Development of dentition is a commonly studied process as a representative of the development of ectodermal derivates. A key step is the formation of a signaling center called the enamel knot (EK), which organizes tooth crown formation. In the mouse lower jaw, the anterior part of the tooth-forming region undergoes a series of complex events before the first molar primary EK can form more posteriorly and the tooth can progress through the cap stage. Although much is known about the molecular factors involved in tooth development, disentangling their specific roles is difficult. In this study, we circumvented this problem by isolating the posterior part of the tooth-forming region at embryonic day 13.5 and cultivating it in vitro. By treating them with molecules activating or inhibiting Sonic hedgehog (Shh) and fibroblast growth factor (Fgf) pathways, we demonstrate that Shh plays the role of an inhibitor of EK formation, and we suggest that the FGF pathways may have both positive and negative roles, as seen in hair. By RNA-sequencing of the cultivated isolates after 0, 16, or 24 h in vitro, respectively, we screened for genes whose expression varies with EK and cap formation and pointed to Cdkn2b and Sema3b as 2 promising candidates in this process.

• MeSH
• fibroblastové růstové faktory fyziologie   MeSH
• moláry embryologie   MeSH
• myši MeSH
• odontogeneze * fyziologie   genetika   MeSH
• proteiny hedgehog fyziologie   metabolismus   MeSH
• signální transdukce MeSH
• vývojová regulace genové exprese MeSH
• zubní korunka (anatomie) * embryologie   MeSH
• zubní sklovina * embryologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The outcome of tooth autotransplantation depends mainly on the transplant tooth's anatomy-the type of donor tooth and the developmental stage of root formation. Mature teeth display a higher complication rate due to lower pulp revascularization potential, requiring root canal treatment (RCT) pre- or postoperatively to avoid postoperative complications, which extends treatment duration and cost. This report details a 39-year-old patient's autotransplantation of a mature wisdom tooth to replace the first molar after unsuccessful root canal retreatment. During the surgery, an extraoral root resection of the transplanted tooth was performed prior to placement to avoid the need to elevate the Schneiderian membrane, which displayed imperfect healing following the surgical removal of a cystic lesion in the maxillary sinus. RCT was not performed before nor after the procedure. At the 3-year follow-up, the tooth was asymptomatic. The vitality of the autotransplanted tooth was difficult to determine using standard vitality tests, which depend on patients' subjective responses, but the use of pulse oximetry objectively confirmed this. This case not only shows the possibility of a mature tooth transplant revascularization in an older patient but also gives a possible postoperative protocol of how to objectively confirm and measure the revascularization of the autotransplanted tooth.

• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

The lateral line system enables fishes and aquatic-stage amphibians to detect local water movement via mechanosensory hair cells in neuromasts, and many species to detect weak electric fields via electroreceptors (modified hair cells) in ampullary organs. Both neuromasts and ampullary organs develop from lateral line placodes, but the molecular mechanisms underpinning ampullary organ formation are understudied relative to neuromasts. This is because the ancestral lineages of zebrafish (teleosts) and Xenopus (frogs) independently lost electroreception. We identified Bmp5 as a promising candidate via differential RNA-seq in an electroreceptive ray-finned fish, the Mississippi paddlefish (Polyodon spathula; Modrell et al., 2017, eLife 6: e24197). In an experimentally tractable relative, the sterlet sturgeon (Acipenser ruthenus), we found that Bmp5 and four other Bmp pathway genes are expressed in the developing lateral line, and that Bmp signalling is active. Furthermore, CRISPR/Cas9-mediated mutagenesis targeting Bmp5 in G0-injected sterlet embryos resulted in fewer ampullary organs. Conversely, when Bmp signalling was inhibited by DMH1 treatment shortly before the formation of ampullary organ primordia, supernumerary ampullary organs developed. These data suggest that Bmp5 promotes ampullary organ development, whereas Bmp signalling via another ligand(s) prevents their overproduction. Taken together, this demonstrates opposing roles for Bmp signalling during ampullary organ formation.

• MeSH
• kostní morfogenetické proteiny * metabolismus   genetika   MeSH
• proudový orgán * embryologie   metabolismus   MeSH
• rybí proteiny metabolismus   genetika   MeSH
• ryby genetika   MeSH
• signální transdukce * MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The ribosome, owing to its exceptional conservation, harbours a remarkable molecular fossil known as the protoribosome. It surrounds the peptidyl transferase center (PTC), responsible for peptide bond formation. While previous studies have demonstrated the PTC activity in RNA alone, our investigation reveals the intricate roles of the ribosomal protein fragments (rPeptides) within the ribosomal core. This research highlights the significance of rPeptides in stability and coacervation of two distinct protoribosomal evolutionary stages. The 617nt 'big' protoribosome model, which associates with rPeptides specifically, exhibits a structurally defined and rigid nature, further stabilized by the peptides. In contrast, the 136nt 'small' model, previously linked to peptidyltransferase activity, displays greater structural flexibility. While this construct interacts with rPeptides with lower specificity, they induce coacervation of the 'small' protoribosome across a wide concentration range, which is concomitantly dependent on the RNA sequence and structure. Moreover, these conditions protect RNA from degradation. This phenomenon suggests a significant evolutionary advantage in the RNA-protein interaction at the early stages of ribosome evolution. The distinct properties of the two protoribosomal stages suggest that rPeptides initially provided compartmentalization and prevented RNA degradation, preceding the emergence of specific RNA-protein interactions crucial for the ribosomal structural integrity.

