Function of proprotein convertase subtilisin/kexin type 9 and its role in central nervous system diseases: An update on clinical evidence.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has attracted lots of attention in preventing the clearance of plasma low-density lipoprotein cholesterol (LDL-C). PCSK9 inhibitors are developed to primarily reduce the cardiovascular risk by lowering LDL-C level. Recently, a number of pleiotropic extrahepatic functions of PCSK9 beyond the regulation of cholesterol metabolism, particularly its effects on central nervous system (CNS) diseases have been increasingly identified. Emerging clinical evidence have revealed that PCSK9 may play a significant role in neurocognition, depression, Alzheimer's disease, and stroke. The focus of this review is to elucidate the functions of PCSK9 and highlight the effects of PCSK9 in CNS diseases, with the aim of identifying the potential risks that may arise from low PCSK9 level (variant or inhibitor) in the clinical practice.

S100A4 exerts robust mucosal adjuvant activity for co-administered antigens in mice.

The lack of clinically applicable mucosal adjuvants is a major hurdle in designing effective mucosal vaccines. We hereby report that the calcium-binding protein S100A4, which regulates a wide range of biological functions, is a potent mucosal adjuvant in mice for co-administered antigens, including the SARS-CoV-2 spike protein, with comparable or even superior efficacy as cholera toxin but without causing any adverse reactions. Intranasal immunization with recombinant S100A4 elicited antigen-specific antibody and pulmonary cytotoxic T cell responses, and these responses were remarkably sustained for longer than 6 months. As a self-protein, S100A4 did not stimulate antibody responses against itself, a quality desired of adjuvants. S100A4 prolonged nasal residence of intranasally delivered antigens and promoted migration of antigen-presenting cells. S100A4-pulsed dendritic cells potently activated cognate T cells. Furthermore, S100A4 induced strong germinal center responses revealed by both microscopy and mass spectrometry, a novel label-free technique for measuring germinal center activity. Importantly, S100A4 did not induce olfactory bulb inflammation after nasal delivery, which is often a safety concern for nasal vaccination. In conclusion, S100A4 may be a promising adjuvant in formulating mucosal vaccines, including vaccines against pathogens that infect via the respiratory tract, such as SARS-CoV-2.

[Spatiotemporal Variations in Fine Particulate Matter and the Impact of Air Quality Control in Zhengzhou].

To study the spatiotemporal variations in fine particulate matter (PM2.5) and the impact of air quality management in autumn and winter in Zhengzhou, five sites were selected to collect PM2.5 samples from the autumn of 2017 to the winter of 2018, and the characteristics of the chemical components were analyzed. The positive matrix factorization (PMF) model was also applied to identify the sources of PM2.5, and the effect of air quality control was evaluated to provide support for air quality control in autumn and winter in the next stage. The PM2.5 concentrations in the four seasons in Zhengzhou were ranked as winter > autumn > spring > summer. The PM2.5 concentration at Zhengzhou University (ZZU) was the highest (8.7% higher than the average concentration), and the PM2.5 concentrations at the other sites were slightly lower than the average concentration. The concentration of water-soluble ions (WSIs) was low in spring and summer and high in autumn and winter. The average proportions of SO42-, NO3-, and NH4+ in the nine WSIs were as high as 22.5%, 43.6%, and 23.4%, respectively. The proportion of Cl- in winter was higher than that in the other seasons owing to coal combustion (6.7% and 6.6% in 2017 and 2018, respectively). Owing to wind and sand, the proportions of Ca2+ and Mg2+ in spring were the highest (4.4% and 0.4%, respectively), and those at the Jiancezhan (JCZ) and ZZU sites were higher than those at the other sites. K+, as a marker of biomass burning, had a higher proportion in spring, autumn, and winter. The proportion of K+ in the spring of 2018 was 1.9%, those in the autumn and winter of 2017 were 1.6% and 2.1%, respectively, and those in the autumn and winter of 2018 were 1.3% and 1.8%, respectively. JCZ, Hangkonggang (HKG), and Xinmi (XM) had higher proportions of NO3-, and the proportions of SO42- were lower. Secondary organic carbon (SOC) pollution was serious in autumn and winter, and the concentration accounted for more than half of the organic carbon (OC). In 2018, the SOC/OC at the JCZ and ZZU sites decreased compared with that in 2017, but that at the other three sites increased significantly, thereby indicating that different air pollutant emissions in these regions had different performances in response to control policies. The chemical composition reconstruction results showed that the proportion of sulfate was highest in summer (25.0%), the contribution of nitrate was higher in autumn (23.1% and 25.1% for 2017 and 2018, respectively) and winter (20.6% and 23.0% for 2017 and 2018, respectively), the proportion of crustal material was higher in spring (18.2%), and the contribution of secondary organic aerosol (SOA) was the highest in winter (14.1% and 20.5% for 2017 and 2018, respectively). SOA had higher contributions at the JCZ and HKG sites (16.9% and 16.4%, respectively), and ZZU was affected more by primary organic aerosol (14.3%) and crustal materials (12.1%). The PMF results showed that secondary inorganic salts (37.5%), SOA (15.4%), traffic (14.9%), industry (4.8%), coal combustion (16.0%), fugitive dust (6.5%), and biomass burning (2.8%) were the main pollution sources of PM2.5 in Zhengzhou. SOA and coal combustion contributed more in winter and fugitive dust contributed more in spring, followed by autumn. Biomass burning contributed more in spring and autumn. The urban sites JCZ and ZZU and the characteristic site HKG near the airport were more affected by traffic sources (16.9%, 16.2%, and 16.0%, respectively) than the other sites. The impact of biomass burning on the non-urban sites XM and HKG was slightly larger (both 2.7%), and the contribution of coal combustion to the suburban site XM was higher (16.8%). Owing to the construction around ZZU, the loading of fugitive dust at ZZU was higher than that at other sites. Comparing the results of the two-year autumn and winter, the contribution of SOA, traffic, and industry increased in the autumn and winter of 2018, whereas the contribution of secondary inorganic salts, coal combustion, and biomass burning decreased and the contribution of fugitive dust in winter also decreased. The results showed that the control strategies in autumn and winter had significant effects on the primary sources, including fugitive dust, coal combustion, and industry, and SOA precursor volatile organic compounds should be targeted for further pollution control.

Evaluation of the association between extravascular lung water and prognosis of sepsis: A protocol of systematic review.

BACKGROUND: The purpose of this study is to explore the association between extravascular lung water (EVLW) and prognosis of sepsis (PS). METHODS: We will carry out comprehensive literature search in electronic databases (PUBMED/MEDLINE, EMBASE, CENTRAL, WorldSciNet, PsycINFO, Allied and Complementary Medicine Database, CBM, and CNKI) and additional sources. All electronic databases will be searched from their initial to the present without language restrictions. Case-controlled studies reporting the association between EVLW and PS will be evaluated for inclusion. Outcomes of interest will include mortality rate, extravascular lung water index, pulmonary vascular permeability index, blood lactate clearance, oxygenation index, blood gas analysis, PaO2/FiO2, cardiac output index, global end diastolic volume index, intrathoracic blood volume index, systemic resistance index, acute physiology and chronic health scoring system II, and infection-related organ failure scoring system. Study quality will be evaluated using Newcastle-Ottawa Tool, and statistical analysis will be performed utilizing RevMan 5.4 software. RESULTS: This study will summarize the most recent evidence to investigate the association between EVLW and PS. CONCLUSIONS: The results of this study will provide an exhaustive view of the association between EVLW and PS. STUDY REGISTRATION OSF: osf.io/vhnxw.

Mzb1 protects against myocardial infarction injury in mice via modulating mitochondrial function and alleviating inflammation.

Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle dilation and cardiac dysfunction, eventually developing into heart failure. Mzb1 (Marginal zone B and B1 cell specific protein 1) is a B-cell-specific and endoplasmic reticulum-localized protein. Mzb1 is an inflammation-associated factor that participates a series of inflammatory processes, including chronic periodontitis and several cancers. In this study we investigated the role of Mzb1 in experimental models of MI. MI was induced in mice by ligation of the left descending anterior coronary artery, and in neonatal mouse ventricular cardiomyocytes (NMVCs) by H2O2 treatment in vitro. We showed that Mzb1 expression was markedly reduced in the border zone of the infarct myocardium of MI mice and in H2O2-treated NMVCs. In H2O2-treated cardiomyocytes, knockdown of Mzb1 decreased mitochondrial membrane potential, impaired mitochondrial function and promoted apoptosis. On contrary, overexpression of Mzb1 improved mitochondrial membrane potential, ATP levels and mitochondrial oxygen consumption rate (OCR), and inhibited apoptosis. Direct injection of lentiviral vector carrying Len-Mzb1 into the myocardial tissue significantly improved cardiac function and alleviated apoptosis in MI mice. We showed that Mzb1 overexpression significantly decreased the levels of Bax/Bcl-2 and cytochrome c and improved mitochondrial function in MI mice via activating the AMPK-PGC1α pathway. In addition, we demonstrated that Mzb1 recruited the macrophages and alleviated inflammation in MI mice. We conclude that Mzb1 is a crucial regulator of cardiomyocytes after MI by improving mitochondrial function and reducing inflammatory signaling pathways, implying a promising therapeutic target in ischemic cardiomyopathy.

Association between microRNA 25 expression in serum and lung cancer: A protocol for systematic review and meta-analysis.

BACKGROUND: This study aims to identify the association between microRNA 25 (mRNA 25) expression in serum and lung cancer (LC). METHODS: This planned study will cover all eligible case-controlled studies that report association between mRNA 25 expression in serum and LC. It will include published studies from inception to the present in Cochrane Library, PUBMED, EMBASE, Web of Science, Allied and Complementary Medicine Database, VIP database, and China National Knowledge Infrastructure regardless language and geographical location. We will also search other sources, such as conference abstracts and reference lists of related known studies and experts in the domain consulted to avoid missing potential studies. Two contributors will independently examine and select studies, collect all necessary data, and judge study quality for all included studies. We will perform statistical analysis using RevMan V.5.3 software and Stata V.12.0 software. RESULTS: This study will summarize current evidence to present first systematic review of research on the association between mRNA 25 expression in serum and LC. CONCLUSION: This study will present comprehensive evidence to determine whether mRNA 25 expression in serum is associated with LC, and will provide helpful evidence for the future studies. SYSTEMATIC REVIEW REGISTRATION: INPLASY202040056.

LINC00174 is an oncogenic lncRNA of hepatocellular carcinoma and regulates miR-320/S100A10 axis.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Multiple long non-coding RNAs (lncRNAs) are recently identified as crucial oncogenic factors or tumour suppressors. In this study, we explored the effects of LINC00174 on the progression of HCC. Expression levels of LINC00174 and microRNA-320 (miR-320) in HCC tissue samples were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The association between pathological indices and LINC00174 was also analysed. Human HCC cell lines Hep3B and Huh7 were used as cell models. CCK-8 and bromodeoxyuridine (BrdU) assays were used to assess the effect of LINC00174 on HCC cell line proliferation. Flow cytometry was used to study the effect of LINC00174 on HCC apoptosis. Transwell assay was conducted to detect the effect of LINC00174 on migration and invasion. Furthermore, luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to confirm the binding relationship between miR-320 and LINC00174. Additionally, western blot was used to detect the regulatory function of LINC00174 on oncogene S100 calcium binding protein A10 (S100A10). We demonstrated that LINC00174 expression in HCC clinical samples was significantly increased and this was correlated with higher T stage. Its overexpression remarkably accelerated proliferation and metastasis of HCC cells while reduced apoptosis. Accordingly, knockdown of it suppressed the malignant phenotypes of HCC cells. Overexpression of LINC00174 significantly reduced the expression of miR-320 by sponging it, in turn enhanced the expression of S100A10. In conclusion, LINC00174 is a sponge of tumour suppressor miR-320, enhances the expression of S100A10 indirectly and functions as an oncogenic lncRNA in HCC. SIGNIFICANCE OF THE STUDY: LINC00174 is a novel lncRNA, whose function is rarely investigated. It is reported that it is oncogenic in colorectal cancer, while its role in HCC remains unclear. Herein, we report that LINC00174 is significantly up-regulated in HCC tissues and promotes the malignant phenotypes. We demonstrate that LINC00174 functions as a sponge for miR-320, increases the expression level of oncogene S100A10 in HCC. This study helps clarify the mechanism of HCC tumorigenesis and progression, and uncover the role of LINC00174 in human disease.

CRISPR/Cas9 mediated gene knockout reveals a more important role of PBP1 than PBP2 in the perception of female sex pheromone components in Spodoptera litura.

Three different pheromone binding proteins (PBPs) can typically be found in the sensilla lymph of noctuid moth antennae, but their relative contributions in perception of the sex pheromone is rarely verified in vivo. Previously, we demonstrated that SlitPBP3 plays a minor role in the sex pheromone detection in Spodoptera litura using the CRISPR/Cas9 system. In the present study, the roles of two other SlitPBPs (SlitPBP1 and SlitPBP2) are further verified using the same system. First, by co-injection of Cas9 mRNA/sgRNA into newly laid eggs, a high rate of target mutagenesis was induced, 51.5% for SlitPBP1 and 46.8% for SlitPBP2 as determined by restriction enzyme assay. Then, the homozygous SlitPBP1 and SlitPBP2 knockout lines were obtained by cross-breeding. Finally, using homozygous knockout male moths, we performed electrophysiological (EAG recording) and behavioral analyses. Results showed that knockout of either SlitPBP1 or SlitPBP2 in males decreased EAG response to each of the 3 sex pheromone components (Z9,E11-14:Ac, Z9,E12-14:Ac and Z9-14:Ac) by 53%, 60% and 63% (for SlitPBP1 knockout) and 40%, 43% and 46% (for SlitPBP2 knockout), respectively. These decreases in EAG responses were similar among 3 pheromone components, but were more pronounced in SlitPBP1 knockout males than in SlitPBP2 knockout males. Consistently, behavioral assays with the major component (Z9,E11-14:Ac) showed that SlitPBP1 knockout males responded in much lower percentages than SlitPBP2 knockout males in terms of orientation to the pheromone, along with reduction in close range behaviors such as hairpencil display and mating attempt. Taken together, this study provides direct functional evidence for the roles of SlitPBP1 and SlitPBP2, as well as their relative importance (SlitPBP1 > SlitPBP2) in the sex pheromone perception. This information is valuable in understanding mechanisms of sex pheromone perception and may facilitate the development of PBP-targeted pest control techniques.

Expression Profile and Functional Characterization Suggesting the Involvement of Three Chemosensory Proteins in Perception of Host Plant Volatiles in Chilo suppressalis (Lepidoptera: Pyralidae).

The high sensitivity of the olfactory system is essential for feeding and oviposition in moth insects, and some chemosensory proteins (CSPs) are thought to play roles in this system by binding and carrying hydrophobic odorants across the aqueous sensillar lymph. In this study, to identify the olfactory CSPs from a repertoire of 21 CSP members in the notorious rice pest Chilo suppressalis (Walker) (Lepidoptera: Pyralidae), tissue expression patterns were firstly examined by quantitative real-time polymerase chain reaction (qPCR). It showed that CSP2 was antennae specific and seven more CSPs (CSP1, 3, 4, 6, 15, 16, and 17) were antennae biased in expression, suggesting their olfactory roles; while other CSPs were multiple-tissue expressed and non-antennae biased, suggesting other functions for these genes. To further determine the ligand binding specificity, three putative olfactory genes (CSP1-3) were expressed in Escherichia coli cells, and binding affinity of these three recombinant CSP proteins were measured for 35 plant volatiles by the ligand binding assays. CSP1 and CSP2 exhibited high binding affinities (Ki ≤ 10.00 µM) for four (2-tridecanone, benzaldehyde, laurinaldehyde and 2-pentadecanone) and two (2-heptanol and (+)-cedrol) host plant volatiles, respectively; the three CSPs also showed moderate binding affinity (Ki = 10.01-20.00 µM) for 16 plant volatiles. Our study suggests that the three CSPs play essential roles in the perception of host plant volatiles, providing bases for the elucidation of olfactory mechanisms in this important pyralid pest.

Evaluation of the diagnostic performance of panfungal polymerase chain reaction assay in invasive fungal diseases.

Timely diagnosis of invasive fungal diseases (IFDs) is important, as delays in treatment initiation are associated with increased mortality rates. However, early diagnosis of IFDs in immunocompromised patients remains difficult. The conventional diagnostic methods currently used for IFDs are not sufficiently effective. Molecular tests, such as polymerase chain reaction (PCR)-based assays, have great potential to improve the early diagnosis of IFDs due to their sensitivity and specificity. In the present study, the diagnostic performance of panfungal PCR assays in IFD patients who received bone marrow transplantation was evaluated. The results suggested that panfungal PCR assay offered a quick and convenient guide for clinical decision-making by identifying higher numbers of fungal species in comparison with the conventional blood culture method. Furthermore, panfungal PCR assay exhibited a sensitivity of 93% and a specificity of 71% in the diagnosis of IFD patients based on the EORTC/MSG criteria. Thus, the present study concluded that the reported PCR-based method was effective and sensitive in early IFD diagnosis and should be integrated into clinical decision-making for the treatment of IFDs in the future.