👤 Alma Jukic

Menopause may coincide with rising Lp(a) levels, a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Characterizing changes in Lp(a) across menopause may inform risk stratification and testing recommendations. . We examined changes in serum Lp(a) levels by menopausal status among women with Lp(a) measured at visits 1 and 2 in the UK Biobank. Lp(a) analyses were examined by menopausal status: those who underwent menopause (N=415), those who remained premenopausal (N=532), and those who remained postmenopausal (N=3,615) between visits. We examined the change in Lp(a) between visits stratified by visit 1 Lp(a) levels. The primary outcome was incident Lp(a) ≥125 nmol/L at visit 2, estimated using Poisson regression with adjustment for baseline age. Data were available for 4,562 women (mean age at visit 1 = 57±7 years; median Lp(a) at visit 1 = 22 (IQR: 47) nmol/L; median time between visits = 4 (IQR: 1) years). At visit 1, median Lp(a) was slightly higher in postmenopausal women (23 nmol/L) than premenopausal women (19 nmol/L). Overall, median changes in Lp(a) between visits 1 and 2 were modest. Among women with intermediate visit 1 Lp(a) levels (75-125 nmol/L), those who transitioned through menopause experienced a median increase of 34.9 (-6.7, 53.0) nmol/L between visits, an approximately fourfold greater increase than for women who remained pre- (7.9 nmol/L) or postmenopausal (8.0 nmol/L). Further, 56% of women with intermediate visit 1 Lp(a) levels who transitioned through menopause between visits had incident Lp(a) ≥125 nmol/L at visit 2, compared with 29% and 28% of women who remained pre- or postmenopausal, representing an age-adjusted risk ratio of 2.26 (95% CI: 1.31, 3.90). Relying on a single lifetime Lp(a) measurement may miss clinically relevant increases during menopause. Repeat testing in women as they age may improve identification of those at high risk for ASCVD. Show less

Hair cells of the inner ear and lateral-line system rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is crucial for ribbon-synapse maturation in hair cells. In both mouse and zebrafish models, the loss of Nrxn3 results in significantly fewer intact ribbon synapses. We show in zebrafish that, initially, Nrxn3 loss does not alter pre- and postsynapse numbers but, later, synapses fail to pair, leading to postsynapse loss. We also demonstrate that Nrxn3 subtly influences synapse selectivity in zebrafish lateral-line hair cells that detect anterior flow. Loss of Nrxn3 leads to a 60% loss of synapses in zebrafish, which dramatically reduces pre- and postsynaptic responses. Despite fewer synapses, auditory responses in zebrafish and mice are unaffected. This work demonstrates that Nrxn3 is a crucial and conserved molecule required for the maturation of ribbon synapses. Understanding how ribbon synapses mature is essential to generating new therapies to treat synaptopathies linked to auditory or vestibular dysfunction. Show less

Hair cells of the inner ear rely on specialized ribbon synapses to transmit sensory information to the central nervous system. The molecules required to assemble these synapses are not fully understood. We show that Nrxn3, a presynaptic adhesion molecule, is critical for ribbon-synapse assembly in hair cells. In both mouse and zebrafish models, loss of Nrxn3 results in significantly fewer intact ribbon synapses. In zebrafish we demonstrate that a 60% loss of synapses in Show less

Defects in cholesterol synthesis result in a wide variety of symptoms, from neonatal lethality to the relatively mild dysmorphic features and developmental delay found in individuals with Smith-Lemli-Opitz syndrome. We report here the identification of mutations in sterol-C4-methyl oxidase–like gene (SC4MOL) as the cause of an autosomal recessive syndrome in a human patient with psoriasiform dermatitis, arthralgias, congenital cataracts, microcephaly, and developmental delay. This gene encodes a sterol-C4-methyl oxidase (SMO), which catalyzes demethylation of C4-methylsterols in the cholesterol synthesis pathway. C4-Methylsterols are meiosis-activating sterols (MASs). They exist at high concentrations in the testis and ovary and play roles in meiosis activation. In this study, we found that an accumulation of MASs in the patient led to cell overproliferation in both skin and blood. SMO deficiency also substantially altered immunocyte phenotype and in vitro function. MASs serve as ligands for liver X receptors α and β(LXRα and LXRβ), which are important in regulating not only lipid transport in the epidermis, but also innate and adaptive immunity. Deficiency of SMO represents a biochemical defect in the cholesterol synthesis pathway, the clinical spectrum of which remains to be defined. Show less