Mutation of SMARCA4 (BRG1), the ATPase of BAF (mSWI/SNF) and PBAF complexes, contributes to a range of malignancies and neurologic disorders. Unfortunately, the effects of SMARCA4 missense mutations have remained uncertain. Here we show that SMARCA4 cancer missense mutations target conserved ATPase surfaces and disrupt the mechanochemical cycle of remodeling. We find that heterozygous expression of mutants alters the open chromatin landscape at thousands of sites across the genome. Loss of DNA accessibility does not directly overlap with Polycomb accumulation, but is enriched in 'A compartments' at active enhancers, which lose H3K27ac but not H3K4me1. Affected positions include hundreds of sites identified as superenhancers in many tissues. Dominant-negative mutation induces pro-oncogenic expression changes, including increased expression of Myc and its target genes. Together, our data suggest that disruption of enhancer accessibility represents a key source of altered function in disorders with SMARCA4 mutations in a wide variety of tissues.

• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• chromatin chemie   MeSH
• DNA-helikasy genetika   MeSH
• dominantní geny * MeSH
• epigenomika MeSH
• genotyp MeSH
• heterozygot MeSH
• jaderné proteiny genetika   MeSH
• kultivační média MeSH
• lidé MeSH
• missense mutace MeSH
• multivariační analýza MeSH
• mutace * MeSH
• myší embryonální kmenové buňky cytologie   MeSH
• myši transgenní MeSH
• myši MeSH
• nádory genetika   MeSH
• polycomb proteiny genetika   MeSH
• restrukturace chromatinu MeSH
• sekvenční analýza RNA MeSH
• transkripční faktory genetika   MeSH
• zesilovače transkripce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• adenosintrifosfatasy MeSH
• chromatin MeSH
• DNA-helikasy MeSH
• jaderné proteiny MeSH
• kultivační média MeSH
• polycomb proteiny MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• transkripční faktory MeSH

Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.

• MeSH
• buněčné linie MeSH
• dítě MeSH
• ekzém genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• HEK293 buňky MeSH
• imunoglobulin E krev   MeSH
• insulinu podobný růstový faktor I biosyntéza   MeSH
• kojenec MeSH
• Laronův syndrom genetika   MeSH
• lidé MeSH
• lidský růstový hormon metabolismus   MeSH
• missense mutace genetika   MeSH
• mladiství MeSH
• responzivní elementy genetika   MeSH
• transkripční faktor STAT5 genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• IGF1 protein, human MeSH Prohlížeč
• imunoglobulin E MeSH
• insulinu podobný růstový faktor I MeSH
• lidský růstový hormon MeSH
• STAT5B protein, human MeSH Prohlížeč
• transkripční faktor STAT5 MeSH

Microphthalmia transcription factor (MITF) positively regulates transcription of differentiation-related genes in several cell lineages, including melanocytes. Recent data also indicate a new important role for MITF as a factor that appears to be required for survival of melanoma cells, suggesting a possibility that abrogation of MITF function in transformed melanocytes could lead to a decreased survival via attenuating anti-apoptotic signals. Therefore, to gain a better understanding of the role which MITF plays in melanoma cell survival, it is important to find efficient means of abolishing the transactivation of its target genes. Recently, a dominant negative MITF lacking the N-terminus has been shown to down-regulate tyrosinase and Trp1 expression in normal melanocytes and mouse B16 melanoma cells. Here, a dominant negative mutant of the melanocyte-specific isoform of MITF is described carrying deletions of both N- and C-terminal transactivation domains. Cotransfection of this mutant resulted in a complete inhibition of the wild type MITF function as tested on both the reporter-linked tyrosinase promoter and an endogenous, ectopic MITF-triggered tyrosinase gene in U2-OS cells. The dominant negative construct also strongly repressed the activity of a hyperactive MITF-Vp16 chimera. Importantly, deletion of both activation domains was necessary to eliminate the residual transcription activity observed when only the N-terminal domain was removed and to achieve the repressive effect in human melanoma cells. If the activity of MITF plays a role in the long-term survival of malignant melanocytes, overexpression of a strong dominant negative MITF mutant might be a useful strategy to suppress its transactivation function.

