Pseudomonas aeruginosa is a prevalent opportunistic human pathogen, particularly associated with cystic fibrosis. Among its virulence factors are the LecA and LecB lectins. Both lectins play an important role in the adhesion to the host cells and display cytotoxic activity. In this study, we successfully synthesized hardly hydrolysable carbohydrate ligands targeting these pathogenic lectins, including two bispecific glycans. The interactions between LecA/LecB lectins and synthetic glycans were evaluated using hemagglutination (yeast agglutination) inhibition assays, comparing their efficacy with corresponding monosaccharides. Additionally, the binding affinities of bispecific glycans were assessed using isothermal titration calorimetry (ITC). Structural insight into the lectin-ligand interaction was obtained by determining the crystal structures of LecA/LecB lectins in complex with one of the bispecific ligands using X ray crystallography. This comprehensive investigation into the inhibitory potential of synthetic glycosides against P. aeruginosa lectins sheds light on their potential application in antimicrobial therapy.

• Keywords
• Agglutination, Inhibition, Lectins, Pseudomonas aeruginosa, Synthetic carbohydrates,
• MeSH
• Adhesins, Bacterial chemistry   metabolism   MeSH
• Disaccharides * chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Lectins * chemistry   antagonists & inhibitors   MeSH
• Humans MeSH
• Ligands MeSH
• Polysaccharides chemistry   pharmacology   MeSH
• Pseudomonas aeruginosa * drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adhesins, Bacterial MeSH
• Disaccharides * MeSH
• LecA protein, bacteria MeSH Browser
• LecB protein, Pseudomonas aeruginosa MeSH Browser
• Lectins * MeSH
• Ligands MeSH
• Polysaccharides MeSH

UNLABELLED: Invasive cell growth and migration is usually considered a specifically metazoan phenomenon. However, common features and mechanisms of cytoskeletal rearrangements, membrane trafficking and signalling processes contribute to cellular invasiveness in organisms as diverse as metazoans and plants - two eukaryotic realms genealogically connected only through the last common eukaryotic ancestor (LECA). By comparing current understanding of cell invasiveness in model cell types of both metazoan and plant origin (invadopodia of transformed metazoan cells, neurites, pollen tubes and root hairs), we document that invasive cell behavior in both lineages depends on similar mechanisms. While some superficially analogous processes may have arisen independently by convergent evolution (e.g. secretion of substrate- or tissue-macerating enzymes by both animal and plant cells), at the heart of cell invasion is an evolutionarily conserved machinery of cellular polarization and oriented cell mobilization, involving the actin cytoskeleton and the secretory pathway. Its central components - small GTPases (in particular RHO, but also ARF and Rab), their specialized effectors, actin and associated proteins, the exocyst complex essential for polarized secretion, or components of the phospholipid- and redox- based signalling circuits (inositol-phospholipid kinases/PIP2, NADPH oxidases) are aparently homologous among plants and metazoans, indicating that they were present already in LECA. REVIEWER: This article was reviewed by Arcady Mushegian, Valerian Dolja and Purificacion Lopez-Garcia.

• MeSH
• Actins metabolism   MeSH
• Cytoskeleton metabolism   MeSH
• Humans MeSH
• Cell Movement physiology   MeSH
• Pollen Tube cytology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• Actins MeSH

Lung cancer epidemic has not ended. According to the data on the incidence and mortality in the Czech Republic it is obvious that both parameters decline in males; the rise in women probably ends. According to the present epidemiological parameters the number of new cases is still very high. Number of adenocarcinomas is slightly rising. No improvement has been achieved in the early diagnostics of TNM stage I and II, which are diagnosed in less than 21 %. It brings low number of indications for resection therapy, which in 2003 achieved 10.8 % for men and 10.1 % for women. Positive appears the higher number of verified tumours (72 % in men and 69 % in women) and the higher percentage of those who survived over 5 years (6.3 % in men and 9.4 % in women) in comparison with the situation 10 years earlier. The presented paper describes regional differences in the incidence of lung carcinoma (apparent gradient between the western and eastern part of the country) and the promptness of the diagnostics and the treatment indications.

