The design of MB327, a bispyridinium compound that ameliorates the nicotinic effects of acute organophosphorus nerve agent (NA) intoxication, followed an observation made by the German pharmacologist Klaus Schoene in the 1970s, who noted therapeutic activity in bispyridinium molecules missing the usual oxime group, CHNOH. Some of these compounds protected mice against soman. One structurally related to obidoxime called HY10 had this action. Its oxime moieties were capped by tert-butyl groups: CH=NOtBu. We modified HY10 by changing the bridge between the pyridinium units from a dimethylene ether to a trimethylene group (CH2OCH2 → CH2CH2CH2) and prepared a novel relative of trimedoxime, called LB1, whose synthesis and stereochemistry are described. Unlike obidoxime or trimedoxime, LB1 because of its capped oxime groups, cannot directly reactivate NA inhibited acetylcholinesterase. Its antidotal activity in mice is now reported. The therapeutic efficacy of LB1, atropine alone, atropine with LB1, atropine with an oxime (HI-6, obidoxime or trimedoxime), and atropine with an oxime and LB1, was studied by determining the LD50 values of the NAs soman, sarin, or tabun in mice treated with these compounds or mixtures. LB1 exceeded MB327 in toxicity and its activity was insufficient for a useful addition to the current standard antidotal treatment (protective ratio data are compared to those of MB327). Although this study produced largely negative biological results, the therapeutically beneficial mechanism of the effective bispyridinium non-oxime analogues is unclear, and has been demonstrated only in vivo. The present study points out directions in structural optimisation unlikely to yield the desired therapeutic outcomes and provides a literature review that could promote creative thinking for the design of widely-desirable non-oxime therapeutics for anticholinesterase inhibitors.

• Klíčová slova
• Bispyridinium, LB1, Mechanism, Mice, Nerve agent, Pyridinecarboxaldoxime,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota * chemická syntéza   chemie   farmakologie   terapeutické užití   MeSH
• atropin terapeutické užití   farmakologie   MeSH
• cholinesterasové inhibitory toxicita   MeSH
• myši MeSH
• nervová bojová látka * toxicita   MeSH
• organofosforové sloučeniny * toxicita   MeSH
• oximy chemie   MeSH
• pyridinové sloučeniny * chemická syntéza   chemie   terapeutické užití   farmakologie   MeSH
• soman toxicita   MeSH
• trimedoxim chemie   chemická syntéza   farmakologie   terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota * MeSH
• atropin MeSH
• cholinesterasové inhibitory MeSH
• MB327 MeSH Prohlížeč
• nervová bojová látka * MeSH
• organofosforové sloučeniny * MeSH
• oximy MeSH
• pyridinové sloučeniny * MeSH
• soman MeSH
• trimedoxim MeSH

Climate change requires mitigation approaches, from nature-based to experimental geoengineering. We examined public attitudes toward six strategies-reforestation in previously forested areas, afforestation in new terrains, direct CO2 capture with underground storage, biomass energy with CO2 capture, stratospheric sulfate aerosols, and orbital mirrors-via a representative Czech survey (N = 3,007). Binary logistic regressions reveal how age, education, employment, and residence shape perceptions of efficacy, risks, and ethics. Results show strong favor for reforestation and afforestation due to ecological benefits and long-term promise; sulfate aerosols and orbital mirrors face skepticism. Surprisingly, participants with only primary education showed greater openness to geoengineering than university graduates. Older respondents favored biomass-based carbon capture but less so certain high-tech solutions. Our findings highlight the importance of policies aligned with diverse public views, ensuring both established and novel measures are harmonized into an effective climate mitigation strategy. These results indicate demographic contexts shape acceptance of climate interventions.

• Klíčová slova
• Environmental policy, Environmental science,
• Publikační typ
• časopisecké články MeSH

Rainfed wheat is of paramount importance to global food security, representing the most extensively cultivated crop worldwide. In a considerable number of regions, wheat yields fail to reach the anticipated production levels. Although an increase in nitrogen (N) and phosphorus (P) fertilizer inputs can enhance yield and help to close the yield gap, excessive use can lead to environmental pollution and disrupt biogeochemical cycles. The objective of this study is to ascertain the optimal rates of N and P application required to achieve 50 %, 70 %, and 80 % of the water-limited potential yield (Yw) for rainfed wheat. By integrating the Global Yield Gap Atlas with regression models and meta-analysis, we evaluated the global N and P requirements for rainfed wheat. The results demonstrate that to achieve a yield target of 50 % Yw, a reduction of 40 % in the application of N is required. Conversely, a 10 % reduction in N application is necessary to reach a yield target of 70 % Yw. To reach 80 % Yw, an increase of 13 % in the application of N is required. Regarding P, a reduction of 12 % is required in order to achieve a 50 % Yw, whereas both 70 % and 80 % Yw targets necessitate an increase of 15 %. These findings offer crucial insights for policymakers and agricultural stakeholders, providing a basis for enhancing food security, improving sustainability, and addressing the global yield gap challenge.

• Klíčová slova
• Fertilizer, GYGA results, Potential yield, Rainfed wheat, Yield gap,
• MeSH
• dusík * analýza   MeSH
• fosfor * analýza   MeSH
• průmyslová hnojiva * analýza   MeSH
• pšenice * růst a vývoj   MeSH
• zemědělství * metody   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dusík * MeSH
• fosfor * MeSH
• průmyslová hnojiva * MeSH

Bone strength is reduced In various neuromuscular disorders (NMDs). We aimed to assess the awareness and practice of bone strength management in NDMs among clinicians and patients. We performed two online surveys; among health care providers (HCPs) of the European Reference Network for Neuromuscular Disorders (ERN EURO-NMD) and among patients. The survey among 52 HCPs showed that awareness of potentially impaired bone strength in people with NMDs was reasonable to good: the vast majority of HCPs asked often or almost always about bone fractures during history-taking (81 %). Bone strength was less often assessed: often or almost always at diagnosis (50 %) and at follow-up (58 %). Medical training on this topic was considered poor to very poor in 50 % of HCPs. Prevention and treatment of reduced bone strength was variable and multidisciplinary care was sub-optimal. The survey among 581 patients provided important additional insights. Many patients were followed-up outside ERN EURO-NMD centers and treatment was variable. These parallel surveys provided a broad view on the awareness and management of bone strength in people with NMDs. The findings are expected to increase the appreciation of this important aspect of NMD care, and direct future research foci and care guidelines.

• Klíčová slova
• Bone health, Bone strength, Fracture, Immobilization, Management, Neuromuscular disorders,
• MeSH
• dospělí MeSH
• kostní denzita * fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• neuromuskulární nemoci * komplikace   patofyziologie   terapie   epidemiologie   MeSH
• průzkumy a dotazníky MeSH
• senioři MeSH
• uvědomování si * MeSH
• zdraví - znalosti, postoje, praxe * MeSH
• zdravotnický personál MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

Cellulose is a highly versatile and abundant biopolymer that holds significant promise for enhancing capture technologies due to its inherent properties. However, to maximize its effectiveness in carbon dioxide (CO2) adsorption, it is essential to enhance its properties through chemical or physical modifications. By developing cellulose-based materials with tailored functionalities, we can create sustainable sorbents that not only contribute to reducing greenhouse gas emissions but also leverage low-cost and environmentally friendly resources, making them suitable for large-scale applications in carbon capture technologies. This study demonstrates the synthesis of carboxymethyl cellulose-polypyrrole (CMC-PP) nanocomposite and its coating with (3-aminopropyl)triethoxysilane (APTS) or (3-mercaptopropyl)trimethoxysilane (MPTS) to derive CMC-PP-NH2 and CMC-PP-SH nanocomposites, respectively. The designed composites' physicochemical properties were studied using various analytical techniques. The CO2 and N2 capture capabilities of CMC-PP, CMC-PP-NH2, and CMC-PP-SH nanocomposites were investigated. Among them, the CMC-PP-SH nanocomposite has exhibited the highest CO2 adsorption capacity of 49.6 cm3g-1. Adsorption isotherms fitting using the dual-site Langmuir model and calculation of standard enthalpy changes (Qst) reveal that the thiol groups in CMC-PP-SH provide the most favourable interactions for CO2 capture. These findings demonstrate the potential utilization of silane coatings to develop advanced materials for effective gas adsorption and separation technologies.

