The Pathway-Selective Dependence of Nitric Oxide for Long-Term Potentiation in the Anterior Cingulate Cortex of Adult Mice.

Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse in retrograde into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is selectively required for the synaptic potentiation of the interhemispheric projection in the anterior cingulate cortex (ACC). Unilateral low-frequency stimulation (LFS) induced a short-term synaptic potentiation on the contralateral ACC through the corpus callosum (CC). The use of the antagonists of the NMDA receptor (NMDAR), or the inhibitor of the L-type voltage-dependent Ca2+ channels (L-VDCCs), blocked the induction of this ACC-ACC potentiation. In addition, the inhibitor of NO synthase, or inhibitors for its downstream signaling pathway, also blocked this ACC-ACC potentiation. However, the application of the NOS inhibitor blocked neither the local electric stimulation-induced LTP nor the stimulation-induced recruitment of silent responses. Our results present strong evidence for the pathway-selective roles of NO in the LTP of the ACC.

Recruitment of cortical silent responses by forskolin in the anterior cingulate cortex of adult mice.

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.

Selective enhancement of fear extinction by inhibiting neuronal adenylyl cyclase 1 (AC1) in aged mice.

Adenylyl cyclase 1 (AC1) is a selective subtype of ACs, which is selectively expressed in neurons. The activation of AC1 is activity-dependent, and AC1 plays an important role in cortical excitation that contributes to chronic pain and related emotional disorders. Previous studies have reported that human-used NB001 (hNB001, a selective AC1 inhibitor) produced analgesic effects in different animal models of chronic pain. However, the potential effects of hNB001 on learning and memory have been less investigated. In the present study, we found that hNB001 affected neither the induction nor the expression of trace fear, but selectively enhanced the relearning ability during the extinction in aged mice. By contrast, the same application of hNB001 did not affect recent, remote auditory fear memory, or remote fear extinction in either adult or aged mice. Furthermore, a single or consecutive 30-day oral administration of hNB001 did not affect acute nociceptive response, motor function, or anxiety-like behavior in either adult or aged mice. Our results are consistent with previous findings that inhibition of AC1 did not affect general sensory, emotional, and motor functions in adult mice, and provide strong evidence that inhibiting the activity of AC1 may be beneficial for certain forms of learning and memory in aged mice.

Sound-induced analgesia cannot always be observed in adult mice.

Music seems promising as an adjuvant pain treatment in humans, while its mechanism remains to be illustrated. In rodent models of chronic pain, few studies reported the analgesic effect of music. Recently, Zhou et al. stated that the analgesic effects of sound depended on a low (5 dB) signal-to-noise ratio (SNR) relative to ambient noise in mice. However, despite employing multiple behavioral analysis approaches, we were unable to extend these findings to a mice model of chronic pain listening to the 5 dB SNR.

A Systematic Review and Meta-Analysis of Therapeutic Efficacy and Safety of Alirocumab and Evolocumab on Familial Hypercholesterolemia.

OBJECTIVES: The aim of this study was to provide the first study to systematically analyze the efficacy and safety of PCSK9-mAbs in the treatment of familial hypercholesterolemia (FH). METHODS: A computer was used to search the electronic Cochrane Library, PubMed/MEDLINE, and Embase databases for clinical trials using the following search terms: "AMG 145", "evolocumab", "SAR236553/REGN727", "alirocumab", "RG7652", "LY3015014", "RN316/bococizumab", "PCSK9", and "familial hypercholesterolemia" up to November 2020. Study quality was assessed with the Cochrane Collaboration's tool, and publication bias was evaluated by a contour-enhanced funnel plot and the Harbord modification of the Egger test. After obtaining the data, a meta-analysis was performed using R software, version 4.0.3. RESULTS: A meta-analysis was performed on 7 clinical trials (926 total patients). The results showed that PCSK9-mAbs reduced the LDL-C level by the greatest margin, WMD -49.14%, 95% CI: -55.81 to -42.47%, on FH versus control groups. PCSK9-mAbs also significantly reduced lipoprotein (a) (Lp (a)), total cholesterol (TC), triglycerides (TG), apolipoprotein-B (Apo-B), and non-high-density lipoprotein cholesterol (non-HDL-C) levels and increased HDL-C and apolipoprotein-A1 (Apo-A1) levels of beneficial lipoproteins. Moreover, no significant difference was found between PCSK9-mAbs treatment and placebo in common adverse events, serious events, and laboratory adverse events. CONCLUSION: PCSK9-mAbs significantly decreased LDL-C and other lipid levels with satisfactory safety and tolerability in FH treatment.

An Overview of miRNAs Involved in PASMC Phenotypic Switching in Pulmonary Hypertension.

Pulmonary hypertension (PH) is occult, with no distinctive clinical manifestations and a poor prognosis. Pulmonary vascular remodelling is an important pathological feature in which pulmonary artery smooth muscle cells (PASMCs) phenotypic switching plays a crucial role. MicroRNAs (miRNAs) are a class of evolutionarily highly conserved single-stranded small noncoding RNAs. An increasing number of studies have shown that miRNAs play an important role in the occurrence and development of PH by regulating PASMCs phenotypic switching, which is expected to be a potential target for the prevention and treatment of PH. miRNAs such as miR-221, miR-15b, miR-96, miR-24, miR-23a, miR-9, miR-214, and miR-20a can promote PASMCs phenotypic switching, while such as miR-21, miR-132, miR-449, miR-206, miR-124, miR-30c, miR-140, and the miR-17~92 cluster can inhibit it. The article reviews the research progress on growth factor-related miRNAs and hypoxia-related miRNAs that mediate PASMCs phenotypic switching in PH.

The efficacy and safety of rivaroxaban in coronary artery disease patients with heart failure and sinus rhythm: a systematic review and meta-analysis.

PURPOSE: To explore the efficacy and safety of rivaroxaban in patients with coronary artery disease (CAD), heart failure (HF) and sinus rhythm (SR). METHODS: Comprehensive literature searches were conducted using the PubMed, Cochrane Library, Embase, CNKI and Wanfang databases from inception to February 2021. Randomized controlled trials (RCTs) focusing on the efficacy and safety of new oral anticoagulant (NOAC) therapy in CAD and HF patients in SR were eligible. Statistical analyses were performed using R Programming Language. RESULTS: Three RCTs included 10,658 adult patients treated with antiplatelet drugs with or without rivaroxaban were ultimately analysed. The average follow-up period was 20.4-24 months. Rivaroxaban had a favourable point estimate in myocardial infarction (MI) and stroke (MI rivaroxaban group (3.83%, 203/5306) vs. APT group (4.52%, 214/4731), RR = 0.78, 95% CI 0.65-0.94, P < 0.01, I2 = 0%), (stroke: rivaroxaban group (1.60%, 85/5306) vs. APT group (2.52%, 119/4731), RR = 0.64, 95% CI 0.49-0.85, P < 0.01, I2 = 12%) compared with the placebo. Rivaroxaban was comparable to the placebo for all-cause death and major bleeding (all-cause death: rivaroxaban group (12.27%, 688/5606) vs. APT group (14.59%, 737/5052), RR = 0.73, 95% CI 0.49-1.06, P > 0.05, I2 = 87%), (major bleeding: rivaroxaban group (1.52%, 85/5586) vs. APT group (1.37%, 69/5043), RR = 1.18, 95% CI 0.86-1.62, P > 0.05, I2 = 0%). CONCLUSIONS: In SR patients with CAD and HF, the rates of MI and stroke associated with rivaroxaban combined with APT were lower than those associated with APT alone, and the two treatments had similar rates of all-cause death and major bleeding.

Nakagami-m Parametric Imaging for Atherosclerotic Plaque Characterization Using the Coarse-to-Fine Method.

The Nakagami model was used to analyze the statistical differences in ultrasound backscattered signals between different plaque types. To improve image resolution, Nakagami-m parametric imaging using the coarse-to-fine method based on the maximum likelihood estimation (CTF-BOW) was proposed for atherosclerotic plaque characterization. Simulation results confirmed that the CTF-BOW method significantly outperforms the sliding window method in precision, smoothness and resolution. Preliminary in vivo results (n = 45) indicated that the ranges of the m parameters for calcified, mixed and echolucent plaques are, respectively, 0.2852-0.5225, 0.6532-0.8784 and 0.8908-1.4011, with no overlap. Results revealed that the CTF-BOW method significantly improves image resolution without sacrificing accuracy and can distinguish between calcified, mixed and echolucent plaques. Moreover, it was found that the parameter m is related to the composition of the plaque, indicating that Nakagami-m parametric imaging has the potential to characterize plaques.

Ultrasound Contrast Plane Wave Imaging Based on Bubble Wavelet Transform: In Vitro and In Vivo Validations.

The aim of the study described here was to develop an ultrasound contrast plane wave imaging (PWI) method based on pulse-inversion bubble wavelet transform imaging (PIWI) to improve the contrast-to-tissue ratio of contrast images. A pair of inverted "bubble wavelets" with plane waves was constructed according to the modified Herring equation. The original echoes were replaced by the maximum wavelet correlation coefficients obtained from bubble wavelet correlation analysis. The echoes were then summed to distinguish microbubbles from tissues. In in vivo experiments on rabbit kidney, PIWI improved the contrast-to-tissue ratio of contrast images up to 4.5 ± 1.5 dB, compared with that obtained in B-mode (p < 0.05), through use of a pair of inverted plane waves. The disruption rate and infusion time of microbubbles in PIWI-based PWI were then quantified using two perfusion parameters, area under the curve and half transmit time estimated from time-intensity curves, respectively. After time-intensity curves were denoised by detrended fluctuation analysis, the average area under the curve and half transit time of PIWI-based PWI were 55.94% (p < 0.05) and 20.51% (p < 0.05) higher than those of conventional focused imaging, respectively. Because of its high contrast-to-tissue ratio and low disruption of microbubbles, PIWI-based PWI has a long infusion time and is therefore beneficial for transient monitoring and perfusion assessment of microbubbles circulating in vessels.

Effect of erythromycin exposure on the growth, antioxidant system and photosynthesis of Microcystis flos-aquae.

Erythromycin, a macrolide antibiotic, is commonly used in human life. This compound and its derivatives have been detected in various aquatic compartments and may pose a serious threat to aquatic organisms. This study investigated the effects of erythromycin on the growth, antioxidant system and photosynthesis of Microcystis flos-aquae. The results showed that at 0.001-0.1 µg L(-1), erythromycin could stimulate the growth of M. flos-aquae and increase its photosynthetic activity; however, it did not significantly increase the activities of superoxide dismutase (SOD) and catalase (CAT) or the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). In contrast, the growth of M. flos-aquae was significantly inhibited (p<0.01) at high levels of erythromycin, reaching an inhibition rate of 81.6% at 40 µg L(-1) erythromycin. At the same time, the activities of SOD and CAT along with MDA content also increased significantly (p<0.01), indicating that the high concentrations of erythromycin caused a severe oxidative stress on algae. However, the balance between oxidants and antioxidant enzymes were disrupted because ROS content simultaneously increased. In addition, the fluorescence parameters of M. flos-aquae decreased significantly with both exposure time and increasing concentration of erythromycin, indicating that photosynthesis was inhibited.

