The Kinesin-2 Family
Claire T. Friel in The Kinesin Superfamily Handbook, 2020
The Kinesin-2 family carry out transport functions and members of this family are crucial for intraflagellar transport. The family can be divided into the homodimeric and heterotrimeric members. The Kinesin-2 heavy chain contains an N-terminal motor domain, a central coiled-coil domain and a C-terminal tail domain. One interesting characteristic of some Kinesin-2 family members is their propensity to spiral around microtubules with a left-handed pitch. The paradigmatic physiological role of the Kinesin-2 family is anterograde intraflagellar transport. However, heterotrimeric and homodimeric Kinesin-2s have many other cytoplasmic transport functions in cells. Based on the diverse cellular functions of Kinesin-2, it is not surprising that defects in Kinesin-2-based transport are implicated in a diverse range of diseases. Kinesin-2s have also been shown to associate with beta-catenin and cadherins, implicating these motors in cell adhesion and cell polarity.
The Molecular Model and the Cytotoxic Action of UV Light
K. H. Chadwick in Understanding Radiation Biology, 2019
The important role for oxidative damage in the UVA effect implies that pairs of oxidative deoxyribonucleic acid (DNA) single stranded damage form the critical lesion and not pyrimidine dimers. Ultraviolet (UV) light falls between visible light and X-rays and gamma rays on the spectrum of electromagnetic radiation and is strongly associated with skin cancer. The UV range is usually divided up into UVA, UVB and UVC. The review by Cadet et al. reveals a wide range of photoproducts induced in the cell by UVA exposure and also reveals the importance of the oxidative damage, such as DNA single strand breaks and 8-oxo-7,8-dihydroguanine DNA base damage for the biological effect. Some good experimental data supporting the ‘paired dimer’ lesion as critical for UV cellular effects are to be found in the work of Wade and Lohman. They measured UV-induced cell survival in chicken embryo cells before and after photo-reactivation and correlated survival with number of endonuclease-sensitive sites, which are presumed to be dimers.
Thromboembolism
Philip Steer, Gwyneth Lewis in Crises in Childbirth Why Mothers Survive, 2018
Deep venous thrombosis (DVT) and pulmonary embolism are leading causes of maternal mortality during pregnancy and the puerperium in the developed world. Early recognition, diagnosis and treatment of thromboembolism reduce morbidity and mortality. From 1952, the Confidential Enquiries into Maternal Deaths have provided comprehensive data on mortality from thromboembolic events. Advanced maternal age and operative delivery are major risk factors for the development of DVT. The incidence of clinically diagnosed DVT is estimated to be 0.08–1.2% following vaginal delivery, increasing to 2.2–3.0% after Caesarean section. Antithrombin III deficiency is the most thrombogenic, but is uncommon, and the associated risk of thromboembolism in pregnant women who are not receiving anticoagulant treatment is about 30%. D-dimer, which is a breakdown product of fibrin, is used as a screening test for venous thromboembolism in the non-pregnant state, as it has a high negative predictive value. The specific therapy of choice in pregnant women presenting with venous thromboembolism is anticoagulation.
Characterization of mAb dimers reveals predominant dimer forms common in therapeutic mAbs
Published in mAbs, 2016
Friederike Plath, Philippe Ringler, Alexandra Graff-Meyer, Henning Stahlberg, Matthias E. Lauer, Arne C. Rufer, Melissa A. Graewert, Dmitri Svergun, Gerald Gellermann, Christof Finkler, Jan O. Stracke, Atanas Koulov, Volker Schnaible
The formation of undesired high molecular weight species such as dimers is an important quality attribute for therapeutic monoclonal antibody formulations. Therefore, the thorough understanding of mAb dimerization and the detailed characterization mAb dimers is of great interest for future pharmaceutical development of therapeutic antibodies. In this work, we focused on the analyses of different mAb dimers regarding size, surface properties, chemical identity, overall structure and localization of possible dimerization sites. Dimer fractions of different mAbs were isolated to a satisfactory purity from bulk material and revealed 2 predominant overall structures, namely elongated and compact dimer forms. The elongated dimers displayed one dimerization site involving the tip of the Fab domain. Depending on the stress applied, these elongated dimers are connected either covalently or non-covalently. In contrast, the compact dimers exhibited non-covalent association. Several interaction points were detected for the compact dimers involving the hinge region or the base of the Fab domain. These results indicate that mAb dimer fractions are rather complex and may contain more than one kind of dimer. Nevertheless, the overall appearance of mAb dimers suggests the existence of 2 predominant dimeric structures, elongated and compact, which are commonly present in preparations of therapeutic mAbs.
Lack of dimer formation ability in rat strains with low aldehyde oxidase activity
Published in Xenobiotica, 2007
K. Itoh, H. Maruyama, M. Adachi, K. Hoshino, N. Watanabe, Y. Tanaka
Aldehyde oxidase (AO) is a homodimer with a molecular weight of 300 kDa. To clarify the reasons for the well-known differences in rat strains, we set out to study the relationship between AO activity and the expression levels of its dimer. AO-catalyzed 2-oxidation activity of (S)-RS-8359 was measured in liver cytosols from ten rat strains. The expression levels of AO dimeric protein were evaluated by the native-PAGE/Western blot. Rat strains with low AO activity showed only a monomer, whereas strains with high activity overwhelmingly exhibited a dimer. Exceptionally, one strain in the high AO activity group displayed complex mixed expression patterns of low and high AO activity groups. However, there was a good relationship between AO activity and the expression levels of a dimer, but not of a monomer. The results suggest that rat strains with low AO activity lack the ability to produce a dimer necessary for catalytic activity, and AO differences in rat strains should be discussed in terms of the expression levels of the dimer itself.
Can D-Dimer Measurement Reduce the Frequency of Radiological Assessment in Patients Receiving Palliative Imatinib for Gastrointestinal Stromal Tumor (GIST)?
Published in Cancer Investigation, 2015
Mehran Afshar, Patrick Hamilton, Jenny Seligmann, Simon Lord, Paul Baxter, Maria Marples, Dan Stark, Peter S. Hall
Imatinib therapy has improved outcomes in advanced GISTs. Current guidelines suggest monitoring with CT scanning every 12 weeks. There are no validated biomarkers to assist disease evaluation. We identified 50 patients treated with imatinib for GIST in a single tertiary center. We assessed the prognostic value of D-dimers by Cox regression, and the utility as a biomarker for radiological progression (rPD) using receiver-operator curve (ROC) analysis. In asymptomatic patients with D-dimer levels
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