Radiation Curing of Phosphorus Telomer-Based Coatings Using UV LEDs or Medium-Pressure Mercury Lamp.

In the presented study, UV LEDs (365 nm) or a medium-pressure mercury lamp (UV-ABC) were verified as UV radiation sources initiating the photocrosslinking process of varnishes based on novel photopolymerizable phosphorus (meth)acrylate oligomers. Coating formulations were composed of (meth)acrylic/styrene telomers with terminal P-atoms (prepared via a UV phototelomerization process) and different photoinitiators (HAPs, APOs, or APO blends). The kinetics of the UV crosslinking process of the coating formulations depending on UV irradiation and the UV range was investigated by the photo-DSC method. Moreover, the hardness of the varnishes and the conversion of double bonds using the FTIR method were tested. The photopolymerization rate and the photoinitiation index, depending on the type of photoinitiator, were as follows: APOs < APO blends < HAPs. However, the highest coating hardness results were obtained using the least reactive photoinitiator from the APO group, i.e., Omnirad TPOL, or a mixture of three different types of acylphosphine (Omnirad BL 750). The greater effectiveness of the above-mentioned APOs over HAP was also demonstrated when using a UV LED lamp at 365 nm with a low UV dose and UV irradiance, thanks to the presence of phosphoric acid diester in the coating composition, acting as both a telogen and an antioxidant.

New Pressure-Sensitive Acrylic Adhesives for Low Energy Substrates Prepared via UV-Induced Telomerization with a Fluorine-Based Telogen.

Novel pressure-sensitive adhesives (PSA) for low energy substrates were prepared by a solvent-free UV-initiated telomerization process using n-butyl acrylate, butyl methacrylate, and lauryl methacrylate (LMA), with trifluoroethanol (TFEtOH) as a telogen, and acylphosphine oxide (APO) as a radical photoinitiator. A crosslinking monomer (an aliphatic urethane acrylate, L9033) and a radical UV-photoinitiator (α-hydroxyalkylphenone) were also tested as components of the adhesive compositions. The influence of LMA and TFEtOH on the UV-phototelomerization process kinetics and the physicochemical features of the obtained fluorotelomers, as well as the concentration of L9033 on the PSA adhesion to a polyethylene surface, were investigated. FT-IR results indicated that the fluorine groups were successfully introduced into the telomer structure. The highest adhesion relative to a polyethylene substrate (12.3 N/25 mm), and the highest hydrophobicity (with a contact angle of 95° for a water/PSA system) were observed for adhesives based on a telomer syrup containing 5 wt. parts of TFEtOH and 30 wt. parts of LMA (per 100 wt. parts of the monomer mixture). Additionally, it was revealed that a higher aliphatic urethane acrylate content and a higher UV dose increased the adhesion feature.

Shape-Morphing of an Artificial Protein Cage with Unusual Geometry Induced by a Single Amino Acid Change.

Artificial protein cages are constructed from multiple protein subunits. The interaction between the subunits, notably the angle formed between them, controls the geometry of the resulting cage. Here, using the artificial protein cage, "TRAP-cage", we show that a simple alteration in the position of a single amino acid responsible for Au(I)-mediated subunit-subunit interactions in the constituent ring-shaped building blocks results in a more acute dihedral angle between them. In turn, this causes a dramatic shift in the structure from a 24-ring cage with an octahedral symmetry to a 20-ring cage with a C2 symmetry. This symmetry change is accompanied by a decrease in the number of Au(I)-mediated bonds between cysteines and a concomitant change in biophysical properties of the cage.

Influence of Acrylic Acid on Kinetics of UV-Induced Cotelomerization Process and Properties of Obtained Pressure-Sensitive Adhesives.

