Plicní arteriální hypertenze (PAH) je vzácné a potenciálně fatální onemocnění malých plicních cév, jejichž vazokonstrikce a remodelace vede k nárůstu plicní cévní rezistence a k tlakovému zatížení pravé komory srdeční. I přes významný pokrok ve specifické léčbě PAH, která má přede- vším vazodilatační a částečně antiremodelační potenciál, zůstává mortalita PAH relativně vysoká. Sotatercept je rekombinantní fúzní protein, který ovlivněním signální cesty aktivinu rebalancuje proproliferativní působení této signální cesty a antiproliferativní působení signální cesty kostního morfogenetického proteinu. V rozsáhlém klinickém programu se sotaterceptem u nemocných s PAH, kteří již byli léčeni specifickou léčbou, vedlo podání přípravku formou podkožní injekce v intervalu 3 týdny k významnému zlepšení hemodynamiky, zátěžové kapacity, funkce pravé komory srdeční, kvality života a k oddálení doby do klinického zhoršení. Ke klinicky významným nežádoucím účinkům patří vzestup koncentrace hemoglobinu se zvýšením rizika tromboembolických komplikací, pokles počtu trombocytů, rozvoj teleangiektazií a riziko krvácení. Na základě rozsáhlé evidence o významné účinnosti a dobré bezpečnosti sotaterceptu se tento lék stává součástí kombinačních terapeutických schémat u PAH. Součástí léčby musí být pečlivá monitorace možných nežádoucích účinků, především pravidelné sledování koncentrace hemoglobinu a počtu trombocytů

Pulmonary arterial hypertension (PAH) is a rare and potentially fatal disease of the small pulmonary vessels, whose vasoconstriction and remodeling leads to an increase in pulmonary vascular resistance and pressure load on the right ventricle. Despite significant advances in specific treatments for PAH, which have primarily vasodilatory and partially antiremodeling potential, mortality in PAH remains relatively high. Sotatercept is a recombinant fusion protein that, by affecting the activin signaling pathway, rebalances the proproliferative action of this signaling pathway and the antiproliferative action of the bone morphogenetic protein signaling pathway. In a large clinical program with sotatercept in patients with PAH who were already treated with specific therapy, administration of the drug by subcutaneous injection at 3-week intervals resulted in significant improvements in hemodynamics, exercise capacity, right ventricular function, quality of life, and delayed time to clinical deterioration. Clinically significant adverse effects include a rise in haemoglobin concentration with an increased risk of thromboembolic complications, a decrease in platelet count, the development of telangiectasia and the risk of bleeding. On the basis of the extensive evidence of significant efficacy and good safety of sotatercept, it is becoming part of combination therapy regimens for PAH. Careful monitoring of possible adverse effects, especially regular monitoring of haemoglobin concentration and platelet count, must be part of the treatment.

The soil microbiota exhibits an important function in the ecosystem, and its response to climate change is of paramount importance for sustainable agroecosystems. The macronutrients, micronutrients, and additional constituents vital for the growth of plants are cycled biogeochemically under the regulation of the soil microbiome. Identifying and forecasting the effect of climate change on soil microbiomes and ecosystem services is the need of the hour to address one of the biggest global challenges of the present time. The impact of climate change on the structure and function of the soil microbiota is a major concern, explained by one or more sustainability factors around resilience, reluctance, and rework. However, the past research has revealed that microbial interventions have the potential to regenerate soils and improve crop resilience to climate change factors. The methods used therein include using soil microbes' innate capacity for carbon sequestration, rhizomediation, bio-fertilization, enzyme-mediated breakdown, phyto-stimulation, biocontrol of plant pathogens, antibiosis, inducing the antioxidative defense pathways, induced systemic resistance response (ISR), and releasing volatile organic compounds (VOCs) in the host plant. Microbial phytohormones have a major role in altering root shape in response to exposure to drought, salt, severe temperatures, and heavy metal toxicity and also have an impact on the metabolism of endogenous growth regulators in plant tissue. However, shelf life due to the short lifespan and storage time of microbial formulations is still a major challenge, and efforts should be made to evaluate their effectiveness in crop growth based on climate change. This review focuses on the influence of climate change on soil physico-chemical status, climate change adaptation by the soil microbiome, and its future implications.

