The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the ...recruitment of the ARF–GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C–cytohesin–ARF6 signaling during hippocampal development remains elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 (CRL5) controls the stability of ARL4C and its signaling effectors to regulate hippocampal morphogenesis. Both RBX2 knockout and Cullin 5 knockdown cause hippocampal pyramidal neuron mislocalization and development of multiple apical dendrites. We used quantitative mass spectrometry to show that ARL4C, Cytohesin-1/3, and ARF6 accumulate in the RBX2 mutant telencephalon. Furthermore, we show that depletion of ARL4C rescues the phenotypes caused by Cullin 5 knockdown, whereas depletion of CYTH1 or ARF6 exacerbates overmigration. Finally, we show that ARL4C, CYTH1, and ARF6 are necessary for the dendritic outgrowth of pyramidal neurons to the superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered ARL4C, CYTH1, and ARF6 as CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.
Abstract
Varicella-zoster virus (VZV), a member of the
Alphaherpesvirinae
subfamily, causes severe diseases in humans of all ages. The viral capsids play critical roles in herpesvirus infection, ...making them potential antiviral targets. Here, we present the 3.7-Å-resolution structure of the VZV A-capsid and define the molecular determinants underpinning the assembly of this complicated viral machinery. Overall, the VZV capsid has a similar architecture to that of other known herpesviruses. The major capsid protein (MCP) assembles into pentons and hexons, forming extensive intra- and inter-capsomer interaction networks that are further secured by the small capsid protein (SCP) and the heterotriplex. The structure reveals a pocket beneath the floor of MCP that could potentially be targeted by antiviral inhibitors. In addition, we identified two alphaherpesvirus-specific structural features in SCP and Tri1 proteins. These observations highlight the divergence of different herpesviruses and provide an important basis for developing antiviral drugs.
► We investigate the role of update rules in the spatial snowdrift game on regular lattices. ► Compared with UI and replicator rules, the cooperation can be further promoted by the Moran rule. ► fc ...and the cluster formation pattern for these three update rules are carefully explored. ► The frequency of cooperators is insensitive to the random initial set of players.
In this paper, we investigate the role of update or imitation rules in the spatial snowdrift game on regular lattices. Three different update rules, including unconditional imitation (UI), replicator dynamics (RD) and the Moran process, are utilized to update the strategies of focal players during the game process in the spatial snowdrift on the lattice. We observe that the aggregate cooperation level between players is largely elevated by using the Moran process in the spatial snowdrift game, when compared to the UI or replicator dynamics. Meanwhile, we carefully explore the dynamical evolution of frequency of cooperators and the cluster formation pattern for these three update rules. Moreover, it is also shown that the evolutionary behavior under the Moran update is independent of and insensitive to the randomly initial configurations of cooperators and defectors. The current results clearly indicate that the introduction of moderate randomness in the strategy update will highly promote the maintenance and persistence of cooperation among selfish individuals, which will be greatly instrumental to deeply understand the evolution of cooperation within many natural, biological and social systems.
Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of ...DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP3) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.
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•Neuron-astrocyte interactions in a human DS stem cell model•DS astroglia exhibited more frequent spontaneous Ca2+ fluctuations•Spontaneous DS astroglia Ca2+ reduced excitability of co-cultured neurons•Abolishing astrocytic spontaneous Ca2+ rescued suppressed neuronal activity
To understand how Down syndrome (DS) affects neural networks, Mizuno et al. used a DS-patient-derived stem cell model and calcium imaging to investigate the functional defects of DS astrocytes and their effects on neuronal excitability. Their study reveals that DS astroglia exhibited more frequent spontaneous calcium fluctuations, which impair neuronal excitability.
A liposome vesicle is an ideal carrier for carbon nanotubes (CNTs) serving as the water channel that allows for the fast transport of water molecules, thus enhancing membrane permeability. However, a ...low quantity of CNTs inserted into the liposome vesicle is an important factor that limits the further improvement of the membrane flux. In the present study, a positively charged lipid, (2,3-dioleoyloxy-propyl)-trimethylammonium-chloride (DOTAP), was introduced to 1,2-dioleoyl-sn-glycero-3-phosphoethanolamineon (DOPE) liposome vesicles to tailor the vesicle charge so as to evaluate the effect of positively charged DOTAP on the insertion of CNTs into liposomes and the separation performance of thin-film nanocomposite (TFN) membranes. The results show that the addition of DOTAP increased the quantity of CNTs inserted into the liposome vesicles, as the shrinkage rate (k) and permeability (Pf) of the liposome vesicles presented an obvious increase with the increased content of DOTAP in the liposome vesicles. Moreover, it contributed to a 252.3% higher water flux for TFN membranes containing DOPE/DOTAP2:1-CNT liposomes (the mass ratio between DOPE and DOTAP was 2:1) than thin-film composite (TFC) membranes. More importantly, it presented a 106.7% higher water flux for TFN membranes containing DOPE/DOTAP4:1-CNT liposomes (the mass ratio between DOPE and DOTAP was 4:1), which originated from the greater number of water channels that the CNTs provided in the liposome vesicles. Overall, positively charged DOTAP effectively tailored the vesicle charge, which provided a better carrier for the insertion of a greater quantity of CNTs and contributed to the higher permeability of the TFN membranes.
Krüppel-like factors (KLFs) are a family of transcription factors which play important roles in the heart under pathological and developmental conditions. We previously identified and cloned Klf6 ...whose homozygous mutation in mice results in embryonic lethality suggesting a role in cardiovascular development. Effects of KLF6 on pathological regulation of the heart were investigated in the present study.
Mice heterozygous for Klf6 resulted in significantly diminished levels of cardiac fibrosis in response to angiotensin II infusion. Intriguingly, a similar phenotype was seen in cardiomyocyte-specific Klf6 knockout mice, but not in cardiac fibroblast-specific knockout mice. Microarray analysis revealed increased levels of the extracellular matrix factor, thrombospondin 4 (TSP4), in the Klf6-ablated heart. Mechanistically, KLF6 directly suppressed Tsp4 expression levels, and cardiac TSP4 regulated the activation of cardiac fibroblasts to regulate cardiac fibrosis.
Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts.
Background:
Secondhand smoke (SHS), a major indoor pollutant, is a significant risk factor for cardiovascular morbidity and mortality including arrhythmias and sudden cardiac death. Exposure to SHS ...can produce autonomic imbalance, as evidenced by reduced heart rate variability (HRV)—a clinical metric of cardiac vagal regulation. Currently, the mechanisms through which SHS changes the vagal preganglionic neuronal inputs to the heart to produce this remains unknown.
Objectives:
To characterize the effect of SHS on both the excitability and action potential (AP) characteristics of anatomically identified cardiac vagal neurons (CVNs) in the nucleus ambiguus and examine whether SHS alters small conductance calcium-activated potassium (SK) channel activity of these CVNs.
Methods:
Adult male mice were exposed to four weeks of filtered air or SHS (3 mg/m
3
) 6 h/day, 5 day/week. Using patch-clamp recordings on identified CVNs in brainstem slices, we determined neuronal excitability and AP characteristics with depolarizing step- and ramp-current injections.
Results:
Four weeks of SHS exposure reduced spiking responses to depolarizing current injections and increased AP voltage threshold in CVNs. Perfusion with apamin (20 nM) magnified these SHS-induced effects, suggesting reduced SK channel activity may serve to minimize the SHS-induced decreases in CVNs excitability. Medium afterhyperpolarization (a measurement of SK channel activity) was smaller in the SHS group, further supporting a lower SK channel activity. AP amplitude, rise rate, fast afterhyperpolarization amplitude (a measurement of voltage-gated channel activity), and decay rate were higher in the SHS group at membrane voltages more positive to 0 mV, suggesting altered inactivation properties of voltage-dependent channels underlying APs.
Discussion:
SHS exposure reduced neuronal excitability of CVNs with compensatory attenuation of SK channel activity and altered AP characteristics. Neuroplasticity of CVNs could blunt regulatory cardiac vagal signaling and contribute to the cardiovascular consequences associated with SHS exposure, including reduced HRV.
In performance modeling of parallel synchronous iterative applications, the longest individual execution time among parallel processors determines the iteration time and often must be estimated for ...performance analysis. This involves the mean maximum calculation which has been a challenge in computer modeling for a long time. For large systems, numerical methods are not suitable because of heavy computation requirements and inaccuracy caused by rounding. On the other hand, previous approximation methods face challenges of accuracy and generality, especially for heterogeneous computing environments. This paper presents an interesting property of extreme values to enable Effective Mean Maximum Approximation (EMMA). Compared to previous mean maximum execution time approximation methods, this method is more accurate and general to different computational environments.
LU decomposition for dense matrices is an important linear algebra kernel that is widely used in both scientific and engineering applications. To efficiently perform large matrix LU decomposition on ...FPGAs with limited local memory, a block LU decomposition algorithm on FPGAs applicable to arbitrary matrix size is proposed. Our algorithm applies a series of transformations, including loop blocking and space-time mapping, onto sequential nonblocking LU decomposition. We also introduce a high performance and memory efficient hardware architecture, which mainly consists of a linear array of processing elements (PEs), to implement our block LU decomposition algorithm. Our design can achieve optimum performance under various hardware resource constraints. Furthermore, our algorithm and design can be easily extended to the multi-FPGA platform by using a block-cyclic data distribution and inter-FPGA communication scheme. A total of 36 PEs can be integrated into a Xilinx Virtex-5 XC5VLX330 FPGA on our self-designed PCI-Express card, reaching a sustained performance of 8.50 GFLOPS at 133 MHz for a matrix size of 16,384, which outperforms several general-purpose processors. For a Xilinx Virtex-6 XC6VLX760, a newer FPGA, we predict that a total of 180 PEs can be integrated, reaching 70.66 GFLOPS at 200 MHz. Compared to the previous work, our design can integrate twice the number of PEs into the same FPGA and has significantly higher performance.
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