A new environmentally friendly method of photoreactive pressure-sensitive adhesives (PSAs) preparation was demonstrated. PSAs based on n-butyl acrylate (BA), acrylic acid (AA) and 4-acryloyloxy benxophenone (ABP) were prepared via the UV-induced cotelomerization process in the presence of a radical photoinitiator (acylphosphine oxide) and telogen (tetrabromomethane). Hydroxyterminated polybutadiene was used as a crosslinking agent. Influence of AA concentration (0-10 wt %) on kinetics of the cotelomerization process was investigated using a photodifferential scanning calorimetry method, selected physicochemical features of obtained photoreactive BA/AA/ABP cotelomers (molecular masses, polydispersity, monomers conversion and dynamic viscosity) and self-adhesive properties of obtained PSAs (adhesion, tack and cohesion) were studied, as well. It turned out that AA content is the important factor that influences monomers conversion (thereby the volatile parts content in prepolymer) and PSAs' properties. As the acrylic acid content increases, the reaction rate increases, but the total monomers conversion and the solid content of the prepolymer decreases. Additionally, the adhesion and cohesion of PSAs were grown up, and their tackiness decreased. However, the AA content has no effect on molecular weights (Mw and Mn) and polydispersity (c.a. 1.5) of photoreactive cotelomers. The optimal AA content necessary to obtain a prepolymer with low volatile parts content and good PSA properties was determined.

An ultra-stable gold-coordinated protein cage displaying reversible assembly.

Symmetrical protein cages have evolved to fulfil diverse roles in nature, including compartmentalization and cargo delivery1, and have inspired synthetic biologists to create novel protein assemblies via the precise manipulation of protein-protein interfaces. Despite the impressive array of protein cages produced in the laboratory, the design of inducible assemblies remains challenging2,3. Here we demonstrate an ultra-stable artificial protein cage, the assembly and disassembly of which can be controlled by metal coordination at the protein-protein interfaces. The addition of a gold (I)-triphenylphosphine compound to a cysteine-substituted, 11-mer protein ring triggers supramolecular self-assembly, which generates monodisperse cage structures with masses greater than 2 MDa. The geometry of these structures is based on the Archimedean snub cube and is, to our knowledge, unprecedented. Cryo-electron microscopy confirms that the assemblies are held together by 120 S-Aui-S staples between the protein oligomers, and exist in two chiral forms. The cage shows extreme chemical and thermal stability, yet it readily disassembles upon exposure to reducing agents. As well as gold, mercury(II) is also found to enable formation of the protein cage. This work establishes an approach for linking protein components into robust, higher-order structures, and expands the design space available for supramolecular assemblies to include previously unexplored geometries.

Toxicity Mechanism of Low Doses of NaGdF4:Yb3+,Er3+ Upconverting Nanoparticles in Activated Macrophage Cell Lines.

Gadolinium-doped nanoparticles (NPs) are regarded as promising luminescent probes. In this report, we studied details of toxicity mechanism of low doses of NaGdF4-based fluorescent nanoparticles in activated RAW264.7, J774A.1 macrophages. These cell lines were specifically sensitive to the treatment with nanoparticles. Using nanoparticles of three different sizes, but with a uniform zeta potential (about -11 mV), we observed rapid uptake of NPs by the cells, resulting in the increased lysosomal compartment and subsequent superoxide induction along with a decrease in mitochondrial potential, indicating the impairment of mitochondrial homeostasis. At the molecular level, this led to upregulation of proapoptotic Bax and downregulation of anti-apoptotic Bcl-2, which triggered the apoptosis with phosphatidylserine externalization, caspase-3 activation and DNA fragmentation. We provide a time frame of the toxicity process by presenting data from different time points. These effects were present regardless of the size of nanoparticles. Moreover, despite the stability of NaGdF4 nanoparticles at low pH, we identified cell acidification as an essential prerequisite of cytotoxic reaction using acidification inhibitors (NH4Cl or Bafilomycin A1). Therefore, approaching the evaluation of the biocompatibility of such materials, one should keep in mind that toxicity could be revealed only in specific cells. On the other hand, designing gadolinium-doped NPs with increased resistance to harsh conditions of activated macrophage phagolysosomes should prevent NP decomposition, concurrent gadolinium release, and thus the elimination of its toxicity.

[Usefulness of measurement of nitric oxide in exhaled air in diagnostics and treatment of allergic rhinitis and asthma in children and adolescents].

