Artificial Uterus and Artificial Embryos: Unsolved Tasks.

Ex utero embryo culture is one of the important tasks that has not been completely solved. In the first part of the current review, we focus on potential roles ex utero mammalian embryo culture could play, such as in infertility treatment or ex utero embryo treatment. Particularly, we discuss ex utero genetic therapy of embryos for correction and prevention of congenital pathologies.

[CDK8/19 in Stress Response in Mouse Embryonic Fibroblast Model].

Transcriptional cyclin-dependent kinases 8 and 19 (CDK8 and CDK19) are enzymatic components of the Mediator complex. CDK19 is presumably a minor paralog of CDK8 and is thought to compensate for lack of CDK8 in certain cases, but evidence for unique functions of the two kinases remains sporadic. Experiments with tumor cell lines have yielded the vast majority of information on the role and mechanisms of action of the kinases, and the results might be irrelevant because of the changes accumulated by tumor cells.

Ectopic Recruitment of the CTCF N-Terminal Domain with Two Proximal Zinc-Finger Domains as a Tool for 3D Genome Engineering.

Enhancer-promoter interactions occur in the chromatin loci delineated by the CCCTC-binding zinc-finger protein CTCF. CTCF binding is frequently perturbed in genetic disorders and cancer, allowing for misregulation of genes. Here, we developed a panel of chimeric proteins consisting of either full-length or truncated CTCF fused with programmable DNA-binding module dCas9 and fluorescent tracker EGFP.

The Hypomethylating Agent 5-Azacitidine Potentiates the Effect of RAS and Sp1 Inhibitors in Neuroblastoma Cells.

Neuroblastoma is a malignant solid tumor caused by the transformation of neural crest cells. Neuroblastoma predominantly occurs in children and is associated with a poor prognosis. In this regard, the development of novel approaches to neuroblastoma treatment, including combination therapy, is relevant.

G-quadruplexes as potential traps for superenhancer marker BRD4: ligand-sensitive binding and co-separation in vitro.

G-quadruplexes (G4s) are prevalent at promoters and superenhancers (SEs), exclude nucleosomes, and recruit transcription factors. This study sought to determine whether the nucleosome exclusion affects the recruitment of the SE marker BRD4, which typically binds to acetylated histones and facilitates SE-promoter contacts via the phase separation-dependent mechanism. Analyses of the available whole-genome data revealed that SEs with the highest G4 density were depleted of nucleosomes but not of BRD4.

[DICER1-syndrome with manifestation of genital embryonal rhabdomyosarcoma in the first year of life: case report].

DICER1 syndrome is a rare monogenic disease with autosomal dominant inheritance. DICER1 protein is involved in the regulation of gene expression by microRNAs. Changes in the expression of DICER1 can be associated with various cancers.

Epigenome Engineering Using dCas Systems for Biomedical Applications and Biotechnology: Current Achievements, Opportunities and Challenges.

Epigenome engineering, particularly utilizing CRISPR/dCas-based systems, is a powerful strategy to modulate gene expression and genome functioning without altering the DNA sequence. In this review we summarized current achievements and prospects in dCas-mediated epigenome editing, primarily focusing on its applications in biomedicine, but also providing a wider context for its applications in biotechnology. The diversity of CRISPR/dCas architectures is outlined, recent innovations in the design of epigenetic editors and delivery methods are highlighted, and the therapeutic potential across a wide range of diseases, including hereditary, neurodegenerative, and metabolic disorders, is examined.

XMU-MP-1, Inhibitor of STE20-like MST1/2 Kinases of the Hippo Signaling Pathway, Suppresses the Cell Cycle, Activates Apoptosis and Autophagy, and Induces Death of Hematopoietic Tumor Cells.

: Currently, there is limited knowledge on the molecular mechanisms of the "non-canonical" Hippo signaling pathway in hematopoietic tumor cells. We have shown that targeting the MST1/2 kinases, which are the key molecules in this signaling pathway, may be an effective approach to the treatment of hematologic tumors. : The methods used in this study include cell growth assays, caspase assays, Western blot hybridizations, flow cytometry, and whole-transcriptome analyses.

Clinical and Allelic Heterogeneity in a Small Cohort of Patients with Inherited Epidermolysis Bullosa.

