23 research outputs found
Specific antibodies induced by immunization with hepatitis B virus-like particles carrying hepatitis C virus envelope glycoprotein 2 epitopes show differential neutralization efficiency
Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains
In this study, a search for new therapeutic agents that may improve the antibacterial
activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend
the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a
set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of
5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more
efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance
oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative
(13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics
against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related
to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives
tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity
indicates the high potential of imidazolones to become commercially available antibiotic adjuvants
The effect of glycan shift on antibodies against HCV E2 412-425 epitope elicited by chimeric sHBsAg-based virus-like particles
Two of the most important mechanisms of hepatitis C virus (HCV) immune evasion are the high variability of the amino acid sequence and epitope shielding via heavy glycosylation of the envelope (E) proteins. Previously, we showed that chimeric sHBsAg (hepatitis B virus [HBV] small surface antigen)-based virus-like particles (VLPs) carrying highly conserved epitope I from the HCV E2 glycoprotein (sHBsAg_412–425) elicit broadly neutralizing antibodies (bnAbs). However, many reports have identified escape mutations for such bnAbs that shift the N-glycosylation site from N417 to N415. This shift effectively masks the recognition of epitope I by antibodies raised against the wild-type glycoprotein. To investigate if glycan-shift-mediated immune evasion could be overcome by targeted vaccination strategies, we designed sHBsAg-based VLPs carrying epitope I with an N417S change (sHBsAg_N417S). Studies in BALB/c mice revealed that both sHBsAg_412–425 and sHBsAg_N417S VLPs were immunogenic, eliciting antibodies that recognized peptides encompassing epitope I regardless of the N417S change. However, we observed substantial differences in E1E2 glycoprotein binding and cell culture-derived HCV (HCVcc) neutralization between the sera elicited by sHBsAg_412–425 and those elicited by sHBsAg_N417S VLPs. Our results suggest a complex interplay among antibodies targeting epitope I, the E1E2 glycosylation status, and the epitope or global E1E2 conformation. Additionally, we observed striking similarities in the E1E2 glycoprotein binding patterns and HCVcc neutralization between sHBsAg_412–425 sera and AP33, suggesting that the immunization of mice with sHBsAg_412–425 VLPs can elicit AP33-like antibodies. This study emphasizes the role of antibodies against epitope I and represents an initial effort toward designing an antigen that elicits an immune response against epitope I with a glycan shift change
Hydrophobicity modulation via the substituents at positions 2 and 4 of 1,3,5-triazine to enhance therapeutic ability against Alzheimer's disease for potent serotonin 5-HT6R agents
Synthesis, computational and experimental pharmacological studies for (thio)ether-triazine 5-HT6R ligands with noticeable action on AChE/BChE and chalcogen-dependent intrinsic activity in search for new class of drugs against Alzheimer's disease
Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives
New records of three species of the genus Micarea (lichenized Ascomycota) in Poland
The article presents new data on distribution of Micarea botryoides, M. misella and M. nitschkeana in Poland. The localities, maps, and ecological remarks are given. M. botryoides is reported from several localities, which have been noted recently, M. misella and M. nitschkeana are known from some earlier published records and from several recent ones
Is the Survivability of Silver Fir under Condition of Strong Ungulate Pressure Related to Mycobiota of Bark-Stripping Wounds?
The aim of the research was to check whether the healing of bark-stripping wounds of the silver fir tree trunks reduces the share of wood-decomposing fungi, which may be the result of inter-species interactions. The study carried out in Gorce National Park in Polish Western Carpathians analyzed drill holes of sapwood from three types of wounds (fresh, healed and old) on fir trunks with a diameter at breast height (DBH) of 4.0–16.9 cm as a result of bark-stripping by red deer (Cervus elaphus). In the wood of fresh wounds Alternaria alternata (Fr.) Keissl. and Arthrinium arundinis (Corda) Dyko & B. Sutton had the largest share in mycobiota. Phompsis spp. and the species Sydowia polyspora (Bref. & Tavel) E. Müll. and Epicoccum nigrum Link were also isolated. The dominants in old wounds were Eutypa spp., Phomopsis spp. and Cylindrobasidium evolvens (Fr.) Jülich. Healed wounds were dominated by Trichoderma atroviride P. Karst, a fungus antagonistic to many fungal pathogens. Such properties are shared by A. arundinis, especially common in fresh wound wood. It seems that these fungi support the process of wounded tree regeneration (healing of wounds) and limit the activity of wood-decaying fungi in old age, which makes fir survival very high. Thus, even a strong red deer pressure cannot be considered the basic factor determining the dynamics of fir in this part of the Carpathians
Diet composition of carnivore species in the Gorce National Park
The aim of the study was to assess the diet composition of four carnivore species inhabiting the Gorce National Park (Western Carpathians, S Poland), i.e., grey wolf (Canis lupus), Eurasian lynx (Lynx lynx), red fox (Vulpes vulpes), and pine marten (Martes martes). The food analysis was based on scats collected between June 2016 and February 2017 along seven transects of a total length 96.13 km. Altogether 187 faeces were found, 95 of grey wolf, 20 of lynx, 49 of red fox, and 23 of pine marten, respectively. The dominant food category of wolf and lynx were ungulates, comprising respectively 98% and 95% of the consumed biomass. The trophic niche overlap between wolf and lynx was very high (Pianka’s index Ojk=0.99). However, there were differences in the consumed prey species. Wolves fed on red deer (Cervus elaphus), roe deer (Capreolus capreolus) and wild boar (Sus scrofa), while lynxes foraged equally on two ungulates, red deer and roe deer. Medium−sized carnivores showed greater variety in consumed food. Both pine marten and red fox had higher values of Levins’ index of the trophic niche breadth than larger carnivores and highly overlapped their diets (Ojk=0.96). Pine marten and red fox consumed mostly small mammals.
Additionally, martens consumed frequently fruits, whereas red foxes foraged on carrion of ungulates. This might explain the fact that wolf and lynx overlapped their trophic niches more with red fox than with the pine marten
Impact of demographic factors on usage of stress coping strategies chosen by elderly people
Background. Old age is a particular time in which people experience plenty of changes – both progressive and regressive. Their social and economic position is changing, and human beings are confronted with a lot of difficult situations, such as the death of a spouse, illness, retirement – which particularly require them to apply a proper strategy of coping with stress.
Objectives. The aim of this study was to analyze the relationship between the demographic factors and strategies of coping with stress used by elderly people.
Material and methods . The study was carried out on a group of 296 residents of Szczecin who are over 60 years old. It was conducted by means of a diagnostic survey with the use of the Inventory to Measure Coping Strategies with Stress – Mini-COPE, as well as an original questionnaire form. The statistical analysis was conducted by means of SPSS Statistics 21.0 (p ≤ 0.05).
Results . The results have proven the existence of a relationship between the strategies of coping with stress used by individuals over 60 and factors such as gender, level of education, economic status and financial situation.
Conclusions . When coping with stress, men and women apply different strategies. In case of individuals over 60, the higher level of education and financial status they declare, the more eager they are to use active strategies of coping with stress. Seniors with a lower level of education and lower economic status have more trouble adapting to difficult situations. They have problems with taking the initiative and actively dealing with stressful events. They also more often use psychoactive substances as part of their coping mechanism
Induction and Selection of Sox17-Expressing Endoderm Cells Generated from Murine Embryonic Stem Cells
Embryonic stem (ES) cells offer a valuable source for generating insulin-producing cells. However, current differentiation protocols often result in heterogeneous cell populations of various developmental stages. Here we show the activin A-induced differentiation of mouse ES cells carrying a homologous dsRed-IRES-puromycin knock-in within the Sox17 locus into the endoderm lineage. Sox17-expressing cells were selected by fluorescence-assisted cell sorting (FACS) and characterized at the transcript and protein level. Treatment of ES cells with high concentrations of activin A for 10 days resulted in up to 19% Sox17-positive cells selected by FACS. Isolated Sox17-positive cells were characterized by defini- tive endoderm-specific Sox17/Cxcr4/Foxa2 transcripts, but lacked pluripotency-associated Oct4 mRNA and protein. The Sox17-expressing cells showed downregulation of extraembryonic endoderm (Sox7, Afp, Sdf1)-, mesoderm (Foxf1, Meox1)- and ectoderm (Pax6, NeuroD6)-specific transcripts. The presence of Hnf4α, Hes1 and Pdx1 mRNA demonstrated the expression of primitive gut/foregut cell-specific markers. Ngn3, Nkx6.1 and Nkx2.2 transcripts in Sox17-positive cells were determined as properties of pancreatic endocrine progenitors. Immunocytochemistry of activin A-induced Sox17-positive embryoid bodies revealed coexpression of Cxcr4 and Foxa2. Moreover, the histochemical demonstration of E-cadherin-, Cxcr4-, Sox9-, Hnf1β- and Ngn3-positive epithelial-like structures underlined the potential of Sox17-positive cells to further differentiate into the pancreatic lineage. By reducing the heterogeneity of the ES cell progeny, Sox17-expressing cells are a suitable model to evaluate the effects of growth and differentiation factors and of culture conditions to delineate the differentiation process for the generation of pancreatic cells in vitro.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich