Chloride channels regulate differentiation and barrier functions of the mammalian airway.

The conducting airway forms a protective mucosal barrier and is the primary target of airway disorders. The molecular events required for the formation and function of the airway mucosal barrier, as well as the mechanisms by which barrier dysfunction leads to early onset airway diseases, remain unclear. In this study, we systematically characterized the developmental landscape of the mouse airway using single-cell RNA sequencing and identified remarkably conserved cellular programs operating during human fetal development. We demonstrated that in mouse, genetic inactivation of chloride channel Ano1/Tmem16a compromises airway barrier function, results in early signs of inflammation, and alters the airway cellular landscape by depleting epithelial progenitors. Mouse Ano1-/-mutants exhibited mucus obstruction and abnormal mucociliary clearance that resemble the airway defects associated with cystic fibrosis. The data reveal critical and non-redundant roles for Ano1 in organogenesis, and show that chloride channels are essential for mammalian airway formation and function

Exploring the mechanisms under Zuogui Pill’s treatment of ischemic stroke through network pharmacology and in vitro experimental verification

Due to its high mortality, incidence and disability rates, ischemic stroke poses heavy economic burdens to families and society. Zuogui Pill (ZGP) is a classic Chinese medicine for tonifying the kidney, which is effective for the recovery of neurological function after ischemic stroke. However, Zuogui Pill has not been evaluated for its potential effects on ischemic strokes. Using network pharmacology, the research aimed to explore the mechanisms of Zuogui Pill on ischemic stroke, which were further validated in SH-SY5Y cells injured by oxygen and glucose deprivation/reperfusion (OGD/R). Network analysis of Zuogui Pill identified 86 active ingredients and 107 compound-related targets correlated with ischemic stroke. Additionally, 11 core active compounds were obtained, such as Quercetin, beta sitosterol, and stigmasterol. Most of the compounds have been proven to have pharmacological activities. Based on pathway enrichment studies, Zuogui Pill may exert neuroprotection through MAPK signaling, PI3K-Akt signaling and apoptosis, as well as enhance neurite outgrowth and axonal regeneration effect via mTOR signaling, p53 signaling and Wnt signaling pathways. In vitro experiment, the viability of ischemic neuron treated with Zuogui Pill was increased, and the ability of neurite outgrowth was significantly improved. Western blot assays shown that the pro-neurite outgrowth effect of Zuogui Pill on ischemic stroke may be relate to PTEN/mTOR signal pathway. The results of the study provided new insights into Zuogui Pill’s molecular mechanism in treatment of ischemic stroke, as well as clinical references for its use

Therapeutic Index Estimation of Antiepileptic Drugs: A Systematic Literature Review Approach

To determine whether data obtained from the medical literature can be used to estimate the therapeutic index of 5 antiepileptic drugs (AEDs): carbamazepine, lamotrigine, phenobarbital, phenytoin, and valproate

Therapeutic Drug Monitoring, Electronic Health Records, and Pharmacokinetic Modeling to Evaluate Sirolimus Drug Exposure–Response Relationships in Renal Transplant Patients

Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI

The water lily genome and the early evolution of flowering plants

Water lilies belong to the angiosperm order Nymphaeales. Amborellales, Nymphaeales and Austrobaileyales together form the so-called ANA-grade of angiosperms, which are extant representatives of lineages that diverged the earliest from the lineage leading to the extant mesangiosperms1–3. Here we report the 409-megabase genome sequence of the blue-petal water lily (Nymphaea colorata). Our phylogenomic analyses support Amborellales and Nymphaeales as successive sister lineages to all other extant angiosperms. The N. colorata genome and 19 other water lily transcriptomes reveal a Nymphaealean whole-genome duplication event, which is shared by Nymphaeaceae and possibly Cabombaceae. Among the genes retained from this whole-genome duplication are homologues of genes that regulate flowering transition and flower development. The broad expression of homologues of floral ABCE genes in N. colorata might support a similarly broadly active ancestral ABCE model of floral organ determination in early angiosperms. Water lilies have evolved attractive floral scents and colours, which are features shared with mesangiosperms, and we identified their putative biosynthetic genes in N. colorata. The chemical compounds and biosynthetic genes behind floral scents suggest that they have evolved in parallel to those in mesangiosperms. Because of its unique phylogenetic position, the N. colorata genome sheds light on the early evolution of angiosperms.Supplementary Tables: This file contains Supplementary Tables 1-21.National Natural Science Foundation of China, the open funds of the State Key Laboratory of Crop Genetics and Germplasm Enhancement (ZW201909) and State Key Laboratory of Tree Genetics and Breeding, the Fujian provincial government in China, the European Union Seventh Framework Programme (FP7/2007-2013) under European Research Council Advanced Grant Agreement and the Special Research Fund of Ghent University.http://www.nature.com/naturecommunicationsam2021BiochemistryGeneticsMicrobiology and Plant Patholog

RANKL expression in periodontal disease: Where does RANKL come from?

Periodontitis is an inflammatory disease characterized by periodontal pocket formation and alveolar bone resorption. Periodontal bone resorption is induced by osteoclasts and receptor activator of nuclear factor-κB ligand (RANKL) which is an essential and central regulator of osteoclast development and osteoclast function. Therefore, RANKL plays a critical role in periodontal bone resorption. In this review, we have summarized the sources of RANKL in periodontal disease and explored which factors may regulate RANKL expression in this disease

Study on the Protection and Transmission of Oral Folk Literature of Oroqen People

Oral folk literature is an indispensable part of the intangible cultural heritage of the Oroqen people. In recent years, the protection and inheritance of Oroqen folk oral literature have achieved some results, but they are still facing challenges due to the extremely small population of this ethnic group and the dying of the ethnic language. This article focuses on the intangible cultural heritage of Oroqen folk oral literature and puts forward sustainable and specific suggestions on its protection and inheritance by summarizing useful experience and analyzing practical difficulties found in previous research on national mythology, folk songs and national rap

Carbonatites in China: A review for genesis and mineralization

Carbonatites are commonly related to the accumulation of economically valuable substances such as REE, Cu, and P. The debate over the origin of carbonatites and their relationship to associated silicate rocks has been ongoing for about 45 years. Worldwide, the rocks characteristically display more geochemical enrichments in Ba, Sr and REE than sedimentary carbonate rocks. However, carbonatite’s geochemical features are disputed because of secondary mineral effects. Rock-forming carbonates from carbonatites at Qinling, Panxi region, and Bayan Obo in China show REE distribution patterns ranging from LREE enrichment to flat patterns. They are characterized by a Sr content more than 10 times higher than that of secondary carbonates. The coarse- and fine-grained dolomites from Bayan Obo H8 dolomite marbles also show similar high Sr abundance, indicating that they are of igneous origin. Some carbonates in Chinese carbonatites show REE (especially HREE) contents and distribution patterns similar to those of the whole rocks. These intrusive carbonatites display lower platinum group elements and stronger fractionation between Pt and Ir relative to high-Si extrusive carbonatite. This indicates that most intrusive carbonatites may be carbonate cumulates. Maoniuping and Daluxiang in Panxi region are large REE deposits. Hydrothermal fluorite ore veins occur outside of the carbonatite bodies and are emplaced in wallrock syenite. The fluorite in Maoniuping has Sr and Nd isotopes similar to carbonatite. The Daluxiang fluorite shows Sr and REE compositions different from those in Maoniuping. The difference is reflected by both the carbonatites and rock-forming carbonates, indicating that REE mineralization is related to carbonatites. The cumulate processes of carbonate minerals make fractionated fluids rich in volatiles and LREE as a result of low partition coefficients for REE between carbonate and carbonatite melt and an increase from LREE to HREE. The carbonatite-derived fluid has interacted with wallrock to form REE ore veins. The amount of carbonatite dykes occurring near the Bayan Obo orebodies may support the same mineralization model, i.e. that fluids evolved from the carbonatite dykes reacted with H8 dolomite marble, and thus the different REE and isotope compositions of coarse- and fine-grained dolomite may be related to reaction processes