Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury

Regenerative responses to axonal injury involve changes in gene expression; however, little is known about how such changes can be induced from a distant site of injury. In this study, we describe a nerve crush assay in Drosophila melanogaster to study injury signaling and regeneration mechanisms. We find that Wallenda (Wnd), a conserved mitogen-activated protein kinase (MAPK) kinase kinase homologous to dual leucine zipper kinase, functions as an upstream mediator of a cell-autonomous injury signaling cascade that involves the c-Jun NH(2)-terminal kinase MAPK and Fos transcription factor. Wnd is physically transported in axons, and axonal transport is required for the injury signaling mechanism. Wnd is regulated by a conserved E3 ubiquitin ligase, named Highwire (Hiw) in Drosophila. Injury induces a rapid increase in Wnd protein concomitantly with a decrease in Hiw protein. In hiw mutants, injury signaling is constitutively active, and neurons initiate a faster regenerative response. Our data suggest that the regulation of Wnd protein turnover by Hiw can function as a damage surveillance mechanism for responding to axonal injury

Molecular mechanisms that enhance synapse stability despite persistent disruption of the spectrin/ankyrin/microtubule cytoskeleton

Neuromuscular junctions crippled by a disrupted microtubule cytoskeleton are rescued by stress-induced activation of MAPK-JNK-Fos signaling

PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism

<p>Abstract</p> <p>Background</p> <p>Genetic analysis of the human prion protein gene (<it>PRNP</it>) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the <it>PRNP </it>locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of <it>PRNP </it>open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population.</p> <p>Methods</p> <p>DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation.</p> <p>Results</p> <p>147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had <it>PRNP </it>codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full <it>PRNP </it>gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.</p> <p>Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism.</p> <p>Conclusions</p> <p>This analysis of <it>PRNP </it>genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.</p

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95%CI: 1.20–2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95%CI: 1.08–3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis

Case Study of H.R. 695: The Security and Freedom Through Encryption (SAFE) Act

This paper reviews the history of encryption policy, and analyzes the course of actions taken by the President, Congress, business and public interests, and various bureaucratic entities toward an updated, coherent policy on the encryption issue through the medium of H.R. 695. A summary assessment of the present situation and likely results are offered. Statement of Issue Technology at the turn of the millennium emulates the state of atomic energy fifty years ago. At the end of the war, following the destruction of Hiroshima and Nagasaki, attention turned to the peaceful application of atomic energy. The ability to split the atom was viewed as the bane of civilization, but potentially a boon as well. Nuclear power is the most pervasive and lasting example of peacetime use. Ironically, the U.S. is the one country least at peace about the role and residue of atomic energy. In similar fashion, the application of technology is considered a potential silver bullet, a leveler of the playing field through providing seemingly limitless power, space, and access to the person sitting at the keyboard. The present administration, and Vice President Al Gore most particularly, has agressively pursued a technology leadership role for the U.S. in the global marketplace, and has mandated widespread use of computer technology in a vast arena of federally managed programs. The technical progress in electronic communications, both voice and data, has expanded broadly the ability to transact legal and illegal business through electronic means. Legal business uses involving encryption include private messaging, secure transactions, database security, and source authentication. Criminal uses include preventing detection and obscuring evidence. These contradictory uses have resulted in the adm..

State Systemic Improvement Planning: Impact on System and Student Outcomes

In the wake of reports of continued gaps between youth with and without disabilities in regard to graduation rates and postschool outcomes, the U.S. Department of Education (USDOE), Office of Special Education Programs (OSEP) began examining their process for monitoring state implementation of the Individuals with Disabilities Education Improvement Act (IDEA). OSEP’s revised accountability system, known as Results-Driven Accountability, better aligns accountability systems to support states in improving results for infants, toddlers, and youth with disabilities and their families. Currently required from states, is a comprehensive multiyear State Systemic Improvement Plan (SSIP) focused on improving results for students with disabilities. The purpose of this article is to describe the phases of the SSIP and provide an example of how this new accountability system is working in the Republic of the Marshall Islands (RMI). As with all other states, territories, and freely associated states, RMI is required to develop and implement an SSIP