• MeSH
• ekosystém MeSH
• klimatické změny * MeSH
• mikrobiota * MeSH
• půda chemie   MeSH
• půdní mikrobiologie * MeSH
• regulátory růstu rostlin metabolismus   MeSH
• zemědělské plodiny mikrobiologie   růst a vývoj   MeSH
• zemědělství metody   MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

OBJECTIVES: This study quantified blood bicarbonate (HCO3-) kinetics and gastrointestinal upset to determine the gender-related ergogenic potential of sodium bicarbonate (0.15-, 0.25- and 0.35 gSB·kgFat-free mass (FFM)-1) in high intensity functional training. DESIGN: Double-blind randomized placebo-controlled crossover. METHODS: Thirty female and male athletes performed two bouts of the Wingate Anaerobic Test (WAnTPRE-HIFT and WAnTPOST-HIFT) interspaced with two 3-min bouts of Wall Balls and Burpees 120 min after ingestion of three sodium bicarbonate doses. Blood HCO3- was determined pre-ingestion, after supplementation and before/post exercise. Gastrointestinal upset was evaluated 120 min post-ingestion. Control (CTRL) measurements were performed. RESULTS: There were significant gender × treatment interactions for: changes in blood HCO3- at 60 min post-ingestion (p = 0.014; η2p = 0.104; at 0.15 gSB·kgFFM-1 males experienced higher increase than females); peak power (p = 0.015; η2p = 0.103) and average power (p = 0.005; η2p = 0.124) during WAnTPOST-HIFT, and changes in peak power between the Wingate Anaerobic Test bouts (p = 0.049; η2p = 0.081). Sodium bicarbonate compared to PLA had no significant impact on Wall Balls and Burpees performance. The dose of 0.35 gSB·kgFFM-1 resulted in higher less severe gastrointestinal symptoms compared to CTRL and 0.15 gSB·kgFFM-1 (p = 0.001; W = 0.178); and higher total gastrointestinal upset compared to CTRL, PLA and 0.15 gSB·kgFFM-1 (p < 0.001; W = 0.323). CONCLUSIONS: There were dose- and gender-related differences in extracellular buffering capacity and ergogenic potential of sodium bicarbonate. The study suggested a detrimental impact of gastrointestinal upset on performance.

• MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• hydrogenuhličitan sodný * aplikace a dávkování   farmakologie   krev   MeSH
• klinické křížové studie * MeSH
• látky zvyšující výkon aplikace a dávkování   farmakologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• sexuální faktory MeSH
• zátěžový test MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

OBJECTIVES: The efficacy and safety of macitentan, an endothelin receptor antagonist, were assessed in a 52-week, prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessing the efficacy and safety of macitentan in Fontan-palliated adult and adolescent patients (RUBATO-DB) and an open-label extension trial (RUBATO-OL). METHODS: Patients aged 12 years and older with New York Heart Association functional class II or III underwent total cavopulmonary connection more than 1 year before screening and showed no signs of Fontan failure/clinical deterioration. In RUBATO-DB, the primary efficacy end point was change in peak oxygen consumption from baseline to week 16; secondary end points were change from baseline over 52 weeks in peak oxygen consumption and change in mean count/minute of daily physical activity via accelerometer from baseline to week 16. Safety was assessed throughout both studies. RESULTS: In RUBATO-DB, 137 patients were randomized to macitentan 10 mg (n = 68) or placebo (n = 69); 92.7% completed 52-week double-blind treatment. At week 16, mean ± SD change in peak oxygen consumption was -0.16 ± 2.86 versus -0.67 ± 2.66 mL/kg/minute with macitentan versus placebo (median unbiased treatment difference estimate, 0.62 mL/kg/minute [99% repeated CI, -0.62 to 1.85]; P = .19). No treatment effect was observed in either of the secondary end points. During RUBATO-DB, most common adverse events with macitentan were headache, nasopharyngitis, and pyrexia. Across RUBATO-DB and RUBATO-OL, most common adverse events were COVID-19, headache, and fatigue. RUBATO-OL was prematurely discontinued because RUBATO-DB did not meet its primary or secondary end point. CONCLUSIONS: The primary end point of RUBATO-DB was not met; macitentan did not improve exercise capacity versus placebo in patients with Fontan palliation. Macitentan was generally well tolerated over long-term treatment.