• MeSH
• Adult MeSH
• Incidence MeSH
• Middle Aged MeSH
• Humans MeSH
• Lung Neoplasms diagnosis   epidemiology   therapy   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• English Abstract MeSH
• Journal Article MeSH
• Review MeSH
• Geographicals
• Czech Republic epidemiology   MeSH

The acrosin zymogen proacrosin exists in two molecular forms which are believed to be single-chain polypeptides. During autoactivation in a cell-free system, the 55 and 53 kDa zymogens are sequentially converted into the 49, 36, 31 and 25 kDa forms. A similar mechanism of maturation was revealed, when the calcium ionophore A23187 was added to suspensions of boar spermatozoa. The 49 kDa form has been identified as the first active acrosin form in the maturation cascade. However, this form is indistinguishable from the 53 kDa zymogen in SDS-PAGE at nonreducing conditions. Two carbohydrate chains were evidenced on the acrosin molecule. The chain attached to the Asn3 of the acrosin light chain was enzymatically cleaved without loss of acrosin activity. By contrast, the carbohydrate chain linked to the acrosin heavy chain could be cleaved only after acrosin denaturation. Based on the susceptibility of acrosin to endoglycosidases F and H, a biantennary structure of both carbohydrate chains is proposed.

• MeSH
• Electrophoresis, Gel, Two-Dimensional MeSH
• Acrosin isolation & purification   metabolism   MeSH
• Enzyme Activation MeSH
• Electrophoresis, Polyacrylamide Gel MeSH
• Glycoproteins isolation & purification   metabolism   MeSH
• Isoenzymes isolation & purification   metabolism   MeSH
• Molecular Weight MeSH
• Swine MeSH
• Enzyme Precursors metabolism   MeSH
• Spermatozoa enzymology   physiology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acrosin MeSH
• Glycoproteins MeSH
• Isoenzymes MeSH
• Enzyme Precursors MeSH

Naphyrone, also known as NRG-1, is a novel psychoactive substance (NPS), a cathinone with stimulatory properties available on the grey/illicit drug market for almost a decade. It is structurally related to infamously known powerful stimulants with the pyrovalerone structure, such as alpha-pyrrolidinovalerophenone (α-PVP) or methylenedioxypyrovalerone (MDPV) that are labeled as a cheap replacement for cocaine and other stimulants. Despite the known addictive potential of α-PVP and MDPV, there are no studies directly evaluating naphyrone's addictive potential e.g., in conditioned place preference (CPP) test or using self-administration. Therefore, our study was designed to evaluate the addictive potential in a CPP test in male Wistar rats and compare its effect to another powerful stimulant with a high addictive potential - methamphetamine. Naphyrone increased time spent in the drug-paired compartment with 5 and 20 mg/kg s.c. being significant and 10 mg/kg s.c. reaching the threshold (p = 0.07); the effect was comparable to that of methamphetamine 1.5 mg/kg s.c. The lowest dose, naphyrone 1 mg/kg s.c., had no effect on CPP. Interestingly, no dose response effect was detected. Based on these data, we are able to conclude that naphyrone has an addictive potential and may possess a significant risk to users.

• Keywords
• Addictive potential, CPP, Conditioned place preference test, Naphyrone, Novel psychoactive substances,
• MeSH
• Alkaloids pharmacology   MeSH
• Behavior, Animal drug effects   MeSH
• Conditioning, Classical drug effects   MeSH
• Rats MeSH
• Methamphetamine administration & dosage   pharmacology   MeSH
• Disease Models, Animal MeSH
• Pentanones administration & dosage   pharmacology   MeSH
• Substance-Related Disorders * MeSH
• Rats, Wistar MeSH
• Pyrrolidines administration & dosage   pharmacology   MeSH
• Central Nervous System Stimulants administration & dosage   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one MeSH Browser
• Alkaloids MeSH
• cathinone MeSH Browser
• Methamphetamine MeSH
• Pentanones MeSH
• Pyrrolidines MeSH
• Central Nervous System Stimulants MeSH

Introduction: N-2-methoxy-benzylated ("NBOMe") analogues of phenethylamine are a group of new psychoactive substances (NPS) with reported strong psychedelic effects in sub-milligram doses linked to a number of severe intoxications, including fatal ones. In our present work, we provide a detailed investigation of pharmacokinetics and acute behavioural effects of 2C-B-Fly-NBOMe (2-(8-bromo-2,3,6,7-tetrahydrobenzo [1,2-b:4,5-b']difuran-4-yl)-N-[(2-methoxybenzyl]ethan-1-amine), an analogue of popular psychedelic entactogen 2C-B (4-Bromo-2,5-dimethoxyphenethylamine). Methods: All experiments were conducted on adult male Wistar rats. Pharmacokinetic parameters of 2C-B-Fly-NBOMe (1 mg/kg subcutaneously; s. c.) in blood serum and brain tissue were analysed over 24 h using liquid chromatography-mass spectrometry (LC/MS). For examination of behavioural parameters in open field test (OFT) and prepulse inhibition (PPI) of acoustic startle reaction (ASR), 2C-B-Fly-NBOMe (0.2, 1 and 5 mg/kg s. c.) was administered in two temporal onsets: 15 and 60 min after administration. Thermoregulatory changes were evaluated in individually and group-housed animals over 8 h following the highest dose used in behavioural experiments (5 mg/kg s. c.). Results: Peak drug concentrations were detected 30 and 60 min after the drug application in serum (28 ng/ml) and brain tissue (171 ng/g), respectively. The parental compound was still present in the brain 8 h after administration. Locomotor activity was dose-dependently reduced by the drug in both temporal testing onsets. ASR was also strongly disrupted in both temporal onsets, drug's effect on PPI was weaker. 2C-B-Fly-NBOMe did not cause any significant thermoregulatory changes. Discussion: Our results suggest that 2C-B-Fly-NBOMe penetrates animal brain tissue in a relatively slow manner, induces significant inhibitory effects on motor performance, and attenuates sensorimotor gating. Its overall profile is similar to closely related analogue 2C-B and other NBOMe substances.

• Keywords
• 2C-B-Fly-NBOMe, NBOMe series, new psychoactive substance, pharmacokinetics, prepulse inhibition, thermoregulation,
• Publication type
• Journal Article MeSH

BACKGROUND: Eukaryotic gene expression is controlled by a number of RNA-binding proteins (RBP), such as the proteins from the Puf (Pumilio and FBF) superfamily (PufSF). These proteins bind to RNA via multiple Puf repeat domains, each of which specifically recognizes a single RNA base. Recently, three diversified PufSF proteins have been described in model organisms, each of which is responsible for the maturation of ribosomal RNA or the translational regulation of mRNAs; however, less is known about the role of these proteins across eukaryotic diversity. RESULTS: Here, we investigated the distribution and function of PufSF RBPs in the tree of eukaryotes. We determined that the following PufSF proteins are universally conserved across eukaryotes and can be broadly classified into three groups: (i) Nop9 orthologues, which participate in the nucleolar processing of immature 18S rRNA; (ii) 'classical' Pufs, which control the translation of mRNA; and (iii) PUM3 orthologues, which are involved in the maturation of 7S rRNA. In nearly all eukaryotes, the rRNA maturation proteins, Nop9 and PUM3, are retained as a single copy, while mRNA effectors ('classical' Pufs) underwent multiple lineage-specific expansions. We propose that the variation in number of 'classical' Pufs relates to the size of the transcriptome and thus the potential mRNA targets. We further distinguished full set of PufSF proteins in divergent metamonad Giardia intestinalis and initiated their cellular and biochemical characterization. CONCLUSIONS: Our data suggest that the last eukaryotic common ancestor (LECA) already contained all three types of PufSF proteins and that 'classical' Pufs then underwent lineage-specific expansions.

• Keywords
• Giardia intestinalis, LECA, Puf superfamily proteins, RNA processing, RNA-binding protein,
• MeSH
• Eukaryota genetics   metabolism   MeSH
• Phylogeny MeSH
• RNA, Messenger metabolism   MeSH
• RNA-Binding Proteins chemistry   genetics   metabolism   MeSH
• Protein Biosynthesis * MeSH
• RNA, Ribosomal, 18S metabolism   MeSH
• Amino Acid Sequence MeSH
• Sequence Alignment MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Messenger MeSH
• RNA-Binding Proteins MeSH
• RNA, Ribosomal, 18S MeSH

Naphthylpyrovalerone (naphyrone) is a pyrovalerone cathinone that potently inhibits monoamine transporters and provides stimulatory-entactogenic effects. Little is known about the safety of naphyrone or its effects in vivo, and more research is needed to acquire knowledge about its fundamental effects on physiology and behaviour. Our objective was to investigate naphyrone's pharmacokinetics, acute toxicity, hyperthermic potential and stimulatory and psychotomimetic properties in vivo in male Wistar rats. Pharmacokinetics after 1 mg/kg subcutaneous (sc.) naphyrone were measured over 6 h in serum, the brain, liver and lungs. Rectal temperature (degree Celsius) was measured over 10 h in group-versus individually housed rats after 20 mg/kg sc. In the behavioural experiments, 5, 10 or 20 mg/kg of naphyrone was administered 15 or 60 min prior to testing. Stimulation was assessed in the open field, and sensorimotor processing in a prepulse inhibition (PPI) task. Peak concentrations of naphyrone in serum and tissue were reached at 30 min, with a long-lasting elevation in the brain/serum ratio, consistent with observations of lasting hyperlocomotion in the open field and modest increases in body temperature. Administration of 20 mg/kg transiently enhanced PPI. Naphyrone crosses the blood-brain barrier rapidly and is eliminated slowly, and its long-lasting effects correspond to its pharmacokinetics. No specific signs of acute toxicity were observed; therefore, clinical care and harm-reduction guidance should be in line with that available for other stimulants and cathinones.

• Keywords
• locomotion, naphyrone, novel psychoactive substance, pharmacokinetics, prepulse inhibition, thermoregulation,
• MeSH
• Rats MeSH
• Pentanones pharmacokinetics   pharmacology   MeSH
• Rats, Wistar MeSH
• Pyrrolidines pharmacokinetics   pharmacology   MeSH
• Central Nervous System Stimulants pharmacokinetics   pharmacology   MeSH
• Body Temperature drug effects   MeSH
• Body Temperature Regulation drug effects   MeSH
• Illicit Drugs pharmacokinetics   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-naphthalen-2-yl-2-pyrrolidin-1-ylpentan-1-one MeSH Browser
• Pentanones MeSH
• Pyrrolidines MeSH
• Central Nervous System Stimulants MeSH
• Illicit Drugs MeSH

N-(2-methoxybenzyl)phenethylamines (NBOMes) are a family of potent 5-HT2A agonists containing substances emerging on the illicit drug market as a replacement for N,N-diethyllysergamide (LSD). Despite the increasing use of NBOMes for diagnostic, research and recreational purposes, only a limited number of studies have focussed on their in vivo effect. Here, we investigated pharmacokinetics, systemic toxicity, thermoregulation in individually and group-housed animals, and acute behavioural effects after subcutaneous administration of 2,5-dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe; 0.2, 1, and 5 mg/kg) in Wistar rats. Drug concentration peaked 1 h after the administration of 5 mg/kg in both blood serum and brain tissue with a half-life of 1.88 and 2.28 h, respectively. According to Organisation for Economic Co-operation and Development 423 toxicity assay, the drug is classified into category 3 with a lethal dose of 300 mg/kg and an estimated LD50 value of 200 mg/kg. Histological examination of organs collected from rats injected with the lethal dose revealed subtle pathological changes, highly suggestive of acute cardiovascular arrest due to malignant arrhythmia. Altered thermoregulation after 5 mg/kg was demonstrated by reduced body temperature in individually housed rats (p < 0.01). Behavioural effects assessed by the Open Field test and Prepulse Inhibition of Startle Response revealed that the two lower doses (0.2 and 1 mg/kg) caused a reduction in locomotor activity (p < 0.01), increased anxiety (p < 0.05) and 5 mg/kg additionally impaired sensorimotor gating (p < 0.001). In summary, 25CN-NBOMe readily passes the blood-brain barrier and exhibits a moderate level of toxicity and behavioural effect comparable with other NBOMes.

• Keywords
• 25CN-, NBOMe, Wistar rat, behavioural study, novel psychoactive substances, toxicity,
• MeSH
• Phenethylamines MeSH
• Hallucinogens * pharmacology   MeSH
• Rats MeSH
• Rats, Wistar MeSH
• Body Temperature Regulation MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Phenethylamines MeSH
• Hallucinogens * MeSH

The large phylogenetic distance separating eukaryotic genes and their archaeal orthologs has prevented identification of the position of the eukaryotic root in phylogenomic studies. Recently, an innovative approach has been proposed to circumvent this issue: the use as phylogenetic markers of proteins that have been transferred from bacterial donor sources to eukaryotes, after their emergence from Archaea. Using this approach, two recent independent studies have built phylogenomic datasets based on bacterial sequences, leading to different predictions of the eukaryotic root. Taking advantage of additional genome sequences from the jakobid Andalucia godoyi and the two known malawimonad species (Malawimonas jakobiformis and Malawimonas californiana), we reanalyzed these two phylogenomic datasets. We show that both datasets pinpoint the same phylogenetic position of the eukaryotic root that is between "Unikonta" and "Bikonta," with malawimonad and collodictyonid lineages on the Unikonta side of the root. Our results firmly indicate that (i) the supergroup Excavata is not monophyletic and (ii) the last common ancestor of eukaryotes was a biflagellate organism. Based on our results, we propose to rename the two major eukaryotic groups Unikonta and Bikonta as Opimoda and Diphoda, respectively.

• Keywords
• Diphoda, LECA, Opimoda, eukaryote phylogeny, phylogenomics,
• MeSH
• Bacteria classification   genetics   metabolism   MeSH
• Genes, Bacterial MeSH
• Bacterial Proteins physiology   MeSH
• Datasets as Topic MeSH
• Eukaryota * MeSH
• Phylogeny MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Bacterial Proteins MeSH