Nitric oxide is produced by enzymes called nitric oxide synthases. It fulfills many important functions in the human body, but produced in excess amount has a proinflammatory activity. Fractional exhaled nitric oxide measurements are used in the diagnosis and monitoring of eosinophilic inflammation in the lower airways, but should not be used as an independent parameter to make a diagnosis of asthma or for the monitoring of asthma treatment. Evaluation of fractional exhaled nitric oxide concentrations is also used to determine the pathogenesis of symptoms in patients with rhinitis. In addition, they are helpful in detecting and monitoring eosinophilic inflammation in the lower respiratory tract that coexists with inflammation in the upper airways. Fractional exhaled nitric oxide concentrations may be abnormal (lowered or elevated) in other chronic diseases, such as cystic fibrosis, primary ciliary dyskinesia and inflammatory bowel diseases. Many factors, e.g. atopy, genetic polymorphisms of NOS, and the lipid profile affect the fractional exhaled nitric oxide measurement. Nasal nitric oxide measurement is useful in assessing the prevalence and severity of eosinophilic inflammation in the upper respiratory tract.

The Discovery and Development of Drug Combinations for the Treatment of Various Diseases from Patent Literature (1980-Present).

The search for a miracle drug that would help to alleviate multiple ailments, dates back many thousands of years before our era and continues until today. Various techniques have been used to obtain a formulation, that would give the desired therapeutic effect. The most popular approach includes drug coctails and multicomponent drugs. Polytherapy is widely accapted as an effective tool for the treatment of several diseases, however it is often faced with important drawbacks that may sometimes result in fatal adverse effects associated with unpredictable drug interactions. Conversly, hybrid compounds were found to be an attractive way to counterbalance the unwanted side effects derived from the administration of individual drug components. Futhermore, they can serve as effective and improved remedies for patients suffering from several diseases simultaneously, as different receptorrelated pharmacophores are used as structural components. This review covers patent literature from 1980 till now that highlights the progress that has been made in the discovery of hybrid compounds potentially useful in the treatment on various disorders, including pain states, neurodegenerative or infectious diseases. Additionally, this review was further enriched with findings from original research papers.

Antinociceptive effect induced by a combination of opioid and neurotensin moieties vs. their hybrid peptide [Ile(9)]PK20 in an acute pain treatment in rodents.

Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile(9)]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile(9)]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails.

Peptide-induced immune regulation by a promiscuous and immunodominant CD4T-cell epitope of Timothy grass pollen: a role of Cbl-b and Itch in regulation.

BACKGROUND: T-cell targeted peptide epitope tolerogens from grass pollen allergens may be useful in treating seasonal allergic rhinitis, but there is urgent need for optimisation of approaches from improved understanding of mechanism. OBJECTIVE: We sought to identify human leukocyte antigen (HLA)-DR1-restricted epitopes from the Timothy grass pollen allergen, Phleum pratense, and characterise T-cell immune regulation following intranasal administration of a single, immunodominant epitope. METHODS: T-cell epitopes within P pratense were identified using HLA-DR1 transgenic mice and tetramer-guided epitope mapping (TGEM) in HLA-DR1-positive individuals with grass allergy. An immunodominant epitope was tested in HLA-DR1 transgenics for impact on responses to whole Phl p5 b or peptide. Microarrays and quantitative PCR were used to characterise T-cell immunity. RESULTS: Peptide 26 (p26) was identified in HLA-DR1 transgenic mice and by TGEM analysis of HLA-DR1-positive individuals with grass allergy. p26 shows promiscuous binding to a wide range of HLA class II alleles, making it of relevance across immunogenetically diverse patients. The epitope is conserved in rye and velvet grass, making it applicable across a spectrum of grass pollen allergy. Intranasal pretreatment of mice with p26 results in significantly reduced T-cell responses. Transcriptomic array analysis in mice showed T-cell regulation in the intranasal treatment group associated with increased expression of members of the Cbl-b and Itch E3 ubiquitin ligase pathway. CONCLUSIONS: We defined an immunodominant P pratense epitope, p26, with broad binding across multiple HLA class II alleles. Intranasal treatment of mice with p26 results in T-cell regulation to whole allergen, involving the Cbl-b and Itch regulatory pathway.

Effects of LTB4 receptor antagonism on pulmonary inflammation in rodents and non-human primates.

Asthma, chronic obstructive pulmonary disease (COPD) and acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are characterized by neutrophilic inflammation and elevated levels of leukotriene B4 (LTB4). However, the exact role of LTB4 pathways in mediating pulmonary neutrophilia and the potential therapeutic application of LTB4 receptor antagonists in these diseases remains controversial. Here we show that a novel dual BLT1 and BLT2 receptor antagonist, RO5101576, potently inhibited LTB4-evoked calcium mobilization in HL-60 cells and chemotaxis of human neutrophils. RO5101576 significantly attenuated LTB4-evoked pulmonary eosinophilia in guinea pigs. In non-human primates, RO5101576 inhibited allergen and ozone-evoked pulmonary neutrophilia, with comparable efficacy to budesonide (allergic responses). RO5101576 had no effects on LPS-evoked neutrophilia in guinea pigs and cigarette smoke-evoked neutrophilia in mice and rats. In toxicology studies RO5101576 was well-tolerated. Theses studies show differential effects of LTB4 receptor antagonism on neutrophil responses in vivo and suggest RO5101576 may represent a potential new treatment for pulmonary neutrophilia in asthma.

The function of interleukin 17 in the pathogenesis of rheumatoid arthritis.

Interleukin (IL)-17 is a 30- to 35-kDa homodimeric polypeptide cytokine cloned in 1993 and originally named cytotoxic T lymphocyte-associated antigen-8 (CTLA-8). Sequencing the human genome resulted in the discovery of an additional five members of the IL-17 family that were consecutively named IL-17B to IL-17F. IL-17A is exclusively produced by a newly identified CD4+ T-helper subset that was recently named Th17. Differentiation of these cells from naive CD4+ T cells requires both TGF-beta and IL-6. IL-15 and, especially, IL-23 are required for these cells' survival and efficient IL-17 production. IL-17 binding to an IL-17 receptor expressed on epithelial, endothelial, and fibroblastic stromal cells triggers the activation of transcription factor NF-kappaB and mitogen-activated protein kinase (p-38), which in turn results in the secretion of IL-1, TNF-alpha, IL-6, IL-8, or prostaglandin E2. The IL-17 family plays a key role in the regulation of immune and inflammatory response, in the homeostasis of several tissues, and the progression of autoimmune diseases. In addition, IL-17 exerts synergistic effects with TNF-alpha and IL-1 in the induction of joint inflammation and cartilage and joint destruction. Given these properties, it is not surprising that in certain pathological conditions, for example rheumatoid arthritis, Th17 cells emerge as a new pathological cell type that, by IL-17 production and release, contributes to their pathogeneses.

Dual roles of glycosyl torsion angle conformation and stereochemical configuration in butadiene oxide-derived N1 beta-hydroxyalkyl deoxyinosine adducts: a structural perspective.

