3,173 research outputs found
The Minimum Spectral Radius of Graphs with the Independence Number
In this paper, we investigate some properties of the Perron vector of
connected graphs. These results are used to characterize that all extremal
connected graphs with having the minimum (maximum) spectra radius among all
connected graphs of order with the independence number ,
respectively.Comment: 28 pages, 3 figure
Ixazomib enhances parathyroid hormone-induced β-catenin/T-cell factor signaling by dissociating β-catenin from the parathyroid hormone receptor.
The anabolic action of PTH in bone is mostly mediated by cAMP/PKA and Wnt-independent activation of β-catenin/T-cell factor (TCF) signaling. β-Catenin switches the PTH receptor (PTHR) signaling from cAMP/PKA to PLC/PKC activation by binding to the PTHR. Ixazomib (Izb) was recently approved as the first orally administered proteasome inhibitor for the treatment of multiple myeloma; it acts in part by inhibition of pathological bone destruction. Proteasome inhibitors were reported to stabilize β-catenin by the ubiquitin-proteasome pathway. However, how Izb affects PTHR activation to regulate β-catenin/TCF signaling is poorly understood. In the present study, using CRISPR/Cas9 genome-editing technology, we show that Izb reverses β-catenin-mediated PTHR signaling switch and enhances PTH-induced cAMP generation and cAMP response element-luciferase activity in osteoblasts. Izb increases active forms of β-catenin and promotes β-catenin translocation, thereby dissociating β-catenin from the PTHR at the plasma membrane. Furthermore, Izb facilitates PTH-stimulated GSK3β phosphorylation and β-catenin phosphorylation. Thus Izb enhances PTH stimulation of β-catenin/TCF signaling via cAMP-dependent activation, and this effect is due to its separating β-catenin from the PTHR. These findings provide evidence that Izb may be used to improve the therapeutic efficacy of PTH for the treatment of osteoporosis and other resorptive bone diseases
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TRPM5 Channels Contribute to Persistent Neural Activity and Working Memory
Working memory is a type of memory that is active only for a short period of time (Fuster and Alexander, 1971; Goldman-Rakic, 1992). A common example of working memory is our ability to hold a phone number in our minds transiently, until it is dialed. Working memory is critical for many cognitive tasks, such as making decisions and guiding subsequent actions (Goldman-Rakic, 1992; Wickelgren, 2001). Deficits in working memory are associated with numerous pathological conditions, including schizophrenia, attention deficit hyperactivity disorder, aging, and stress (Birnbaum et al., 2004; Goldman-Rakic, 1992; Goldman-Rakic and Selemon, 1997). Therefore, it is important to understand the neural basis of working memory.
During performance of a working memory task, pyramidal neurons in prefrontal cortex (PFC) are able to maintain sustained firing during a delay period between an informative cue and the appropriate behavioral response (Goldman-Rakic, 1995). Thus, stimulus-specific persistent neural activity is thought to be a neural substrate for holding memories over short time delays (Major and Tank, 2004). Once persistent activity is triggered within a neuron or neural circuit, its activity can be maintained after the stimulus has terminated.
Three general (non-mutually exclusive) mechanisms of persistent activity have been hypothesized: recurrent network activity (Compte et al., 2000; Wang, 2001), short-term synaptic plasticity (Mongillo et al., 2008) and intrinsic biophysical cellular properties. Several studies have demonstrated the role of intrinsic biophysical cellular properties in persistent activity (Egorov et al., 2002; Egorov et al., 2006; Fransen et al., 2006). This firing behavior is linked to cholinergic muscarinic receptor activation and phospholipase C (PLC) signaling in the absence of synaptic reverberations.
Two fundamental questions are: (1) What mechanism underlies the generation of sustained firing at a single cell level? (2) What role does intrinsic persistent firing play in working memory? Pharmacological studies suggest that persistent activity relies on activity of Ca2+-activated non-selective cation (CAN) current (ICAN) (Egorov et al., 2002; Egorov et al., 2006). However, the molecules that constitute CAN channels in the brain are not well studied, and the importance of CAN channels to working memory is unknown. I seek to identify molecular mechanisms to convert subthreshold input into intrinsic persistent neural firing in PFC layer 5 pyramidal neurons.
I hypothesize that CAN channels are responsible for the intrinsic properties that mediate persistent neural activity in PFC layer 5 neurons. During muscarinic receptor activation, bursts of action potentials will lead to Ca2+ influx. CAN channels will be activated due to the increased intercellular Ca2+ and promote a slow afterdepolarization (sADP), a transition state between subthreshold input and suprathreshold sustained firing. If the sADP is strong enough, it will trigger subsequent spikes, causing further opening of voltage-dependent Ca2+ channels and Ca2+ influx, and thus further opening of CAN channels. Therefore, ICAN will be maintained by a positive feedback loop, generating persistent activity. I have combined electrophysiology, pharmacology, genetics and behavioral analyses to address the potential roles of CAN channels and persistent activity in working memory.
First, I confirmed that in the presence of the muscarinic agonist carbachol a brief burst of action potentials triggers a prominent sADP and persistent activity in these neurons. Second, I confirmed that this sADP and persistent firing require activation of a PLC signaling cascade and intracellular calcium signaling. Third, I obtained direct evidence that the transient receptor potential melastatin 5 channel (TRPM5), which is thought to function as a CAN channel in non-neural cells, makes an important contribution to sADP and persistent activity in the layer 5 neurons.
Importantly, Trpm5-/- mice show deficits in a Delayed-Non-Match-to-Sample maze (DNMTS) task, a working memory task in the mouse model. Furthermore, PFC-specific expression of TRPM5 using a virally-mediated delivery system in Trpm5-/- mice produced a partial rescue of deficits in the working memory tasks, indicating the importance of TRPM5 in mPFC for performance of these tasks. Lastly, I found that PFC-specific expression of TRPM5 partially rescued the electrophysiological defects in Trpm5-/- mice. By identifying an ion channel contributing to working memory, this work opens the possibility of discovering new drugs for treating working memory deficit
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