Under stressful conditions, bacterial RelA-SpoT Homolog (RSH) enzymes synthesize the alarmone (p)ppGpp, a nucleotide second messenger. (p)ppGpp rewires bacterial transcription and metabolism to cope with stress, and, at high concentrations, inhibits the process of protein synthesis and bacterial growth to save and redirect resources until conditions improve. Single-domain small alarmone synthetases (SASs) are RSH family members that contain the (p)ppGpp synthesis (SYNTH) domain, but lack the hydrolysis (HD) domain and regulatory C-terminal domains of the long RSHs such as Rel, RelA, and SpoT. We asked whether analysis of the genomic context of SASs can indicate possible functional roles. Indeed, multiple SAS subfamilies are encoded in widespread conserved bicistronic operon architectures that are reminiscent of those typically seen in toxin-antitoxin (TA) operons. We have validated five of these SASs as being toxic (toxSASs), with neutralization by the protein products of six neighboring antitoxin genes. The toxicity of Cellulomonas marina toxSAS FaRel is mediated by the accumulation of alarmones ppGpp and ppApp, and an associated depletion of cellular guanosine triphosphate and adenosine triphosphate pools, and is counteracted by its HD domain-containing antitoxin. Thus, the ToxSAS-antiToxSAS system with its multiple different antitoxins exemplifies how ancient nucleotide-based signaling mechanisms can be repurposed as TA modules during evolution, potentially multiple times independently.
- MeSH
- Adenine Nucleotides metabolism MeSH
- Bacteria growth & development metabolism MeSH
- Bacterial Proteins metabolism MeSH
- Databases, Genetic MeSH
- Stress, Physiological physiology MeSH
- Guanosine Pentaphosphate metabolism MeSH
- Guanosine Tetraphosphate metabolism MeSH
- Guanosine Triphosphate metabolism MeSH
- Ligases metabolism MeSH
- Pyrophosphatases metabolism MeSH
- Gene Expression Regulation, Bacterial genetics MeSH
- Signal Transduction MeSH
- Toxin-Antitoxin Systems physiology MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Detailed knowledge regarding sensor based technologies for the detection of food contamination often remains concealed within scientific journals or divided between numerous commercial kits which prevents optimal connectivity between companies and end-users. To overcome this barrier The End user Sensor Tree (TEST) has been developed. TEST is a comprehensive, interactive platform including over 900 sensor based methods, retrieved from the scientific literature and commercial market, for aquatic-toxins, mycotoxins, pesticides and microorganism detection. Key analytical parameters are recorded in excel files while a novel classification system is used which provides, tailor-made, experts' feedback using an online decision tree and database introduced here. Additionally, a critical comparison of reviewed sensors is presented alongside a global perspective on research pioneers and commercially available products. The lack of commercial uptake of the academically popular electrochemical and nanomaterial based sensors, as well as multiplexing platforms became very apparent and reasons for this anomaly are discussed.
- MeSH
- Biosensing Techniques classification methods MeSH
- Databases, Factual MeSH
- Food Contamination analysis MeSH
- Humans MeSH
- Mycotoxins chemistry isolation & purification MeSH
- Nanostructures chemistry MeSH
- Pesticides chemistry isolation & purification MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Souhrn: Cíl práce: Historie a současný pohled na léčbu hyperaktivního močového měchýře. Metodika: Článek byl vypracován s využitím databází Medline Pubmed a Scopus. Vyhledány byly články publikované do prosince 2020. Součástí článku je popis vnitřních postupů na našem pracovišti. Výsledky a Závěr: Hyperaktivní měchýř je onemocněním značně zhoršujícím kvalitu života našich pacientek. Základem léčby jsou nefarmakologické postupy, jako je cvičení pánevního dna. Efekt těchto postupů je však omezený. Znatelnou úlevu od obtíží přináší léčba farmakologická. Tu zahajujeme nasazením trospia. Při nedostatečném efektu pokračujeme propiverinem, solifenacinem, fesoterodinem, darifenacinem či mirabegronem. Až při selhání farmakologických postupů je indikována léčba elektrickou stimulací či aplikací botulotoxinu. Souhrnně lze říci, že při správně zvolené metodě nalezne úlevu od potíží každá pacientka.