• Klíčová slova
• CO(2) capture, Carboxymethyl cellulose (CMC), Nanocomposites, Polypyrrole, Silane functionalization,
• Publikační typ
• časopisecké články MeSH

Despite the ecosystem functions offered by sponges in freshwater habitats, fragmentary studies have targeted their microbiome and the bioaccumulation of legacy and emerging organic micropollutants, making it difficult to test hypotheses about sponge-microbe specificity and response to environmental factors and stressors. The sponge species Ephydatia muelleri and Spongilla lacustris, coexisting in two sites of the Pasvik River (northern Fennoscandia), were analyzed for persistent organic pollutant (POPs) and chemicals of emerging concern (CECs), along with quali-quantitative microbiological features. River water and sediment were similarly treated to establish if the obtained data were site- or sponge-specific. CECs mainly occurred in abiotic matrices, with trimethoprim and ciprofloxacin prevailing in water and sediment, respectively. Only ciprofloxacin and diclofenac were detected in sponges, with higher concentrations generally determined in S. lacustris than E. muelleri. Overall, POP concentrations were in the order polycyclic aromatic hydrocarbons > chlorobenzenes > polychlorobiphenyls > polychloronaphthalenes, with higher values in sponges with respect to abiotic matrices. Generally, POPs occurred at higher concentrations in S. lacustris than E. muelleri. Enzyme activity measurements displayed diverse trends across samples and sites, with E. muelleri displaying higher glycolytic activity than S. lacustris. Prokaryotic abundance in sponges generally exceeded that found in abiotic matrices. Proteobacteria, Planctomycetota, Actinobacteriota, Verrucomicrobiota, and Cyanobacteria predominated in sponge samples, with slight differences between sponge species and sampling sites, whereas Desulfobacterota and Acidobacterota were retrieved mostly in sediment samples. The sponge-associated bacterial communities appeared to be differently affected by pollutant concentration at the site level. Overall, this study highlights the ecological role of freshwater sponges, shedding light on their microbial associations, pollutant bioaccumulation, and potential as bioindicators of aquatic ecosystem health. The findings emphasize the importance of considering both microbial diversity and contaminant accumulation for a holistic understanding of the roles played by freshwater sponges in human-impacted environments.

• Klíčová slova
• Emerging contaminants, Freshwater sponges, Persistent organic pollutants, Prokaryotic communities, Sub-arctic,
• MeSH
• chemické látky znečišťující vodu * analýza   MeSH
• geologické sedimenty mikrobiologie   chemie   MeSH
• mikrobiota * účinky léků   MeSH
• monitorování životního prostředí * MeSH
• perzistentní organické znečišťující látky metabolismus   MeSH
• Porifera * mikrobiologie   MeSH
• řeky * mikrobiologie   chemie   MeSH
• sladká voda mikrobiologie   chemie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické látky znečišťující vodu * MeSH
• perzistentní organické znečišťující látky MeSH

