The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present Phenopacket Store. Phenopacket Store v.0.1.19 includes 6,668 phenopackets representing 475 Mendelian and chromosomal diseases associated with 423 genes and 3,834 unique pathogenic alleles curated from 959 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.

• MeSH
• algoritmy MeSH
• databáze genetické MeSH
• fenotyp * MeSH
• genomika * metody   MeSH
• lidé MeSH
• software * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Tumor suppressor p53 is a key player in the cell response to DNA damage that suffers by frequent inactivating aberrations. Some of them disturb p53 oligomerization and influence cell decision between proliferation, growth arrest and apoptosis. Active p53 resides mostly in the nucleus, degradation occurs in the cytoplasm. Acute myeloid leukemia (AML)-related mutation of NPM (NPMmut) induces massive mislocalization of p53 to the cytoplasm, which might be related to leukemia initiation. Since both proteins interact and execute their function as oligomers, we investigated the role of perturbed p53 oligomerization in the p53 mislocalization process in live cells by FLIM (fluorescence lifetime imaging microscopy), fluorescence anisotropy imaging (FAIM), fluorescence cross-correlation spectroscopy (FCCS) and immunochemical methods. On a set of fluorescently labeled p53 variants, monomeric R337G and L344P, dimeric L344A, and multimeric D352G and A353S, we correlated their cellular localization, oligomerization and interaction with NPMmut. Interplay between nuclear export signal (NES) and nuclear localization signal (NLS) of p53 was investigated as well. While NLS was found critical for the nuclear p53 localization, NES plays less significant role. We observed cytoplasmic translocation only for multimeric A353S variant with sufficient stability and strong interaction with NPMmut. Less stable multimer D352G and L344A dimer were not translocated, monomeric p53 variants always resided in the nucleus independently of the presence of NPMmut and NES intactness. Oligomeric state of NPMmut is not required for p53 translocation, which happens also in the presence of the nonoligomerizing NPMmut variant. The prominent structural and functional role of the R337 residue is shown.

• MeSH
• akutní myeloidní leukemie * genetika   metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• cytoplazma metabolismus   MeSH
• jaderné lokalizační signály metabolismus   MeSH
• jaderné proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• multimerizace proteinu MeSH
• mutace * MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   chemie   MeSH
• nukleofosmin MeSH
• signály pro jaderný export MeSH
• transport proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Atrial fibrillation (AF) is the most common arrhythmia experienced by critically ill patients. It has been associated with adverse short-and long-term outcomes, including an increased risk of thromboembolic events, heart failure, and death. Due to complex and multifactorial pathophysiology, a heterogenous patient population, and a lack of clinical tools for risk stratification validated in this population, AF in critical illness is challenging to predict, prevent, and manage. Personalized management strategies that consider patient factors such as underlying cardiac structure and function, potentially reversible arrhythmogenic triggers, and risk for complications of AF are needed. Furthermore, evaluation of the effects of these interventions on long-term outcomes is warranted. Critical illness survivors who have had AF represent a unique population who require systematic follow-up after discharge. However, the frequency, type, and intensity of follow-up is unknown. This state-of-the-art review aims to summarize the evidence, contextualize the current guidelines within the setting of critical illness, and highlight gaps in knowledge and research opportunities to further our understanding of this arrhythmia and improve patient outcomes.

• MeSH
• fibrilace síní * terapie   patofyziologie   komplikace   MeSH
• hodnocení rizik MeSH
• kritický stav * terapie   MeSH
• lidé MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

G-quadruplexes (G4s) are functional elements of the human genome, some of which inhibit DNA replication. We investigated replication of G4s within highly abundant microsatellite (GGGA, GGGT) and transposable element (L1 and SVA) sequences. We found that genome-wide, numerous motifs are located preferentially on the replication leading strand and the transcribed strand templates. We directly tested replicative polymerase ε and δ holoenzyme inhibition at these G4s, compared to low abundant motifs. For all G4s, DNA synthesis inhibition was higher on the G-rich than C-rich strand or control sequence. No single G4 was an absolute block for either holoenzyme; however, the inhibitory potential varied over an order of magnitude. Biophysical analyses showed the motifs form varying topologies, but replicative polymerase inhibition did not correlate with a specific G4 structure. Addition of the G4 stabilizer pyridostatin severely inhibited forward polymerase synthesis specifically on the G-rich strand, enhancing G/C strand asynchrony. Our results reveal that replicative polymerase inhibition at every G4 examined is distinct, causing complementary strand synthesis to become asynchronous, which could contribute to slowed fork elongation. Altogether, we provide critical information regarding how replicative eukaryotic holoenzymes navigate synthesis through G4s naturally occurring thousands of times in functional regions of the human genome.