Objective: Historical and current view on the therapy of overactive bladder. Methods: This review summarizes the historical approach and current therapy of overactive bladder. The articles were gathered from Pubmed and Scopus databases. Studies published before December 2020 were used for the review. Results and Conclusion: Overactive bladder is a condition that quite a lot reduces the quality of life of our patients. Our therapeutic approach starts with non-pharmacological treatment, such as pelvic floor exercises. The next step is a pharmacological approach. The entry level drug is trospium. If the effect is not sufficient, propiverine, solifenacin, fesoterodine, darifenacin or mirabegron are used. Electrostimulation or botulinum toxin A application is an option only in cases that didn’t respond to pharmacological treatment. It is safe to say, that in the end, there is a way of reducing the severity of overactive bladder symptoms for every patient.
- MeSH
- Botulinum Toxins, Type A therapeutic use MeSH
- Cholinergic Antagonists therapeutic use MeSH
- Electric Stimulation Therapy MeSH
- Urinary Bladder, Overactive * therapy MeSH
- Humans MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Review MeSH
The production of toxic plant secondary metabolites (phytotoxins) for defense is a widespread phenomenon in the plant kingdom and is even present in agricultural crops. These phytotoxins may have similar characteristics to anthropogenic micropollutants in terms of persistence and toxicity. However, they are only rarely included in environmental risk assessments, partly because a systematic overview of phytotoxins is missing. Here, we present a newly developed, freely available database, Toxic Plants-PhytoToxins (TPPT), containing 1586 phytotoxins of potential ecotoxicological relevance in Central Europe linked to 844 plant species. Our database summarizes phytotoxin patterns in plant species and provides detailed biological and chemical information as well as in silico estimated properties. Using the database, we evaluated phytotoxins regarding occurrence, approximated from the frequencies of Swiss plant species; environmental behavior based on aquatic persistence and mobility; and toxicity. The assessment showed that over 34% of all phytotoxins are potential aquatic micropollutants and should be included in environmental investigations.
The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.
- MeSH
- Botulinum Toxins, Type A * adverse effects MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Humans MeSH
- Nervous System Diseases * drug therapy MeSH
- Neuromuscular Agents * adverse effects MeSH
- Deglutition Disorders * drug therapy MeSH
- Torticollis * drug therapy MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
- MeSH
- Algorithms MeSH
- Chemical Warfare Agents chemistry MeSH
- Ligands MeSH
- Molecular Conformation MeSH
- Molecular Structure MeSH
- Drug Discovery MeSH
- Ricin antagonists & inhibitors chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Molecular Docking Simulation MeSH
- Binding Sites MeSH
- Hydrogen Bonding MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Cíl: Popsat charakteristiku a patofyziologii BTX. Účinnost BTX byla hodnocena prostřednictvím metaanalýzy klinických studií využívajících placebo kontroly. Vzhledem k nedostupnosti kontrolovaných studií ve vulvo-perineální oblasti jsme se rozhodli je nahradit kontrolovanými studiemi prováděnými na příčně pruhovaných svalech v různých jiných oblastech lidského těla. Předpokládáme, že biochemická reakce je buď totožná, nebo velmi podobná. Tato práce nastiňuje námi navrhovaná doporučení týkající se aplikací ve vulvo-perineální oblasti, včetně odpovídajícího dávkování. Metody a pacienti: Byl proveden rozbor klinických studií týkajících se aplikace BTX. Hodnoceny byly databáze z let 2000 až 2023. Nebyly zaznamenány žádné vhodné placebem kontrolované studie specificky na svalech vulvo-perineální oblasti. Kritéria placebem kontrolované BTX studie splnilo devět studií pacientů se svalovou spasticitou po cévní mozkové příhodě. Pacienti byli léčeni BTX A, Botoxem nebo Dysportem. Hodnocení změny svalové spasticity zahrnovalo výpočet rozdílu Modified Ashworth Scale (MAS) před a 4-6 týdnů po léčbě u léčené a placebo skupiny. Cohenovo d bylo použito k určení velikosti tohoto rozsahu (effect size). Velikost celkového efektu u metaanalýzy byla 0,97; P < 0,001, což ukazuje na její významný statistický rozměr. Homogenita nebyla porušena, P = 0,076. Heterogenita prezentuje mírné zkreslení, I2 = 46 %. Forest Plot graf tento nález potvrzuje. Trychtýřový graf obsahuje inkorporované studie a prezentuje nevýznamné zkreslení metaanalýzy. Rozdílné dávkování BTX souvisí s faktem, že běžně používaný Botox a Dysport mají vzájemný poměr přepočtu jednotek 1 IU:2,5 IU v tomto pořadí. Dávka Botoxu ≤ 400 jednotek je považována za bezpečnou, s odds ratio (OR) 0,97 bez významného nárůstu nežádoucích účinků (AE); dávka > 600 jednotek má OR 2,98, doprovázená výrazným zvýšením AE. Aplikace Botoxu pro vulvo-perineální oblast je přibližně 100 IU, rozdělená do několika dávek. Po jednom měsíci lze aplikovat booster dávku stejného rozsahu. Diskuze: Shrnuli jsme základní fyziopatologii BTX a prokázali jeho účinnost při zmírňování bolesti a spastické bolesti u pacientů. Prezentovali jsme vhodné dávkování BTX ve vulvo-perineální oblasti a diskutovali o možné limitaci léčby.