• MeSH
• antagonisté endotelinového receptoru terapeutické užití   škodlivé účinky   MeSH
• časové faktory MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• Fontanova operace * škodlivé účinky   MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• paliativní péče MeSH
• prospektivní studie MeSH
• pyrimidiny * terapeutické užití   škodlivé účinky   MeSH
• spotřeba kyslíku účinky léků   MeSH
• sulfonamidy * terapeutické užití   škodlivé účinky   MeSH
• tolerance zátěže účinky léků   MeSH
• vrozené srdeční vady chirurgie   patofyziologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH

Neural networks are responsible for processing sensory stimuli and driving the synaptic activity required for brain function and behavior. This computational capacity is expensive and requires a steady supply of energy and building blocks to operate. Importantly, the neural networks are composed of different cell populations, whose metabolic profiles differ between each other, thus endowing them with different metabolic capacities, such as, for example, the ability to synthesize specific metabolic precursors or variable proficiency to manage their metabolic waste. These marked differences likely prompted the emergence of diverse intercellular metabolic interactions, in which the shuttling and cycling of specific metabolites between brain cells allows the separation of workload and efficient control of energy demand and supply within the central nervous system. Nevertheless, our knowledge about brain bioenergetics and the specific metabolic adaptations of neural cells still warrants further studies. In this review, originated from the Fourth International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Schmerlenbach, Germany (2022), we describe and discuss the specific metabolic profiles of brain cells, the intercellular metabolic exchanges between these cells, and how these bioenergetic activities shape synaptic function and behavior. Furthermore, we discuss the potential role of faulty brain metabolic activity in the etiology and progression of Alzheimer's disease, Parkinson disease, and Amyotrophic lateral sclerosis. We foresee that a deeper understanding of neural networks metabolism will provide crucial insights into how higher-order brain functions emerge and reveal the roots of neuropathological conditions whose hallmarks include impaired brain metabolic function.

• MeSH
• energetický metabolismus * fyziologie   MeSH
• lidé MeSH
• metabolické sítě a dráhy * fyziologie   MeSH
• mozek * metabolismus   MeSH
• nervová síť * metabolismus   MeSH
• neurony * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The circadian clock in choroid plexus (ChP) controls processes involved in its physiological functions, but the signals that synchronize the clock have been sparsely studied. We found that the ChP clock in the fourthventricle (4V) is more robust than that in the lateral ventricle (LV) and investigated whether both clocks use information about mealtime as a signal to synchronize with the current activity state. Exposure of mPer2Luc mice to a 10-day reverse restricted feeding (rRF) protocol, in which food was provided for 6 h during daytime, advanced the phase of the ChP clock in 4V and LV, as evidenced by shifted (1) PER2-driven bioluminescence rhythms of ChP explants ex vivo and (2) daily profiles in clock gene expression in both ChP tissues in vivo. In contrast, clocks in other brain regions (DMH, ARC, LHb) of the same mice did not shift. The 4V ChP responded more strongly than the LV ChP to rRF by modulating the expression of genes to ensure a decrease in resistance to cerebrospinal fluid drainage and increase the secretory capacity of ChP cells. Mechanistically, rRF affects the ChP clock through food-induced increases in insulin, glucose and temperature levels, as in vitro all three signals significantly shifted the clocks in both ChP tissues, similar to rRF. The effect of glucose was partially blocked by OSMI-1, suggesting involvement of O-linked N-acetylglucosamine posttranslational modification. We identified mechanisms that can signal to the brain the time of feeding and the associated activity state via resetting of the ChP clock.