• MeSH
• aminochinoliny MeSH
• DNA-polymerasa II * antagonisté a inhibitory   metabolismus   MeSH
• DNA-polymerasa III * antagonisté a inhibitory   metabolismus   MeSH
• DNA chemie   MeSH
• G-kvadruplexy * MeSH
• genom lidský * MeSH
• holoenzymy metabolismus   MeSH
• kyseliny pikolinové farmakologie   MeSH
• lidé MeSH
• mikrosatelitní repetice MeSH
• proteiny vázající poly-ADP-ribosu MeSH
• replikace DNA * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pressure overload. We also investigated the effects of a drug inhibiting RIP3, a proposed convergent point for both these necrosis-like cell death modes. In rat hearts, left ventricular function, remodelling, pro-cell death, and pro-inflammatory events were investigated, and the pharmacodynamic action of RIP3 inhibitor (GSK'872) was assessed. Regardless of the HF aetiology, the heart cells were dying due to necroptosis, albeit the upstream signals may be different. Pyroptosis was observed only in post-MI HF. The dysregulated miRNAs in post-MI hearts were accompanied by higher levels of a predicted target, HMGB1, its receptors (TLRs), as well as the exacerbation of inflammation likely originating from macrophages. The RIP3 inhibitor suppressed necroptosis, unlike pyroptosis, normalised the dysregulated miRNAs and tended to decrease collagen content and affect macrophage infiltration without affecting cardiac function or structure. The drug also mitigated the local heart inflammation and normalised the higher circulating HMGB1 in rats with post-MI HF. Elevated serum levels of HMGB1 were also detected in HF patients and positively correlated with C-reactive protein, highlighting pro-inflammatory axis. In conclusion, in MI-, but not pressure overload-induced HF, both necroptosis and pyroptosis operate and might underlie HF pathogenesis. The RIP3-targeting pharmacological intervention might protect the heart by preventing pro-death and pro-inflammatory mechanisms, however, additional strategies targeting multiple pro-death pathways may exhibit greater cardioprotection.

• MeSH
• funkce levé komory srdeční účinky léků   MeSH
• inhibitory proteinkinas * farmakologie   MeSH
• kardiomyocyty * účinky léků   patologie   enzymologie   MeSH
• krysa rodu rattus MeSH
• mikro RNA metabolismus   genetika   MeSH
• modely nemocí na zvířatech MeSH
• nekroptóza * účinky léků   MeSH
• nekróza MeSH
• potkani Sprague-Dawley MeSH
• pyroptóza * účinky léků   MeSH
• remodelace komor účinky léků   MeSH
• serin-threoninkinasy interagující s receptory * antagonisté a inhibitory   metabolismus   MeSH
• srdeční selhání * patologie   enzymologie   patofyziologie   farmakoterapie   etiologie   genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

• MeSH
• deep learning * MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• genetická variace MeSH
• genetické asociační studie MeSH
• genomika metody   MeSH
• hormony štítné žlázy metabolismus   genetika   MeSH
• lidé MeSH
• mentální retardace vázaná na chromozom X genetika   metabolismus   MeSH
• mladiství MeSH
• mutace ztráty funkce MeSH
• předškolní dítě MeSH
• přenašeče monokarboxylových kyselin * genetika   metabolismus   MeSH
• stupeň závažnosti nemoci MeSH
• svalová atrofie genetika   metabolismus   patologie   MeSH
• svalová hypotonie genetika   metabolismus   MeSH
• symportéry * genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

We present new developments for an ab-initio model of the neutron relative biological effectiveness (RBE) in inducing specific classes of DNA damage. RBE is evaluated as a function of the incident neutron energy and of the depth inside a human-sized reference spherical phantom. The adopted mechanistic approach traces neutron RBE back to its origin, i.e. neutron physical interactions with biological tissues. To this aim, we combined the simulation of radiation transport through biological matter, performed with the Monte Carlo code PHITS, and the prediction of DNA damage using analytical formulas, which ground on a large database of biophysical radiation track structure simulations performed with the code PARTRAC. In particular, two classes of DNA damage were considered: sites and clusters of double-strand breaks (DSBs), which are known to be correlated with cell fate following radiation exposure. Within a coherent modelling framework, this approach tackles the variation of neutron RBE in a wide energy range, from thermal neutrons to neutrons of hundreds of GeV, and reproduces effects related to depth in the human-sized receptor, as well as to the receptor size itself. Besides providing a better mechanistic understanding of neutron biological effectiveness, the new model can support better-informed decisions for radiation protection: indeed, current neutron weighting (ICRP)/quality (U.S. NRC) factors might be insufficient for use in some radiation protection applications, because they do not account for depth. RBE predictions obtained with the reported model were successfully compared to the currently adopted radiation protection standards when the depth information is not relevant (at the shallowest depth in the phantom or for very high energy neutrons). However, our results demonstrate that great care is needed when applying weighting factors as a function of incident neutron energy only, not explicitly considering RBE variation in the target. Finally, to facilitate the use of our results, we propose look-up RBE tables, explicitly considering the depth variable, and an analytical representation of the maximal RBE vs. neutron energy.