• MeSH
• konformace nukleové kyseliny MeSH
• molekulární modely MeSH
• peptidy chemie   metabolismus   MeSH
• peptidyltransferasy metabolismus   chemie   MeSH
• ribozomální proteiny * metabolismus   chemie   MeSH
• ribozomy * metabolismus   MeSH
• RNA metabolismus   chemie   MeSH
• stabilita RNA MeSH
• Publikační typ
• časopisecké články MeSH

Hepatocellular carcinoma (HCC) is primary liver cancer, frequently diagnosed at advanced stages with limited therapeutic options. MicroRNAs (miRNAs) regulate target gene expression and through inhibitory competitive binding of miRNA influence cellular processes including carcinogenesis. Extensive evidence proved that certain miRNA's are specifically expressed in neoplastic tissues of HCC patients and are confirmed as important factors that can participate in the regulation of key signalling pathways in cancer cells. As such, miRNAs have a great potential in the clinical diagnosis and treatment of HCC and can improve the limitations of standard diagnosis and treatment. Long non-coding RNAs (lncRNAs) have a critical role in the development and progression of HCC. HCC-related lncRNAs have been demonstrated to exhibit abnormal expression and contribute to transformation process (such as proliferation, apoptosis, accelerated vascular formation, and gain of invasive potential) through their interaction with DNA, RNA, or proteins. LncRNAs can bind mRNAs to release their target mRNA and enable its translation. These lncRNA-miRNA networks regulate cancer cell expression and so its proliferation, apoptosis, invasion, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and autophagy. In this narrative review, we focus on miRNA and lncRNA in HCC tumor tissue and their interaction as current tools, and biomarkers and therapeutic targets unravelled in recent years.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• biochemie MeSH
• metabolické nemoci MeSH
• patologie MeSH

• Konspekt
• Patologie. Klinická medicína
• Učební osnovy. Vyučovací předměty. Učebnice
• NLK Obory
• biochemie
• patologie
• NLK Publikační typ
• učebnice vysokých škol

Detailed knowledge of human B-cell development is crucial for the proper interpretation of inborn errors of immunity and malignant diseases. It is of interest to understand the kinetics of protein expression changes during development, but also to properly interpret the major and possibly alternative developmental trajectories. We have investigated human samples from healthy individuals with the aim of describing all B-cell developmental trajectories. We validated a 30-parameter mass cytometry panel and demonstrated the utility of "vaevictis" visualization of B-cell developmental stages. We used the trajectory inference tool "tviblindi" to exhaustively describe all trajectories leading to all developmental ends discovered in the data. Focusing on Natural Effector B cells, we demonstrated the dynamics of expression of nuclear factors (PAX-5, TdT, Ki-67, Bcl-2), cytokine and chemokine receptors (CD127, CXCR4, CXCR5) in relation to the canonical B-cell developmental stage markers. We observed branching of the memory development, where follicular memory formation was marked by CD73 expression. Lastly, we performed an analysis of two example cases of abnormal B-cell development caused by mutations in RAG-1 and Wiskott-Aldrich syndrome gene in patients with primary immunodeficiency. In conclusion, we developed, validated, and presented a comprehensive set of tools for the investigation of B-cell development in the bone marrow compartment.

• MeSH
• algoritmy * MeSH
• B-lymfocyty * imunologie   MeSH
• buněčná diferenciace * imunologie   genetika   MeSH
• homeodoménové proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Reproductive isolation and hybrid sterility are mechanisms that maintain the genetic integrity of species and prevent the introgression of heterospecific genes. However, crosses of closely related species can lead to complex evolution, such as the formation of all-female lineages that reproduce clonally. Bighead catfish (Clarias macrocephalus) and North African catfish (C. gariepinus) diverged 40 million years ago. They are cultivated and hybridized in Thailand for human consumption. Male hybrids are sterile due to genome-wide chromosome asynapsis during meiosis. Although female hybrids are sometimes fertile, their chromosome configuration during meiosis has not yet been studied. METHODS: We analyzed meiosis in the hybrid female catfish at pachytene (synaptonemal complexes) and diplotene (lampbrush chromosomes), using immunostaining to detect chromosome pairing and double-stranded break formation, and FISH with species-specific satellite DNAs to distinguish the parental chromosomes. RESULTS: More than 95% of oocytes exhibited chromosome asynapsis in female hybrid catfish; however, they were able to progress to the diplotene stage and form mature eggs. The remaining oocytes underwent premeiotic endoreplication, followed by synapsis and crossing over between sister chromosomes, similar to known clonal lineages in fish and reptiles. DISCUSSION: The occurrence of clonal reproduction in female hybrid catfish suggests a unique model for studying gametogenic alterations caused by hybridization and their potential for asexual reproduction. Our results further support the view that clonal reproduction in certain hybrid animals relies on intrinsic mechanisms of sexually reproducing parental species, given their multiple independent origins with the same mechanism.

• Publikační typ
• časopisecké články MeSH

Chronická myeloidní leukemie (CML) je myeloprolifera- tivní onemocnění charakterizované přítomností Philadelphského chromozomu – translokací BCR::ABL1 – spojenou se vznikem fúzního proteinu Bcr-Abl s vlastní tyrosinkinázovou aktivitou. V terapii CML jsou již mnoho let využívány tyrosinkinázové inhibitory (TKI) Bcr-Abl, které blokují nadměrnou aktivitu tohoto proteinu. Postupně byly do klinického užití zavedeny TKI 1. generace imatinib, TKI 2. generace dasatinib, nilotinib a bosutinib a TKI 3. generace ponatinib. Nejmodernějším lékem, který lze využít u pacien tů s CML, je asciminib, první zástupce skupiny inhibitorů STAMP, který působí jako alosterický inhibitor kinázy Bcr-Abl a je účinný i v přítomnosti mutací BCR::ABL1 spojených s rezistencí vůči TKI. U mladších pa cien tů bez významných komorbidit je při selhání TKI 2. generace a u pokročilejších fází onemocnění vhodnou léčebnou strategií také alognní transplantace krvetvorných buněk.

Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia chromosome, i.e. BCR::ABL1 translocation, associated with the formation of the Bcr-Abl fusion protein with intrinsic tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) of Bcr-Abl have been used in CML therapy for many years to block the excessive activity of this protein. The first- generation TKI imatinib, the second-generation TKIs dasatinib, nilotinib and bosutinib, and the third-generation TKI ponatinib have gradually been introduced into clinical use. The most recent drug that can be used in CML patients is asciminib, the first representative of the STAMP inhibitor group, which acts as an allosteric inhibitor of the Bcr-Abl kinase and is effective even in the presence of BCR::ABL1 mutations associated with TKI resistance. In younger patients without significant comorbidities, allogeneic hematopoietic cell transplantation is also an appropriate treatment strategy in the case of failure of the 2nd generation TKIs and in more advanced stages of the disease.

IgA nefropatie je nejčastější primární glomerulonefritida. V patogenezi onemocnění hrají zásadní roli imunitní komplexy, složené z galaktózy-deficitního IgA1 a autoprotilátek, které aktivují komplement a vyvolávají imunitní zánět glomerulů, progredující renální insuficienci až selhání ledvin. V současné době jsou léčebné možnosti u tohoto onemocnění limitované. Nepochybně potřebujeme cílenou léčbu, která ovlivní tvorbu patogenních protilátek obsahujících Gd-IgA1 a imunokomplexů. Tento článek shrnuje nové léčebné možnosti, které zasahují na úrovni vlastní patogeneze IgAN, ovlivňují komplementem zprostředkovaný zánět, tvorbu galaktóza-deficitního IgA1 i patogenních protilátek deplecí B a CD38 pozitivních plazmatických buněk.

IgA nephropathy is the most common primary glomerulonephritis worldwide. Immune complexes, composed of galactose-deficient IgA1 and Gd-IgA1 autoantibodies, are deposited in the mesangial area of the glomeruli where they induce complement-mediated inflammation. This may result in the reduced kidney function which can progress to end stage kidney disease. Treatment options are very limited. Treatments which directly affect the formation of pathogenic Gd-IgA1 antibodies and anti-Gd-IgA1 antibody-containing immune complexes are needed. This article reviews potential therapies that may affect the main axis of pathogenesis of IgA nephropathy. New treatment options are aimed at the immunopathogenesis of IgAN including depletion or modulation of Gd-IgA1 producing B cells, plasma cells, alternate and/or lectin pathway of complement.

• MeSH
• glifloziny farmakologie   terapeutické užití   MeSH
• hormony kůry nadledvin farmakologie   terapeutické užití   MeSH
• IgA nefropatie * diagnóza   farmakoterapie   imunologie   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• komplement - faktor B antagonisté a inhibitory   MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• progrese nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH