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Neurodevelopmental disorders encompass a wide range of childhood-onset medical conditions caused by different genetic mutations and interaction with environmental factors, affect ~2% of the population, and are a leading cause of intellectual disability and autism spectrum disorder. Evidence is accumulating that either loss or gain in dosage of proteins involved in cognitive and behavioural processes can be deleterious to the nervous system by causing a failure in the ability to maintain neuronal homeostasis. My studies are focused on the MECP2 duplication syndrome, one of the most common genomic rearrangements in males, characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death. To determine whether the phenotypes of MECP2 duplication are reversible upon normalization of MeCP2 levels, I first generated and characterized a new mouse model that over-expresses a conditional allele of Mecp2 that could be deleted in the adult animal (Nature 2015). Upon normalization of MeCP2 in adult symptomatic mice, several phenotypes were rescued at the behavioral, physiological, and molecular levels. Next, I reduced MeCP2 using an antisense oligonucleotide (ASO) strategy, which has greater translational potential. I found that ASO treatment induced a broad phenotypic rescue in adult symptomatic MECP2 duplication mice, abolished abnormal EEG discharges and behavioral seizures, and corrected abnormal gene expression in the hippocampus. I am currently characterizing a novel “humanized” mouse model of MECP2 duplication syndrome that will precisely mimic the human condition by having two copies of human MECP2 and no copies of the mouse gene. These mice will serve as the ideal model for preclinical tests as they represent the closest construct validity model for the human condition. In addition, I am generating and characterizing neurons and cortical spheroids induced from patients’ derived pluripotent stem cells (iPSCs).

The integrity of the genome transmitted to the next generation intrinsically relies on cells of the germ line. Processes that ensure germ cell development, genomic stability, and reproductive lifespan are essential for the long-term success of a species. Dónal O'Carroll is interested in characterizing spermatogonial stem cell (SSC) populations that support fertility as well the regenerative capacity of the testis throughout adult life. In addition, O'Carroll lab tackles fundamental questions regarding the mammalian male germ line and heredity from an RNA perspective. Specifically, their research explores the contribution of non-coding RNA (miRNA, piRNA and lncRNA) and RNA modification pathways within germ cell development as well as testicular homeostasis/regeneration. The research objectives focus on the contribution of these emerging pathways on the underlying circuitry of self-renewal that underpins the SSC, as well as the coordination of the various cellular/differentiation processes of spermatogenesis.

Despite much effort in the past decades, uncertainties in both climate impacts and health effects of atmospheric aerosols remain large. During the last ten years, aerosol mass spectrometry (AMS) has shown that sub-micron aerosol chemical composition is roughly 50:50 inorganic and organic worldwide, with secondary highly oxidized organics dominating the latter. Parallel application of ToFMS has provided the first observation of molecular cluster ions involved in atmospheric nucleation. Chemical ionization mass spectrometry (CIMS) has extended detection to neutral molecules and clusters, detecting highly oxidized multifunctional (HOM) organics in the gas phase. Ambient sampling and photochemical chamber experiments have resolved the interaction of H2SO4 and HOM in nanoparticle nucleation and growth. These results will be discussed in the context of their impact on atmospheric aerosols, clouds and climate.

The Na,K-ATPase, an αβ hetero-oligomer, maintains the gradients of Na and K across the cell membrane vital to all animal cells. While the function of its catalytic α-subunit is well understood the role of β for transport and even tissue specific assembly of α-β isoforms has been less clear. We studied the effect of three β subunits on the cardiac α2 isoform and could show that β2 and β3 subunits greatly reduce K-affinity and show greater selectivity towards cardiotonic steroids. These findings help to understand the role of Na,K-ATPase in cardiac physiology and offer potential pharmaceutical applications.