Structural Remodeling of Active Zones Is Associated with Synaptic Homeostasis.

Perturbations to postsynaptic glutamate receptors (GluRs) trigger retrograde signaling to precisely increase presynaptic neurotransmitter release, maintaining stable levels of synaptic strength, a process referred to as homeostatic regulation. However, the structural change of homeostatic regulation remains poorly defined. At wild-type Drosophila neuromuscular junction synapse, there is one Bruchpilot (Brp) ring detected by superresolution microscopy at active zones (AZs). In the present study, we report multiple Brp rings (i.e., multiple T-bars seen by electron microscopy) at AZs of both male and female larvae when GluRs are reduced. At GluRIIC-deficient neuromuscular junctions, quantal size was reduced but quantal content was increased, indicative of homeostatic presynaptic potentiation. Consistently, multiple Brp rings at AZs were observed in the two classic synaptic homeostasis models (i.e., GluRIIA mutant and pharmacological blockade of GluRIIA activity). Furthermore, postsynaptic overexpression of the cell adhesion protein Neuroligin 1 partially rescued multiple Brp rings phenotype. Our study thus supports that the formation of multiple Brp rings at AZs might be a structural basis for synaptic homeostasis.SIGNIFICANCE STATEMENT Synaptic homeostasis is a conserved fundamental mechanism to maintain efficient neurotransmission of neural networks. Active zones (AZs) are characterized by an electron-dense cytomatrix, which is largely composed of Bruchpilot (Brp) at the Drosophila neuromuscular junction synapses. It is not clear how the structure of AZs changes during homeostatic regulation. To address this question, we examined the structure of AZs by superresolution microscopy and electron microscopy during homeostatic regulation. Our results reveal multiple Brp rings at AZs of glutamate receptor-deficient neuromuscular junction synapses compared with single Brp ring at AZs in wild type (WT). We further show that Neuroligin 1-mediated retrograde signaling regulates multiple Brp ring formation at glutamate receptor-deficient synapses. This study thus reveals a regulatory mechanism for synaptic homeostasis.

Association Between Carotid-Cerebral Pulse Wave Velocity and Acute Ischemic Stroke: Clinical Trial Protocol.

BACKGROUND: Pulse wave velocity is commonly regarded as the most effective and noninvasive indicator for evaluating arterial stiffness, while increased arterial stiffness is known to be related to atherosclerosis, which has been proved to play a significant role on the onset of acute ischemic stroke. However, it is still only used in the assessment of central and peripheral arteries. Our previous studies have found that carotid-cerebral pulse wave velocity measured using transcranial Doppler may be a promising method for the assessment of human cerebral arterial stiffness. This trial was designed to examine the association between carotid-cerebral pulse wave velocity and acute ischemic stroke. METHODS: In a single-center, single-arm, prospective clinical trial, patients with acute ischemic stroke who had anterior circulation infarcts confirmed by magnetic resonance imaging are eligible to receive measurement of carotid-cerebral pulse wave velocity, which is measured in the supine position with transcranial Doppler that using 2-MHz and 4-MHz ultrasound probes by 2 experienced operators. Subjects will be received follow-up for 1 year. Vascular and nonvascular death at follow-up will be assessed as primary outcomes. Secondary outcomes include intracerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, recurrence or aggravation of ischemic stroke. CONCLUSION: This trial will be the first to evaluate carotid-cerebral pulse wave velocity in patients with acute ischemic stroke using transcranial Doppler. The results may provide more valuable theoretical basis for the prevention, treatment, and prognosis of acute ischemic stroke.

