Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis

Mutations in leucine-rich repeat kinase 2 (LRRK2) are an established cause of inherited Parkinson's disease (PD). LRRK2 is expressed in both neurons and glia in the central nervous system, but its physiological function(s) in each of these cell types is uncertain. Through sequential screens, we report a functional interaction between LRRK2 and Clathrin adaptor protein complex 2 (AP2). Analysis of LRRK2 KO tissue revealed a significant dysregulation of AP2 complex components, suggesting LRRK2 may act upstream of AP2. In line with this hypothesis, expression of LRRK2 was found to modify recruitment and phosphorylation of AP2. Furthermore, expression of LRRK2 containing the R1441C pathogenic mutation resulted in impaired clathrin-mediated endocytosis (CME). A decrease in activity-dependent synaptic vesicle endocytosis was also observed in neurons harboring an endogenous R1441C LRRK2 mutation. Alongside LRRK2, several PD-associated genes intersect with membrane-trafficking pathways. To investigate the genetic association between Clathrin-trafficking and PD, we used polygenetic risk profiling from IPDGC genome wide association studies (GWAS) datasets. Clathrin-dependent endocytosis genes were found to be associated with PD across multiple cohorts, suggesting common variants at these loci represent a cumulative risk factor for disease. Taken together, these findings suggest CME is a LRRK2-mediated, PD relevant pathway.Neurological Motor Disorder

The Structure of Clusters with Bimodal Distributions of Galaxy Radial Velocities. I. A1035

The structure of the A1035 cluster of galaxies (10h32m +40d13', cz ~ 22000 km/s), which exhibits a bimodal distribution of galaxy radial velocities (\Delta V\approx 3000 km/s), is analyzed using three methods of determining the relative distances to clusters from early-type galaxies: the Kormendy relation corrected for the dependence of residuals on galaxy magnitude, the photometric plane, and the fundamental plane. We use the data obtained with the 1-m telescope of the Special Astrophysical Observatory of the Russian Academy of Sciences and SDSS (DR5) data to show that A1035 consists of two gravitationally unbound independent clusters. These clusters with the velocity dispersions of 566 km/s and 610 km/s and masses within R_200 equal to 2.7 10^14 and 3.5 10^14 M_sun, respectively, obey the Hubble law.Comment: 13 pages, 3 tables, 6 figure

The Large Scale Structure in the Universe: From Power-Laws to Acoustic Peaks

The most popular tools for analysing the large scale distribution of galaxies are second-order spatial statistics such as the two-point correlation function or its Fourier transform, the power spectrum. In this review, we explain how our knowledge of cosmic structures, encapsulated by these statistical descriptors, has evolved since their first use when applied on the early galaxy catalogues to the present generation of wide and deep redshift surveys, incorporating the most challenging discovery in the study of the galaxy distribution: the detection of Baryon Acoustic Oscillations.Comment: 20 pages, 12 figures, to appear in "Data Analysis in Cosmology", Lecture Notes in Physics, 2008, eds. V. J. Martinez, E. Saar, E. Martinez-Gonzalez, and M.J. Pons-Borderia, Springer-Verla

Diabetic gastroparesis: Therapeutic options

Gastroparesis is a condition characterized by delayed gastric emptying and the most common known underlying cause is diabetes mellitus. Symptoms include nausea, vomiting, abdominal fullness, and early satiety, which impact to varying degrees on the patient’s quality of life. Symptoms and deficits do not necessarily relate to each other, hence despite significant abnormalities in gastric emptying, some individuals have only minimal symptoms and, conversely, severe symptoms do not always relate to measures of gastric emptying. Prokinetic agents such as metoclopramide, domperidone, and erythromycin enhance gastric motility and have remained the mainstay of treatment for several decades, despite unwanted side effects and numerous drug interactions. Mechanical therapies such as endoscopic pyloric botulinum toxin injection, gastric electrical stimulation, and gastrostomy or jejunostomy are used in intractable diabetic gastroparesis (DG), refractory to prokinetic therapies. Mitemcinal and TZP-101 are novel investigational motilin receptor and ghrelin agonists, respectively, and show promise in the treatment of DG. The aim of this review is to provide an update on prokinetic and mechanical therapies in the treatment of DG

Information and digital literacies; a review of concepts

A detailed literature reviewing, analysing the multiple and confusing concepts around the ideas of information literacy and digital literacy at the start of the millennium. The article was well-received, and is my most highly-cited work, with over 1100 citations

Toll-Like Receptors change morphine-induced antinociception, tolerance and dependence: studies using male and female TLR and Signalling gene KO mice

Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling po- tentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 -/- mice. In silico docking simu- lations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [3H](-)-naloxone or [3H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR- opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.Jacob H.L. Thomas, Liang Lui, Andrew Abell, William Tieu, Andrew A. Somogyi, Juliana E. Bajic, Mark R. Hutchinso

Spiropyran-based nanocarrier: a new Zn2+ -responsive delivery system with real-time intracellular sensing capabilities

A new spiropyran-based stimuli-responsive delivery system is fabricated. It encapsulates and then releases an extraneous compound in response to elevated levels of Zn²⁺ , a critical factor in cell apoptosis. A C₁₂-alkyl substituent on the spiropyran promotes self-assembly into a micelle-like nanocarrier in aqueous media, with nanoprecipitation and encapsulation of added payload. Zn²⁺ binding occurs to an appended bis(2-pyridylmethyl)amine group at biologically relevant micromolar concentration. This leads to switching of the spiropyran (SP) isomer to the strongly fluorescent ring opened merocyanine-Zn²⁺ (MC-Zn²⁺ ) complex, with associated expansion of the nanocarriers to release the encapsulated payload. Payload release is demonstrated in solution and in HEK293 cells by encapsulation of a blue fluorophore, 7-hydroxycoumarin, and monitoring its release using fluorescence spectroscopy and microscopy. Furthermore, the use of the nanocarriers to deliver a caspase inhibitor, Azure B, into apoptotic cells in response to an elevated Zn²⁺ concentration is demonstrated. This then inhibits intracellular caspase activity, as evidenced by confocal microscopy and in real-time by time-lapsed microscopy. Finally, the nanocarriers are shown to release an encapsulated proteasome inhibitor (5) in Zn²⁺ -treated breast carcinoma cell line models. This then inhibits intracellular proteasome and induces cytotoxicity to the carcinoma cells.Sabrina Heng, Xiaozhou Zhang, Jinxin Pei, Alaknanda Adwal, Philipp Reineck, Brant C. Gibson, Mark R. Hutchinson and Andrew D. Abel