Infants of diabetic mothers are at risk of cardiomyopathy at birth and myocardial infarction in adulthood, but prevention is hindered because mechanisms remain unknown. We previously showed that maternal glucolipotoxicity increases the risk of cardiomyopathy and mortality in newborn rats through fuel-mediated mitochondrial dysfunction. Here we demonstrate ongoing cardiometabolic consequences by cross-fostering and following echocardiography, cardiomyocyte bioenergetics, mitochondria-mediated turnover, and cell death following metabolic stress in aged adults. Like humans, cardiac function improves by weaning with no apparent differences in early adulthood but declines again in aged diabetesexposed offspring. This is preceded by impaired oxidative phosphorylation, exaggerated age-related increase in mitochondrial number, and higher oxygen consumption. Prenatally exposed male cardiomyocytes have more mitolysosomes indicating high baseline turnover; when exposed to metabolic stress, mitophagy cannot increase and cardiomyocytes have faster mitochondrial membrane potential loss and mitochondria-mediated cell death. Details highlight age-and sex-specific roles of mitochondria in developmentally programmed adult heart disease.

Highlights d The LINC complex is required for normal development of epithelial acini with lumens d LINC complex disruption increases myosin regulatory light chain phosphorylation d Increased myosin activity causes collapse of the dynamically fluctuating acinus d The LINC complex mechanically stabilizes the epithelial acinus

The nuclear lamina is primarily composed of type-V intermediate filaments, the A- and B-type lamins, which give mechanical support to the nuclear envelope, contribute to heterochromatin organization and regulate a myriad of nuclear processes. Over a dozen human diseases, collectively named laminopathies, are associated with mutations in the genes that encode the nuclear lamins. Although the etiology of the laminopathies is well understood, the molecular mechanisms by which they lead to disease remain unclear. Also poorly understood are the mechanisms by which the lamins contribute to a variety of nuclear and cellular functions. The identification of proteins associated with the lamins is likely to provide insight into these fundamental mechanisms. In recent years a unique method for identifying protein-protein and proximity-based interactions has emerged, called BioID (proximity-dependent biotin identification). BioID utilizes a mutant biotin ligase from bacteria that is fused to a protein of interest (bait). When expressed in living cells and stimulated with excess biotin, this BioID fusion protein promiscuously biotinylates directly interacting and vicinal endogenous proteins. Following biotin-affinity capture, the biotinylated proteins can be identified using mass spectrometry (MS). BioID thus enables screening for physiologically relevant protein associations that occur over time in living cells. The application of BioID is amenable to insoluble proteins such as lamins that are often refractory to study by other methods and is capable of identifying weak and/or transient interactions. In this review, we discuss the use of BioID as a powerful tool to help elucidate novel interacting partners of lamins.

The consumption of Brassica vegetables provides beneficial effects through organic isothiocyanates (ITCs), products of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC l-sulforaphane (l-SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the anticancer properties of ITCs like l-SFN have been extensively studied and l-SFN has been the subject of multiple human clinical trials, the scope of this work has largely been limited to those derivatives found in nature. Previous studies have demonstrated that structural changes in an ITC can lead to marked differences in a compound's potency to 1) inhibit the growth of cancer cells, and 2) alter cellular transcriptional profiles. This study describes the preparation of a library of non-natural aryl ITCs and the development of a bifurcated screening approach to evaluate the dose- and time-dependence on antiproliferative and chemopreventive properties against human MCF-7 breast cancer cells. Antiproliferative effects were evaluated using a commercial MTS cell viability assay. Chemopreventive properties were evaluated using an antioxidant response element (ARE)-promoted luciferase reporter assay. The results of this study have led to the identification of 1) several key structure-activity relationships and 2) lead ITCs for continued development.