Inherited epidermolysis bullosa (EB) comprises a group of genetic disorders characterized by fragile skin that blisters easily. Targeted therapies for EB necessitate personalized approaches, underscoring the importance of precise diagnostics through genetic analysis and skin biopsy using transmission electron microscopy and/or immunohistochemistry. This study highlights the application of whole-exome sequencing (WES) to identify key pathogenic variants associated with EB.

The Role of CDKs in the Regulation of the Monocyte/Macrophage Immune Response.

Monocytes/macrophages play an important role in controlling the onset and progression of inflammatory responses by changing their activation state. Inflammation accompanies some slowly progressing pathologies, such as neurodegenerative diseases, rheumatoid arthritis, atherosclerosis, and other inflammatory disorders. Monocyte/- macrophage differentiation and polarization are accompanied by transcriptional profile changes.

Pyruvate Kinase PKM2: Basic and Translational Aspects in Molecular Diagnosis of Human Malignancies.

The M2 isoform of the glycolytic enzyme pyruvate kinase PKM (PKM2) is at a central focus of current research on cancer metabolism. It functions as a highly adaptive metabolic master regulator, orchestrating a switch between modes of (1) energy generation highly efficient conversion of phosphoenolpyruvate (PEP) to pyruvate yielding ATP, and (2) accumulation of glycolytic intermediates, which are funneled into various biosynthetic pathways (i.e.

Experience in developing the human genome standard E701.

The first Russian human genome standard E701 was developed through a collaborative research involving four laboratories: Pirogov Russian National Research Medical University, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I.Kulakov, National Research Center Kurchatov Institute, and National Medical Research Radiological Centre.

Comparison of the L3-23K and L5-Fiber Regions for Arming the Oncolytic Adenovirus Ad5-Delta-24-RGD with Reporter and Therapeutic Transgenes.

The insertion of a transgene downstream of the L3-23K or L5-Fiber region was reported as a vital strategy for arming E3 non-deleted oncolytic adenoviruses. However, depending on the percentage of codons with G/C at the third base position (GC3%) and the type of splicing acceptor, an insert downstream of the L5-Fiber region may substantially affect virus fitness. Since the insertion of transgenes downstream of the L3-23K and L5-Fiber regions has never been compared in terms of their expression levels and impact on virus fitness, we assessed the total virus yield, cytolytic efficacy, and plaque size of Ad5-delta-24-RGD (Ad5Δ24RGD) armed with , , the suppressor of RNA silencing , soluble wild-type human/mouse and high-affinity human programmed cell death receptor-1 (PD-1/) ectodomains, and soluble human hyaluronidase PH20/.

Diverse β-bungarotoxin isoforms manifest different affinities to voltage-gated potassium channels of Kv1.x subfamily.

β-Bungarotoxins (β-BuTx), consisting of covalently bound phospholipase A subunit (A-chain), a member of group Ia of secretory phospholipases A, and non-enzymatic subunit (B-chain) structurally related to Kunitz-type protease inhibitors, block presynaptic neuromuscular transmission via a not completely defined mechanism of action. In vivo physiological studies revealed that the B-chain is targeting voltage-gated potassium channels of not identified subtypes. In our work, six β-BuTx isoforms were isolated from Bungarus multicinctus krait venom and characterized by mass spectrometry revealing that isoforms differ in the A- and B-chain composition.

New and Effective Inhibitor of Class I HDACs, Eimbinostat, Reduces the Growth of Hematologic Cancer Cells and Triggers Apoptosis.

Histone deacetylases (HDACs) are critical epigenetic modulators involved in regulating various molecular mechanisms essential for cell development and growth. Alterations in HDAC activity have been linked to the progression of numerous cancers, including lymphoma. Over the past decade, the FDA has approved several HDAC inhibitors for lymphoma treatment, leading to heightened interest in this emerging class of drugs.

Drosophila architectural proteins M1BP and Opbp cooperatively form the active promoter of a ribosomal protein gene.

Background: In Drosophila, architectural proteins are frequently found in promoters, including those of genes with extremely high expression levels, such as ribosomal protein genes (RPGs). The involvement of several of these proteins in gene regulation in Drosophila has been shown, but the exact mechanisms of their possible cooperative action have not been fully elucidated.

Results: In this study we dissected the contribution of the architectural proteins Opbp and M1BP, which are co-localized at several RPG promoters near the transcription start site, to promoter functioning.

Development of an AAV-RNAi strategy to silence the dominant variant GNAO1 c.607G>A linked to encephalopathy.

Heterozygous mutations in GNAO1 cause an ultra-rare neurodevelopmental disease called GNAO1 encephalopathy, characterized by infantile epilepsy and movement disorder. Here, we provide a functional characterization of the hotspot mutation GNAO1 c.607G>A (p.

Unveiling Another Dimension: Advanced Visualization of Cancer Invasion and Metastasis via Micro-CT Imaging.

Invasion and metastasis are well-known hallmarks of cancer, with metastatic disease accounting for 60% to 90% of cancer-related deaths [...

Treacle's ability to form liquid-like phase condensates is essential for nucleolar fibrillar center assembly, efficient rRNA transcription and processing, and rRNA gene repair.

We investigated the role of the nucleolar protein Treacle in organizing and regulating the nucleolus in human cells. Our results support Treacle's ability to form liquid-like phase condensates through electrostatic interactions among molecules. The formation of these biomolecular condensates is crucial for segregating nucleolar fibrillar centers from the dense fibrillar component and ensuring high levels of ribosomal RNA (rRNA) gene transcription and accurate rRNA processing.

Heterozygous deletion of 10q24.31-q24.33- a new syndrome associated with multiple congenital anomalies: case report and literature review.

Background: Congenital anomalies and neurodevelopmental disorders are complex conditions often requiring comprehensive diagnostic approaches. Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has greatly improved the detection of pathogenic variants, including copy number variations (CNVs), which account for up to 35% of genetic causes in neurological patients. Combining CNV and single nucleotide variant (SNV) analysis through WES enhances diagnostic accuracy, especially in cases with unclassified congenital anomalies.

Knockout of cyclin-dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice.

CDK8 and CDK19 paralogs are regulatory kinases associated with the transcriptional Mediator complex. We have generated mice with the systemic inducible knockout on the background of constitutive knockout. double knockout (iDKO) males, but not single or KO, had an atrophic reproductive system and were infertile.

ACE-dependent Alzheimer's disease: Further assessment of the impact of ACE mutations on blood ACE levels.

Background: Carriers of damaging mutations in the angiotensin-I-converting enzyme (ACE) that result in low ACE levels may be at increased risk for late-onset Alzheimer's disease (AD).

Methodology/principal Findings: We measured blood ACE levels in EDTA-plasma from 74 subjects with 12 different heterozygous ACE mutations. Using a panel of monoclonal antibodies to ACE and two ACE substrates, we assessed the impact of these mutations on ACE phenotypes.

Effect of Free Long-Chain Fatty Acids on Anagen Induction: Metabolic or Inflammatory Aspect?

Hair growth is a highly complex process regulated at multiple levels, including molecular pathways, stem cell behavior, metabolic processes, and immune responses. The hair follicle exhibits metabolic compartmentalization, with some cells relying on glycolysis and others on oxidative phosphorylation. Interestingly, in mice, the onset of the anagen phase can be stimulated by locally suppressing oxidative phosphorylation in the skin.

The Recovery of Epidermal Proliferation Pattern in Human Skin Xenograft.

Abnormalities in epidermal keratinocyte proliferation are a characteristic feature of a range of dermatological conditions. These include hyperproliferative states in psoriasis and dermatitis as well as hypoproliferative states in chronic wounds. This emphasises the importance of investigating the proliferation kinetics under conditions of healthy skin and identifying the key regulators of epidermal homeostasis, maintenance, and recovery following wound healing.

Role of the cytoskeleton in cellular reprogramming: effects of biophysical and biochemical factors.

The cytoskeleton plays a crucial role in regulating cellular behavior, acting as both a structural framework and a mediator of mechanical and biochemical signals that influence cell fate. In the context of cellular reprogramming, modifications to the cytoskeleton can have profound effects on lineage commitment and differentiation efficiency. This review explores the impact of mechanical forces such as substrate stiffness, topography, extracellular fluid viscosity, and cell seeding density on cytoskeletal organization and mechanotransduction pathways, including Rho/ROCK and YAP/TAZ signaling.