State-Dependent Inhibition of Nav1.8 Sodium Channels by VX-150 and VX-548.

Nav1.8 sodium channels (Nav1.8) are an attractive therapeutic target for pain because they are prominent in primary pain-sensing neurons with little expression in most other kinds of neurons.

Cannabidiol inhibits Na channels through two distinct binding sites.

Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Na1.

Use-Dependent Relief of Inhibition of Nav1.8 Channels by A-887826.

Sodium channel inhibitors used as local anesthetics, antiarrhythmics, or antiepileptics typically have the property of use-dependent inhibition, whereby inhibition is enhanced by repetitive channel activation. For targeting pain, Nav1.8 channels are an attractive target because they are prominent in primary pain-sensing neurons, with little or no expression in most other kinds of neurons, and a number of Nav1.

Uncovering a new route to pain therapy.

High-voltage-activated calcium channels (HVACCs) are promising targets for developing analgesics given their roles in controlling synaptic transmission, neuronal excitability and neuropeptide release in primary nociceptive neurons. Despite previous efforts in developing HVACCs inhibitors of various drug modalities, it remains undetermined whether targeting HVACCs directly by a gene therapy approach could lead to pain alleviation in vivo. To test this, Sun and colleagues adopted a post-translational ubiquitination-based knockdown method targeting HVACCs in primary sensory neurons.

Effect of Induction Chemotherapy With Paclitaxel, Cisplatin, and Capecitabine vs Cisplatin and Fluorouracil on Failure-Free Survival for Patients With Stage IVA to IVB Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear.

Objective: To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma.

Design, Setting, And Participants: This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019.

Cannabidiol activates neuronal Kv7 channels.

Cannabidiol (CBD), a chemical found in the plant, is a clinically effective antiepileptic drug whose mechanism of action is unknown. Using a fluorescence-based thallium flux assay, we performed a large-scale screen and found enhancement of flux through heterologously expressed human Kv7.2/7.

Rapid odor processing by layer 2 subcircuits in lateral entorhinal cortex.

Olfactory information is encoded in lateral entorhinal cortex (LEC) by two classes of layer 2 (L2) principal neurons: fan and pyramidal cells. However, the functional properties of L2 cells and how they contribute to odor coding are unclear. Here, we show in awake mice that L2 cells respond to odors early during single sniffs and that LEC is essential for rapid discrimination of both odor identity and intensity.

Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 DRG sensory neurons.

Bacterial products can act on neurons to alter signaling and function. In the present study, we found that dorsal root ganglion (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes edema factor (EF) and lethal factor (LF).

Cannabidiol Inhibition of Murine Primary Nociceptors: Tight Binding to Slow Inactivated States of Na1.8 Channels.

The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined the effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15-20 action potentials evoked by 1 s current injections in control to 1-3 action potentials with 2 μm CBD.

Maternal immune activation alters visual acuity and retinogeniculate axon pruning in offspring mice.

Individuals with autism spectrum disorder (ASD) have been found to have a variety of sensory processing deficits. Here we report that maternal immune activation, a known factor for ASD, alters visual acuity in the offspring mice. By intraperitoneally injecting polyinosinic-polycytidylic acid (polyI:C) to induce maternal immune activation during embryonic days 10 to 14, we found that polyI:C treatment impairs visual acuity in young adult offspring mice as examined by their optomotor responses.

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation.

Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application.

Numerical simulation of seawater intrusion to coastal aquifers and brine water/freshwater interaction in south coast of Laizhou Bay, China.

Seawater intrusion and brine water/freshwater interaction have significantly affected agriculture, industry and public water supply at Laizhou Bay, Shandong Province, China. In this study, a two-dimensional SEAWAT model is developed to simulate the seawater intrusion to coastal aquifers and brine water/fresh water interaction in the south of Laizhou Bay. This model is applied to predict the seawater intrusion and brine water/freshwater interface development in the coming years.

Direct Conservative Domain in the Continuous Galerkin Method for Groundwater Models.

The continuous Galerkin finite element method is commonly considered locally nonconservative because a single element with fluxes computed directly from its potential distribution is unable to conserve its mass and fluxes across edges that are discontinuous. Some literature sources have demonstrated that the continuous Galerkin method can be locally conservative with postprocessed fluxes. This paper proposes the concept of a direct conservative domain (DCD), which could conserve mass when fluxes are computed directly from the potential distribution.

Hydrogeochemical characterization and groundwater quality assessment in intruded coastal brine aquifers (Laizhou Bay, China).

The aquifer in the coastal area of the Laizhou Bay is affected by salinization processes related to intense groundwater exploitation for brine resource and for agriculture irrigation during the last three decades. As a result, the dynamic balances among freshwater, brine, and seawater have been disturbed and the quality of groundwater has deteriorated. To fully understand the groundwater chemical distribution and evolution in the regional aquifers, hydrogeochemical and isotopic studies have been conducted based on the water samples from 102 observation wells.