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Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects.

Aortic stiffness (AoS) is a maladaptive response to hemodynamic stress and both modifiable and non-modifiable risk factors, and elevated AoS increases afterload for the heart. AoS is a non-invasive marker of cardiovascular health and metabolic dysfunction. Implementing AoS as a diagnostic tool is challenging as it increases with age and varies amongst races. AoS is associated with lifestyle factors such as alcohol and smoking, as well as hypertension and comorbid conditions including metabolic syndrome and its components. Multiple studies have investigated various biomarkers associated with increased AoS, and this area is of particular interest given that these markers can highlight pathophysiologic pathways and specific therapeutic targets in the future. These biomarkers include those involved in the inflammatory cascade, anti-aging genes, and the renin-angiotensin aldosterone system. In the future, targeting AoS rather than blood pressure itself may be the key to improving vascular health and outcomes. In this review, we will discuss the current understanding of AoS, measurement of AoS and the challenges in interpretation, associated biomarkers, and possible therapeutic avenues for modulation of AoS.

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