• MeSH
• cirkadiánní hodiny * fyziologie   genetika   MeSH
• cirkadiánní proteiny Period metabolismus   genetika   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• plexus chorioideus * metabolismus   fyziologie   MeSH
• regulace genové exprese MeSH
• stravovací zvyklosti * fyziologie   MeSH
• ventriculi laterales metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Chronic bronchitis is increasingly reported as a healthcare challenge in clinical settings partially due to the disease's bad prognosis and unresponsiveness to therapy, including the ineffectiveness of glucocorticoids. The ineffectiveness could have a link with genetic polymorphism of receptor genes resulting in inappropriate glucocorticoid pharmacodynamics. We sought to identify the role of gene polymorphism in the response of patients with chronic bronchitis to prednisolone therapy. To do so, a total of 60 newly diagnosed chronic bronchitis patients enrolled in the present study. Prednisolone at a dose of 30mg/day for two weeks was given and respiratory parameters [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were measured before and after therapy. Blood samples were withdrawn for genetic profiling of genes involved in glucocorticoids pharmacodynamics, including BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) measured for their homozygous versus heterozygous gene splice variants.Results: Gene splice variants for BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) homozygous (73.3%, 98.7%, and 95%) represented a higher percentage than heterozygous (26.7%, 1.7%, and 5%). The respiratory parameters FEV1, FVC, and FEV1/FVC have shown significantly (p<0.05) better values at baseline in homozygous versus heterozygous, correspondingly, the responsiveness to therapy has shown significantly (p<0.05) better values in homozygous versus heterozygous.Conclusion: The study has provided a good template for genetic behaviour toward individualised medicine in our locality providing that these genes could be a cornerstone for discovering issues related to the pharmacodynamics profiling of drugs in clinical settings.

• MeSH
• chronická bronchitida * diagnóza   genetika   MeSH
• glukokortikoidy farmakologie   MeSH
• lidé MeSH
• polymerázová řetězová reakce metody   MeSH
• polymorfismus genetický genetika   MeSH
• prednisolon farmakologie   terapeutické užití   MeSH
• protein - isoformy genetika   MeSH
• receptory glukokortikoidů * genetika   účinky léků   MeSH
• respirační funkční testy metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• klinická studie MeSH
• práce podpořená grantem MeSH

Nedd4-2 E3 ligase regulates Na+ homeostasis by ubiquitinating various channels and membrane transporters, including the epithelial sodium channel ENaC. In turn, Nedd4-2 dysregulation leads to various conditions, including electrolytic imbalance, respiratory distress, hypertension, and kidney diseases. However, Nedd4-2 regulation remains mostly unclear. The present study aims at elucidating Nedd4-2 regulation by structurally characterizing Nedd4-2 and its complexes using several biophysical techniques. Our cryo-EM reconstruction shows that the C2 domain blocks the E2-binding surface of the HECT domain. This blockage, ubiquitin-binding exosite masking by the WW1 domain, catalytic C922 blockage and HECT domain stabilization provide the structural basis for Nedd4-2 autoinhibition. Furthermore, Ca2+-dependent C2 membrane binding disrupts C2/HECT interactions, but not Ca2+ alone, whereas 14-3-3 protein binds to a flexible region of Nedd4-2 containing the WW2 and WW3 domains, thereby inhibiting its catalytic activity and membrane binding. Overall, our data provide key mechanistic insights into Nedd4-2 regulation toward fostering the development of strategies targeting Nedd4-2 function.

