Kinome-wide interaction modelling using alignment-based and alignment-independent approaches for kinase description and linear and non-linear data analysis techniques

Background  

Protein kinases play crucial roles in cell growth, differentiation, and apoptosis. Abnormal function of protein kinases can lead to many serious diseases, such as cancer. Kinase inhibitors have potential for treatment of these diseases. However, current inhibitors interact with a broad variety of kinases and interfere with multiple vital cellular processes, which causes toxic effects. Bioinformatics approaches that can predict inhibitor-kinase interactions from the chemical properties of the inhibitors and the kinase macromolecules might aid in design of more selective therapeutic agents, that show better efficacy and lower toxicity.     

Structural studies of the O-antigenic oligosaccharide from Vibrio salmonicida strain C2 isolated from Atlantic cod, Gadus morhua L

We report the chemical structure of the oligosaccharide part of Vibrio salmonicida lipopolysaccharide serotype C2, isolated from Atlantic cod (Gadus morhua L.). The structure was established by NMR spectroscopy and mass spectrometry. It is concluded that the oligosaccharide has the following structure in which L-alpha-D-Hepp is L-glycero-alpha-D-manno-heptopyranose, D-alpha-D-Hepp is D-glycero-alpha-D-manno-heptopyranose, alpha-NonA is 5-acetamidino-7-acetamido-3,5,7,9-tetradeoxy-L-glycero-alpha-D-galacto-nonulosonic acid, and PEA is phosphoethanolamine. [chemical structure: see text]     

The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model

Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides. beta-MSH, gamma1-MSH, gamma2-MSH, alpha-MSH, MS05, Ac-MS06 and Ac-[Ser12]MS06 caused dose dependent inhibition of the lipopolysaccharide (LPS)-induced increase of NO overproduction in the mice forebrain whereas MSH core modified peptides Ac-[Asp9,Ser12]MS06, [Asp9]alpha-MSH and [Asp16]beta-MSH were devoid of this effect in doses up to 10 nmol per mouse. When the minimal effective dose required for inhibition of NO production was correlated with the in vitro binding activity to MC receptor subtypes a strong and significant correlation was found for the MC3 receptor (r = 0.90; p = 0.0008), whereas weak correlation was present for the other receptors. Our results suggest that the MC3 receptor is the major player in mediating the anti-inflammatory activity of MCs in the central nervous system.     

The psychotropic drug olanzapine (Zyprexa) increases the area of acid glycerophospholipid monolayers

The typical antipsychotics chlorpromazine (CPZ) and trifluoperazine (TFP) increase the mean molecular area (mma) of acidic, but not neutral, glycerophospholipids in monolayers at pH 7.36 measured by the Langmuir technique. The atypical antipsychotic olanzapine (OLP(1)) is structurally similar to TFP. We have therefore studied the effects of OLP on glycerophospholipid monolayers and in comparison with CPZ. Olanzapine (10 microM, in subphase, pH 7.36) influenced the isotherms (surface pressure versus mma) in monolayers of the neutral dipalmitoyl phosphatidylcholine (DPPC) and the acidic dipalmitoyl phosphatidylserine (DPPS) or 1-palmitoyl-2-oleoylphosphatidylserine (POPS) in the increasing order of mma: DPPS相似文献   

The ontogeny and extrahepatic expression of complement factor C3 in Atlantic salmon (Salmo salar)

Fish embryos and hatchlings are exposed to pathogens long before maturation of their lymphoid organs. Little is known about defence mechanisms during the earliest stages of life, but innate mechanisms may be essential for survival. The complement system in fish is well developed and represents a major part of innate immunity. Complement factor 3 (C3) is central subsequent to activation of all pathways of the complement system, leading to inflammatory reactions, such as chemotaxis, opsonisation and lysis of pathogens. Hepatocytes represent the major source of C3, but modern molecular biological methods have confirmed that C3 is synthesised at multiple sites. Our main objective was to study the ontogeny of C3 in Atlantic salmon by mapping the commencement of synthesis and localisation of proteins. Eggs, embryos, hatchlings and adult fish were analysed for the presence of C3 mRNA and proteins. From immunohistochemical studies, C3 proteins were detected at several extrahepatic sites, such as the skeletal muscle, developing notochord and chondrocytes of the gill arch. Immunoblotting revealed presence of C3 proteins in the unfertilised egg, but C3 mRNA was only detected after fertilisation by real-time RT-PCR. Taken together, the results implicated the maternal transfer of C3 proteins as well as novel non-immunological functions during development.     

Triage of women with low-grade cervical lesions--HPV mRNA testing versus repeat cytology

Background

In Norway, women with low-grade squamous intraepithelial lesions (LSIL) are followed up after six months in order to decide whether they should undergo further follow-up or be referred back to the screening interval of three years. A high specificity and positive predictive value (PPV) of the triage test is important to avoid unnecessary diagnostic and therapeutic procedures.

Materials and Methods

At the University Hospital of North Norway, repeat cytology and the HPV mRNA test PreTect HPV-Proofer, detecting E6/E7 mRNA from HPV types 16, 18, 31, 33 and 45, are used in triage of women with ASC-US and LSIL. In this study, women with LSIL cytology in the period 2005–2008 were included (n = 522). Two triage methods were evaluated in two separate groups: repeat cytology only (n = 225) and HPV mRNA testing in addition to repeat cytology (n = 297). Histologically confirmed cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) was used as the study endpoint.

Results

Of 522 women with LSIL, 207 had biopsies and 125 of them had CIN2+. The sensitivity and specificity of repeat cytology (ASC-US or worse) were 85.7% (95% confidence interval (CI): 72.1, 92.2) and 54.4 % (95% CI: 46.9, 61.9), respectively. The sensitivity and specificity of the HPV mRNA test were 94.2% (95% CI: 88.7, 99.7) and 86.0% (95% CI: 81.5, 90.5), respectively. The PPV of repeat cytology was 38.4% (95% CI: 29.9, 46.9) compared to 67.0% (95% CI: 57.7, 76.4) of the HPV mRNA test.

Conclusion

HPV mRNA testing was more sensitive and specific than repeat cytology in triage of women with LSIL cytology. In addition, the HPV mRNA test showed higher PPV. These data indicate that the HPV mRNA test is a better triage test for women with LSIL than repeat cytology.