• MeSH
• dvouřetězcové zlomy DNA účinky záření   MeSH
• fantomy radiodiagnostické * MeSH
• lidé MeSH
• metoda Monte Carlo * MeSH
• neutrony * MeSH
• poškození DNA * MeSH
• relativní biologická účinnost * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: This study aimed to investigate the associations between radiographic damage, serum biomarkers, and clinical assessments in Czech patients with hand osteoarthritis (HOA) over a five-year follow-up period. METHODS: The study cohort comprised 129 patients diagnosed with HOA, including 72 patients with an erosive subtype and 57 patients with a non-erosive subtype. Radiographs were evaluated using the Kallman scoring system by two independent readers. Blood samples were analysed for markers of dyslipidaemia, bone metabolism, and inflammation. Clinical assessments focused on symptom severity and functional impairment. We employed generalised additive modelling (GAM) to analyse the associations between the Kallman score, serum biomarkers and clinical outcomes. RESULTS: The Kallman score was consistently higher in the erosive subtype compared to the non-erosive subtype across all time points and demonstrated a positive correlation with age in both groups. We demonstrated significant positive associations between radiographic progression and erythrocyte sedimentation rate across both HOA subtypes. Additionally, positive associations with the number of swollen joints and health assessment questionnaire scores were observed in all HOA patients, particularly in those with non-erosive subtypes. In contrast, markers of dyslipidaemia (e.g. LDL‐c or atherogenic index) were negatively associated with radiographic progression. No biomarker reliably differentiated between the erosive and non-erosive subtypes. CONCLUSIONS: Our longitudinal study revealed a significant association between systemic/local inflammation, dyslipidaemia, functional impairment and structural progression in HOA. However, these findings warrant further validation through additional studies to confirm these associations.

• MeSH
• biologické markery * krev   MeSH
• časové faktory MeSH
• dyslipidemie * krev   diagnostické zobrazování   MeSH
• funkční status MeSH
• klouby ruky * diagnostické zobrazování   MeSH
• krevní sedimentace MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• mediátory zánětu krev   MeSH
• osteoartróza * diagnostické zobrazování   krev   MeSH
• posuzování pracovní neschopnosti MeSH
• prediktivní hodnota testů MeSH
• progrese nemoci * MeSH
• radiografie MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• zánět krev   diagnostické zobrazování   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: There is a growing importance of loneliness measurement through valid and reliable instruments. However, to establish valid and reliable measures, there is a need to explore their psychometric properties in different research settings and language environments. For this reason, this study aimed to validate the Three Item Loneliness Scale (TILS) in the Czech Republic within a Slavonic language environment. METHODS: A sample of Czech adults (n = 3236) was used consisting primarily of university students. We utilized Classical Test Theory to assess TILS internal consistency, temporal stability, and factor structure. Item Response Theory (IRT) was used to estimate Differential Item Functioning (DIF), the discrimination and difficulty of the TILS items and to estimate the measurement precision of the whole scale. Construct validity was explored through the Spearman correlation coefficient using personality traits, depression, and anxiety. RESULTS: The results showed satisfactory reliability and validity of the TILS in the Czech Republic. The scale's internal consistency and temporal stability were found to be satisfactory (Cronbach's α = 0.81, McDonald's ω = 0.82, ICC = 0.71). The parallel analysis supported the unidimensionality of the TILS. The IRT results indicated that the highest measurement precision was reached in individuals with lower and above-average levels of loneliness. Significant correlations between the TILS scores, anxiety, depression, and personality traits supported the construct validity of the scale. Although the DIF analysis identified statistically significant differences in responses to items TILS_2 and TILS_3 based on education level and employment status (with no significant differences observed for TILS_1), the effect sizes of these differences were small. This indicates that, despite statistical significance, the practical impact on the scale's validity across these groups is minimal. CONCLUSIONS: The validated TILS provides a reliable and valid tool for assessing loneliness in the Czech Republic. Its brevity makes it a practical option for researchers and clinicians seeking to measure loneliness time-efficiently. Future studies should explore how adding new items could increase the measurement precision of the TILS.

• MeSH
• deprese psychologie   diagnóza   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• osamocení * psychologie   MeSH
• průzkumy a dotazníky normy   MeSH
• psychometrie * MeSH
• reprodukovatelnost výsledků MeSH
• úzkost psychologie   diagnóza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH

PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• ektopické lymfoidní struktury * imunologie   patologie   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• karboplatina aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   účinky léků   MeSH
• nádory vaječníků * farmakoterapie   imunologie   patologie   MeSH
• neoadjuvantní terapie metody   MeSH
• paclitaxel aplikace a dávkování   terapeutické užití   farmakologie   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   farmakologie   MeSH
• serózní cystadenokarcinom farmakoterapie   patologie   imunologie   MeSH
• stres endoplazmatického retikula účinky léků   imunologie   MeSH
• tumor infiltrující lymfocyty imunologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH