How do neural connectivity and time delays influence bimanual coordination?

Multilevel crosstalk as a neural basis for motor control has been widely discussed in the literature. Since no natural process is instantaneous, any crosstalk model should incorporate time delays, which are known to induce temporal coupling between functional elements and stabilize or destabilize a particular mode of coordination. In this article, we systematically study the dynamics of rhythmic bimanual coordination under the influence of varying connection topology as realized by callosal fibers, cortico-thalamic projections, and crossing peripheral fibers. Such connectivity contributes to various degrees of neural crosstalk between the effectors which we continuously parameterize in a mathematical model. We identify the stability regimes of bimanual coordination as a function of the degree of neural crosstalk, movement amplitude and the time delays involved due to signal processing. Prominent examples include explanations of the decreased stability of the antiphase mode of coordination in split brain patients and the role of coupling in mediating bimanual coordination.     

Apoptosis in skin cancer development and regression

Non-melanoma skin cancers (NMSC) are the most common malignant tumors in white population and their incidence has been increasing worldwide. Molecular events regulating cell survival, apoptosis, growth arrest as well as cell differentiation, are important contributors to the overall kinetics of benign and malignant cell growth and play a role in their development, progression and regression. Failure of these pathways can result in the loss of control over proliferation and lead to tumor development through the inactivation of tumor suppressor genes or the activation of oncogenes. Also, immunological mechanisms have been implicated in a phenomenon of tumor progression as well as spontaneous tumor regression. We have tried to summarize the main events in etiopatogenesis, development, progression and in some cases skin cancer regression. Further studies are needed to elucidate completely the details of apoptotic control in normal skin and determine factors resulting in apoptotic disbalance and disease.     

Conformation of DNA GG intrastrand cross-link of antitumor oxaliplatin and its enantiomeric analog

Downstream processes that discriminate between DNA adducts of a third generation platinum antitumor drug oxaliplatin and conventional cisplatin are believed to be responsible for the differences in their biological effects. These different biological effects are explained by the ability of oxaliplatin to form DNA adducts more efficient in their biological effects. In this work conformation, recognition by HMG domain protein and DNA polymerization across the major 1,2-GG intrastrand cross-link formed by cisplatin and oxaliplatin in three sequence contexts were compared with the aid of biophysical and biochemical methods. The following major differences in the properties of the cross-links of oxaliplatin and cisplatin were found: i), the formation of the cross-link by oxaliplatin is more deleterious energetically in all three sequence contexts; ii), the cross-link of oxaliplatin bends DNA slightly but systematically less in all sequence contexts tested; iii), the affinity of HMG domain protein to the cross-link of oxaliplatin is considerably lower independent of the sequence context; and iv), the Klenow fragment of DNA polymerase I pauses considerably more at the cross-link of oxaliplatin in all sequence contexts tested. We have also demonstrated that the chirality at the carrier ligand of oxaliplatin can affect its biological effects.     

Insulin withdrawal induces apoptosis via a free radical-mediated mechanism

Diabetes is characterized by chronic hyperglycemia as well as insulin deficiency or resistance. However, the majority of research has focused on the consequences of hyperglycemia in development of diabetic complications, whereas the effects of insulin deficiency or resistance, independent of hyperglycemia, have received little attention. Since insulin is a well known cytoprotective factor, we hypothesized that its removal could significantly impact cell survival. To examine this possibility, cultured neonatal cardiomyocytes were subjected to insulin withdrawal and examined for apoptosis. Insulin deficient cells succumbed to apoptosis, an effect associated with impaired PI3-kinase/Akt signaling and reduction in the Bcl-2 to Bax ratio. Perhaps more importantly, superoxide generation was altered in cells subjected to insulin withdrawal. Removal of insulin caused a significant increase in reactive oxygen species production and resulted in oxidative mitochondrial DNA damage the latter effect is associated with impaired expression of mitochondrially encoded proteins that make up the electron transport chain. Significantly, the effects of insulin withdrawal could be mitigated by treatment with the antioxidant, Tiron. Collectively, these data demonstrate that insulin deficiency leads to apoptosis and suggest a role for oxidative mitochondrial DNA damage in this cascade.     

Solution structure and proposed domain domain recognition interface of an acyl carrier protein domain from a modular polyketide synthase

Polyketides are a medicinally important class of natural products. The architecture of modular polyketide synthases (PKSs), composed of multiple covalently linked domains grouped into modules, provides an attractive framework for engineering novel polyketide-producing assemblies. However, impaired domain-domain interactions can compromise the efficiency of engineered polyketide biosynthesis. To facilitate the study of these domain-domain interactions, we have used nuclear magnetic resonance (NMR) spectroscopy to determine the first solution structure of an acyl carrier protein (ACP) domain from a modular PKS, 6-deoxyerythronolide B synthase (DEBS). The tertiary fold of this 10-kD domain is a three-helical bundle; an additional short helix in the second loop also contributes to the core helical packing. Superposition of residues 14-94 of the ensemble on the mean structure yields an average atomic RMSD of 0.64 +/- 0.09 Angstrom for the backbone atoms (1.21 +/- 0.13 Angstrom for all non-hydrogen atoms). The three major helices superimpose with a backbone RMSD of 0.48 +/- 0.10 Angstrom (0.99 +/- 0.11 Angstrom for non-hydrogen atoms). Based on this solution structure, homology models were constructed for five other DEBS ACP domains. Comparison of their steric and electrostatic surfaces at the putative interaction interface (centered on helix II) suggests a model for protein-protein recognition of ACP domains, consistent with the previously observed specificity. Site-directed mutagenesis experiments indicate that two of the identified residues influence the specificity of ACP recognition.     

Lentiviral Modulation of Wnt/β-Catenin Signaling Affects In Vivo LTP

Wnt signaling is involved in hippocampal development and synaptogenesis. Numerous recent studies have been focused on the role of Wnt ligands in the regulation of synaptic plasticity. Inhibitors and activators of canonical Wnt signaling were demonstrated to decrease or increase, respectively, in vitro long-term potentiation (LTP) maintenance in hippocampal slices (Chen et al. in J Biol Chem 281:11910–11916, 2006; Vargas et al. in J Neurosci 34:2191–2202, 2014, Vargas et al. in Exp Neurol 264:14–25, 2015). Using lentiviral approach to down- and up-regulate the canonical Wnt signaling, we explored whether Wnt/β-catenin signaling is critical for the in vivo LTP. Chronic suppression of Wnt signaling induced an impairment of in vivo LTP expression 14 days after lentiviral suspension injection, while overexpression of Wnt3 was associated with a transient enhancement of in vivo LTP magnitude. Both effects were related to the early phase LTP and did not affect LTP maintenance. A loss-of-function study demonstrated decreased initial paired pulse facilitation ratio, β-catenin, and phGSK-3β levels. A gain-of-function study revealed not only an increase in PSD-95, β-catenin, and Cyclin D1 protein levels, but also a reduced phGSK-3β level and enhanced GSK-3β kinase activity. These results suggest a presynaptic dysfunction predominantly underlying LTP impairment while postsynaptic modifications are primarily involved in transient LTP amplification. This study is the first demonstration of the involvement of Wnt/β-catenin signaling in synaptic plasticity regulation in an in vivo LTP model.     

Media mirrors? Framing Hungarian Romani migration to Canada in Hungarian and Canadian press

ABSTRACT

The most recent migration of Roma from Central-Eastern Europe to Canada started in the 1990s. Several thousand people from former socialist countries, including Hungarian Roma, moved overseas. There were many reasons but for Roma, the motivations not only included a drastic loss of employment, but re-emerging systemic and increasingly violent racism. This article focuses on the discursive framing of these motivations and the reaction within both Hungarian and Canadian newspapers from 1999 to 2013. In the article we show how the press engaged in framing and counter-framing the policies and politics of the host country through their coverage of “the Hungarian Roma” issue. Specifically, we focus on the differing and shifting spheres of consensus and the changing political/policy contexts by conducting an in-depth comparison of the changing media frames in Hungarian and Canadian newspaper coverage. We show how the “Hungarian Roma issue” becomes an example and reflection of the changing political culture.