 7 inclusion and synergizes with nusinersen to rescue SMA mice.

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long-lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small-molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identifie

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… N Engl J Med 377: 1723–1732 Fong JY, Pignata L, Goy PA, Kawabata KC, Lee SCW, Koh CM, Musiani D, Massignani E, Kotini AG, Penson A et al (2019) Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. …

Role of circular RNAs in cancer therapy resistance.

Over the past decade, circular RNAs (circRNAs) have gained recognition as a novel class of genetic molecules, many of which are implicated in cancer pathogenesis via different mechanisms, including drug resistance, immune escape, and radio-resistance. ExosomalcircRNAs, in particular, facilitatecommunication between tumour cells and micro-environmental cells, including immune cells, fibroblasts, and other components. Notably, micro-environmental cells can reportedly influence tumour progression and treatment resistance by releasing exosomalcircRNAs. circRNAs often exhibit tissue- and cancer-spe

Reciprocal regulation between m6 A modifications and non-coding RNAs: emerging roles in cancer therapeutic resistance.

In recent years, the interplay between N6-methyladenosine (m6A) modifications and non-coding RNAs (ncRNAs) has emerged as a pivotal research area, owing to their crucial involvement in the pathophysiological mechanisms underlying various diseases. A significant hurdle in cancer therapy is therapeutic resistance, which frequently contributes to adverse patient outcomes. Recent investigations have underscored the vital role that interactions between m6A modifications and ncRNAs play in mediating cancer therapeutic resistance via the MAPK, PI3K/Akt/mTOR, Wnt/β-catenin, HIPPO, and NF-κB pathways.

BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting.

The BCL-2 family of proteins plays a central role in the regulation of apoptosis, with BCL-2 and BCL-xL representing two of its most prominent antiapoptotic members. This review explores the molecular regulation of BCL-2 and BCL-xL genes, emphasizing the structural domains that define the functions of the broader BCL-2 family. Beyond their canonical roles in preventing mitochondrial outer membrane permeabilization, both proteins contribute significantly to cancer development. Their overexpression enhances invasiveness and tumor progression, supports angiogenesis, and critically modulates cellu

Next-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification.

Next-generation sequencing (NGS) technology has expanded in the last decades with significant improvements in the reliability, sequencing chemistry, pipeline analyses, data interpretation and costs. Such advances make the use of NGS feasible in clinical practice today. This review describes the recent technological developments in NGS applied to the field of oncology. A number of clinical applications are reviewed, i.e., mutation detection in inherited cancer syndromes based on DNA-sequencing, detection of spliceogenic variants based on RNA-sequencing, DNA-sequencing to identify risk modifiers

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… Identification of Pathogenic Germline RNA-Splice Mutations Using RNA-Seq Splicing, the process of removal of the introns in the pre-mRNA molecule leaving the exons adjacent to each other in the mRNA molecule is highly regulated by the RNA-splicing machinery and depends on specific genetic sequences … In addition, computer-based tools and pipeline analyses do not predict accurately the effects of the majority of the variants on gene-expression or RNA splicing. …

Insights into the role of RNA m6A modification in the metabolic process and related diseases.

According to the latest consensus, many traditional diseases are considered metabolic diseases, such as cancer, type 2 diabetes, obesity, and cardiovascular disease. Currently, metabolic diseases are increasingly prevalent because of the ever-improving living standards and have become the leading threat to human health. Multiple therapy methods have been applied to treat these diseases, which improves the quality of life of many patients, but the overall effect is still unsatisfactory. Therefore, intensive research on the metabolic process and the pathogenesis of metabolic diseases is imperati

The Glucocorticoid Receptor: Isoforms, Functions, and Contribution to Glucocorticoid Sensitivity.

Glucocorticoids exert pleiotropic effects on all tissues to regulate cellular and metabolic homeostasis. Synthetic forms are used therapeutically in a wide range of conditions for their anti-inflammatory benefits, at the cost of dose and duration-dependent side effects. Significant variability occurs between tissues, disease states, and individuals with regard to both the beneficial and deleterious effects. The glucocorticoid receptor (GR) is the site of action for these hormones and a vast body of work has been conducted understanding its function. Traditionally, it was thought that the anti-

Current Advances in RNA Therapeutics for Human Diseases.

Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairl

Unraveling the advances of non-coding RNAs on the tumor microenvironment: innovative strategies for cancer therapies.

Non-coding RNAs (ncRNAs) are crucial molecules that do not encode proteins but play roles in regulating various biological processes. Recent research highlights that ncRNAs not only control gene expression within cells but also facilitate intercellular communication via exosomes and other carriers. This function is vital in the tumor microenvironment (TME). Our review covers the structure and functions of different ncRNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). We examine how these ncRNAs influence tumor initiation and progression. Additionall