BACKGROUND AND OBJECTIVES: IV-administered ocrelizumab (OCR) is approved for the treatment of relapsing and primary progressive multiple sclerosis (RMS/PPMS). OCARINA II (NCT05232825) was designed to demonstrate noninferiority in drug exposure of OCR subcutaneous (SC) vs IV administration. METHODS: This phase 3, randomized, open-label study enrolled OCR-naive patients aged 18-65 years with RMS/PPMS and an Expanded Disability Status Scale score of 0-6.5. Patients received OCR IV 600 mg or OCR SC 920 mg (controlled period), followed by OCR SC 920 mg every 24 weeks, up to week 96 (OCR IV/SC and OCR SC/SC). The primary end point was OCR area under the serum concentration-time curve from day 1 to week 12 (AUCW1‒12); other end points included clinical, biomarker, and pharmacodynamic outcomes and safety data. RESULTS: Baseline demographics were balanced across OCR IV/SC and OCR SC/SC arms (N = 118/118, 40.0 ± 11.9/39.9 ± 11.4 years, 59.3%/65.3% female, 89.0%/89.0% with RMS). The study demonstrated noninferiority of OCR SC 920 mg to OCR IV 600 mg for the primary end point AUCW1-12 and also over the dosing interval for AUCW1‒24 (geometric mean ratios [90% CI] 1.29 [1.23-1.35] and 1.27 [1.21-1.34], respectively). At week 48, 111 of 118 (OCR IV/SC) and 114 of 118 (OCR SC/SC) had received OCR SC. A near-complete suppression of MRI activity was reported in OCR IV/SC and OCR SC/SC: 0 of 113 and 0 of 113 patients had T1 lesions while 1 of 114 and 1 of 113 had 2 and 1 new/enlarging T2 lesions, respectively. Two patients (1.9%) in each arm had 1 relapse, and 1 patient (0.9%; OCR SC/SC) had 2 relapses. In both arms, rapid and sustained B-cell depletion was observed and serum neurofilament light chain reduction was comparable. Patients receiving at least 1 dose of OCR SC 920 mg in the OCR IV/SC and OCR SC/SC arms reported adverse events (AEs): 75.4% and 86.4%, and serious AEs: 5.9% and 2.5%. The most frequently reported AEs were injection reactions (IRs, 51.5%); local and systemic IRs were experienced by 117 of 233 patients (50.2%) and 27 of 233 patients (11.6%), respectively. All IRs were mild/moderate; intensity and duration decreased with subsequent injections. DISCUSSION: The OCR SC formulation demonstrated noninferiority to OCR IV formulation regarding drug exposure, providing comparable efficacy and safety and an additional treatment option for patients with multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that a single SC injection of 920 mg of OCR achieves a noninferior 12-week area under serum concentration-time curve to that of 2 IV infusions of 300-mg OCR administered 2 weeks apart. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT05232825; submitted: January 27, 2022; first patient enrolled: May 3, 2022; available at: clinicaltrials.gov/study/NCT05232825?term=NCT05232825&rank=1.

• MeSH
• chronicko-progresivní roztroušená skleróza * farmakoterapie   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   terapeutické užití   farmakokinetika   škodlivé účinky   MeSH
• imunologické faktory * aplikace a dávkování   farmakokinetika   MeSH
• injekce subkutánní MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• hodnocení ekvivalence MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• humanizované monoklonální protilátky * MeSH
• imunologické faktory * MeSH
• ocrelizumab MeSH Prohlížeč

Multidrug resistance (MDR) represents one of the major concerns in cancer therapy as it may cause reduced efficacy of chemotherapeutic drugs due to the overexpression of ABC transporters, particularly P-glycoprotein (P-gp). This study explores the potential of novel amphiphilic diblock (DB) copolymers composed of poly[N-(2-hydroxypropyl)methacrylamide]-based copolymers (PHPMA) and poly(propylene oxide) (PPO) to overcome MDR mechanisms. The DB copolymers and their doxorubicin (Dox) conjugates significantly increased Dox accumulation in P-gp positive cells, markedly sensitizing them to Dox cytotoxic activity. The underlying mechanisms included depletion of intracellular ATP with subsequent inhibition of P-gp mediated drug efflux, an altered mitochondrial membrane potential, and increased ROS production. Moreover, the DB-Dox conjugates inhibited tumor growth in vivo more effectively compared to the corresponding PHPMA-based drug delivery system. Copolymers with additionally loaded PPO in the micelle core demonstrated superior efficacy in terms of P-gp inhibition, ATP depletion, and chemosensitizing effect in vitro, as well as antitumor activity in vivo. DB copolymers effectively depleted ATP levels both in vitro and in vivo using patient-derived xenograft (PDX) models, underscoring their capacity to enhance the effectiveness of standard chemotherapy and translational potential.

• Klíčová slova
• Diblock copolymers, Drug delivery system, HPMA copolymer, Intracellular ATP depletion, Multidrug resistance, P-glycoprotein inhibition, PPO, Sensitization to chemotherapy,
• MeSH
• adenosintrifosfát metabolismus   MeSH
• chemorezistence účinky léků   MeSH
• doxorubicin * aplikace a dávkování   chemie   terapeutické užití   MeSH
• lidé MeSH
• methakryláty chemie   MeSH
• micely MeSH
• mnohočetná léková rezistence účinky léků   MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• nosiče léků * chemie   MeSH
• P-glykoprotein * metabolismus   MeSH
• polymery chemie   MeSH
• polypropyleny * chemie   MeSH
• propylenglykoly * chemie   aplikace a dávkování   MeSH
• protinádorová antibiotika * aplikace a dávkování   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adenosintrifosfát MeSH
• doxorubicin * MeSH
• methakryláty MeSH
• micely MeSH
• nosiče léků * MeSH
• P-glykoprotein * MeSH
• polymery MeSH
• polypropylene glycol MeSH Prohlížeč
• polypropyleny * MeSH
• propylenglykoly * MeSH
• protinádorová antibiotika * MeSH

Lipidated anorexigenic peptides are highly promising compounds for the treatment of obesity and related diseases. However, their exact mechanism of action still remains unknown. We labelled a lipidated analogue of an anorexigenic prolactin-releasing peptide (palm11-PrRP31) with an extremely stable ClickZip lanthanide tag, facilitating tracking of the peptide within the organism. We then employed a separation method based on liquid chromatography combined with inductively coupled plasma mass spectrometry (LC-ICP-MS). This technique involved the use of an unconventional mobile phase containing 5 % 1,2-hexanediol in H2O (v/v) with the addition of 2 % formic acid. Using a rapid. 6-min analysis, we were able to quantify the ClickZip tag - and thus indirectly the fate of the labelled peptides in the living organism - independently of free Ln3+ ions. The detection limits for the various lanthanide chemical forms were extremely low, ranging between 0.9 and 3.4 ng/L. We demonstrated the suitability of the method for analysing real biological samples like blood plasma, and confirmed the accuracy of our results. Prior to LC-ICP-MS analysis, we optimised a process involving the microwave-assisted digestion of liver samples to preserve the integrity of the ClickZip tag. We also identified several metabolites of the labelled peptides in the liver, urine, and blood plasma, highlighting the utility of the method for revealing the mechanism of action behind the labelled lipopeptides.

• Klíčová slova
• 1,2-Hexanediol, Anorexigenic peptides, Method validation, Sample digestion,
• MeSH
• chromatografie kapalinová metody   MeSH
• click chemie MeSH
• hmotnostní spektrometrie * metody   MeSH
• hormon uvolňující prolaktin chemie   MeSH
• játra chemie   metabolismus   MeSH
• lanthanoidy chemie   MeSH
• myši MeSH
• peptidy chemie   analýza   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hormon uvolňující prolaktin MeSH
• lanthanoidy MeSH
• peptidy MeSH

The structure, function, and molecular mechanisms of lichen survival in harsh habitats like Antarctica and Alpine localities, where environmental extremes change frequently, are highly interesting yet largely underexplored. We used high resolution microscopy, Raman spectroscopy, and chlorophyll a fluorescence to investigate the basic structure and function, i.e., intrathalline distribution and allocation of photobionts, as well as the heat dissipation process in three Antarctic lichens: Dermatocarpon polyphyllizum (DP), Umbilicaria antarctica (UA), and Leptogium puberulum (LP). Microscopic images of their transverse slices revealed visual insights into the heterogeneous distribution of photobionts within their structurally distinct thalli. Raman spectra showed shifts in the carotenoid Raman ν1(CC) band between lichens with algal (DP and UA) and cyanobacterial (LP) photobionts, and interestingly, they revealed biosynthesis of scytonemin, a UV-screening pigment, in cyanolichen LP. We found that increasing actinic irradiance has a nearly equal effect on the shape of chlorophyll fluorescence transients also during dark relaxation in lichens with algal photobionts, but it differed greatly for cyanolichen LP. The dark relaxation kinetics of non-photochemical quenching (NPQ) in experimental lichens differed significantly between lichens with algal photobionts DP and UA; however, this parameter could not be calculated in cyanolichen LP. The components of NPQ revealed that rapidly relaxing energy dependent quenching, ΦqE, is active and protects the thallus of DP predominantly; however, in UA state transition quenching, ΦqT, predominates. The diversity in NPQ across the three examined lichens revealed intriguing aspects of heat dissipation in their photobionts as a mechanism for survival under Antarctica conditions.

• Klíčová slova
• Carotenoids, Chlorophyll a fluorescence transient, High resolution microscopy, Optical signal, Raman spectra, Scytonemin,
• MeSH
• chlorofyl a * metabolismus   MeSH
• chlorofyl * metabolismus   analýza   MeSH
• lišejníky * metabolismus   chemie   fyziologie   MeSH
• Ramanova spektroskopie * MeSH
• sinice metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Antarktida MeSH
• Názvy látek
• chlorofyl a * MeSH
• chlorofyl * MeSH