Effects of Allelochemicals from Ficus microcarpa on Chlorella pyrenoidosa

This study was performed in order to isolate and identify unknown allelochemicals from Ficus microcarpa, and to investigate the inhibitory to bloom-forming of green alga Chlorella pyrenoidosa. Through gradient elution, fraction C2, whose inhibition of alga growth in diverse extracts was the strongest was shown to cause significant reductions of maximum quantum yield, as well as electron transport rates of C. pyrenoidosa. The study data also showed that the increase of fraction C2 concentration decreased the activity of total superoxide dismutase (SOD), but increased the activities of catalase (CAT) and malondialdehyde (MDA) content. These results demonstrate that the active fraction C2 not only induced the photoinhibition or photodamage of PSII reaction centers, but also triggered the synthesis of reactive oxygen species which may change cell membrane penetrability, thereby leading to the eventual death of C. pyrenoidosa. Furthermore, the gas chromatography/mass spectrometry (GC/MS) analyses showed that the most potential allelochemical in active fraction C2 was 2-Propyl phenol, which may exhibit potent allelopathy.

Response of the cyanobacterium Microcystis flos-aquae to levofloxacin.

The effects of levofloxacin (LEV) on Microcystis flos-aquae and its mechanism were investigated by determining the responses of some parameters of M. flos-aquae to LEV stress, including growth inhibition ratio, chlorophyll a content, superoxide dismutase (SOD) and catalase (CAT) activities, malondialdehyde (MDA) content, F v/F 0 and F v/F m, etc. The results indicated that LEV at 0.001-0.1 µg L(-1) could stimulate the growth of M. flos-aquae and increase the chlorophyll a content but did not induce a significant increase in the activity of antioxidant enzymes (SOD and CAT) and the content of MDA. When the LEV concentration exceeds 10 µg L(-1), the growth of M. flos-aquae could be significantly inhibited (the highest inhibition ratio can be up to 88.38 % at 100 µg L(-1)) and chlorophyll a content, SOD and CAT activities, and MDA content also significantly decreased in a concentration-dependent manner, indicating that high concentrations of LEV caused a severe oxidative stress on algal cells, resulting in a large number of reactive oxygen species produced in algal cells and thereby inhibiting the growth of algae. At the same time, the F v/F m and F v/F 0 values of M. flos-aquae decreased significantly with both exposure time and increasing test concentration of LEV, showing that the process of photosynthesis was inhibited.

Non-invasive vascular radial/circumferential strain imaging and wall shear rate estimation using video images of diagnostic ultrasound.

The aim of this work was to develop a convenient method for radial/circumferential strain imaging and shear rate estimation that could be used as a supplement to the current routine screening for carotid atherosclerosis using video images of diagnostic ultrasound. A reflection model-based correction for gray-scale non-uniform distribution was applied to B-mode video images before strain estimation to improve the accuracy of radial/circumferential strain imaging when applied to vessel transverse cross sections. The incremental and cumulative radial/circumferential strain images can then be calculated based on the displacement field between consecutive B-mode images. Finally, the transverse Doppler spectra acquired at different depths along the vessel diameter were used to construct the spatially matched instantaneous wall shear values in a cardiac cycle. Vessel phantom simulation results revealed that the signal-to-noise ratio and contrast-to-noise ratio of the radial and circumferential strain images were increased by 2.8 and 5.9 dB and by 2.3 and 4.4 dB, respectively, after non-uniform correction. Preliminary results for 17 patients indicated that the accuracy of radial/circumferential strain images was improved in the lateral direction after non-uniform correction. The peak-to-peak value of incremental strain and the maximum cumulative strain for calcified plaques are evidently lower than those for other plaque types, and the echolucent plaques had higher values, on average, than the mixed plaques. Moreover, low oscillating wall shear rate values, found near the plaque and stenosis regions, are closely related to plaque formation. In conclusion, the method described can provide additional valuable results as a supplement to the current routine ultrasound examination for carotid atherosclerosis and, therefore, has significant potential as a feasible screening method for atherosclerosis diagnosis in the future.