The human body can experience pain or muscle spasms due to a wide range of factors. The pursuit of optimal pain management and alleviation has led to the use of botulinum toxin (BTX). Aim: To describe the characteristics and pathophysiology of BTX. The efficacy of BTX was assessed through a meta- analysis of clinical trials employing placebo controls. Due to the unavailability of controlled trials on the vulvo-perineal area, we opted to replace them with controlled trials conducted on striated muscles in various human body regions. We assume that the biochemical reaction is either identical or very similar. This paper outlines our proposed recommendations regarding applications in the vulvo-perineal region, including the corresponding dosage. Methods and Patients: A review of clinical trials pertaining to BTX was performed. Databases from 2000 to 2023 were evaluated. No placebo-controlled studies were conducted specifically on the muscles of the vulvo-perineal area. Nine trials of patients with muscle spasticity after stroke fulfilled the criteria. Patients were treated with BTX A Botox or Dysport. The assessment of muscle spasticity change involved calculating the mean difference of the Modified Ashworth Scale (MAS) before and 4-6 weeks post-treatment. Cohen‘s d was employed to indicate the effect size. The overall study‘s effect size was 0.97; P<.001, indicating a large effect size of the meta-analysis. Homogeneity was not distorted, P = 0.076. Heterogeneity implies slight distortion, I 2 = 46%. The forest plot confirms this finding. The Funnel Plot encompasses a wide range of studies, suggesting consistent findings and limited bias. The dosage of BTX pertains to the fact that commonly used Botox and Dysport have a calculation ratio of 1 IU to 2.5 IU. A Botox dosage ≤400 units is considered safe, with an odds ratio (OR) of 0.97 without a notable rise in adverse events (AEs); a dosage of >600 units has an OR of 2.98, accompanied by a notable increase in AEs. The Botox dosage for the vulvo-perineal area is approximately 100 IU divided into several punctures. After one month, a booster dose is available. Discussion: We summarized the fundamental physiopathology of BTX and demonstrated its efficacy in mitigating pain and spastic pain among patients. We presented a suitable dosage of BTX in the vulvo-perineal area and discussed potential dosage limitations.
Clostridium difficile is a leading nosocomial pathogen and molecular typing is a crucial part of monitoring its occurrence and spread. Over a three-year period (2013-2015), clinical C. difficile isolates from 32 Czech hospitals were collected for molecular characterisation. Of 2201 C. difficile isolates, 177 (8%) were non-toxigenic, 2024 (92%) were toxigenic (tcdA and tcdB) and of these, 677 (33.5%) carried genes for binary toxin production (cdtA, cdtB). Capillary-electrophoresis (CE) ribotyping of the 2201 isolates yielded 166 different CE-ribotyping profiles, of which 53 were represented by at least two isolates for each profile. Of these, 29 CE-ribotyping patterns were common to the Leeds-Leiden C. difficile reference strain library and the WEBRIBO database (83.7% isolates), and 24 patterns were recognized only by the WEBRIBO database (11.2% isolates). Isolates belonging to these 53 CE-ribotyping profiles comprised 94.9% of all isolates. The ten most frequent CE-ribotyping profiles were 176 (n=588, 26.7%), 001 (n=456, 20.7%), 014 (n=176, 8%), 012 (n=127, 5.8%), 017 (n=85, 3.9%), 020 (n=68, 3.1%), 596 (n=55, 2.5%), 002-like (n=45, 2.1%), 010 (n=35, 1.6%) and 078 (n=34, 1.6%). Multi-locus sequence typing (MLST) of seven housekeeping genes performed in one isolate of each of 53 different CE-ribotyping profiles revealed 40 different sequence types (STs). We conclude that molecular characterisation of Czech C. difficile isolates revealed a high diversity of CE-ribotyping profiles; the prevailing RTs were 001 (20.7%) and 176 (027-like, 26.7%).
