This is the first report, to our knowledge, of changes in mitochondrial fusion/fission proteins in cardiovascular disease. These changes have implications for mitochondrial function and apoptosis, contributing to the cell loss which is part of the downward progression of the failing heart.

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond.

Early olfactory axons follow a specific pathway to reach the developing telencephalon. We observed that a subpopulation of these axons, the pioneer olfactory axons, penetrate into the ventricular zone of a highly restricted region of the telencephalon at E13 and E14. At E15, this same telencephalic region evaginates to form the olfactory bulb. To investigate the possibility that the pioneer olfactory axons induce the olfactory bulb by influencing precursor cell populations, we compared cell cycle kinetics and differentiation in the olfactory bulb primordium and the adjacent neocortex using cumulative bromdeoxyuridine labeling. The results showed that, 24 hr after the arrival of the first pioneer axons, the duration of the cell cycle is prolonged significantly in the olfactory bulb primordium. In addition, twice as many cells have exited the mitotic cycle in the olfactory bulb primordium versus the adjacent cortex. These findings suggest that pioneer olfactory axons play a role in the induction of the olfactory bulb by selectively modulating cell cycle kinetics in the olfactory bulb primordium. Afferent axons may influence target morphogenesis by modulating target precursor cell proliferation in other developing neural structures.

Nerve growth factor (NGF), a classic neurotrophic factor, promotes neuronal survival, maintenance, regeneration and differentiation in the peripheral nervous system and parts of the central nervous system. NGF activity is mediated by cell surface bound receptors including the low affinity NGF receptor (LNGFr) which is expressed by some peripheral and central neurons and is present on peripheral nerve Schwann cells during development and regeneration. The olfactory system is a useful model for the study of the role of LNGFr in neuronal development and regeneration. The growth of olfactory axons into the brain begins in the embryo and continues through the first few postnatal weeks. In mature animals there is persistent turnover and generation of olfactory receptor neurons (ORNs) and continuous growth of new axons into the olfactory bulb. These new axons grow along the preexisting olfactory pathway. In the mature olfactory system, LNGFr has been observed in the glomerular layer of the olfactory bulb, the target of ORNs. However, neither the cellular localization nor the developmental expression of LNGFr has been characterized. Here, we tested the hypothesis that LNGFr expression is developmentally regulated in the olfactory nerve and is reinduced following injury to the mature olfactory nerve. LNGFr-immunoreactivity (IR) was first observed in the olfactory mucosa at embryonic day (E)13 and in the olfactory nerve at E14. LNGFr-IR increased in the nerve during embryonic development, began to decrease at around postnatal day (P)5 and was scarcely detectable in normal adults. The staining pattern suggests that LNGFr is located on the olfactory nerve Schwann cells. Streaks of LNGFr-IR were present in the adult olfactory nerve. We reasoned that these streaks might represent transient reexpression of LNGFr associated with normal olfactory neuron turnover and replacement. Consistent with this hypothesis, LNGFr was robustly reexpressed in the adult olfactory nerve following lesion of the olfactory epithelium. Starting late in development (E21) and in the adult, LNGFr-IR was also observed on fibers in deep layers of the olfactory bulb. LNGFr-IR was also observed in neurons of the nucleus of the diagonal band (NDB) in the basal forebrain. NDB is the sole source of cholinergic afferents of the olfactory bulb. Thus, we tested the hypothesis that LNGFr in the deep layers of the olfactory bulb is located on NDB axons by making lesions of NDB. Following the lesion, LNGFr-IR disappeared in the deep layers of the olfactory bulb but remained in the glomerular layer.(ABSTRACT TRUNCATED AT 400 WORDS)

Methyl-CpG binding protein 2 (MeCP2) is critical for proper brain development and expressed at near-histone levels in neurons, but the mechanism of its genomic localization remains poorly understood. Using high-resolution MeCP2-binding data, we show that DNA sequence features alone can predict binding with 88% accuracy. Integrating MeCP2 binding and DNA methylation in a probabilistic graphical model, we demonstrate that previously reported genome-wide association with methylation is in part due to MeCP2's affinity to GC-rich chromatin, a result replicated using published data. Furthermore, MeCP2 co-localizes with nucleosomes. Finally, MeCP2 binding downstream of promoters correlates with increased expression in Mecp2-deficient neurons.