559 research outputs found
Human iPSC-derived neurons and cerebral organoids establish differential effects of germline NF1 gene mutations
Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability
Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis
Neurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T\u3eC, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1
Generalized model for dynamic percolation
We study the dynamics of a carrier, which performs a biased motion under the
influence of an external field E, in an environment which is modeled by dynamic
percolation and created by hard-core particles. The particles move randomly on
a simple cubic lattice, constrained by hard-core exclusion, and they
spontaneously annihilate and re-appear at some prescribed rates. Using
decoupling of the third-order correlation functions into the product of the
pairwise carrier-particle correlations we determine the density profiles of the
"environment" particles, as seen from the stationary moving carrier, and
calculate its terminal velocity, V_c, as the function of the applied field and
other system parameters. We find that for sufficiently small driving forces the
force exerted on the carrier by the "environment" particles shows a
viscous-like behavior. An analog Stokes formula for such dynamic percolative
environments and the corresponding friction coefficient are derived. We show
that the density profile of the environment particles is strongly
inhomogeneous: In front of the stationary moving carrier the density is higher
than the average density, , and approaches the average value as an
exponential function of the distance from the carrier. Past the carrier the
local density is lower than and the relaxation towards may
proceed differently depending on whether the particles number is or is not
explicitly conserved.Comment: Latex, 32 pages, 4 ps-figures, submitted to PR
Isolated communities of Epsilonproteobacteria in hydrothermal vent fluids of the Mariana Arc seamounts
Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of John Wiley & Sons for personal use, not for redistribution. The definitive version was published in FEMS Microbiology Ecology 73 (2010): 538-549, doi:10.1111/j.1574-6941.2010.00910.x.Low-temperature hydrothermal vent fluids represent access points to diverse microbial
communities living in oceanic crust. This study examined the distribution, relative abundance,
and diversity of Epsilonproteobacteria in 14 low-temperature vent fluids from 5 volcanically
active seamounts of the Mariana Arc using a 454 tag sequencing approach. Most vent fluids
were enriched in cell concentrations compared to background seawater, and quantitative PCR
results indicated all fluids were dominated by bacteria. Operational taxonomic unit (OTU)-based
statistical tools applied to 454 data show that all vents from the northern end of the Marian Arc
grouped together, to the exclusion of southern arc seamounts, which were as distinct from one
another as they were from northern seamounts. Statistical analysis also showed a significant
relationship between seamount and individual vent groupings, suggesting that community
membership may be linked to geographical isolation and not geochemical parameters. However,
while there may be large-scale geographic differences, distance is not the distinguishing factor in
microbial community composition. At the local scale, most vents host a distinct population of
Epsilonprotoebacteria, regardless of seamount location. This suggests there may be barriers to
exchange and dispersal for these vent endemic microorganisms at hydrothermal seamounts of the
Mariana Arc.This work was supported by a National Research
Council Research Associateship Award and L’Oréal USA Fellowship (J.A.H.), NASA
Astrobiology Institute Cooperative Agreement NNA04CC04A (M.L.S.), the Alfred P. Sloan
Foundation’s ICoMM field project, and the W. M. Keck Foundation. This publication is
[partially] funded by the Joint Institute for the Study of the Atmosphere and Ocean (JISAO)
under NOAA Cooperative Agreement No. NA17RJ1232, Contribution #1814
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