- MeSH
- Bacterial Toxins analysis genetics MeSH
- Clostridioides difficile classification genetics isolation & purification MeSH
- Child MeSH
- Adult MeSH
- Genetic Variation * MeSH
- Genotype MeSH
- Clostridium Infections epidemiology microbiology MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Molecular Epidemiology MeSH
- Multilocus Sequence Typing MeSH
- Hospitals MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Ribotyping MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic epidemiology MeSH
Environmental microorganisms usually exhibit a high level of genomic plasticity and metabolic versatility that allow them to be well-adapted to diverse environmental challenges. This study used shotgun metagenomics to decipher the functional and metabolic attributes of an uncultured Paracoccus recovered from a polluted soil metagenome and determine whether the detected attributes are influenced by the nature of the polluted soil. Functional and metabolic attributes of the uncultured Paracoccus were elucidated via functional annotation of the open reading frames (ORFs) of its contig. Functional tools deployed for the analysis include KEGG, KEGG KofamKOALA, Clusters of Orthologous Groups of proteins (COG), Comprehensive Antibiotic Resistance Database (CARD), and the Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT V6) for antibiotic resistance genes, TnCentral for transposable element, Transporter Classification Database (TCDB) for transporter genes, and FunRich for gene enrichment analysis. Analyses revealed the preponderance of ABC transporter genes responsible for the transport of oligosaccharides (malK, msmX, msmK, lacK, smoK, aglK, togA, thuK, treV, msiK), monosaccharides (glcV, malK, rbsC, rbsA, araG, ytfR, mglA), amino acids (thiQ, ynjD, thiZ, glnQ, gluA, gltL, peb1C, artP, aotP, bgtA, artQ, artR), and several others. Also detected are transporter genes for inorganic/organic nutrients like phosphate/phosphonate, nitrate/nitrite/cyanate, sulfate/sulfonate, bicarbonate, and heavy metals such as nickel/cobalt, molybdate/tungstate, and iron, among others. Antibiotic resistance genes that mediate efflux, inactivation, and target protection were detected, while transposable elements carrying resistance phenotypes for antibiotics and heavy metals were also annotated. The findings from this study have established the resilience, adaptability, and survivability of the uncultured Paracoccus in the hydrocarbon-polluted soil.
- MeSH
- ATP-Binding Cassette Transporters genetics MeSH
- Anti-Bacterial Agents pharmacology MeSH
- Bacterial Toxins * MeSH
- Clostridioides difficile * genetics MeSH
- Metagenome MeSH
- Paracoccus * genetics MeSH
- Soil chemistry MeSH
- Metals, Heavy * MeSH
- DNA Transposable Elements MeSH
- Hydrocarbons MeSH
- Publication type
- Journal Article MeSH
Bacillus anthracis is a spore-forming, Gram-positive microorganism. It is a causative agent of anthrax, a highly infectious disease. It belongs to the "Bacillus cereus group", which contains other closely related species, including Bacillus cereus, Bacillus thuringiensis, Bacillus mycoides, Bacillus weihenstephanensis, and Bacillus pseudomycoides. B. anthracis naturally occurs in soil environments. The BA5345 genetic marker was used for highly specific detection of B. anthracis with TaqMan probes. The detection limit of a real-time PCR assay was estimated at the level of 16.9 copies (CI95% - 37.4 to 37.86, SD = 0.2; SE = 0.118). Oligonucleotides designed for the targeted sequences (within the tested locus) revealed 100 % homology to B. anthracis strain reference sequences deposited in the database (NCBI) and high specificity to all tested B. anthracis strains. Additional in silico analysis of plasmid markers pag and cap genes with B. anthracis strains included in the database was carried out. Our study clearly indicates that the BA5345 marker can be used with success as a chromosomal marker in routine identification of B. anthracis; moreover, detection of plasmid markers indicates virulence of the examined strains.
- MeSH
- Antigens, Bacterial genetics MeSH
- Bacillus anthracis genetics isolation & purification pathogenicity MeSH
- Bacillus cereus genetics pathogenicity MeSH
- Bacterial Proteins genetics MeSH
- Bacterial Toxins genetics MeSH
- DNA, Bacterial analysis MeSH
- Virulence Factors genetics MeSH
- Genetic Markers MeSH
- Real-Time Polymerase Chain Reaction MeSH
- Plasmids genetics MeSH
- Sensitivity and Specificity MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
