Causal association between self-reported fatigue and coronary artery disease: a bidirectional two-sample Mendelian randomization analysis

BackgroundObservational studies have reported the association between fatigue and coronary artery disease (CAD), but the causal association between fatigue and CAD is unclear.MethodWe conducted a bidirectional Mendelian randomization (MR) study using publicly available genome-wide association studies (GWAS) data. The inverse-variance weighted (IVW) method was used as the primary analysis. We performed three complementary methods, including weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) to evaluate the sensitivity and horizontal pleiotropy of the results.ResultSelf-reported fatigue had a causal effect on coronary artery atherosclerosis (CAA) (OR 1.047, 95%CI 1.033–1.062), myocardial infarction (MI) (OR 1.027 95%CI 1.014–1.039) and coronary heart disease (CHD) (OR 1.037, 95%CI 1.021–1.053). We did not find a significant reverse causality between self-reported fatigue and CAD. Given the heterogeneity revealed by MR-Egger regression, we employed the IVW random effect model. For the examination of fatigue on CHD and the reverse analysis of CAA, and MI on fatigue, the MR-PRESSO test found horizontal pleiotropy. No significant outliers were found.ConclusionThe MR analysis reveals a causal relationship between self-reported fatigue and CAD. The results should be interpreted with caution due to horizontal pleiotropy

Transient ischemic attack and coronary artery disease: a two-sample Mendelian randomization analysis

BackgroundAlthough observational studies have shown that patients who experienced transient ischemic attacks (TIAs) had a higher risk of coronary artery disease (CAD), the causal relationship is ambiguous.MethodsWe conducted a two-sample Mendelian randomization (MR) study to analyze the causal relationship between TIA and CAD using data from the FinnGen genome-wide association study. Analysis was performed using the inverse-variance weighted (IVW) method. The robustness of the results was evaluated using MR-Egger regression, the weighted median, MR pleiotropy residual sum, and outlier (MR-PRESSO) and multivariable MR analysis.ResultsResults from IVW random-effect model showed that TIA was associated with an increased risk of coronary artery atherosclerosis (OR 1.17, 95% CI 1.06–1.28, P = 0.002), ischemic heart disease (OR 1.15, 95% CI 1.04–1.27, P = 0.007), and myocardial infarction (OR1.15, 95% CI 1.02–1.29, P = 0.025). In addition, heterogeneity and horizontal pleiotropy were observed in the ischemic heart disease results, while the sensitivity analysis revealed no evidence of horizontal pleiotropy in other outcomes.ConclusionsThis MR study demonstrated a potential causal relationship between TIA and CAD. Further research should be conducted to investigate the mechanism underlying the association

Biogenesis aberration: One of the mechanisms of thrombocytopenia in COVID-19

Background: The pathogenesis of COVID-19, including thrombocytopenia, has not been fully clarified. The lungs are a major organ of platelet production and thrombocytopenia induced by severe COVID-19 was proposed.Methods: the change of platelet level was analysed with clinical parameters in 95 hospitalized COVID-19 patients in Wuhan Third Hospital. The production of platelets in the lungs was explored in an ARDS rat model.Results: The level of platelets was negatively correlated with disease severity and was recovered with disease improvement. The non-survivors were accompanied by lower levels of platelet. The odds ratio (OR) of the valley level of the platelet count (PLTlow) was greater than 1, suggesting that PLTlow could be a death exposure factor. The platelet/lymphocyte ratio (PLR) was positively associated with severity of COVID-19, and the platelet/lymphocyte ratio threshold of 248.5 was best correlated with death risk (sensitivity 0.641 and specificity 0.815). To demonstrate the possible biogenesis aberration of platelet in lungs, an LPS-induced ARDS rat model was applied. Lower level of platelet in peripheral and less production of platelet from lungs in ARDS were demonstrated. Though megakaryocyte (MK) number in ARDS lungs is higher than controls, the immature platelet fraction (IPF) in postpulmonary blood is still at the same level as prepulmonary in ARDS rat, indicating that ARDS rats generated fewer platelets in lungs.Conclusion: Our data suggested that COVID-19-induced severe lung inflammation may impair platelet production in the lung. Thrombocytopenia may be mainly caused by platelet consumption for multiorgan thrombosis; however, biogenesis aberration of platelet in the lung induced by diffuse interstitial pulmonary damage cannot be ruled out

CTLA-4 expression, regulation and associations in autoimmune myasthenia gravis

Myasthenia gravis (MG) is a neuromuscular disease with muscle weakness due to an autoimmune attack against the nicotinic acetylcholine receptor (nAChR) on the skeletal muscle endplate. Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) plays a global inhibitory role in the immune system and has a crucial role in autoimmunity. We focused our research on the CTLA-4 molecule, exploring its expression, regulation, and genetic variations, especially in association with MG. Single nucleotide polymorphisms (SNPs) contribute most significantly to the variation in a population. To determine an association between the genetic polymorphisms of the Ctla-4 and MG, the A/G SNP in CDS 1 at position +49 (A/G+49) and a C/T SNP in promoter at position 318 (C/T-318) were analyzed. The allele G+49 and genotype G/G+49 were more frequently present in MG patients with thymoma. Patients with this genotype also had signs of immune activation manifested as elevated levels of serum IL-Beta and a higher percentage of CD28 4, T lymphocytes. Ctla-4 variations may thus contribute to the pathophysiology of MG. The expression of CTLA-4 was investigated in patients with MG. We found that the patients had low expression of CTLA-4 by peripheral T cells and a decreased response to ConA. Moreover, the patients had higher serum levels of soluble CTLA-4 (sCTLA-4) which were positively correlated with the concentration of anti-nAChR antibodies. The functional correlations to genetic polymorphisms are most interesting. By constructing Ctla-4 promoter reporters, we demonstrated that the T-318 allele was associated with a higher promoter activity than the C-318 allele. To define the function of the microsatellite polymorphism in the 3'-UTR, we analyzed allele-specific expression in individuals heterozygous for (AT)n of different lengths, and found that mRNA expression of CTLA-4 from alleles with longer AT repeats was less than mRNA from shorter alleles. The difference in allele expression was due to alteration in mRNA stability. The degradation of mRNA was faster in individuals homozygous for the longer AT repeats than in those homozygous for the shorter alleles. The expression profile of CTLA-4 in humans has not been completely elucidated. We found a constitutive expression of CTLA-4 by peripheral T cells, mainly in the cytoplasm. IL-2 upregulated both intracellular and surface expression of CTLA-4 in a dose-dependent manner. More than half of the CTLA-4+ T cells expressed CD25. Also human monocytes expressed intracellular CTLA-4 and surface expression of CTLA-4 was achieved by IFN-gamma treatment. CTLA-4 expression was induced by PMA and IFN-gamma in the monocytic cell lines U937 and THP-1. CTLA-4 engagement by antibodies inhibited cell proliferation and down-regulated expression of the activation markers CD86, CD54, HLA-DR and HLA-DQ. CTLA-4 engagement blocked NF-kappaB and AP- I transcription factor activities. Thus, CTLA-4 might act early to reduce the activity of several key nuclear transcription factors important for monocyte activation. CTLA-4 might thus contribute to the manifestation of MG due to abnormal expression caused by genetic variations. The properties of CTLA-4 should be further investigated with regard to its therapeutic potentials

Highly Efficient Numerical Integrator for the Circular Restricted Three-Body Problem

The dynamic equation of a mass point in the circular restricted three-body problem is governed by Coriolis and centrifugal force, in addition to a co-rotating potential relative to the frame. In this paper, we provide an explicit, symmetric integrator for this problem. Such an integrator is more efficient than the symplectic Euler method and the Gauss Runge–Kutta method as regards this problem. In addition, we proved the integrator is symplectic by the discrete Hamilton’s principle. Several groups of numerical experiments demonstrated the precision and high efficiency of the integrator in the examples of the quadratic potential and the bounded orbits in the circular restricted three-body problem

Aggregation Behavior of Nano-Silica in Polyvinyl Alcohol/Polyacrylamide Hydrogels Based on Dissipative Particle Dynamics

Due to the aggregation behavior of nano-silica in aqueous solution, the use of nano-silica without surface modification for synthesizing hydrogels is still a challenging task. This paper presents our study on the use of dissipative particle dynamics simulations to discover the aggregation behavior of nano-silica in polyvinyl alcohol (PVA)/polyacrylamide (PAM) blended hydrogels. By simulations, we aimed at investigating the effects of such factors as nano-silica content, polymer component ratio, temperature and shear rate on the aggregation behavior of nano-silica in terms of the mesoscopic morphologies and the relative concentration distribution functions. Our results reveal that the dispersion of nano-silica is seen if the nano-silica content is increased to 1.5%, and the aggregation of nano-silica becomes noticeable in blended hydrogels with an increase in the nano-silica content. This finding agrees well with the experimental results obtained by means of scanning electron microscopy. Furthermore, it is also found that the dispersion of nano-silica becomes more uniform with an increase in PAM content, temperature and shear rate. These findings greatly enrich our understanding of the aggregation behavior of nano-silica in PVA/PAM blended hydrogels

Highly Efficient Numerical Integrator for the Circular Restricted Three-Body Problem

The dynamic equation of a mass point in the circular restricted three-body problem is governed by Coriolis and centrifugal force, in addition to a co-rotating potential relative to the frame. In this paper, we provide an explicit, symmetric integrator for this problem. Such an integrator is more efficient than the symplectic Euler method and the Gauss Runge–Kutta method as regards this problem. In addition, we proved the integrator is symplectic by the discrete Hamilton’s principle. Several groups of numerical experiments demonstrated the precision and high efficiency of the integrator in the examples of the quadratic potential and the bounded orbits in the circular restricted three-body problem

Evapotranspiration partitioning and crop coefficient of maize in dry semi-humid climate regime

Guanzhong Plain is one of the most critical maize production areas in Northwest China. It is essential to study the maize irrigation requirement and improve water use efficiency in this area. There is a lack of knowledge about the evaporation portioning and irrigation requirements of crops grown in this region. Based on evapotranspiration observed in a maize cropland using the eddy covariance (EC) technique during four growing seasons (2013, 2014, 2015, and 2017), the seasonal variation of evapotranspiration components and the crop coefficients (Kc) for summer maize in a dry semi-arid area were determined. Energy partitioning has an obvious seasonal variation during growing seasons. The pattern of evapotranspiration partitioning has a clear seasonal variation with the development of the canopy. The pattern of the ratio of transpiration (T) to evapotranspiration (ET) is consistent with the canopy development. For four growing seasons, on a seasonal basis, the ratios of T to ET and E to ET were comparable. In addition, the locally developed crop coefficients were 0.57, 1.01, and 0.50 for the initial, mid, and late stages, respectively. The single crop coefficient derived from local datasets can provide a good prediction of ET. The Kc values reported in this paper were consistent with previous studies conducted in other regions using EC systems but were generally lower than the Kc values derived from ET data measured by lysimeters, the Bowen Ratio Energy Balance system, and the soil water balance method. This indicates that the variability of the locally developed crop coefficient caused by measurement methods is higher than the variability caused by climate