PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

• MeSH
• dítě MeSH
• dominantní geny MeSH
• fenotyp MeSH
• geny recesivní MeSH
• jaderné proteiny * genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mladiství MeSH
• mozek patologie   MeSH
• mutace MeSH
• nemoci mozku * genetika   patologie   MeSH
• neurovývojové poruchy * genetika   MeSH
• předškolní dítě MeSH
• vývojové poruchy u dětí * genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans. METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG). RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions with known human CD genes. PANTHER analysis identified six biological processes shared with established human CD genes. Two genes (Rgs2 and Galnt9) were involved in pathways related to human corneal diseases, including cGMP-PKG signaling, mucin-type O-glycan biosynthesis, and oxytocin signaling. Other candidates were implicated in pathways such as pluripotency of stem cells, MAPK signaling, WNT signaling, actin cytoskeleton regulation, and cellular senescence. CONCLUSIONS: This study identified 14 genes linked to LACD in knockout mice, 12 of which are novel in corneal biology. These genes may serve as potential therapeutic targets for treating corneal diseases in aging human populations.

• MeSH
• dědičné dystrofie rohovky * genetika   metabolismus   MeSH
• fenotyp MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• stárnutí * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration. METHOD: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively. RESULTS: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues. CONCLUSIONS: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.

• MeSH
• individualizovaná medicína metody   MeSH
• lidé MeSH
• mitochondriální proteiny MeSH
• mitofagie * fyziologie   účinky léků   MeSH
• neurodegenerativní nemoci * farmakoterapie   metabolismus   MeSH
• specifické proteázy ubikvitinu metabolismus   antagonisté a inhibitory   MeSH
• thiolesterhydrolasy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Postoperative pain is a prevalent problem, often lasting from days to years. To minimize opioid use and associated risks of dependency, Enhanced Recovery After Surgery (ERAS) protocols increasingly incorporate multimodal analgesics. Sodium channel-selective blockers are a promising non-opioid alternative, yet their application in postoperative pain remains underexplored. This systematic review evaluates their efficacy in managing postoperative, neuropathic, and neuralgia-related pain. A systematic review was conducted using controlled keywords across multiple databases to identify studies on sodium channel-selective blockers published up to 2024. Eligible studies included clinical trials, observational studies, case series, and reports involving patients aged 18 or older. Data were extracted on therapeutic outcomes, dosages, complications, and comparisons with other analgesics. Five studies met the inclusion criteria, involving 804 patients, 81.58% of whom were women. One study addressed postoperative pain, while the remaining five focused on neuropathy- and neuralgia-related pain. All studies reported significant pain reduction in at least one treatment group compared with placebo. In the study on postoperative pain, the sodium channel-selective blocker significantly reduced pain scores without requiring opioid analgesia. Across all studies, only two patients needed concomitant opioid therapy, and one discontinued treatment due to adverse effects. Dosages varied, with no reports of severe complications. Comparative analyses showed that sodium channel-selective blockers were as effective, if not superior, to traditional pain medications in reducing pain intensity. Sodium channel-selective blockers demonstrate significant potential in pain management with minimal opioid reliance. While effective for neuropathic pain, further studies are essential to validate their role in acute postoperative settings and refine their use in multimodal analgesia regimens.

• MeSH
• analgetika terapeutické užití   MeSH
• blokátory sodíkových kanálů * terapeutické užití   MeSH
• lidé MeSH
• management bolesti * metody   MeSH
• neuralgie * farmakoterapie   etiologie   MeSH
• opioidní analgetika terapeutické užití   aplikace a dávkování   MeSH
• pooperační bolest * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here, we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From these data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

• MeSH
• ergothionein * metabolismus   farmakologie   MeSH
• kondiční příprava zvířat * MeSH
• lidé MeSH
• mitochondrie * metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• sulfurtransferasy * metabolismus   MeSH
• svalové mitochondrie * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Neuroinflammation is a key factor in the progression of neurodegenerative diseases, driven by the dysregulation of molecular pathways and activation of the brain's immune system, resulting in the release of pro-inflammatory and oxidative molecules. This chronic inflammation is exacerbated by peripheral leukocyte infiltration into the central nervous system. Medicinal plants, with their historical use in traditional medicine, have emerged as promising candidates to mitigate neuroinflammation and offer a sustainable alternative for addressing neurodegenerative conditions in a green healthcare framework. This review evaluates the effects of medicinal plants on neuroinflammation, emphasizing their mechanisms of action, effective dosages, and clinical implications, based on a systematic search of databases such as PubMed, SCOPUS, and Web of Science. The key findings highlight that plants like Cleistocalyx nervosum var. paniala, Curcuma longa, Cannabis sativa, and Dioscorea nipponica reduce pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), inhibit enzymes (COX-2 and iNOS), and activate antioxidant pathways, particularly Nrf2. NF-κB emerged as the primary pro-inflammatory pathway inhibited across studies. While the anti-inflammatory potential of these plants is significant, the variability in dosages and phytochemical compositions limits clinical translation. Here, we highlight that medicinal plants are effective modulators of neuroinflammation, underscoring their therapeutic potential. Future research should focus on animal models, standardized protocols, and safety assessments, integrating advanced methodologies, such as genetic studies and nanotechnology, to enhance their applicability in neurodegenerative disease management.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

