Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na+ Channel 1.6 Enables Isoform-Selective Modulation

Voltage-gated Na+ (Nav) channels are the primary molecular determinant of the action potential. Among the nine isoforms of the Nav channel α subunit that have been described (Nav1.1-Nav1.9), Nav1.1, Nav1.2, and Nav1.6 are the primary isoforms expressed in the central nervous system (CNS). Crucially, these three CNS Nav channel isoforms display differential expression across neuronal cell types and diverge with respect to their subcellular distributions. Considering these differences in terms of their localization, the CNS Nav channel isoforms could represent promising targets for the development of targeted neuromodulators. However, current therapeutics that target Nav channels lack selectivity, which results in deleterious side effects due to modulation of off-target Nav channel isoforms. Among the structural components of the Nav channel α subunit that could be pharmacologically targeted to achieve isoform selectivity, the C-terminal domains (CTD) of Nav channels represent promising candidates on account of displaying appreciable amino acid sequence divergence that enables functionally unique protein–protein interactions (PPIs) with Nav channel auxiliary proteins. In medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a critical brain region of the mesocorticolimbic circuit, the PPI between the CTD of the Nav1.6 channel and its auxiliary protein fibroblast growth factor 14 (FGF14) is central to the generation of electrical outputs, underscoring its potential value as a site for targeted neuromodulation. Focusing on this PPI, we previously developed a peptidomimetic derived from residues of FGF14 that have an interaction site on the CTD of the Nav1.6 channel. In this work, we show that whereas the compound displays dose-dependent effects on the activity of Nav1.6 channels in heterologous cells, the compound does not affect Nav1.1 or Nav1.2 channels at comparable concentrations. In addition, we show that the compound correspondingly modulates the action potential discharge and the transient Na+ of MSNs of the NAc. Overall, these results demonstrate that pharmacologically targeting the FGF14 interaction site on the CTD of the Nav1.6 channel is a strategy to achieve isoform-selective modulation, and, more broadly, that sites on the CTDs of Nav channels interacted with by auxiliary proteins could represent candidates for the development of targeted therapeutics.

Proof-of-principle demonstration of semi-quantum key distribution based on the Mirror protocol

Semi-quantum key distribution (SQKD) is used to establish a string of shared secret keys between a quantum party and a classical party. Here, we report the first proof-of-principle experimental demonstration of SQKD based on the Mirror protocol, which is the most experimentally feasible SQKD protocol, and equipped with time-phase encoding scheme employing the method of selective modulation. The experiment was performed at a repetition frequency of 62.5 MHz and a high raw key rate arrived at 69.8 kbps, and the average quantum bit error rate was found to be 4.56% and 2.78% for the “SWAP-x-Z” ($\mathrm{x}\in \{01,10\}$ x ∈ { 01 , 10 } ) and the “CTRL-X”, respectively. The results demonstrate the feasibility of our system, and this study is helpful for future research on SQKD experiments.

Membrane-initiated estrogen, androgen and progesterone receptor signaling in health and disease

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized (SRs) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.

Selective modulation of cell surface proteins during vaccinia infection: implications for immune evasion strategies

The interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy.

Hubungan antara Mikrobiota dan Psoriasis

As the largest organ of the human body, the skin is colonized by a variety of microorganisms, most of which are harmless and have benefits for the host. This microbiota contributes to the metabolism and immunity of the host. The human microbiota includes bacteria, fungi, viruses and archaea, which inhabit various areas of the body. Most of the microbiota resides in the intestine, only a small part of which inhabit epithelial surfaces such as the mouth, airways, vagina and skin. The total number of microbiota on the surface of the skin is usually in the range 104 to 106 cells per cm2. Psoriasis is one of the most common immune-mediated inflammatory skin diseases. The prevalence of disease has been reported, with a range of 0.09- 11.43% by the WHO Global Report 2016. To date the causes of this disease are not fully understood, genetic and environmental interactions play an important role in disease progression. Recently, immunological approaches have helped to clarify the pathophysiology of the disease significantly. The skin microbiota has been shown to play a role in the pathogenesis of lichenified plaque formation in psoriasis. Corynebacterium, Propionibacterium, Staphylococcus, and also Streptococcus have been identified as the main microbiota. It has not been determined whether these changes in the microbiota are a cause or consequence of psoriasis. For this reason, further research on selective modulation of the skin microbiota is needed. This systematic review aims to elucidate the correlation between the microbiome and pathogenesis of psoriasis and the modulation of the microbiota that could lead to possible therapeutic interventions. Keywords: Microbiota, Psoriasis, Skin

Effects of long-term anti-ischemic drug treatment on Na,K-ATPase isoforms in cardiomyopathic hamsters

We investigated the effects of long-term anti-ischemic therapy with trimetazidine on Na,K-ATPase (NKA) activity and protein expression in cardiomyopathy. NKA isoforms in membrane fractions from cardiomyopathic hamsters of the BIO 14.6 strain were studied and compared with those from healthy Syrian golden hamsters (F1B). Trimetazidine was orally administered to a subset of cardiomyopathic hamsters in the early stage of active disease (30 days) until the congestive stage (350 days). In the congestive stage of cardiac failure, the cardiomyopathic hamsters displayed altered NKA activity (-55 % vs. F1B; p<0.01), which was related to a specific decrease in abundance of the membrane NKA ?1 isoform (-27 % vs. F1B). Trimetazidine partially prevented the cardiomyopathy-induced changes in NKA activity (+38 %) and ?1 membrane expression (+ 66 %) without inducing changes in the expression of the ?2 isoform or 1 isoform of NKA. Cardiac hypertrophy and remodeling were reduced after trimetazidine treatment. Additionally, the abundance of NKA ?1 in membranes was negatively correlated with the ventricular weight/body weight ratio (an index of cardiac hypertrophy) (r2 = 0.99; p<0.0015). These findings suggest that some of the cardioprotective effect of trimetazidine during long-term cardiomyopathy may be achieved via regulation of cardiac remodeling and selective modulation cardiac NKA isoforms.