1,721,020 research outputs found
Nontrivial dark matter scenarios at the energy frontier
No full textWith the only guideline being the existence of dark-matter (DM), searches for dark-matter at the Large Hadron Collider (LHC) have taken a model-independent approach. In this regard, the LHC search strategy is based on the very minimal assumption of a missing transverse energy (MET) from undetected dark-matter with a Jet from Initial State Radiation (ISR). Together with this minimal search strategy, the effective operators or simplified models have been used to interpret the LHC results, but those general approaches cannot cover interesting DM scenarios, for example, the very light dark-matter or co-annihilation region of DM parameter space. In this letter, we review the limits of those conventional methods and present a method that can capture very light DM scenarios and probe the DM co-annihilation region. © 2016, Korean Physical Society. All rights reserved11Nscopuskc
Structural and functional study of ChuY from Escherichia coli strain CFT073
No full textThe uropathogenic Escherichia coli strain CFT073 contains multiple iron and heme transport systems, which facilitate infection of the host urinary tract. To elucidate the molecular and cellular function of ChuY, a hypothetical gene in the heme degradation/utilization pathway, we solved the crystal structure of ChuY at 2.4 angstrom resolution. ChuY has high structural homology with human biliverdin and flavin reductase. We confirmed that ChuY has flavin mononucleotide (FMN) reductase activity, using NAD(P)H as a cofactor, and shows porphyrin ring binding affinity. A chuY deletion-insertion strain showed reduced survival potential compared to wild-type and complemented strains in mammalian cells. Current results suggest ChuY acts as a reductase in heme homeostasis to maintain the virulence potential of E. coli CFT073. (C) 2016 Elsevier Inc. All rights reserved1111sciescopu
Phosphorylation of CYFIP2, a component of the WAVE-regulatory complex, regulates dendritic spine density and neurite outgrowth in cultured hippocampal neurons potentially by affecting the complex assembly
No full textActin dynamics is a critical mechanism underlying many cellular processes in neurons. The heteropentameric WAVE-regulatory complex (WRC), consisting of WAVE, CYFIP1/2, Nap, Abi, and HSPC300, is a key regulator of actin dynamics that activates the Arp2/3 complex to initiate actin polymerization and branching. The WRC is basally inactive because of intermolecular interactions among the components, which can be modulated by bindings of phospholipids and Rac1, and phosphorylations of WAVE and Abi. However, the phosphorylation of other components of WRC and their functional significance remain largely unknown. To address this issue, we focused on CYFIP1/2, in which we found two brain-specific phosphorylation sites (S582 of CYFIP2 and T1068/T1067 of CYFIP1/2) from a publicly available phosphoproteome database. To understand their functional effects, we overexpressed wild-type, phospho-blocking, or phospho-mimetic mutants of CYFIP2 in cultured hippocampal neurons, and found that only T1067A CYFIP2 decreased the density of stubby spines. Moreover, overexpression of wild-type CYFIP2 increased neurite length, but T1067A did not exert this effect. To understand the mechanism, we modeled CYFIP2 phosphorylation in the crystal structure of WRC and found that T1067 phosphorylation could weaken the interaction between CYFIP2 and Nap1 by inducing conformational changes of CYFIP2 -helical bundles. In the co-immunoprecipitation assay, however, wild-type, T1067A, and T1067E CYFIP2 showed similar interaction levels to Nap1, suggesting that T1067 phosphorylation alone is not sufficient to disrupt the interaction. Considering that the activation of WRC requires disassembly of the complex, our results suggest that T1067 phosphorylation, together with other factors, could contribute toward the activation process
© 2017 Wolters Kluwer Health1101sciescopu
Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia
No full textVariants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern. © 2015 Macmillan Publishers Limited. All rights reserved115151sciescopu
A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice
Get PDF© Copyright © 2019 Yook, Kim, Kim, Kang, Kim, Kim and Kim.Mutations in Tbr1, a high-confidence ASD (autism spectrum disorder)-risk gene encoding the transcriptional regulator TBR1, have been shown to induce diverse ASD-related molecular, synaptic, neuronal, and behavioral dysfunctions in mice. However, whether Tbr1 mutations derived from autistic individuals cause similar dysfunctions in mice remains unclear. Here we generated and characterized mice carrying the TBR1-K228E de novo mutation identified in human ASD and identified various ASD-related phenotypes. In heterozygous mice carrying this mutation (Tbr1+/K228E mice), levels of the TBR1-K228E protein, which is unable to bind target DNA, were strongly increased. RNA-Seq analysis of the Tbr1+/K228E embryonic brain indicated significant changes in the expression of genes associated with neurons, astrocytes, ribosomes, neuronal synapses, and ASD risk. The Tbr1+/K228E neocortex also displayed an abnormal distribution of parvalbumin-positive interneurons, with a lower density in superficial layers but a higher density in deep layers. These changes were associated with an increase in inhibitory synaptic transmission in layer 6 pyramidal neurons that was resistant to compensation by network activity. Behaviorally, Tbr1+/K228E mice showed decreased social interaction, increased self-grooming, and modestly increased anxiety-like behaviors. These results suggest that the human heterozygous TBR1-K228E mutation induces ASD-related transcriptomic, protein, neuronal, synaptic, and behavioral dysfunctions in mice11Nsciescopu
Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitability and Seizure Susceptibility
Get PDFNav1.2, a voltage-gated sodium channel subunit encoded by the Scn2a gene, has been implicated in various brain disorders, including epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. Nav1.2 is known to regulate the generation of action potentials in the axon initial segment and their propagation along axonal pathways. Nav1.2 also regulates synaptic integration and plasticity by promoting back-propagation of action potentials to dendrites, but whether Nav1.2 deletion in mice affects neuronal excitability, synaptic transmission, synaptic plasticity, and/or disease-related animal behaviors remains largely unclear. Here, we report that mice heterozygous for the Scn2a gene (Scn2a+/- mice) show decreased neuronal excitability and suppressed excitatory synaptic transmission in the presence of network activity in the hippocampus. In addition, Scn2a+/- mice show suppressed hippocampal long-term potentiation (LTP) in association with impaired spatial learning and memory, but show largely normal locomotor activity, anxiety-like behavior, social interaction, repetitive behavior, and whole-brain excitation. These results suggest that Nav1.2 regulates hippocampal neuronal excitability, excitatory synaptic drive, LTP, and spatial learning and memory in mice. Copyright © 2019 Yoo, Yoo, Lee, Lee, Kim, Han, Bae and Kim
Bayesian analysis and naturalness of (next-to-)minimal supersymmetric models
Get PDFThe Higgs boson discovery stirred interest in next-to-minimal supersymmetric models, due to the apparent fine-tuning required to accommodate it in minimal theories. To assess their naturalness, we compare fine-tuning in a Z₃ conserving semi-constrained Next-to-Minimal Supersymmetric Standard Model (NMSSM) to the constrained MSSM (CMSSM). We contrast popular fine-tuning measures with naturalness priors, which automatically appear in statistical measures of the plausibility that a given model reproduces the weak scale. Our comparison shows that naturalness priors provide valuable insight into the hierarchy problem and rigorously ground naturalness in Bayesian statistics. For the CMSSM and semi-constrained NMSSM we demonstrate qualitative agreement between naturalness priors and popular ne tuning measures. Thus, we give a clear plausibility argument that favours relatively light superpartners.Peter Athron, Csaba Balazs, Benjamin Farmer, Andrew Fowlie, Dylan Harries and Doyoun Ki
Scn2a Haploinsufficiency in Mice Suppresses Hippocampal Neuronal Excitability, Excitatory Synaptic Drive, and Long-Term Potentiation, and Spatial Learning and Memory.
Get PDFNav1.2, a voltage-gated sodium channel subunit encoded by the Scn2a gene, has been implicated in various brain disorders, including epilepsy, autism spectrum disorder, intellectual disability, and schizophrenia. Nav1.2 is known to regulate the generation of action potentials in the axon initial segment and their propagation along axonal pathways. Nav1.2 also regulates synaptic integration and plasticity by promoting back-propagation of action potentials to dendrites, but whether Nav1.2 deletion in mice affects neuronal excitability, synaptic transmission, synaptic plasticity, and/or disease-related animal behaviors remains largely unclear. Here, we report that mice heterozygous for the Scn2a gene (Scn2a +/- mice) show decreased neuronal excitability and suppressed excitatory synaptic transmission in the presence of network activity in the hippocampus. In addition, Scn2a +/- mice show suppressed hippocampal long-term potentiation (LTP) in association with impaired spatial learning and memory, but show largely normal locomotor activity, anxiety-like behavior, social interaction, repetitive behavior, and whole-brain excitation. These results suggest that Nav1.2 regulates hippocampal neuronal excitability, excitatory synaptic drive, LTP, and spatial learning and memory in mice. Copyright © 2019 Shin, Kweon, Kang, Kim, Kim, Kang, Kim, Hwang, Kim, Yang, Kim and Kim
Presynaptic PTPs regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms
No full textSynaptic adhesion molecules regulate synapse development and function. However, whether and how presynaptic adhesion molecules regulate postsynaptic NMDAR function remains largely unclear. Presynaptic LAR family receptor tyrosine phosphatases (LAR-RPTPs) regulate synapse development through mechanisms that include trans-synaptic adhesion; however, whether they regulate postsynaptic receptor functions remains unknown. Here we report that presynaptic PTPσ, a LAR-RPTP, enhances postsynaptic NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity in the hippocampus. This regulation does not involve trans-synaptic adhesions of PTPσ, suggesting that the cytoplasmic domains of PTPσ, known to have tyrosine phosphatase activity and mediate protein-protein interactions, are important. In line with this, phosphotyrosine levels of presynaptic proteins, including neurexin-1, are strongly increased in PTPσ-mutant mice. Behaviorally, PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition. These results suggest that presynaptic PTPσ regulates postsynaptic NMDAR function through trans-synaptic and direct adhesion-independent mechanisms and novelty recognition in social and reward contexts.Copyright Kim et al.11Nsciescopu
De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy
No full textKIF1A is a neuron-specific motor protein
that plays important roles in cargo transport along neurites.
Recessive mutations in KIF1A were previously described
in families with spastic paraparesis or sensory and
autonomic neuropathy type-2. Here, we report 11 heterozygous
de novo missense mutations (p.S58L, p.T99M,
p.G102D, p.V144F, p.R167C, p.A202P, p.S215R,
p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A
in 14 individuals, including two monozygotic twins. Two
mutations (p.T99M and p.E253K) were recurrent, each
being found in unrelated cases. All these de novo mutations
are located in the motor domain (MD) of KIF1A.
Structural modeling revealed that they alter conserved
residues that are critical for the structure and function of
the MD. Transfection studies suggested that at least five
of these mutations affect the transport of the MD along
axons. Individuals with de novo mutations in KIF1A display
a phenotype characterized by cognitive impairment
and variable presence of cerebellar atrophy, spastic paraparesis,
optic nerve atrophy, peripheral neuropathy, and
epilepsy. Our findings thus indicate that de novo missense
mutations in the MD of KIF1A cause a phenotype that
overlaps with, while being more severe, than that associated
with recessive mutations in the same gene.133321sciescopu
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