Association between Cerebral Arterial Stiffness and Large Artery Atherosclerosis in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Carotid-cerebral pulse wave velocity (ccPWV) reflects the segment (C-M segment) stiffness between common carotid artery and ipsilateral middle cerebral artery. The C-M segment atherosclerosis (CMSA) is regarded as a most frequent cause of anterior circulation ischemic stroke. We therefore, attempted to investigate the relationship between cerebral arterial stiffness and CMSA, and provide reliable data for the early diagnosis of CMSA. METHODS: Between June 2012 and August 2016, 81 acute ischemic stroke (AIS) patients with 154 C-M segments successfully evaluated with digital subtraction angiography and ccPWV were enrolled into this study. Patient demographics and clinical data were retrieved from our AIS databases. RESULTS: Multivariate analyses showed that ccPWV was independently associated with CMSA (ß = 39.6, P = .009) and Systolic blood pressure (ß = 7.1, P < .001) in AIS patients. The values of ccPWV had a trend to be higher in the groups with more lesions (F = 45.9, P < .01) and severer stenosis (F = 102.6, P = .000), and was positively correlated with the number of lesions (r = .662, P = .000), and degree of stenosis (r = .858, P = .000) of CMSA. The fractional polynomial plots with 95% CIs also describe the close relationship between ccPWV and the number of lesions and degree of stenosis in CMSA. CONCLUSIONS: Cerebral arterial stiffness is independently associated with the presence of CMSA, closely related to the vascular damage of C-M segment and reflects the vascular structure change of C-M segment in AIS patients. It may have the potential for assessment of CMSA in its initial stage.

Hinokione: an abietene diterpene with pancreatic ß cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into ß cells, thereby promoting the regeneration of pancreatic ß cells.

[Skeletal Class â ¢ patients treated with Fränkel function regulator type â ¢ in the early and late mixed dentition].

OBJECTIVE: To investigate the outcome of skeletal Class Ⅲ patients treated with Fränkel function regulator type Ⅲ (FR Ⅲ)in the early mixed and late mixed dentition. METHODS: The samples consisted of 45 mild and moderate skeletal Class Ⅲ patients(26 males, 19 females; meanage, [7.9±1.3] years) treated with FR Ⅲ. According to Hellman's dental developmental stages, these samples were divided into early-treated group(n=24) and late-treated group(n=21). Lateral cephalograms were taken at the beginning and the end of treatment. Twenty-one measurements on hard and soft tissue were included. RESULTS: After treatment, SNA, ANB, NA-Apo, Wits, U1-SN, U1-NA, Overjet, UL-EP were significantly increased (1.0±1.9)°, (1.2±1.6)°, (2.6±4.2)°, (1.8±2.7) mm, (4.2±7.6)°, (2.6±7.5)°, (3.6±2.3) mm and (0.8±2.2) mm(P<0.05). OP-SN and IMPA were significantly decreased (1.5±3.7)°and (1.4±4.2)°(P<0.05). There were significant differences in SNA, ANB, UL-EP, IMPA, L1-NB between early-treated group and late-treated group(P<0.05). CONCLUSIONS: FR Ⅲ was suitable for the treatment of mild and moderate skeletal Class Ⅲ patients. The result was better in the early-treated patients than in late-treated ones.

Theaflavins inhibit pathogenic properties of P. gingivalis and MMPs production in P. gingivalis-stimulated human gingival fibroblasts.

OBJECTIVES: Theaflavins, the main polyphenols in black tea, possesses a wide range of beneficial pharmacological properties. Porphyromonas gingivalis (P. gingivalis) is a major aetiological agent associated with periodontitis, a chronic inflammatory disease affecting tooth-supporting tissues. The aim of the present study is to investigate the effect of theaflavins on pathogenic properties of P. gingivalis and on periodontitis by inhibiting matrix metalloproteinases (MMPs) production induced by this oral pathogen. METHODS: Microplate dilution assays were performed to determine the effect of theaflavins against planktonic culture and biofilm of P. gingivalis. The effect of theaflavins on gingipain and collagenase activities of P. gingivalis was evaluated using synthetic chromogenic peptides and fluorogenic substrate. Human gingival fibroblasts (HGFs) were stimulated with P. gingivalis in the presence or absence of theaflavins, and then MMP-1, -2 secretion and their mRNA expression were assessed using an enzyme-linked immunosorbent assay (ELISA) and real-time PCR analysis, respectively. RESULTS: Theaflavins exhibited the antimicrobial effects against both planktonic culture and biofilm of P. gingivalis. Theaflavins also markedly inhibited the proteinase activities of P. gingivalis collagenase and gingipains in a dose-dependent manner. Lastly, theaflavins significantly inhibited the secretion and mRNA expression of MMP-1 and MMP-2 by HGFs stimulated with P. gingivalis. CONCLUSION: Theaflavins can affect the virulent properties of P. gingivalis and attenuate the MMP-mediated inflammatory response induced by this pathogen, which suggests that theaflavins may be potentially valuable supplementary therapeutic agent for prevention and treatment of P. gingivalis-associated periodontal diseases.