LRRK2 at the interface of autophagosomes,endosomes and lysosomes

Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases.     

The Effect of Low‐Intensity Exercise Training on Fat Metabolism of Obese Women

Objective: Previous studies have shown that fat metabolism is different in upper body (UB) and lower body (LB) obese women. The present study investigated whether the effect of low‐intensity exercise training on fat metabolism is different in UB and LB obese premenopausal women. Research Methods and Procedures: Twenty‐one healthy, premenopausal women with either LB obesity (waist‐to‐hip ratio of ≤0.79; n = 8) or UB obesity (waist‐to‐hip ratio of ≥0.85; n = 13) participated in the present study. The UB obese women were matched and randomly divided in an exercise training group (UB) and a nonexercising control group (UB‐C). Subjects in the UB and LB groups participated in a low‐intensity exercise training program (40% Vo ₂max) three times per week for 12 weeks. Before and after the intervention, measurements of fat metabolism at rest and during exercise, body composition, and maximal aerobic capacity were performed. Results: Exercise training did not change the respiratory exchange ratio at rest in the UB and LB groups. During exercise, relative fat oxidation increased in the UB group by 19% (p < 0.05), whereas no change in the LB and UB‐C groups was found. Plasma free fatty acid oxidation did not change by exercise training, and nonplasma fatty acid oxidation tended to increase in the UB group compared with the UB‐C group (p = 0.08). Discussion: Low‐intensity exercise training increased the contribution of fat oxidation to total energy expenditure during exercise but not at rest in UB obese women. Exercise training had no significant effect on fat metabolism in the LB obese women.     

The CCK(-like) receptor in the animal kingdom: functions, evolution and structures

In this review, the cholecystokinin (CCK)(-like) receptors throughout the animal kingdom are compared on the level of physiological functions, evolutionary basis and molecular structure. In vertebrates, the CCK receptor is an important member of the G-protein coupled receptors as it is involved in the regulation of many physiological functions like satiety, gastrointestinal motility, gastric acid secretion, gall bladder contraction, pancreatic secretion, panic, anxiety and memory and learning processes. A homolog for this receptor is also found in nematodes and arthropods, called CK receptor and sulfakinin (SK) receptor, respectively. These receptors seem to have evolved from a common ancestor which is probably still closely related to the nematode CK receptor. The SK receptor is more closely related to the CCK receptor and seems to have similar functions. A molecular 3D-model for the CCK receptor type 1 has been built together with the docking of the natural ligands for the CCK and SK receptors in the CCK receptor type 1. These molecular models can help to study ligand-receptor interactions, that can in turn be useful in the development of new CCK(-like) receptor agonists and antagonists with beneficial health effects in humans or potential for pest control.     

Genetic Variability in Markers of HLA-C Expression in Two Diverse South African Populations

An insertion-deletion (indel) polymorphism within the 3′ untranslated region (UTR) of HLA-C has been shown to be involved in the regulation of HLA-C expression. Individuals who carry a deletion at this position exhibit increased HLA-C expression, which associates with lower viral set point in HIV-1 infected individuals. This 263 indel (rs67384697) is reported to be in strong linkage disequilibrium (LD) with a single nucleotide polymorphism (SNP) 35 kilobases upstream of HLA-C (-35T/C; rs9264942) in Caucasian individuals, making this SNP a potential marker for both HLA-C expression and HIV-1 disease progression. We therefore examined genetic variation within the HLA-C 3′ UTR of 265 Black and Caucasian South Africans by direct sequencing and identified haplotypes encompassing the 263 indel and another indel at position 230 in both populations. Concomitant evaluation of variability at the −35 SNP revealed this polymorphism to be an inappropriate marker for the 263 indel in these populations. These findings provide important insights into genetic variability within the regulatory regions of HLA-C that have potential implications for our understanding of the regulation of HLA-C expression and its impact on HIV-1 disease progression.     

NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes

NKX2-5 is expressed in the heart throughout life. We targeted eGFP sequences to the NKX2-5 locus of human embryonic stem cells (hESCs); NKX2-5(eGFP/w) hESCs facilitate quantification of cardiac differentiation, purification of hESC-derived committed cardiac progenitor cells (hESC-CPCs) and cardiomyocytes (hESC-CMs) and the standardization of differentiation protocols. We used NKX2-5 eGFP(+) cells to identify VCAM1 and SIRPA as cell-surface markers expressed in cardiac lineages.     

Adenovirus type 40 and 41 growth in vitro: host range diversity reflected by differences in patterns of DNA replication.

Subgroup F adenoviruses adapt poorly to cell culture, but the reasons for their fastidious nature are as yet ill defined. In an attempt to gain an overview of the differences in replication between adenovirus type 2 (Ad2) and representative strains of Ad40 and Ad41, cell lines which show different degrees of permissiveness to Ad40 and Ad41 were infected and examined with respect to three key functions in the Ad2 life cycle: host protein shutoff, DNA synthesis, and late antigen synthesis. The complexity of growth patterns exhibited by the subgroup F adenoviruses suggests that defectiveness is a multifactorial phenomenon not easily explainable by a single aberrant function. Furthermore, results suggest that there may be replicative defects in subgroup F adenoviruses which are not shared by both serotypes or by all strains.