• MeSH
• aktivace transkripce fyziologie   MeSH
• DNA vazebné proteiny genetika   metabolismus   MeSH
• dominantní geny MeSH
• genetická transkripce fyziologie   MeSH
• herpes simplex virus - protein Vmw65 genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• promotorové oblasti (genetika) fyziologie   MeSH
• regulace genové exprese enzymů fyziologie   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• suprese genetická fyziologie   MeSH
• terciární struktura proteinů genetika   fyziologie   MeSH
• transkripční faktor spojený s mikroftalmií MeSH
• transkripční faktory genetika   metabolismus   MeSH
• tyrosinasa genetika   metabolismus   MeSH
• umělá fúze genů MeSH
• virové geny genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA vazebné proteiny MeSH
• herpes simplex virus - protein Vmw65 MeSH
• MITF protein, human MeSH Prohlížeč
• Mitf protein, mouse MeSH Prohlížeč
• rekombinantní proteiny MeSH
• transkripční faktor spojený s mikroftalmií MeSH
• transkripční faktory MeSH
• tyrosinasa MeSH

The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.

• MeSH
• biomarkery farmakologické metabolismus   MeSH
• chemorezistence genetika   MeSH
• cystein genetika   MeSH
• dospělí MeSH
• erbB receptory antagonisté a inhibitory   MeSH
• glycin genetika   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace fyziologie   MeSH
• nádorové biomarkery genetika   fyziologie   MeSH
• nádory plic diagnóza   farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic diagnóza   farmakoterapie   genetika   MeSH
• prognóza MeSH
• protinádorové látky terapeutické užití   MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny genetika   metabolismus   fyziologie   MeSH
• Ras proteiny genetika   metabolismus   fyziologie   MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• substituce aminokyselin fyziologie   MeSH
• tyrosinkinasy antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnotící studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biomarkery farmakologické MeSH
• cystein MeSH
• erbB receptory MeSH
• glycin MeSH
• inhibitory proteinkinas MeSH
• KRAS protein, human MeSH Prohlížeč
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny MeSH
• Ras proteiny MeSH
• tyrosinkinasy MeSH

The RNA polymerase II complex (pol II) is responsible for transcription of all ∼21,000 human protein-encoding genes. Here, we describe sixteen individuals harboring de novo heterozygous variants in POLR2A, encoding RPB1, the largest subunit of pol II. An iterative approach combining structural evaluation and mass spectrometry analyses, the use of S. cerevisiae as a model system, and the assessment of cell viability in HeLa cells allowed us to classify eleven variants as probably disease-causing and four variants as possibly disease-causing. The significance of one variant remains unresolved. By quantification of phenotypic severity, we could distinguish mild and severe phenotypic consequences of the disease-causing variants. Missense variants expected to exert only mild structural effects led to a malfunctioning pol II enzyme, thereby inducing a dominant-negative effect on gene transcription. Intriguingly, individuals carrying these variants presented with a severe phenotype dominated by profound infantile-onset hypotonia and developmental delay. Conversely, individuals carrying variants expected to result in complete loss of function, thus reduced levels of functional pol II from the normal allele, exhibited the mildest phenotypes. We conclude that subtle variants that are central in functionally important domains of POLR2A cause a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia and developmental delay through a dominant-negative effect on pol-II-mediated transcription of DNA.

• Klíčová slova
• POLR2A, RNA polymerase II complex, RPB1, de novo variants, desert Z score, desert regions, dominant-negative effect, haplo-insufficiency, infantile-onset hypotonia, neurodevelopmental syndrome,
• MeSH
• dítě MeSH
• DNA řízené RNA-polymerasy genetika   MeSH
• fenotyp MeSH
• HeLa buňky MeSH
• heterozygot MeSH
• lidé MeSH
• mladiství MeSH
• mutace * MeSH
• neurovývojové poruchy enzymologie   genetika   patologie   MeSH
• předškolní dítě MeSH
• Saccharomyces cerevisiae genetika   růst a vývoj   metabolismus   MeSH
• svalová hypotonie enzymologie   genetika   patologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA řízené RNA-polymerasy MeSH
• POLR2A RNA polymerase, human MeSH Prohlížeč