The solution structure of the N1-[1-hydroxy-3-buten-2(R)-yl]-2'-deoxyinosine adduct arising from the alkylation of adenine N1 by butadiene epoxide (BDO), followed by deamination to deoxyinosine, was determined in the oligodeoxynucleotide 5'-d(CGGACXAGAAG)-3'.5'-d(CTTCTTGTCCG)-3'. This oligodeoxynucleotide contained the BDO adduct at the second position of codon 61 of the human N-ras protooncogene (underlined) and was named the ras61 R-N1-BDO-(61,2) adduct. 1H NMR revealed a weak C5 H1' to X6 H8 nuclear Overhauser effects (NOE), followed by an intense X6 H8 to X6 H1' NOE. Simultaneously, the X6 H8 to X6 H3' NOE was weak. The resonances arising from the T16 and T17 imino protons were not observed. 1H NOEs between the butadiene moiety and the DNA positioned the adduct in the major groove. Structural refinement based upon a total of 394 NOE-derived distance restraints and 151 torsion angle restraints yielded a structure in which the modified deoxyinosine was in the syn conformation about the glycosyl bond, with a glycosyl bond angle of 83 degrees , and T17, the complementary nucleotide, was stacked into the helix but not hydrogen bonded with the adducted inosine. The refined structure provides a plausible hypothesis as to why these N1 deoxyinosine adducts strongly code for the incorporation of dCTP during trans lesion DNA replication, irrespective of stereochemistry, both in Escherichia coli [Rodriguez, D. A., Kowalczyk, A., Ward, J. B. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2001) Environ. Mol. Mutagen. 38, 292-296] and in mammalian cells [Kanuri, M., Nechev, L. N., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580]. Rotation of the N1 deoxyinosine adduct into the syn conformation may facilitate incorporation of dCTP via Hoogsteen type templating with deoxyinosine, generating A to G mutations. However, conformational differences between the R- and the S-N1-BDO-(61,2) adducts, involving the positioning of the butenyl moiety in the major groove of DNA, suggest that adduct stereochemistry plays a secondary role in modulating the biological response to these adducts.

[Cervical glandular intraepithelial neoplasia topography and the risk of conisation]. / Przedinwazyjne rozrosty gruczolowe w szyjce macicy: topografia zmian i zagrozenia dla konizacji.

OBJECTIVES: The frequency of endocervical adenocarcinoma is increasing in comparison with squamous cell carcinoma and it presents a very difficult diagnostic and therapeutic problem. DESIGN: The aim of this study was: 1) Evaluation of topography of the cervical glandular intraepithelial neoplasia (CGIN) 2) An analysis of the Human Papillomavirus (HPV) infection rate in samples. MATERIALS AND METHODS: 360 amputated uterine cervix samples with histologically-proven diagnosis of cervical intraepithelial neoplasia (CIN-3) were evaluated. The coexistence of pre-invasive lesions in squamous epithelium and endocervical columnar cell were investigated. Moreover CGIN topography and retrospective histopathological analysis were determined. A polymerase chain reaction (PCR) was performed using commercially available PCR Human Papillomavirus Typing Set to detect HPV infection. RESULTS: Among 360 positive cervical intraepithelial glandular neoplasia samples (CIN-3) 71 (19.7%) showed coexisting glandular lesions (CGIN-1, 2, 3). The lesions in endocervical glandular cells of CIGN-type were distributed from the distance up to 14 mm from the surface of cervix. Most of them were located no deeper than 1 mm from the surface of canal epithelium. HPV DNA was found in more than 90 preneoplastic glandular proliferations. The frequency of oncogenic HPV-16 and 18 presence was higher than non-oncogenic HPV. CONCLUSIONS: 1. CIN-3 is associated in about 20% with cervical glandular intraepithelial neoplasia (CGIN). 2. Topography of CGIN is important in planning the management. 3. Most of CIGN are associated with HPV infection.

[The role of prophylactic examinations in detecting thyroid disorders. Preliminary results]. / Rola badan profilaktycznych w wykrywaniu schorzen gruczolu tarczowego. Doniesienie wstepne.

PREFACE: Nonpalpable nodules in the thyroid are frequent and estimated to be found in 50% of people above 50 year of age when goiter in adult population is found in 4-10%. Thyroid nodules in 5% are of neoplastic character and their diligent investigation is necessary with USG, FNA and certain biochemical factors evaluation. Screening is an important part of diagnosing thyroid gland. MATERIAL AND METHODS: Prophylactic examination donated by Krakow's City Government was performed in 140 persons aged 18-71 among whom 93.3% were women. Clinical examination, USG, FNA (when it was necessary), and TSH serum level evaluation were conducted in these patients. RESULTS: In 42.2% (group I) no abnormalities were detected. In 28.5% (group II) USG revealed thyroid nodules when clinical examination was negative. In 29.3% (group III) the presence of palpable nodules was confirmed by USG. In consecutive groups I-III following factors were presented: mean age, frequency of performed FNA's and thyroids volume. CONCLUSION: USG is an efficient method in prophylaxis of thyroid disorders.