• MeSH
• elektronová kryomikroskopie MeSH
• HEK293 buňky MeSH
• lidé MeSH
• molekulární modely MeSH
• proteinové domény MeSH
• proteiny 14-3-3 * metabolismus   chemie   MeSH
• ubikvitinace MeSH
• ubikvitinligasy Nedd4 * metabolismus   chemie   genetika   ultrastruktura   MeSH
• vápník * metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Aging is associated with musculoskeletal pain and postural adaptations which may affect functionality. This study aims to analyse the effect of a combined protocol of self-assisted manual therapy and high-intensity walking on musculoskeletal back pain, functionality, and shoulder posture in older adults, and to establish the short- and medium-term effects of this program. METHODS: A multicentre, double-blind, randomized trial was conducted on older adults. The sample was divided into two groups: the self-assisted manual therapy plus walking at high-intensity group (MTWG) and the Control Group (CG), with the latter undergoing supervised high-intensity walking only. Pain (Pressure Pain Threshold and Visual Analogue Scale), functional capacity (5-times sit-to-stand test), and change in thorax position (acromion position) were assessed at T0 (baseline), T1 (after 4-week intervention) and T2 (follow-up, 4 weeks after the end of the intervention). RESULTS: A total of 95 older adults (41 in the MTWG and 54 in CG) completed the study and were analyzed. After isolating the effect of correlations among our primary outcomes, our analysis revealed statistically significant between-subject (p < 0.01), within-subject (p < 0.001) and between-within subject differences (p < 0.05) in Pressure Pain Threshold scores in favour of the MTWG. We also detected within-subjects (p < 0.001) and between-within subject differences (p < 0.05) in scores for the Visual Analogue Scale, in favour of the MTWG. These patterns of results remained stable at T2. The 5-times sit-to-stand test (p < 0.01) and the acromion position (p < 0.05) improved at T1 for the MTWG but not at T2. CONCLUSIONS: A combined protocol of self-assisted manual therapy and high-intensity walking, compared to high-intensity walking alone, improved musculoskeletal pain, functionality, and posture in older adults in the short term (over one month), with pain reduction maintained in the medium term (at the one-month follow-up).

• Publikační typ
• časopisecké články MeSH

The aim of this study was to test the hypothesis that individuals with an increase in HbA1c (i.e. above the regular but below the diabetic threshold) exhibit an impairment in the Achilles tendon structure and walking capacity, due to the adverse effect of the advanced glycation end-product. One hundred fifty-eight participants matched for gender, age, physical activity and BMI, were divided in two cohorts based on the HbA1c level: normal HbA1c (NGH; <39 mmol/molHb; n = 79) and altered HbA1c (AGH; >=39 mmol/molHb; n = 79). Each participant performed several walking trials to evaluate the kinematic parameters during walling at the self-selected speed and a quantitative MRI scan of the Achilles tendon (AT) to obtain its intrinsic characteristics (i.e. T2* relaxation time short and long component). The AT T2* relaxation time short component (a parameter related to the tendon collagen quality) was reduced in AGH compared to NGH. Furthermore, AGH exhibited a slower self-selected walking speed (NGH: 1.59 ± 0.18 m/s; AGH:1.54 ± 0.16 m/s) and a shorter stride length (NGH: 1.59 ± 0.13 m; AGH:1.55 ± 0.11 m). Our data suggest that a non-pathological increase in HbA1c is able to negatively affect AT collagen quality and walking capacity in healthy people. These results highlight the importance of glycemic control, even below the pathological threshold. Since diabetes could alter several biological pathways, further studies are necessary to determine which mechanisms and their timing, regarding the HbA1c rise, affect tendon composition and, consequently, walking capacity.

• MeSH
• Achillova šlacha * diagnostické zobrazování   fyziologie   metabolismus   MeSH
• biomechanika MeSH
• chůze * fyziologie   MeSH
• diabetes mellitus diagnóza   MeSH
• dospělí MeSH
• glykovaný hemoglobin * metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• produkty pokročilé glykace metabolismus   MeSH
• zdraví dobrovolníci pro lékařské studie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH