Fenobam modulates distinct electrophysiological mechanisms for regulating excessive gamma oscillations in the striatum of dyskinetic rats.

Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 â†’ Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.

What Is Your Diagnosis?

In collaboration with the American College of Veterinary Radiology.

Cloning and activity analysis of the highly expressed gene VviABCG20 promoter in seed and its activity is negatively regulated by the transcription factor VviDof14.

Half-size ATP binding cassette G (ABCG) transporters participate in the growth and development of plants by transporting substrates. The VviABCG20 gene is highly expressed in seed and plays an important role in seed development/abortion. However, little is known about the function of the VviABCG20 promoter (pVviABCG20) and its regulatory factors. In our study, we obtained pVviABCG20s from 15 seeded and seedless grape varieties and there were two types of 'a' and 'b' with 41 bp non-deletion or deletion, respectively. The pVviABCG20 activity was higher in seeds, siliques, flowers and roots of pVviABCG20-GUS Arabidopsis. The GUS activity analysis revealed that the activities of P4 (-586 bp) to P7 (-155 bp) were becoming increasingly weaker, and the P7 activity almost disappears compared with the pVviABCG20 (P0, -1604). Yeast one-hybrid and GUS activity analysis indicated that VviDof14 binds to the AAAG element in the P7' (-586 bp) fragment of the pVviABCG20 and regulated the activity negatively. The quantitative real-time PCR analysis suggested that the expression of VviDof14 in Thompson seedless seeds was higher than that in Pinot noir. Our study laid the foundation for further analysis of the functions of the pVviABCG20 and its regulator VviDof14 in grape seed development/abortion.

Single-cell analysis of early chick hypothalamic development reveals that hypothalamic cells are induced from prethalamic-like progenitors.

The hypothalamus regulates many innate behaviors, but its development remains poorly understood. Here, we used single-cell RNA sequencing (RNA-seq) and hybridization chain reaction (HCR) to profile multiple stages of early hypothalamic development in the chick. Hypothalamic neuroepithelial cells are initially induced from prethalamic-like cells. Two distinct hypothalamic progenitor populations then emerge and give rise to tuberal and mammillary/paraventricular hypothalamic cells. At later stages, the regional organization of the chick and mouse hypothalamus is highly similar. We identify selective markers for major subdivisions of the developing chick hypothalamus and many previously uncharacterized candidate regulators of hypothalamic induction, regionalization, and neurogenesis. As proof of concept for the power of the dataset, we demonstrate that prethalamus-derived follistatin inhibits hypothalamic induction. This study clarifies the organization of the nascent hypothalamus and identifies molecular mechanisms that may control its induction and subsequent development.

Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients.

After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein-protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

Control of neurogenic competence in mammalian hypothalamic tanycytes.

Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we show that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis reveals that NFI (nuclear factor I) factors repress Sonic hedgehog (Shh) and Wnt signaling in tanycytes and modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, fire action potentials, receive synaptic inputs, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, which can potentially be targeted to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

Probing the Mechanism of Hepatotoxicity of Hexabromocyclododecanes through Toxicological Network Analysis.

The prediction and mechanism analysis of hepatotoxicity of contaminants, because of their various phenotypes and complex mechanisms, is still a key problem in environmental research. We applied a toxicological network analysis method to predict the hepatotoxicity of three hexabromocyclododecane (HBCD) diastereoisomers (α-HBCD, ß-HBCD, and γ-HBCD) and explore their potential mechanisms. First, we collected the hepatotoxicity related genes and found that those genes were significantly localized in the human interactome. Therefore, these genes form a disease module of hepatotoxicity. We also collected targets of α-, ß-, and γ-HBCD and found that their targets overlap with the hepatotoxicity disease module. Then, we trained a model to predict hepatotoxicity of three HBCD diastereoisomers based on the relationship between the hepatotoxicity disease module and targets of compounds. We found that 593 genes were significantly located in the hepatotoxicity disease module (Z = 11.9, p < 0.001) involved in oxidative stress, cellular immunity, and proliferation, and the accuracy of hepatotoxicity prediction of HBCD was 0.7095 ± 0.0193 and the recall score was 0.8355 ± 0.0352. HBCD mainly affects the core disease module genes to mediate the adenosine monophosphate-activated kinase, p38MAPK, PI3K/Akt, and TNFα pathways to regulate the immune reaction and inflammation. HBCD also induces the secretion of IL6 and STAT3 to lead hepatotoxicity by regulating NR3C1. This approach is transferable to other toxicity research studies of environmental pollutants.

Population Scale Retrospective Analysis Reveals Potential Risk of Cholestasis in Pregnant Women Taking Omeprazole, Lansoprazole, and Amoxicillin.

In nearly 50% of patients with drug-induced liver injury, the bile flow is impaired known as cholestasis. Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease that happens in pregnancy. Some of the clinical symptoms include pruritus, dark urine, and abnormal liver function tests. A rise of serum bile acids is the most accurate diagnostic evidence. ICP may lead to premature birth, fetal distress, and even postpartum hemorrhage or stillbirth in some severe cases. Higher bile acid levels (> 40 µmol/L) are associated with higher rates of adverse fetal outcomes. Due to the multifactorial nature of ICP, its etiology is still not fully understood. Therefore, the current treatments of ICP are limited to control symptoms and protect fetuses. Among various causing factors, drug exposure during pregnancy is one common factor, and it can be prevented if we know drugs with increasing risk of cholestasis. Here we analyzed over 9.5 million FDA adverse effect reports to identify drugs with increasing risks of cholestasis as an adverse effect. Patients treated for cholestasis or liver diseases were removed. The odds ratio analysis reveals that lansoprazole (LSPZ), omeprazole (OMPZ) and amoxicillin (AMXC) are associated with an increased risk of cholestasis. LSPZ is associated with increased reported cholestasis by a factor of 2.32 (OR with 95% confidence interval [2.21, 2.43]). OMPZ is associated with increased reported cholestasis by a factor of 2.61 [2.54, 2.69]. AMXC is associated with increased reported cholestasis adverse effect by a factor of 6.79 [6.49, 7.11]. The risk of cholestasis associated with these three drugs is further increased in pregnant women. These findings justify careful reassessment of the safety of the three identified drugs.

Analysis of the multidisciplinary team in the surgical treatment of lung cancer by video-assisted thoracoscopic surgery / 中国胸心血管外科临床杂志

@#Objective    To investigate the effect of multidisciplinary team (MDT) on perioperative complications and clinical efficacy of patients who were receiver radical operation to treat lung cancer by video-assisted thoracoscopic surgery (VATS). Methods    Eighty patients in the Thoracic Surgery Department of First Hospital of Lanzhou University from December 2017 to February 2019 who were diagnosed lung cancer were divided into two groups. Forty patients in the MDT group were treated with MDT discussion. The control group consisted of 40 patients who were treated without MDT discussion. The incidence of postoperative complications and clinical efficacy were compared between the two groups . Results    There was no statistical difference in incision infection, atelectasis, pleural effusion and pulmonary leakage between the two groups. However, the incidence of postoperative pulmonary infection (5% vs. 20%, P=0.043) and the overall postoperative complications (17.5% vs. 42.5%, P=0.015) in the MDT group was lower than that in the control group with a statistical difference. In the MDT group, the operative time (140.3±8.0 min vs. 148.8±6.8 min, P<0.001), intraoperative bleeding ( 207.8±19.4 mL vs. 222.0±28.3 mL, P=0.010), lymph node dissection number (25.1±6.2 vs. 20.1±7.0, P=0.001), postoperative drainage (273.0±33.5 mL vs. 24.0±52.5 mL, P<0.001), drainage duration (81.9±6.1 h vs. 85.3±8.1 h, P=0.039), pain on the first day after surgery (4.6±0.7 vs. 5.4±0.7), P<0.001), pain on the second day (2.5±0.7 vs.  3.0±0.8, P=0.002), pain on the third day (1.1±0.8 vs. 1.5±0.6, P=0.014), postoperative activity time (40.7±6.7 h vs. 35.3±7.1 h, P<0.001), postoperative recovery time (6.8±0.9 d vs. 7.4±0.7 d, P=0.003), patient satisfaction (8.1±1.4 vs. 7.2±2.0, P=0.020) were significantly better than those of the control group with statistical differences. But there was no statistical difference in the conversion to thoracotomy between the two group. Conclusion    MDT discussion can reduce the surgical risk and postoperative complications, improve the clinical efficacy and accelerate the postoperative rehabilitation of patients, which has a good clinical significance.