Two new compounds were obtained by assembling the (2-methoxy-5-nitro-anilinium)(18-crown-6)
+
cation with non-polar PF
6
−
and polar SO
3
CF
3
−
anions, respectively. Benefiting from its polar anion, ...the SO
3
CF
3
−
compound reveals a more significant dielectric switching behaviour during phase transition, demonstrating an effective strategy to enhance the dielectric property by adding polar components.
Two new crystalline compounds containing non-polar and polar anions, respectively, reveal distinct dielectric switching responses.
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report ...that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.
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•Neurons in l/vlPAG exhibit scratching behavior related to neural activities•Ablation of Tac1+ but not SST+ neurons decreases itch-induced scratching behavior•Activation of Tac1+ neurons induces spontaneous scratching and grooming behaviors•l/vlPAG Tac1+ neurons modulate spinal itch processing via a RVM-dependent pathway
Gao et al. demonstrate that Tac1-expressing neurons in the l/vlPAG modulate spinal itch processing via a descending pathway. These neurons represent a critical component in the neural circuit that drives the itch-scratching cycle.
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), ...is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.
Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, ...based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.
The introduction of phosphorus functional groups into the skeleton of thioflavones is an attractive task and of great significance. Herein, a metal‐free visible‐light‐induced radical cascade ...cyclization was developed for the preparation of 2‐phosphorylated thioflavones from methylthiolated alkynones and phosphine oxides. In water as a green reaction medium, a large number of such 2‐phosphorylated thioflavones were prepared, catalyzed by 4CzIPN 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene under visible‐light irradiation. These reactions could be performed at ambient temperature and feature simple operation, wide reaction scope, and recyclability of aqueous media.
Let there be light: By using water as a reaction medium, a large number of 2‐phosphorylated thioflavones are prepared through the reaction of methylthiolated alkynones and phosphine oxides catalyzed by 4CzIPN 1,2,3,5‐tetrakis(carbazol‐9‐yl)‐4,6‐dicyanobenzene under visible‐light irradiation.
Objective
Despite the increasing number of genes associated with Charcot–Marie‐Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal ...dominant mutations in aminoacyl‐tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl‐tRNA synthetase 1 (SerRS) for 3 families affected with CMT.
Methods
Whole‐exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays.
Results
Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co‐ordinates on chromosome 1: 108681600–110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.
Interpretation
Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS‐related CMT. ANN NEUROL 2023;93:244–256
A transition‐metal‐free visible‐light‐promoted radical phosphorylation/cyclization of N‐allylbenzamides with phosphine oxides for the synthesis of phosphoryl‐substituted dihydroisoquinolones was ...developed under room temperature. This protocol features mild reaction conditions, simple operation, broad substrate scope as well as scale‐up ability.
Biofilm infections can induce chronic inflammation and stall the normal orchestrated course of wound-healing cascades. Herein, pH-switchable antimicrobial hydrogel with nanofiber networks for biofilm ...eradication and rescuing stalled healing in chronic wounds is reported on the basis of the self-assembly of a designed octapeptide (IKFQFHFD) at neutral pH. This hydrogel is biocompatible and exhibits an acidic pH (pathological environment of infected chronic wounds)-switchable broad-spectrum antimicrobial effect via a mechanism involving cell wall and membrane disruption. The antimicrobial activity of hydrogel is derived from its acidic pH-dependent nanofiber network destabilization and activated release of IKFQFHFD, which is antimicrobial only at acidic pH due to the antimicrobial peptide-like molecular structure. In addition, supramolecular nanofiber networks loaded with drugs of cypate (photothermal agent) and proline (procollagen component) are further developed. In vitro experiments show that loaded drugs exhibit acidic pH (pH ∼ 5.5)-responsive release profiles, and synergistic biofilm eradication and subsequent healing cascade activation of cells proliferation are achieved on the basis of the supramolecular nanofiber networks. Remarkably, the nanofiber networks of hydrogel enable in vivo complete healing of MRSA biofilm infected wound in diabetic mice within 20 days, showing great potential as promising chronic wound dressings. The proposed synergistic strategy for eradicating biofilm and activating subsequent healing cascades may offer a powerful modality for the management of clinical chronic wounds.
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