Trans-Generational Effect of Maternal Lactation during Pregnancy: A Holstein Cow Model

Epigenetic regulation in mammals begins in the first stages of embryogenesis. This prenatal programming determines, in part, phenotype expression in adult life. Some species, particularly dairy cattle, are conceived during the maternal lactation, which is a period of large energy and nutrient needs. Under these circumstances, embryo and fetal development compete for nutrients with the mammary gland, which may affect prenatal programming and predetermine phenotype at adulthood. Data from a specialized dairy breed were used to determine the transgenerational effect when embryo development coincides with maternal lactation. Longitudinal phenotypic data for milk yield (kg), ratio of fat-protein content in milk during first lactation, and lifespan (d) from 40,065 cows were adjusted for environmental and genetic effects using a Bayesian framework. Then, the effect of different maternal circumstances was determined on the residuals. The maternal-related circumstances were 1) presence of lactation, 2) maternal milk yield level, and 3) occurrence of mastitis during embryogenesis. Females born to mothers that were lactating while pregnant produced 52 kg (MonteCarlo standard error; MCs.e. = 0.009) less milk, lived 16 d (MCs.e. = 0.002) shorter and were metabolically less efficient (+0.42% milk fat/protein ratio; MCs.e.<0.001) than females whose fetal life developed in the absence of maternal lactation. The greater the maternal milk yield during embryogenesis, the larger the negative effects of prenatal programming, precluding the offspring born to the most productive cows to fully express their potential additive genetic merit during their adult life. Our data provide substantial evidence of transgenerational effect when pregnancy and lactation coincide. Although this effect is relatively low, it should not be ignored when formulating rations for lactating and pregnant cows. Furthermore, breeding, replacement, and management strategies should also take into account whether the individuals were conceived during maternal lactation because, otherwise, their performance may deviate from what it could be expected.     

Targeting Protein-Protein Interactions with Trimeric Ligands: High Affinity Inhibitors of the MAGUK Protein Family

PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD-93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.     

The Association between Metabolic Syndrome,Bone Mineral Density,Hip Bone Geometry and Fracture Risk: The Rotterdam Study

The association between metabolic syndrome (MS) and bone health remains unclear. We aimed to study the association between MS and hip bone geometry (HBG), femoral neck bone mineral density (FN-BMD), and the risk of osteoporosis and incident fractures. Data of 2040 women and 1510 men participants in the third visit (1997–1999) of the Rotterdam Study (RSI-3), a prospective population based cohort, were available (mean follow-up 6.7 years). MS was defined according to the recent harmonized definition. HBG parameters were measured at the third round visit whereas FN-BMD was assessed at the third round and 5 years later. Incident fractures were identified from medical registry data. After correcting for age, body mass index (BMI), lifestyle factors and medication use, individuals with MS had lower bone width (β = -0.054, P = 0.003), lower cortical buckling ratio (β = -0.81, P = 0.003) and lower odds of having osteoporosis (odds ratio =0.56, P = 0.007) in women but not in men. Similarly, MS was associated with higher FN-BMD only in women (β = 0.028, P=0.001). In the analyses of MS components, the glucose component (unrelated to diabetes status) was positively associated with FN-BMD in both genders (β = 0.016, P = 0.01 for women and β = 0.022, P = 0.004 for men). In men, waist circumference was inversely associated with FN-BMD (β = -0.03, P = 0.004). No association was observed with fracture risk in either sex. In conclusion, women with MS had higher FN-BMD independent of BMI. The glucose component of MS was associated with high FN-BMD in both genders, highlighting the need to preserve glycemic control to prevent skeletal complications.