Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection

We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.     

Design of diblock co-oligomers as low bandgap small molecules for organic solar cells

The properties of a particular kind of small molecule that is built from two oligomers of different monomers, i.e. a diblock co-oligomer, as the electron donor in the active layer of organic solar cells are investigated theoretically. For these molecules, this work shows that it is possible to predict the energies of the frontier molecular orbitals by knowing the same energies for the oligomers that constitute the diblock, opening the possibility of designing new materials with optimal energy levels and optical properties. Furthermore, it was observed that the optical absorption bands of these diblock co-oligomers were broader than that of the constituent oligomers and also of the homopolymers, allowing greater absorption of photons and possibly an improved electric current in the device. It was also shown that these phenomena are size-dependent.     

A novel method for identifying behavioural changes in animal movement data

A goal of animal movement analysis is to reveal behavioural mechanisms by which organisms utilize complex and variable environments. Statistical analysis of movement data is complicated by the fact that the data are multidimensional, autocorrelated and often marked by error and irregular measurement intervals or gappiness. Furthermore, movement data reflect behaviours that are themselves heterogeneous. Here, we model movement data as a subsampling of a continuous stochastic processes, and introduce the behavioural change point analysis (BCPA), a likelihood-based method that allows for the identification of significant structural changes. The BCPA is robust to gappiness and measurement error, computationally efficient, easy to implement and reveals structure that is otherwise difficult to discern. We apply the analysis to a GPS movement track of a northern fur seal ( Callorhinus ursinus ), revealing an unexpectedly complex diurnal behavioural profile, and demonstrate its robustness to the greater errors associated with the ARGOS tracking system. By informing empirical interpretation of movement data, we suggest that the BCPA can eventually motivate the development of mechanistic behavioural models.     

Cellular immunity in patients with multiple primary tumors

Summary Immunological studies for evaluation of cellular immunity were carried out on 22 patients who had two primary malignant tumors and who had no evidence of active disease. The tests performed were for skin reactivity to 3 recall antigens, PPD, Candidine, and Streptokinase and in vitro lymphocyte stimulation by PHA. Of these, 6 patients were anergic to all three recall antigens and 5 other patients to two out of three antigens. A depression of the in vitro reactivity was encountered in 11 patients. The immune incompetence was more evident in patients with simultaneous tumors than in those with metachroneous tumors. The longer the interval between the appearance of the primary and the secondary tumors, the less immunosuppression was seen.Presented at the 24th Israel Medical Association Conference on Immunological Aspects of Cancer, Tel-Aviv, December 26, 1974This work was supported in part by the Office of the Administrator General, Ministry of Justice and the Medical Research Fund under the Sponsorship of the Ministry of Health     

A Blood-Brain Barrier (BBB) Disrupter Is Also a Potent α-Synuclein (α-syn) Aggregation Inhibitor: A NOVEL DUAL MECHANISM OF MANNITOL FOR THE TREATMENT OF PARKINSON DISEASE (PD)*

The development of disease-modifying therapy for Parkinson disease has been a main drug development challenge, including the need to deliver the therapeutic agents to the brain. Here, we examined the ability of mannitol to interfere with the aggregation process of α-synuclein in vitro and in vivo in addition to its blood-brain barrier-disrupting properties. Using in vitro studies, we demonstrated the effect of mannitol on α-synuclein aggregation. Although low concentration of mannitol inhibited the formation of fibrils, high concentration significantly decreased the formation of tetramers and high molecular weight oligomers and shifted the secondary structure of α-synuclein from α-helical to a different structure, suggesting alternative potential pathways for aggregation. When administered to a Parkinson Drosophila model, mannitol dramatically corrected its behavioral defects and reduced the amount of α-synuclein aggregates in the brains of treated flies. In the mThy1-human α-synuclein transgenic mouse model, a decrease in α-synuclein accumulation was detected in several brain regions following treatment, suggesting that mannitol promotes α-synuclein clearance in the cell bodies. It appears that mannitol has a general neuroprotective effect in the transgenic treated mice, which includes the dopaminergic system. We therefore suggest mannitol as a basis for a dual mechanism therapeutic agent for the treatment of Parkinson disease.     

Preeclampsia‐associated stresses activate Gadd45a signaling and sFlt‐1 in placental explants

Accumulating evidence suggests that placental stresses during pregnancy can play an important role in the pathogenesis of preeclampsia. A common signal pathway that senses and converts placental stresses into intracellular stress response may be contributing to this pathology. Based on our previous findings, we extended our investigation to establish that Gadd45a stress signaling regulates sFlt‐1 levels, particularly in placenta, when exposed to various preeclampsia‐associated stresses including AT‐1 receptor agonist (Angiotensin II), hypoxia, and inflammatory cytokines. Using a placental explant model, we found that Gadd45a was induced in response to all the preeclampsia stresses stated above. Although stress induced Gadd45a was associated with the activation of its downstream effectors phospho‐p38 and phospho‐JNK, the subsequent regulation of sFlt‐1 levels occurred through either one of these effectors, but not both. These observations indicate that Gadd45a signaling may work as a hub connecting placental stresses and the pathogenesis of preeclampsia. It also provides evidence to justify testing the role of Gadd45 in the etiology of preeclampsia using in vivo mouse (i.e., Gadd45a null mice) models. J. Cell. Physiol. 228: 362–370, 2013. © 2012 Wiley Periodicals, Inc.     

Characteristic spatial and temporal scales unify models of animal movement

Animal movements have been modeled with diffusion at large scales and with more detailed movement models at smaller scales. We argue that the biologically relevant behavior of a wide class of movement models can be efficiently summarized with two parameters: the characteristic temporal and spatial scales of movement. We define these scales so that they describe movement behavior both at short scales (through the velocity autocorrelation function) and at long scales (through the diffusion coefficient). We derive these scales for two types of commonly used movement models: the discrete-step correlated random walk, with either constant or random step intervals, and the continuous-time correlated velocity model. For a given set of characteristic scales, the models produce very similar trajectories and encounter rates between moving searchers and stationary targets. Thus, we argue that characteristic scales provide a unifying currency that can be used to parameterize a wide range of ecological phenomena related to movement.