BACE1-/- mice exhibit seizure activity that does not correlate with sodium channel level or axonal localization

<p>Abstract</p> <p>Background</p> <p>BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. Examination of BACE1^-/-mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1^-/-mice.</p> <p>Results</p> <p>We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1^-/-mice, occasionally including generalized tonic-clonic and absence seizures. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1^-/-mice relative to BACE1^+/+littermates, and causes excitotoxic cell death in a subset of BACE1^-/-mice. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1^-/-mice. Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Na_v1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility.</p> <p>Conclusions</p> <p>Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.</p

Long-distance attachments and implications for tourism development: the case of the Western Ukrainian diaspora

This study analyzes the perspectives of roots tourism through the experiences of Western Ukrainian diaspora members. Their sense of attachment to the ancestral homeland and their visits to the places of origin are investigated, together with the views by tour operators specialized in roots tourism and public authorities dealing with tourism in the region, evaluating the actual or potential impact in terms of tourism development opportunities. The peculiar history of this territory makes it a distinct research target, with dynamics that are different from the rest of the country. The desire to turn Western Ukraine into a solid tourist destination and the aim of stimulating economic development in a region that is still struggling to re-emerge from its marginality are widespread and form a fertile basis for the growth of diaspora tourism as a solid asset. Lights and shadows emerge from the diaspora tourists’ experiences and perceptions. Specialized tour operators clearly see the enhancement of this form of tourism as an important business opportunity, while public authorities are not currently focusing on this segment, preferring general tourism promotion

Benefits of boredom: an ‘interlopers’ experience of conducting participant observation on the production line

Embracing a lyrical style of writing, the paper discusses the advantages of conducting participant observation and calls for its increased use in business and management research, especially the field of human resource management (HRM). In a sector dominated by quantitative research methods, we are left with many unanswered questions about organisational life. While surveys have provided us with an abundance of ‘hard’ data, it has resulted in a lack of depth and understanding around the employee experience. Reflecting on a research project that explored the concept of high‐performance work systems (HPWS), the paper discusses a chance opportunity to undertake participant observation and how the experience not only changed the focus of the research project but provided a depth and understanding currently missing from the HRM/HPWS paradigm. Structured around ‘lessons learnt’, the paper calls for methodological eclecticism and hopes to encourage others to become ‘interlopers’ and embrace the benefits of conducting participant observation

Self-help groups challenge health care systems in the US and UK

Purpose: This research considers how self-help groups (SHGs) and self- help organizations (SHOs) contribute to consumerist trends in two different societies: United States and United Kingdom. How do the health care systems and the voluntary sectors affect the kinds of social changes that SHGs/SHOs make? Methodology/approach: A review of research on the role of SHGs/SHOs in contributing to national health social movements in the UK and US was made. Case studies of the UK and the US compare the characteristics of their health care systems and their voluntary sector. Research reviews of two community level self-help groups in each country describe the kinds of social changes they made. Findings: The research review verified that SHGs/SHOs contribute to national level health social movements for patient consumerism. The case studies showed that community level SHGs/SHOs successfully made the same social changes but on a smaller scale as the national movements, and the health care system affects the kinds of community changes made. Research limitations: A limited number of SHGs/SHOs within only two societies were studied. Additional SHGs/SHOs within a variety of societies need to be studied. Originality/value of chapter Community SHGs/SHOs are often trivialized by social scientists as just inward-oriented support groups, but this chapter shows that local groups contribute to patient consumerism and social changes but in ways that depend on the kind of health care system and societal context

PDZ domains and their binding partners: structure, specificity, and modification

PDZ domains are abundant protein interaction modules that often recognize short amino acid motifs at the C-termini of target proteins. They regulate multiple biological processes such as transport, ion channel signaling, and other signal transduction systems. This review discusses the structural characterization of PDZ domains and the use of recently emerging technologies such as proteomic arrays and peptide libraries to study the binding properties of PDZ-mediated interactions. Regulatory mechanisms responsible for PDZ-mediated interactions, such as phosphorylation in the PDZ ligands or PDZ domains, are also discussed. A better understanding of PDZ protein-protein interaction networks and regulatory mechanisms will improve our knowledge of many cellular and biological processes

Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) are the molecular basis for the current, I(h), which contributes crucially to intrinsic neuronal excitability. The subcellular localization and biophysical properties of h channels govern their function, but the mechanisms controlling these characteristics, and especially the potential role of auxiliary subunits or other binding proteins, remain unclear. We focused on TRIP8b, an h channel-interacting protein that colocalizes with HCN1 in cortical and hippocampal pyramidal neuron dendrites, and found that it exists in multiple alternative splice variants with distinct effects on h channel trafficking and function. The developmentally regulated splice variants of TRIP8b all shared dual, C terminus-located interaction sites with HCN1. When coexpressed with HCN1 in heterologous cells individual TRIP8b isoforms similarly modulated gating of I(h), causing a hyperpolarizing shift in voltage dependence of channel activation, but differentially upregulated or downregulated I(h) current density and HCN1 surface expression. In hippocampal neurons, coexpression of TRIP8b isoforms with HCN1 produced isoform-specific changes of HCN1 localization. Interestingly, the TRIP8b isoforms most abundant in the brain are those predicted to enhance h channel surface expression. Indeed, shRNA knockdown of TRIP8b in hippocampal neurons significantly reduced native I(h). Thus, although TRIP8b exists in multiple splice isoforms, our data suggest that the predominant role of this protein in brain is to promote h channel surface expression and enhance I(h). Because I(h) expression is altered in models of several diseases, including temporal lobe epilepsy, TRIP8b may play a role in both normal neuronal function and in aberrant neuronal excitability associated with neurological disease