Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage

We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and 2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs^∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.     

Membrane adsorption and binding, cellular uptake and cytotoxicity of cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone: effects of hydrogen bonding and α-chirality in the β-peptoid residues

Cell-penetrating peptides (CPPs) provide a promising approach for enhancing intracellular delivery of therapeutic biomacromolecules by increasing transport through membrane barriers. Here, proteolytically stable cell-penetrating peptidomimetics with α-peptide/β-peptoid backbone were studied to evaluate the effect of α-chirality in the β-peptoid residues and the presence of guanidinium groups in the α-amino acid residues on membrane interaction. The molecular properties of the peptidomimetics in solution (surface and intramolecular hydrogen bonding, aqueous diffusion rate and molecular size) were studied along with their adsorption to lipid bilayers, cellular uptake, and toxicity. The surface hydrogen bonding ability of the peptidomimetics reflected their adsorbed amounts onto lipid bilayers as well as with their cellular uptake, indicating the importance of hydrogen bonding for their membrane interaction and cellular uptake. Ellipsometry studies further demonstrated that the presence of chiral centers in the β-peptoid residues promotes a higher adsorption to anionic lipid bilayers, whereas circular dichroism results showed that α-chirality influences their overall mean residue ellipticity. The presence of guanidinium groups and α-chiral β-peptoid residues was also found to have a significant positive effect on uptake in living cells. Together, the findings provide an improved understanding on the behavior of cell-penetrating peptidomimetics in the presence of lipid bilayers and live cells.     

PRELP protein inhibits the formation of the complement membrane attack complex

PRELP is a 58-kDa proteoglycan found in a variety of extracellular matrices, including cartilage and at several basement membranes. In rheumatoid arthritis (RA), the cartilage tissue is destroyed and fragmented molecules, including PRELP, are released into the synovial fluid where they may interact with components of the complement system. In a previous study, PRELP was found to interact with the complement inhibitor C4b-binding protein, which was suggested to locally down-regulate complement activation in joints during RA. Here we show that PRELP directly inhibits all pathways of complement by binding C9 and thereby prevents the formation of the membrane attack complex (MAC). PRELP does not interfere with the interaction between C9 and already formed C5b-8, but inhibits C9 polymerization thereby preventing formation of the lytic pore. The alternative pathway is moreover inhibited already at the level of C3-convertase formation due to an interaction between PRELP and C3. This suggests that PRELP may down-regulate complement attack at basement membranes and on damaged cartilage and therefore limit pathological complement activation in inflammatory disease such as RA. The net outcome of PRELP-mediated complement inhibition will highly depend on the local concentration of other complement modulating molecules as well as on the local concentration of available complement proteins.     

Changes in body mass index and smoking habits have a different impact on hemoglobin concentration in men and women: A longitudinal follow-up of the tromsø study, 1994–2002

Background: Body mass index (BMI) and smoking have been positively associated with hemoglobin concentration, and both are risk factors for cardiovascular disease.Objective: The aim of this study was to assess whether there were sex differences in how changes in BMI and smoking habits influenced hemoglobin concentration.Methods: In 1994–95 and 2001–02, a longitudinal, population-based study was conducted in the municipality of Tromsø, in northern Norway. Inhabitants aged ≥25 years were invited to participate. Participants replied to a questionnaire regarding health, physical activity, coffee and alcohol consumption, and smoking habits. Blood samples were drawn to analyze hemoglobin concentration.All analyses were performed separately for each sex. Differences between 1994–95 and 2001–02 were examined with t or χ² (McNemar) tests for paired data. Cross-sectional comparisons were made using 2-sample t tests. Different models of univariate and multiple linear regression analyses were used to investigate the impact of the various variables on hemoglobin change.Results: Data from a total of 2105 men and 2945 women were examined. At baseline, mean age was 58.9 years for men (range, 25–78 years) and 57.8 years for women (range, 25–82 years); mean BMI was 26.1 kg/m² for men and 25.8 kg/m² for women. In men, hemoglobin decreased with age, on average from 147.5 to 145.1 g/L. In women, hemoglobin decreased from 135.6 to 134.7 g/L, but increased with increasing age up to 54 years, and thereafter decreased gradually. Mean BMI increased 0.8 kg/m² in men and 1.2 kg/m² in women. In total, 394 of 2057 men (19%) and 499 of 2889 women (17%) stopped smoking or smoked fewer cigarettes per day. In a univariate regression model, an increase of 1 kg/m² in BMI was associated with an increase in hemoglobin of 1.1 g/L (95% CI, 0.84 to 1.27) in men and 0.4 g/L (95% CI, 0.30 to 0.56) in women. In another univariate model, smoking cessation was associated with a decrease in hemoglobin of 1.9 g/L (95% CI, ?3.32 to ?0.56) in men and 1.7 g/L (95% CI, ?2.93 to ?0.56) in women. In men who smoked less and had a BMI increase of >2.5 kg/m², hemoglobin decreased 0.3 g/L. In contrast, hemoglobin decreased 3.4 g/L in men who smoked less and lost weight (P for trend, < 0.001 by changing BMI). Women who smoked less had a decrease in hemoglobin independent of BMI changes.Conclusions: The positive association between an increase in BMI and hemoglobin was stronger in men than in women. The effect of smoking reduction on hemoglobin was attenuated with increasing BMI in men, but not in women.     

Nymphs of the common bed bug (<Emphasis Type="Italic">Cimex lectularius</Emphasis>) produce anti-aphrodisiac defence against conspecific males

Background  

Abdominal wounding by traumatic insemination and the lack of a long distance attraction pheromone set the scene for unusual sexual signalling systems. Male bed bugs (Cimex lectularius) mount any large, newly fed individual in an attempt to mate. Last instar nymphs overlap in size with mature females, which make them a potential target for interested males. However, nymphs lack the female's specific mating adaptations and may be severely injured by the abdominal wounding. We, therefore, hypothesized that nymphs emit chemical deterrents that act as an honest status signal, which prevents nymph sexual harassment and indirectly reduces energy costs for males.     

Housing system and herd size interactions in Norwegian dairy herds; associations with performance and disease incidence

Background  

According to the Norwegian animal welfare regulations, it has been forbidden to build new tie-stall barns since the end of 2004. Previous studies have shown that cow performance and health differ between housing systems. The interaction between housing system and herd size with respect to performance and disease incidence has not been evaluated.     

Do Gene Variants Influencing Adult Adiposity Affect Birth Weight? A Population-Based Study of 24 Loci in 4,744 Danish Individuals

Background

Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn.

Methodology/Principal Findings

Midwife records from the Danish State Archives provided information on mother''s age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10^th percentile), normal (10^th–90^th percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI.

Conclusion

24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life.