INTRODUCTION: Pediatric low-grade gliomas arising from the thalamus or thalamopeduncular junction are rare. Prognostic factors are thus seldom reported in the literature. RESEARCH QUESTION: This systematic review aims to define the factors influencing the prognosis of pediatric patients with thalamic and thalamopeduncular low-grade gliomas. MATERIAL AND METHODS: An extensive literature search in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed and included Web of Science, Scopus, and OVID interface (Medline and Embase). Original articles were selected if they provided data on 10 or more patients under 18 years old with separate or retrievable data for thalamic or thalamopeduncular low-grade gliomas, as well as at least one prognostic factor and its corresponding outcome. The risk of bias and applicability were assessed using The Quality Assessment of Prognostic Accuracy Studies criteria. RESULTS: The study selection process resulted in the inclusion of 14 articles out of the initial pool of 876 references. These 14 articles encompassed data from 446 patients. The prognostic factors reported were the extent of resection in ten studies, age and radiotherapy in four studies, bilateral involvement and molecular genetics in two studies, and sex and dissemination in one study each. Significant prognostic factors included the extent of resection, bilateral involvement, histology, and radiotherapy. DISCUSSION AND CONCLUSION: The reported factors considered significant for prognosis align with previously published data. The maximal safe resection, as a potentially curative modality for thalamic low-grade glioma, and the multidisciplinary approach to each patient should be a standard of care. Given the excellent long-term outlook of these patients, the extent of resection should not be pursued at the risk of neurological function since additional therapeutic possibilities are available today, such as molecular-targeted agents.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.

• MeSH
• databáze genetické MeSH
• exom genetika   MeSH
• genom lidský genetika   MeSH
• genomika * metody   MeSH
• lidé MeSH
• rodokmen MeSH
• výpočetní biologie metody   MeSH
• vzácné nemoci * genetika   diagnóza   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH

In this study, we use an integrative taxonomic approach to redescribe Schyzocotyle nayarensis (Malhotra, 1983) (Cestoda: Bothriocephalidae), based on newly collected specimens from the type-host Raiamas bola (Hamilton, 1822) (Cypriniformes: Danionidae) in Fulbari, Siliguri, West Bengal, India. The detailed morphological assessment, from whole mounts, histology and scanning electron microscopy, offers additional insights into the scolex structure, vitelline follicles, and egg morphology. Molecular data from this and previous studies corroborate the identity and systematics of S. nayarensis as a bothriocephalid closely related to the Asian Fish Tapeworm, Schyzocotyle acheilognathi (Yamaguti, 1934). This study elucidates the historical context and taxonomic ambiguities surrounding S. nayarensis, emphasizing the key role of the scolex in both generic and species identification. Amendments to the diagnosis of Schyzocotyle Akhmerov, 1960 are proposed. A differential diagnosis of the two valid species within the genus, namely S. acheilognathi and S. nayarensis, is also provided. An evaluation of the taxonomic status of Bothriocephalus teleostei Malhotra, 1984, and Capooria barilii Malhotra, 1985 suggests that they may be S. nayarensis. Finally, we posit that none of the ten species of Ptychobothrium Lönnberg, 1889 described from Indian freshwater teleosts belong to this genus but instead appear to be a mix of species belonging to Schyzocotyle, Senga Dollfus, 1934, and possibly even Proteocephalidae La Rue, 1911; all require further study based on newly collected, properly fixed specimens and an integrated taxonomic approach. Finally, future survey studies may reveal hidden diversity of Schyzocotyle species in Indian cyprinoids.

• MeSH
• Cestoda * klasifikace   anatomie a histologie   ultrastruktura   izolace a purifikace   genetika   MeSH
• cestodózy * veterinární   parazitologie   MeSH
• fylogeneze * MeSH
• máloostní parazitologie   MeSH
• mikroskopie elektronová rastrovací * veterinární   MeSH
• nemoci ryb * parazitologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Indie MeSH

Cíl: Molekulární klasifikace endometriálních karcinomů (EK) dělí tyto tumory do čtyř distinktních skupin definovaných genetickým pozadím. Vzhledem k prokázanému klinickému významu se genetické vyšetření EK stává nedílnou součástí dia gnostického postupu. Doporučený dia gnostický algoritmus zahrnuje molekulárně genetický průkaz mutace genu POLE, přičemž všechny další potřebné parametry se vyšetřují pouze imunohistochemicky. Cílem této studie je sdílet naše zkušenosti s molekulární klasifikací EK, která je na našem pracovišti prováděna pomocí imunohistochemie a následně sekvenování nové generace (NGS). Metodika: Do studie byly zařazeny všechny EK dia gnostikované na Šiklově ústavu patologie ve FN Plzeň a v Bioptické laboratoři, s. r. o., od roku 2020 do současnosti. Všechny EK byly prospektivně vyšetřeny nejprve imunohistochemicky (MMR proteiny, p53) a následně molekulárně geneticky pomocí NGS za použití „customizovaného Gyncore panelu“ (zahrnujícího geny POLE, POLD1, MSH2, MSH6, MLH1, PMS2, TP53, PTEN, ARID1A, PIK3CA, PIK3R1, CTNNB1, KRAS, NRAS, BRCA1, BRCA2, BCOR, ERBB2), na jehož základě byly rozčleněny do čtyř molekulárně distinktních skupin [POLE mutované EK (typ 1), hypermutované (MMR deficientní, typ 2), EK bez specifického molekulárního profilu (NSMP, typ 3) a TP53 mutované („copy number high“, typ 4) ]. Výsledky: Soubor zahrnuje celkem 270 molekulárně klasifikovaných EK. Osmnáct případů (6,6 %) bylo klasifikováno jako POLE mutované, 85 případů (31,5 %) jako hypermutované (MMR deficientní), 137 případů (50,7 %) jako EK bez specifického molekulárního profilu, 30 případů (11,1 %) jako TP53 mutované. Dvanáct případů (4,4 %) bylo zařazeno jako „multiple classifier“. Skupina NSMP se často vyznačovala mnohočetnými genetickými alteracemi, přičemž nejčastější byla mutace genu PTEN (44 % v rámci NSMP), následovaly PIK3CA (30 %), ARID1A (21 %) a KRAS (9 %). Závěr: Molekulární klasifikace EK pomocí metody NGS umožňuje v porovnání s doporučeným dia gnostickým algoritmem spolehlivější klasifikaci EK do jednotlivých molekulárních skupin. Kromě toho dovoluje NGS vyšetření odkrýt komplexní genetické pozadí jednotlivých EK, což má význam zvláště v rámci skupiny „bez specifického molekulárního profilu“, kde jsou tato data podkladem pro výzkum léčebných schémat s příslibem cílené terapie tohoto typu nádorů.

Objective: Molecular classification of endometrial carcinomas (EC) divides these neoplasms into four distinct subgroups defined by a molecular background. Given its proven clinical significance, genetic examination is becoming an integral component of the diagnostic procedure. Recommended diagnostic algorithms comprise molecular genetic testing of the POLE gene, whereas the remaining parameters are examined solely by immunohistochemistry. The aim of this study is to share our experiences with the molecular classification of EC, which has been conducted using immunohistochemistry and next-generation sequencing (NGS) at our department. Methods: This study includes all cases of EC diagnosed at Šikl's Department of Pathology and Biopticka Laboratory Ltd. from 2020 to the present. All ECs were prospectively examined by immunohistochemistry (MMR, p53), fol lowed by NGS examination using a customized Gyncore panel (including genes POLE, POLD1, MSH2, MSH6, MLH1, PMS2, TP53, PTEN, ARID1A, PIK3CA, PIK3R1, CTNNB1, KRAS, NRAS, BRCA1, BRCA2, BCOR, ERBB2), based on which the ECs were classified into four molecularly distinct groups [POLE mutated EC (type 1), hypermutated (MMR deficient, type 2), EC with no specific molecular profile (type 3), and TP53 mutated (“copy number high”, type 4)]. Results: The cohort comprised a total of 270 molecularly classified ECs. Eighteen cases (6.6%) were classified as POLE mutated EC, 85 cases (31.5%) as hypermutated EC (MMR deficient), 137 cases (50.7%) as EC of no specific molecular profile, and 30 cases (11.1%) as TP53 mutated EC. Twelve cases (4.4%) were classified as “multiple classifier” endometrial carcinoma. ECs of no specific molecular profile showed multiple genetic alterations, with the most common mutations being PTEN (44% within the group of NSMP), fol lowed by PIK3CA (30%), ARID1A (21%), and KRAS (9%). Conclusion: In comparison with recommended diagnostic algorithms, NGS provides a more reliable classification of EC into particular molecular subgroups. Furthermore, NGS reveals the complex molecular genetic background in individual ECs, which is especially significant within ECs with no specific molecular profile. These data can serve as a springboard for the research of therapeutic programs committed to targeted therapy in this type of tumor.

• MeSH
• imunohistochemie klasifikace   metody   MeSH
• klasifikace metody   MeSH
• lidé MeSH
• molekulární patologie metody   MeSH
• mutace genetika   MeSH
• nádory endometria * diagnóza   genetika   klasifikace   patologie   MeSH
• vysoce účinné nukleotidové sekvenování * klasifikace   metody   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinická studie MeSH
• práce podpořená grantem MeSH