A Copernican revolution of multigenic analysis: A retrospective study on clinical exome sequencing in unclear genetic disorders.

Despite the inevitable shift in medical practice towards a deeper understanding of disease etiology and progression through multigenic analysis, the profound historical impact of Mendelian diseases cannot be overlooked. These diseases, such as cystic fibrosis and thalassemia, are characterized by a single variant in a single gene leading to clinical conditions, and have significantly shaped our medical knowledge and treatments. In this respect, the monogenic approach inevitably results in the underutilization of Next-Generation Sequencing (NGS) data.

The Target Therapy Hyperbole: "KRAS (p.G12C)"-The Simplification of a Complex Biological Problem.

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene variations are linked to the development of numerous cancers, including non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The lack of typical drug-binding sites has long hampered the discovery of therapeutic drugs targeting KRAS. Since "CodeBreaK 100" demonstrated Sotorasib's early safety and efficacy and led to its approval, especially in the treatment of non-small cell lung cancer (NSCLC), the subsequent identification of specific inhibitors for the p.

Maternal Reassurance, Satisfaction, and Anxiety after First-Trimester Screening for Aneuploidies: Comparison between Contingent Screening and Universal Cell-Free DNA Testing.

Background: This study aims to evaluate maternal reassurance, satisfaction, and anxiety after two different strategies for the first-trimester screening for aneuploidies.

Methods: Patients between 11 + 3 and 13 + 6 weeks of gestation attending the first-trimester screening at Department of Mother and Child, University Hospital Federico II, Naples, Italy have been recruited and randomly allocated to contingent screening or universal cell-free fetal DNA testing (cffDNA). Questionnaires to measure reassurance, satisfaction, and anxiety have been filled twice: (Q1) after randomization and (Q2) after receiving results.

What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis.

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268).

An in silico pipeline approach uncovers a potentially intricate network involving spike SARS-CoV-2 RNA, RNA vaccines, host RNA-binding proteins (RBPs), and host miRNAs at the cellular level.

Background: In the last 2 years, we have been fighting against SARS-CoV-2 viral infection, which continues to claim victims all over the world. The entire scientific community has been mobilized in an attempt to stop and eradicate the infection. A well-known feature of RNA viruses is their high mutational rate, particularly in specific gene regions.

Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons.

Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurological dysfunction in a host of neurodegenerative disease models. The precise molecular mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes.

HDAC6 is a target for protection and regeneration following injury in the nervous system.

Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models.

Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke.

Achieving therapeutic efficacy in ischemic stroke represents one of the biggest challenges in translational neurobiology. Despite extensive efforts, tissue plasminogen activator remains the only available intervention for enhancing functional recovery in humans once a stroke has occurred. To expand the repertoire of therapeutic options in stroke, one must consider and target its diverse pathophysiologies that trigger cell loss in a manner that also permits and enhances neuronal plasticity and repair.

Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I:C): mechanism of induction and role in antiviral response.

Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism and has been implicated in neurotoxicity and suppression of the antiviral T-cell response in HIV encephalitis (HIVE). Here we show that the Toll-like receptor 3 (TLR3) ligand poly(I:C) (PIC) induces the expression of IDO in human astrocytes. PIC was less potent than gamma interferon (IFN-gamma) but more potent than IFN-beta in inducing IDO.

TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5.

TLR3 functions as a viral nucleic acid sentinel activated by dsRNA viruses and virus replication intermediates within intracellular vesicles. To explore the spectrum of genes induced in human astrocytes by TLR3, we used a microarray approach and the analog polyriboinosinic polyribocytidylic acid (pIC) as ligand. As expected for TLR activation, pIC induced a wide array of cytokines and chemokines known for their role in inflammatory responses, as well as up-regulation of the receptor itself.

The TLR3 ligand polyI: C downregulates connexin 43 expression and function in astrocytes by a mechanism involving the NF-kappaB and PI3 kinase pathways.

Toll-like receptor 3 (TLR3) is a component of the innate immune response that responds to dsRNA viruses and virus replication intermediates. In this study we show that activation of astrocytes with the dsRNA mimetic polyinosinic-cytidylic acid (pI:C) results in loss of expression of connexin43 (Cx43) mRNA and protein while upregulating the expression of the ionotropic P2 receptor P2X(4)R. Analysis of the signaling pathways involved failed to demonstrate a role for the p38 MAP kinase, ERK, or JNK signaling pathways whereas an inhibitor of the PI3 kinase/Akt pathway effectively blocked the action of pI:C.

The cytokine IL-1beta activates IFN response factor 3 in human fetal astrocytes in culture.

The cytokine IL-1beta is a major activator of primary human fetal astrocytes in culture, leading to the production of a wide range of cytokines and chemokines important in the host defense against pathogens. IL-1beta, like TLR4, signals via the MyD88/IL-1betaR-associated kinase-1 pathway linked to activation of NF-kappaB and AP-1. Recent studies have shown that TLR4 also signals independently of MyD88, resulting in the activation of IFN regulatory factor 3 (IRF3), a transcription factor required for the production of primary antiviral response genes such as IFN-beta.

IL-1-regulated responses in astrocytes: relevance to injury and recovery.

In the central nervous system (CNS), the cellular processes of astrocytes make intimate contact with essentially all areas of the brain. They have also been shown to be functionally coupled to neurons, oligodendrocytes, and other astrocytes via both contact-dependent and non-contact-dependent pathways. These observations have led to the suggestion that a major function of astrocytes in the CNS is to maintain the homeostatic environment, thus promoting the proper functioning of the neuronal network.

Interleukin-1beta induces a reactive astroglial phenotype via deactivation of the Rho GTPase-Rock axis.

The cytokine interleukin-1beta (IL-1beta) is critical to the formation of an astrocytic scar after CNS injury, but the mechanisms by which it induces a reactive phenotype remain unresolved. Here, we show that IL-1beta regulates the phenotype of astrocytes via deactivation of the Rho GTPase-Rho kinase (ROCK) pathway, which governs cellular morphology and migration via effects on F-actin and its interactions with focal adhesions, nonmuscle myosin, and microvillar adapter proteins of the ezrin-radixin-moesin (ERM) family. We found that IL-1beta induced cortical reorganization of F-actin and dephosphorylation of focal adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1 in primary human astrocytes, and that all of these effects were mimicked by Rho-ROCK pathway blockade.