Plant-plant interactions (competition and facilitation) in terrestrial ecosystems include: (1) short-term effects, primarily quantified with experimental removals; and (2) long-term effects, mostly due to soil weathering processes, primarily quantified with observational methods. It has been argued that these effects are likely to vary in contrasting directions with increasing drought stress in arid systems. However, few studies have used appropriate methodology to assess both types of effects and their variation across nurse species and environmental conditions, in particular in arid systems. This knowledge is crucial for predicting variation in the mediating role of facilitation with climate change and assessing the importance of nurse effects in ecological restoration. In the arid climate of central-south Tunisia, understory species' biomass, abundance and composition and soil parameters were compared in shrub-control, shrub-removed and open areas for three shrub species and in two habitats with contrasting soil moisture conditions. Long-term effects were dominant, positive for all three shrub species and associated with increasing nutrient content in shrub patches. Short-term effects, mainly related to water consumption, were weaker, mostly negative and dependent on shrub species. Additionally, long-term effects were less positive and short-term effects more negative in the dry habitat than in the wet habitat. Our study provides evidence of the primary influence of positive (facilitative) long-term effects in this arid system. However, the net effects of shrubs could be less beneficial for other species with increasing aridity under climate change, due to both a decrease in positive long-term effects and an increase in negative short-term effects.

• Klíčová slova
• Arid communities, Canopy effect, Competition, Facilitation, Soil effect,
• MeSH
• biomasa * MeSH
• čas MeSH
• druhová specificita MeSH
• ekologie MeSH
• ekosystém * MeSH
• fyziologický stres MeSH
• klimatické změny * MeSH
• pouštní klima * MeSH
• půda chemie   MeSH
• rostliny * MeSH
• voda * MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Tunisko MeSH
• Názvy látek
• půda MeSH
• voda * MeSH

Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

• MeSH
• dna (nemoc) * klasifikace   diagnóza   genetika   terapie   MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• hyperurikemie * klasifikace   diagnóza   genetika   terapie   MeSH
• konsensus MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• nefrologie normy   MeSH
• nemoci ledvin * klasifikace   diagnóza   genetika   terapie   MeSH
• polycystické ledviny autozomálně dominantní * klasifikace   diagnóza   genetika   terapie   MeSH
• prediktivní hodnota testů MeSH
• terminologie jako téma MeSH
• uromodulin klasifikace   nedostatek   genetika   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• směrnice pro lékařskou praxi MeSH
• Názvy látek
• uromodulin MeSH

Dominance hierarchy is often established via repeated agonistic encounters where consistent winners are considered dominant. Human body odour contains cues to psychological dominance and competition, but it is not known whether competition outcome (a marker of a change in dominance hierarchy) affects the hedonic quality of human axillary odour. Therefore, we investigated the effect of winning and losing on odour quality. We collected odour samples from Mixed Martial Arts fighters approximately 1 h before and immediately after a match. Raters then assessed samples for pleasantness, attractiveness, masculinity and intensity. We also obtained data on donors' affective state and cortisol and testosterone levels, since these are known to be associated with competition and body odour quality. Perceived body odour pleasantness, attractiveness and intensity significantly decreased while masculinity increased after a match irrespective of the outcome. Nonetheless, losing a match affected the pleasantness of body odour more profoundly, though bordering formal level of significance. Moreover, a path analysis revealed that match loss led to a decrease in odour attractiveness, which was mediated by participants' negative affective states. Our study suggests that physical competition and to some extent also its outcome affect the perceived quality of human body odour in specific real-life settings, thus providing cues to dominance-related characteristics. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.

