Loud music and the specific sound stress open the blood-brain barrier new fundamental, biomedical, and social aspects, bioRxiv, 2019-01-01
AbstractThe blood-brain barrier (BBB) poses a significant challenge for drug brain delivery. The limitation of our knowledge about the nature of BBB explains the slow progress in the therapy of brain diseases and absence of methods for drug brain delivery in the clinical practice.Here we show that BBB opens for lowhigh weight molecules and nanocarriers after exposure of loud musicsound of 90 dB and 100 dB (regardless its frequency) as being easily produced by MP3MP4 players, kitchen appliances, loudspeakers at concerts. The role of sound, sound-induced stress and molecular mechanisms behind is discussed in the framework of BBB opening as an informative platform for a novel fundamental knowledge about the nature of BBB and for the development of a non-invasive brain drug delivery technology.Social aspects of musicsound-induced opening of BBB provide completely new information about noise and healthy life conditions that will stimulate new research in this field.
biorxiv neuroscience 100-200-users 2019Neocortical layer 4 in adult mouse differs in major cell types and circuit organization between primary sensory areas, bioRxiv, 2018-12-28
AbstractLayer 4 (L4) of mammalian neocortex plays a crucial role in cortical information processing, yet a complete census of its cell types and connectivity remains elusive. Using whole-cell recordings with morphological recovery, we identified one major excitatory and seven inhibitory types of neurons in L4 of adult mouse visual cortex (V1). Nearly all excitatory neurons were pyramidal and all somatostatin-positive (SOM+) non-fast-spiking neurons were Martinotti cells. In contrast, in somatosensory cortex (S1), excitatory neurons were mostly stellate and SOM+ neurons were non-Martinotti. These morphologically distinct SOM+ interneurons corresponded to different transcriptomic cell types and were differentially integrated into the local circuit with only S1 neurons receiving local excitatory input. We propose that cell-type specific circuit motifs, such as the Martinottipyramidal and non-Martinottistellate pairs, are optionally used across the cortex as building blocks to assemble cortical circuits.
biorxiv neuroscience 100-200-users 2018Single-cell multi-omic profiling of chromatin conformation and DNA methylome, bioRxiv, 2018-12-27
AbstractRecent advances in the development of single cell epigenomic assays have facilitated the analysis of gene regulatory landscapes in complex biological systems. Methods for detection of single-cell epigenomic variation such as DNA methylation sequencing and ATAC-seq hold tremendous promise for delineating distinct cell types and identifying their critical cis-regulatory sequences. Emerging evidence has shown that in addition to cis-regulatory sequences, dynamic regulation of 3D chromatin conformation is a critical mechanism for the modulation of gene expression during development and disease. It remains unclear whether single-cell Chromatin Conformation Capture (3C) or Hi-C profiles are suitable for cell type identification and allow the reconstruction of cell-type specific chromatin conformation maps. To address these challenges, we have developed a multi-omic method single-nucleus methyl-3C sequencing (sn-m3C-seq) to profile chromatin conformation and DNA methylation from the same cell. We have shown that bulk m3C-seq and sn-m3C-seq accurately capture chromatin organization information and robustly separate mouse cell types. We have developed a fluorescent-activated nuclei sorting strategy based on DNA content that eliminates nuclei multiplets caused by crosslinking. The sn-m3C-seq method allows high-resolution cell-type classification using two orthogonal types of epigenomic information and the reconstruction of cell-type specific chromatin conformation maps.
biorxiv genomics 100-200-users 2018Estimating heritability of complex traits in admixed populations with summary statistics, bioRxiv, 2018-12-21
AbstractAll summary statistics-based methods to estimate the heritability of SNPs (hg2) rely on accurate linkage disequilibrium (LD) calculations. In admixed populations, such as African Americans and Latinos, LD estimates are influenced by admixture and can result in biased hg2 estimates. Here, we introduce covariate-adjusted LD score regression (cov-LDSC), a method to provide robust hg2 estimates from GWAS summary statistics and in-sample LD estimates in admixed populations. In simulations, we observed that unadjusted LDSC underestimates hg2 by 10%-60%; in contrast, cov-LDSC is robust to all simulation parameters. We applied cov-LDSC to approximately 170,000 Latino, 47,000 African American 135,000 European individuals in three quantitative and five dichotomous phenotypes. Our results show that most traits have high concordance of hg2 between ethnic groups; for example in the 23andMe cohort, estimates of hg2 for BMI are 0.22 ± 0.01, 0.23 ± 0.03 and 0.22 ± 0.01 in Latino, African American and European populations respectively. However, for age at menarche, we observe population specific heritability differences with estimates of hg2 of 0.10 ± 0.03, 0.33 ± 0.13 and 0.19 ± 0.01 in Latino, African American and European populations respectively.
biorxiv genetics 100-200-users 2018On-site ribosome remodeling by locally synthesized ribosomal proteins in axons, bioRxiv, 2018-12-20
SUMMARYRibosomes are known to be assembled in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Using subcellular proteomics and live-imaging, we show that locally synthesized RPs incorporate into axonal ribosomes in a nucleolus-independent fashion. We revealed that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms a RNA-loop structure in the region immediately upstream of the initiation codon. Inhibition of axonal CUIC-regulated RP translation leads to defects in local translation activity and axon branching, demonstrating the physiological relevance of the axonal ribosome remodeling. These results indicate that axonal translation supplies cytoplasmic RPs to maintainmodify local ribosomal function far from the nucleolus.
biorxiv neuroscience 100-200-users 2018Self-repair protects microtubules from their destruction by molecular motors, bioRxiv, 2018-12-18
Microtubules are dynamic polymers that are used for intracellular transport and chromosome segregation during cell division. Their instability stems from the low energy of tubulin dimer interactions, which sets the growing polymer close to its disassembly conditions. Microtubules function in coordination with kinesin and dynein molecular motors, which use ATP hydrolysis to produce mechanical work and move on microtubules. This raises the possibility that the forces produced by walking motors can break dimer interactions and trigger microtubule disassembly. We tested this hypothesis by studying the interplay between microtubules and moving molecular motors in vitro. Our results show that the mechanical work of molecular motors can remove tubulin dimers from the lattice and rapidly destroy microtubules. This effect was not observed when free tubulin dimers were present in the assay. Using fluorescently labelled tubulin dimers we found that dimer removal by motors was compensated for by the insertion of free tubulin dimers into the microtubule lattice. This self-repair mechanism allows microtubules to survive the damage induced by molecular motors as they move along their tracks. Our study reveals the existence of coupling between the motion of kinesin and dynein motors and the renewal of the microtubule lattice.
biorxiv cell-biology 100-200-users 2018