PINK1/Parkin Mediated Mitophagy, Ca2+ Signalling, and ER-Mitochondria Contacts in Parkinson's Disease

Endoplasmic reticulum (ER)-mitochondria contact sites are critical structures for cellular function. They are implicated in a plethora of cellular processes, including Ca2+ signalling and mitophagy, the selective degradation of damaged mitochondria. Phosphatase and tensin homolog (PTEN)-induced kinase (PINK) and Parkin proteins, whose mutations are associated with familial forms of Parkinson's disease, are two of the best characterized mitophagy players. They accumulate at ER-mitochondria contact sites and modulate organelles crosstalk. Alterations in ER-mitochondria tethering are a common hallmark of many neurodegenerative diseases including Parkinson's disease. Here, we summarize the current knowledge on the involvement of PINK1 and Parkin at the ER-mitochondria contact sites and their role in the modulation of Ca2+ signalling and mitophagy

Organelles: The Emerging Signalling Chart of Mitochondrial Dynamics

Many molecular and functional details of single events in mitochondrial dynamics have been reported, but little is known about their coordination. A recent study describes how cellular Ca2+ signals, via remodelling the actin cytoskeleton, synchronise the formation of endoplasmic reticulum–mitochondria contacts with inner and outer mitochondrial membrane fission

A Coding Variant in the Gene Bardet-Biedl Syndrome 4 (BBS4) Is Associated with a Novel Form of Canine Progressive Retinal Atrophy

Progressive retinal atrophy is a common cause of blindness in the dog and affects >100 breeds. It is characterized by gradual vision loss that occurs due to the degeneration of photoreceptor cells in the retina. Similar to the human counterpart retinitis pigmentosa, the canine disorder is clinically and genetically heterogeneous and the underlying cause remains unknown for many cases. We use a positional candidate gene approach to identify putative variants in the Hungarian Puli breed using genotyping data of 14 family-based samples (CanineHD BeadChip array, Illumina) and whole-genome sequencing data of two proband and two parental samples (Illumina HiSeq 2000). A single nonsense SNP in exon 2 of BBS4 (c.58A > T, p.Lys20*) was identified following filtering of high quality variants. This allele is highly associated (P-CHISQ = 3.425e(-14), n = 103) and segregates perfectly with progressive retinal atrophy in the Hungarian Puli. In humans, BBS4 is known to cause Bardet-Biedl syndrome which includes a retinitis pigmentosa phenotype. From the observed coding change we expect that no functional BBS4 can be produced in the affected dogs. We identified canine phenotypes comparable with Bbs4-null mice including obesity and spermatozoa flagella defects. Knockout mice fail to form spermatozoa flagella. In the affected Hungarian Puli spermatozoa flagella are present, however a large proportion of sperm are morphologically abnormal andPeer reviewe

A split-GFP tool reveals differences in the sub-mitochondrial distribution of wt and mutant alpha-synuclein

Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by dopaminergic neuronal loss that initiates in the substantia nigra pars compacta and by the formation of intracellular inclusions mainly constituted by aberrant \u3b1-synuclein (\u3b1-syn) deposits known as Lewy bodies. Most cases of PD are sporadic, but about 10% are familial, among them those caused by mutations in SNCA gene have an autosomal dominant transmission. SNCA encodes \u3b1-syn, a small 140-amino acids protein that, under physiological conditions, is mainly localized at the presynaptic terminals. It is prevalently cytosolic, but its presence has been reported in the nucleus, in the mitochondria and, more recently, in the mitochondria-associated ER membranes (MAMs). Whether different cellular localizations may reflect specific \u3b1-syn activities is presently unclear and its action at mitochondrial level is still a matter of debate. Mounting evidence supports a role for \u3b1-syn in several mitochondria-derived activities, among which maintenance of mitochondrial morphology and modulation of complex I and ATP synthase activity. \u3b1-syn has been proposed to localize at the outer membrane (OMM), in the intermembrane space (IMS), at the inner membrane (IMM) and in the mitochondrial matrix, but a clear and comparative analysis of the sub-mitochondrial localization of WT and mutant \u3b1-syn is missing. Furthermore, the reasons for this spread sub-mitochondrial localization under physiological and pathological circumstances remain elusive. In this context, we decided to selectively monitor the sub-mitochondrial distribution of the WT and PD-related \u3b1-syn mutants A53T and A30P by taking advantage from a bimolecular fluorescence complementation (BiFC) approach. We also investigated whether cell stress could trigger \u3b1-syn translocation within the different mitochondrial sub-compartments and whether PD-related mutations could impinge on it. Interestingly, the artificial targeting of \u3b1-syn WT (but not of the mutants) to the mitochondrial matrix impacts on ATP production, suggesting a potential role within this compartment

Run 2 Upgrades to the CMS Level-1 Calorimeter Trigger

The CMS Level-1 calorimeter trigger is being upgraded in two stages to maintain performance as the LHC increases pile-up and instantaneous luminosity in its second run. In the first stage, improved algorithms including event-by-event pile-up corrections are used. New algorithms for heavy ion running have also been developed. In the second stage, higher granularity inputs and a time-multiplexed approach allow for improved position and energy resolution. Data processing in both stages of the upgrade is performed with new, Xilinx Virtex-7 based AMC cards.Comment: 10 pages, 7 figure

SMaRT: A Science-based Tiered Framework for Common Ravens

Large-scale increases and expansion of common raven (Corvus corax; raven) populations are occurring across much of North America, leading to increased negative consequences for livestock and agriculture, human health and safety, and sensitive species conservation. We describe a science-based adaptive management framework that incorporates recent quantitative analyses and mapping products for addressing areas with elevated raven numbers and minimizing potential adverse impacts to sensitive species, agricultural damage, and human safety. The framework comprises 5 steps: (1) desktop analysis; (2) field assessments; (3) comparison of raven density estimates to an ecological threshold (in terms of either density or density plus distance to nearest active or previous nest); (4) prescribing management options using a 3-tiered process (i.e., habitat improvements, subsidy reductions, and direct actions using StallPOPd.V4 software); and (5) post-management monitoring. The framework is integrated within the Science-based Management of Ravens Tool (SMaRT), a web-based application outfitted with a user-friendly interface that guides managers through each step to develop a fully customized adaptive plan for raven management. In the SMaRT interface, users can: (1) interact with pre-loaded maps of raven occurrence and density and define their own areas of interest within the Great Basin to delineate proposed survey or treatment sites; (2) enter site-level density estimates from distance sampling methods or perform estimation of raven densities using the rapid assessment protocol that we provide; (3) compare site-level density estimates to an identified ecological threshold; and (4) produce a list of potential management options for their consideration. The SMaRT supports decision-making by operationalizing scientific products for raven management and facilitates realization of diverse management goals including sensitive species conservation, protection of livestock and agriculture, safeguarding human health, and addressing raven overabundance and expansion. We illustrate the use of the framework through SMaRT using an example of greater sage-grouse (Centrocercus urophasianus) conservation efforts within the Great Basin, USA

Characterization of prion disease associated with a two-octapeptide repeat insertion

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk

Performance of ALICE pixel prototypes in high energy beams

The two innermost layers of the ALICE inner tracking system are instrumented with silicon pixel detectors. Single chip assembly prototypes of the ALICE pixels have been tested in high energy particle beams at the CERN SPS. Detection efficiency and spatial precision have been studied as a function of the threshold and the track incidence angle. The experimental method, data analysis and main results are presented.Comment: 10 pages, 9 figures, contribution to PIX2005 Workshop, Bonn (Germany), 5-8 September 200