• Klíčová slova
• cortisol, dominance, hierarchy, olfaction, smell, testosterone,
• MeSH
• bojové sporty MeSH
• čich * MeSH
• čichová percepce * MeSH
• dospělí MeSH
• hydrokortison krev   MeSH
• kompetitivní chování fyziologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• odoranty analýza   MeSH
• testosteron krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• hydrokortison MeSH
• testosteron MeSH

INTRODUCTION: Impaired baroreflex function is associated with a shift in autonomic balance towards sympathetic dominance, which may play important role in the development of arterial hypertension and consequent target organ damage. AIM: To determine the effect of treatment on the cardiovascular autonomic modulation expressed by baroreflex sensitivity (BRS) in hypertensives. METHODS: A total of one hundred fourteen hypertensive patients (58 male/56 female, 65 ± 13 years of age, BMI 30 ± 3.4 kg/m(2)) were enrolled. Control group of 20 subjects with normal blood pressure (BP) (ten male/ten female, 59 ± 8 years of age, body mass index 28.3 ± 2.5 kg/m(2)) without any treatment was also studied. BRS and BRSf were determined by the sequence and spectral method: a 5-min on-invasive beat-to-beat recording of blood pressure and R-R interval with use of Collin CBM-7000 monitor, controlled breathing at a frequency of 0.1 Hz. RESULTS: Significant negative correlation between spontaneous BRS and BP was present in hypertensives (r = -0.52, p < 0.001). All cohort of hypertensive patients had significantly lower BRS than subjects with normal blood pressure (p < 0.05). The greatest decline in BRS values was in hypertensive patients with metabolic syndrome, who had BRS values <5 ms/mmHg. Hypertensives with hypercholesterolaemia on low dose statin therapy (atrovastatin 20 mg) had higher BRS/BRSf values than statin free patients (p < 0.05). Only BRSf not BRS was significantly increased in hypertensives with beta-blockers. CONCLUSION: An inverse correlation between blood pressure and BRS is present in hypertensives. BRS and BRSf is higher in low dose statin-treated patients with essential hypertension.

• Klíčová slova
• Arterial hypertension, Autonomic nervous system, Baroreflex sensitivity, Metabolic syndrome, Statins,
• MeSH
• antihypertenziva aplikace a dávkování   MeSH
• arteriální tlak účinky léků   MeSH
• atorvastatin aplikace a dávkování   MeSH
• autonomní nervový systém účinky léků   patofyziologie   MeSH
• baroreflex účinky léků   MeSH
• časové faktory MeSH
• hyperlipidemie diagnóza   farmakoterapie   patofyziologie   MeSH
• hypertenze diagnóza   farmakoterapie   patofyziologie   MeSH
• kardiovaskulární systém inervace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• statiny aplikace a dávkování   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antihypertenziva MeSH
• atorvastatin MeSH
• statiny MeSH

The boreal forest represents the terrestrial biome most heavily affected by climate change. However, no consensus exists regarding the impacts of these changes on the growth of tree species therein. Moreover, assessments of young tree responses in metrics transposable to forest management remain scarce. Here, we assessed the impacts of climate change on black spruce (Picea mariana [Miller] BSP) and jack pine (Pinus banksiana Lambert) growth, two dominant tree species in boreal forests of North America. Starting with a retrospective analysis including data from 2591 black spruces and 890 jack pines, we forecasted trends in 30-year height growth at the transitions from closed to open boreal coniferous forests in Québec, Canada. We considered three variables: (1) height growth, rarely used, but better-reflecting site potential than other growth proxies, (2) climate normals corresponding to the growth period of each stem, and (3) site type (as a function of texture, stoniness, and drainage), which can modify the effects of climate on tree growth. We found a positive effect of vapor pressure deficit on the growth of both species, although the effect on black spruce leveled off. For black spruce, temperatures had a positive effect on the height at 30 years, which was attenuated when and where climatic conditions became drier. Conversely, drought had a positive effect on height under cold conditions and a negative effect under warm conditions. Spruce growth was also better on mesic than on rocky and sub-hydric sites. For portions of the study areas with projected future climate within the calibration range, median height-change varied from 10 to 31% for black spruce and from 5 to 31% for jack pine, depending on the period and climate scenario. As projected increases are relatively small, they may not be sufficient to compensate for potential increases in future disturbances like forest fires.

• Klíčová slova
• black spruce, boreal forests, climate normals, height growth, jack pine, productivity, surficial deposits,
• MeSH
• borovice * fyziologie   MeSH
• klimatické změny MeSH
• retrospektivní studie MeSH
• smrk * fyziologie   MeSH
• stromy MeSH
• tajga MeSH
• Publikační typ
• časopisecké články MeSH