Autophagy and mitochondria in Pompe disease: nothing is so new as what has long been forgotten

Macroautophagy (often referred to as autophagy) is an evolutionarily conserved intracellular system by which macromolecules and organelles are delivered to lysosomes for degradation and recycling. Autophagy is robustly induced in response to starvation in order to generate nutrients and energy through the lysosomal degradation of cytoplasmic components. Constitutive, basal autophagy serves as a quality control mechanism for the elimination of aggregated proteins and worn-out or damaged organelles, such as mitochondria. Research during the last decade has made it clear that malfunctioning or failure of this system is associated with a wide range of human pathologies and age-related diseases. Our recent data provide strong evidence for the role of autophagy in the pathogenesis of Pompe disease, a lysosomal glycogen storage disease caused by deficiency of acid alpha-glucosidase (GAA). Large pools of autophagic debris in skeletal muscle cells can be seen in both our GAA knockout model and patients with Pompe disease. In this review, we will focus on these recent data, and comment on the not so recent observations pointing to the involvement of autophagy in skeletal muscle damage in Pompe disease.     

Cedar Virus: A Novel Henipavirus Isolated from Australian Bats

The genus Henipavirus in the family Paramyxoviridae contains two viruses, Hendra virus (HeV) and Nipah virus (NiV) for which pteropid bats act as the main natural reservoir. Each virus also causes serious and commonly lethal infection of people as well as various species of domestic animals, however little is known about the associated mechanisms of pathogenesis. Here, we report the isolation and characterization of a new paramyxovirus from pteropid bats, Cedar virus (CedPV), which shares significant features with the known henipaviruses. The genome size (18,162 nt) and organization of CedPV is very similar to that of HeV and NiV; its nucleocapsid protein displays antigenic cross-reactivity with henipaviruses; and it uses the same receptor molecule (ephrin- B2) for entry during infection. Preliminary challenge studies with CedPV in ferrets and guinea pigs, both susceptible to infection and disease with known henipaviruses, confirmed virus replication and production of neutralizing antibodies although clinical disease was not observed. In this context, it is interesting to note that the major genetic difference between CedPV and HeV or NiV lies within the coding strategy of the P gene, which is known to play an important role in evading the host innate immune system. Unlike HeV, NiV, and almost all known paramyxoviruses, the CedPV P gene lacks both RNA editing and also the coding capacity for the highly conserved V protein. Preliminary study indicated that CedPV infection of human cells induces a more robust IFN-β response than HeV.     

Identification of novel benzimidazole derivatives as inhibitors of leukotriene biosynthesis by virtual screening targeting 5-lipoxygenase-activating protein (FLAP)

Pharmacological suppression of leukotriene biosynthesis by 5-lipoxygenase (5-LO)-activating protein (FLAP) inhibitors is a promising strategy to intervene with inflammatory, allergic and cardiovascular diseases. Virtual screening targeting FLAP based on a combined ligand- and structure-based pharmacophore model led to the identification of 1-(2-chlorobenzyl)-2-(1-(4-isobutylphenyl)ethyl)-1H-benzimidazole (7) as developable candidate. Compound 7 potently suppressed leukotriene formation in intact neutrophils (IC(50)=0.31 μM) but essentially failed to directly inhibit 5-LO suggesting that interaction with FLAP causes inhibition of leukotriene synthesis. For structural optimization, a series of 46 benzimidazole-based derivatives of 7 were synthesized leading to more potent analogues (70-72, 82) with IC(50)=0.12-0.19 μM in intact neutrophils. Together, our results disclose the benzimidazole scaffold bearing an ibuprofen fingerprint as a new chemotype for further development of anti-leukotriene agents.     

Exploring uncertainty in the calibration of the molecular clock

Calibration is a critical step in every molecular clock analysis but it has been the least considered. Bayesian approaches to divergence time estimation make it possible to incorporate the uncertainty in the degree to which fossil evidence approximates the true time of divergence. We explored the impact of different approaches in expressing this relationship, using arthropod phylogeny as an example for which we established novel calibrations. We demonstrate that the parameters distinguishing calibration densities have a major impact upon the prior and posterior of the divergence times, and it is critically important that users evaluate the joint prior distribution of divergence times used by their dating programmes. We illustrate a procedure for deriving calibration densities in Bayesian divergence dating through the use of soft maximum constraints.     

Demographics and economic burden of un-owned cats and dogs in the UK: results of a 2010 census

ABSTRACT: BACKGROUND: The population of dogs and cats passing through rescue shelters may be subject to compromised welfare and increased susceptibility to disease. Little information exists to describe this population, its dynamics and associated management practices. The aim of this study was to carry out a census of un-owned cats and dogs in the UK in 2010, and to document the origins, destinations, husbandry and costs associated with the care of these animals. RESULTS: A sampling frame was constructed by searching the databases of publicly registered charities for England, Scotland and Wales, registers of breed rescues, and by internet searches of animal welfare websites. Overall, 2,352 contacts for 1,380 organisations were identified. All were sent a postal questionnaire asking for data on the number of dogs and cats housed, their origins and eventual outcomes, and details of husbandry between January 1st and December 31st 2010. For those which were registered charities (595), financial records were also obtained. A response rate of 38.8 % was obtained. Overall, in 2010, 89,571 dogs and 156,826 cats entered the care of the participating organisations. Approximately half of these animals were relinquished by their owners. Other origins included being found as strays or confiscated for welfare purposes. Seventy-five per cent of dogs and 77.1 % of cats were rehomed. The next most common outcome was euthanasia, accounting for 10.4 % of dogs and 13.2 % cats. For dogs and cats, 44.3 % and 62 % of participants respectively reported having a waiting list, which frequently exceeded the actual capacity of the facility. Over 19,000 people were involved in the care of these animals, on a paid or voluntary basis. Financial records were available for 519/595 (87.2 %) of the registered charities, and their total expenditure in 2010 was GBP340 million. CONCLUSIONS: This study showed that a large number of animals become un-owned each year, which could have considerable implications for their welfare. Despite the resources expended, demand still exceeds capacity for many organisations, and a substantial number of both cats and dogs are euthanased, suggesting that further understanding of how and why these animals become un-owned is essential in order to target interventions.