Inhibitory interneurons in Alzheimer's disease.

Alzheimer's disease is currently the most common neurodegenerative disorder, characterized by distinct cognitive and sensory deficits. The underlying pathogenetic mechanisms, however, still remain elusive. How the molecular and morphological changes associated with Alzheimer's disease affect information processing in neuronal circuits and translate into cognitive dysfunction is unclear. Inhibitory interneurons have recently emerged as one of the earliest and important culprits in mediating dysfunction of neuronal circuits in neurodegeneration. Amyloid-beta and tau protein have been both linked to interneuron dysfunction, and likely play an important, albeit unknown, role in mediating changes in the overall activity of neuronal circuits. Resolving the role of inhibitory interneurons in neurodegeneration-specific changes in neuronal activity is crucial for understanding the impact of Alzheimer's disease on brain function and even for possible identification of effective treatments and diagnostic techniques (Ref. 63).

Next generation tau models in Alzheimer's disease research - virus based gene delivery systems.

Alzheimer's disease (AD) the most common form of dementia is characterized by cognitive decline and progressive loss of neurons in the central nervous system. Despite huge scientific progress, there are only few animal models that recapitulate at least majority of the AD pathology and related symptomatology. Therefore, alternative methods to develop animal models for neurodegenerative diseases are constantly explored. Recently, recombinant adeno-associated viruses (AAVs) are widely used viral vectors in development of novel models for neurodegenerative diseases. AAV vectors expressing full length, mutant or truncated forms of tau demonstrate early and robust pathology characterized by AT8 positivity, NFT formation, motor and cognitive deficits. Furthermore, AAVs have been used in expression of tau in amyloid rodent models thus developing both lesions of amyloid and tau therefore recapitulating AD like features. Major advantage of AAV as a delivery system is the site specific expression of tau, mostly in hippocampus and cortex, and thus elimination of unwanted ectopic transgene expression. These novel models may help in better understanding of AD etiopathogenesis and provide a platform for development and testing of disease modifying drugs in preclinical efficacy studies.

Current trends in the treatment of malignant melanoma.

Currently, skin cancer is one of the most frequent type of cancers. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Melanomas represent 3% of all skin cancers but 65% of skin cancer deaths. Detailed knowledge of melanoma at the molecular level allows the development of new treatment alternatives and to design effective new drugs. There are two approaches in therapy of melanoma in the present is based on immunotherapy and targeted therapy or their combination. Immunotherapy includes immune checkpoint blockades whereas targeted therapy is represented by protein kinase inhibitors. Detailed knowledge of protein structure and the understanding of their role in key signalling pathways in melanoma development lead to the designation of new protein kinase inhibitors in targeted therapy. In the future, it is necessary to conduct further clinical trials and collect more data about overall survival, response rates, appropriate timing and sequence of combination therapy to manage the complexity of melanoma treatment.

Insulin-like growth factor binding proteins and mitogenic activity of partially fractionated sheep amniotic fluid.

Amniotic fluid collected from ewes on various days of gestation was examined for the presence of insulin-like growth factor (IGF) binding proteins. IGF-binding proteins with a molecular mass of 40-45 kDa appeared at day 41 of gestation. The level of these major IGF-binding proteins increased during pregnancy and reached a maximum at day 106. Smaller IGF-binding molecules with an approximate molecular mass of 35 kDa and 25 kDa appeared at day 90, also reaching a concentration peak at day 106. The mitogenic activity of sheep amniotic fluid after chromatography on Sephadex G-50 was separated into two peaks. The peak having lower molecular mass corresponded to an elution profile of 125I-IGF-I. The first peak, having higher molecular mass, was eluted immediately after the void volume of column. Electrophoresis and ligand blotting showed that proteins in the first peak had similar properties as IGF-binding proteins.

Mitogenic activity of high molecular weight forms of insulin-like growth factor-II in amniotic fluid.

Amniotic fluid (AF) collected from ewes and goats at mid gestation displayed mitogenic activity in mouse fibroblasts. Upon fractionation of this material by size exclusion chromatography, the mitogenic activity was resolved into two peaks, whose activity was inhibited by an anti-IGF type 1 receptor blocking antibody. One of the peaks contained IGF-I and IGF-II (mature form), whereas the other contained high M(r) precursor forms of IGF-II. The presence in this latter fraction of IGF-binding proteins (IGFBP) suggests that the AF IGFBPs do not efficiently inhibit the mitogenic activity of the high M(r) forms of IGF-II. In agreement with this conclusion, exogenous IGFBP-1 failed to affect this activity. Analysis of IGF-II in sheep AF showed that the AF concentrations of both forms of IGF-II increased dramatically from mid pregnancy until 106-120 days of gestation, and fell thereafter. The amniotic IGFBPs followed a similar evolution. High M(r) forms of IGF-II were also found in human AF, with a pattern of electrophoretic migration different from that of sheep. We suggest that the precursor forms of IGF-II may play an important role in foetal development.

[Peptide-like substances in sheep amniotic fluid which regulate proliferation of BP-A31 cells]. / Peptidické látky amniónovej tekutiny oviec regulujú proliferáciu buniek BP-A31.

Cell proliferation and differentiation of developing fetus is influenced by hormones as well as insulin-like growth factors and their binding proteins contained in amniotic fluid. Our purpose was to study the actual mitogenic activity of proteins and peptides present in the sheep amniotic fluid. The cell cycle regulatory activity was estimated by using mouse fibroblasts BP-A31 as target cells. The whole amniotic fluid was inactive. However, after removal of small molecules on Sephadex G-10, the fraction eluted in the void volume (M(r) > or = 0.7 kDa) was able to induce the cell division cycle in a significant proportion of quiescent fibroblasts (Fig. 1, fraction A; Fig. 2). By further gel chromatography of this active fraction at acidic condition on Sephadex G-50, two components with mitogenic activity were separated. One component was eluted immediately after the void volume of the column, the other one was coeluted with 125I-IGF-I (Fig. 3). The functional characteristics of mitogenic signal of both components (sensitivity to mitogenic effectors) were similar to those of IGF-I and insulin (Fig. 4). We suppose that a component with higher molecular weight eluted in the vicinity of the void volume of Sephadex G-50 represents probably IGFBPs or other similar proteins.