Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation

Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis

The miR169b/NFYA1 module from the halophyte Halostachys caspica endows salt and drought tolerance in Arabidopsis through multi-pathways

Salt and drought are the major abiotic stress factors plaguing plant growth, development and crop yields. Certain abiotic-stress tolerant plants have developed special mechanisms for adapting to adverse environments in the long process of evolution. Elucidating the molecular mechanisms by which they can exert resistance to abiotic stresses is beneficial for breeding new cultivars to guide agricultural production. Halostachys caspica, a perennial halophyte belonging to Halostachys in Amaranthaceae, is extremely tolerant to harsh environments, which is commonly grown in the saline-alkali arid desert area of Northwest, China. However, the molecular mechanism of stress tolerance is unclear. Nuclear Factor Y-A (NFYA) is a transcription factor that regulates the expression of downstream genes in plant response to adverse environments. It has also been reported that some members of the NFYA family are the main targets of miR169 in plants. In this study, we mainly focused on exploring the functions and preliminary mechanism of the miR169b/NFYA1 module from H. caspica to abiotic stress. The main results showed that RLM-RACE technology validated that HcNFYA1 was targeted by HcmiR169b, qRT-PCR revealed that HcmiR169b was repressed and HcNFYA1 was induced in the H. caspica branches under various abiotic stress as well ABA treatment and Arabidopsis stable transformation platform with molecular methods was applied to elucidate that the HcmiR169b/HcNFYA1 module conferred the salt and drought tolerance to plants by enhancing ABA synthesis and ABA signal transduction pathways, maintaining ROS homeostasis and the stability of cell membrane. HcNFYA1 is expected to be a candidate gene to improve plant resistance to salt and drought stresses

Genetic variants in the PIWI-piRNA pathway gene DCP1A predict melanoma disease-specific survival

The Piwi-piRNA pathway is important for germ cell maintenance, genome integrity, DNA methylation and retrotransposon control and thus may be involved in cancer development. In this study, we comprehensively analyzed prognostic roles of 3,116 common SNPs in PIWI-piRNA pathway genes in melanoma disease-specific survival. A published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used to identify associated SNPs, which were later validated by another GWAS from the Harvard Nurses' Health Study and Health Professionals Follow-up Study. After multiple testing correction, we found that there were 27 common SNPs in two genes (PIWIL4 and DCP1A) with false discovery rate < 0.2 in the discovery dataset. Three tagSNPs (i.e., rs7933369 and rs508485 in PIWIL4; rs11551405 in DCP1A) were replicated. The rs11551405 A allele, located at the 3' UTR microRNA binding site of DCP1A, was associated with an increased risk of melanoma disease-specific death in both discovery dataset [adjusted Hazards ratio (HR) = 1.66, 95% confidence interval (CI) = 1.21-2.27, p =1.50 × 10-3 ] and validation dataset (HR = 1.55, 95% CI = 1.03-2.34, p = 0.038), compared with the C allele, and their meta-analysis showed an HR of 1.62 (95% CI, 1.26-2.08, p =1.55 × 10-4 ). Using RNA-seq data from the 1000 Genomes Project, we found that DCP1A mRNA expression levels increased significantly with the A allele number of rs11551405. Additional large, prospective studies are needed to validate these findings

Understanding PITX2-Dependent Atrial Fibrillation Mechanisms through Computational Models

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-16, pub-electronic 2021-07-19Publication status: PublishedFunder: National Key Research and Development Program of China; Grant(s): 2019YFC0120100, 2019YFC0121907Funder: National Natural Science Foundation of China; Grant(s): 61901192Atrial fibrillation (AF) is a common arrhythmia. Better prevention and treatment of AF are needed to reduce AF-associated morbidity and mortality. Several major mechanisms cause AF in patients, including genetic predispositions to AF development. Genome-wide association studies have identified a number of genetic variants in association with AF populations, with the strongest hits clustering on chromosome 4q25, close to the gene for the homeobox transcription PITX2. Because of the inherent complexity of the human heart, experimental and basic research is insufficient for understanding the functional impacts of PITX2 variants on AF. Linking PITX2 properties to ion channels, cells, tissues, atriums and the whole heart, computational models provide a supplementary tool for achieving a quantitative understanding of the functional role of PITX2 in remodelling atrial structure and function to predispose to AF. It is hoped that computational approaches incorporating all we know about PITX2-related structural and electrical remodelling would provide better understanding into its proarrhythmic effects leading to development of improved anti-AF therapies. In the present review, we discuss advances in atrial modelling and focus on the mechanistic links between PITX2 and AF. Challenges in applying models for improving patient health are described, as well as a summary of future perspectives

Case Report: Mycobacterium kansasii causing infective endocarditis explored by metagenomic next-generation sequencing

In this report, we describe the first case of infective endocarditis caused by Mycobacterium kansasii in a 45-year-old male patient who presented with a 10-day fever and decompensated cirrhosis. Despite negative results in blood culture and pathology, we employed metagenomic next-generation sequencing (mNGS) to analyze the genome sequences of both the host and microbe. The copy number variation (CNV) indicated a high risk of liver disease in the patient, which correlated with biochemical examination findings. Notably, M. kansasii sequences were detected in peripheral blood samples and confirmed through Sanger sequencing. Unfortunately, the patient’s condition deteriorated, leading to his demise prior to heart surgery. Nevertheless, we propose that mNGS could be a novel approach for diagnosing M. kansasii infection, particularly in cases where blood culture and pathology results are unavailable. It is important to consider M. kansasii infection as a potential cause of endocarditis and initiate appropriate anti-infection treatment

The potential impacts of climate change factors on freshwater eutrophication: Implications for research and countermeasures of water management in China

Water eutrophication has become one of the most serious aquatic environmental problems around the world. More and more research has indicated climate change as a major natural factor that will lead to the acceleration of eutrophication in rivers and lakes. However, understanding the mechanism of climate change's effect on water eutrophication is difficult due to the uncertainties caused by its complex, non-linear process. There is considerable uncertainty about the magnitude of future temperature changes, and how these will drive eutrophication in water bodies at regional scales under the effect of human activities. This review collects the existing international and domestic literature from the last 10 years, discussing the most sensitive factors of climate change (i.e., temperature, precipitation, wind, and solar radiation) and analyzing their interaction with water eutrophication. Case studies of serious eutrophication and algal bloom problems in China are discussed to further demonstrate the conclusion. Finally, adaptation countermeasures and related implications are proposed in order to foster the development of sustainability strategies for water management in China

Effects and mechanisms of auricular electroacupuncture on gastric hypersensitivity in a rodent model of functional dyspepsia

Background Functional dyspepsia (FD) is a common functional gastrointestinal disease, and abdominal pain is one of the main symptoms. The aim of this study was to explore the effects and mechanisms of auricular electro-acupuncture (AEA) on gastric hypersensitivity in a rodent model of FD. Methods Ten-day-old pups were gavaged with 0.2 ml of 0.1% iodoacetamide daily for 6 days. AEA at the “stomach” point with different parameters or sham-EA was performed on 8-week-old animals. Gastric sensitivity to gastric distention was measured under different conditions. Autonomic functions were assessed from the spectral analysis of heart rate variability (HRV) derived from the electrocardiogram. Naloxone was injected intraperitoneally before AEA to explore the opioid mechanism. Gastric emptying was measured at the end of the study. Results 1) Gastric sensitivity to gastric distention was higher in the FD rats. AEA with parameters of 0.1s on, 0.4s off, 100Hz, 0.3ms and 0.4–0.5mA, but not other parameters or sham-EA, decreased gastric hypersensitivity in the FD rats. Naloxone did not block the effect of AEA. 2) Lower vagal activity and higher sympathovagal ratio were noted in the FD rats, compared with the controls. AEA increased vagal activity and improved sympathovagal imbalance. Conclusions AEA ameliorates gastric hypersensitivity in FD rats and this effect may be attributed to the improvement of sympathovagal balance.Yeshttp://www.plosone.org/static/editorial#pee