Overexpression of malic enzyme is involved in breast cancer growth and is correlated with poor prognosis.

Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2-positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan-Meier analysis revealed ME1 upregulation was associated with poor disease-specific survival (DSS: p = 0.002) and disease-free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08-2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03-2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non-triple-negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co-cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer.

Health-related quality of life in Chinese SLE patients: evidence from 1568 SLE patients and 2610 healthy controls.

OBJECTIVE: To investigate the effects of systemic lupus erythematosus (SLE) on health-related quality of life (HRQOL), the relationship between disease activity and HRQOL, and potential factors affecting HRQOL in Chinese SLE patients. METHODS: This study recruited 1568 patients and 2610 controls to explore the effects of SLE on HRQOL. The association between disease activity and HRQOL, and the influencing factors of HRQOL were determined in 1568 patients. Then, we prospectively followed 1096 patients to explore the association between reduced disease activity and improved HRQOL, and the influencing factors of improved HRQOL. The Short-Form 36 (SF-36) and SLE disease activity index (SLEDAI) were used to evaluate HRQOL and disease activity. RESULTS: Chinese SLE patients had lower HRQOL than controls in all domains (P < 0.001), especially in role-physical (RP) and role-emotional (RE). Compared with SLE patients from outside China, the HRQOL of Chinese patients appeared to be higher in mental component summary (MCS) but lower in RP and RE. SLEDAI was negatively correlated with HRQOL, which was validated using the results of a follow-up study, where SLEDAI reduction was positively associated with HRQOL improvements (P < 0.05). Furthermore, personality, life nervous and experiences of adverse life events may influence HRQOL and HRQOL improvements. CONCLUSION: SLE significantly affected the HRQOL of Chinese patients, especially in RP and RE. Disease activity was negatively correlated with HRQOL. We also found for the first time some factors affecting HRQOL, which can be regarded as the basis for improving the HRQOL of SLE patients.

Meteorological factors cannot be ignored in machine learning-based methods for predicting dengue, a systematic review.

In recent years, there has been a rapid increase in the application of machine learning methods about predicting the incidence of dengue fever. However, the predictive factors and models employed in different studies vary greatly. Hence, we conducted a systematic review to summarize machine learning methods and predictors in previous studies. We searched PubMed, ScienceDirect, and Web of Science databases for articles published up to July 2023. The selected papers included not only the forecast of dengue incidence but also machine learning methods. A total of 23 papers were included in this study. Predictive factors included meteorological factors (22, 95.7%), historical dengue data (14, 60.9%), environmental factors (4, 17.4%), socioeconomic factors (4, 17.4%), vector surveillance data (2, 8.7%), and internet search data (3, 13.0%). Among meteorological factors, temperature (20, 87.0%), rainfall (20, 87.0%), and relative humidity (14, 60.9%) were the most commonly used. We found that Support Vector Machine (SVM) (6, 26.1%), Long Short-Term Memory (LSTM) (5, 21.7%), Random Forest (RF) (4, 17.4%), Least Absolute Shrinkage and Selection Operator (LASSO) (2, 8.7%), ensemble model (2, 8.7%), and other models (4, 17.4%) were identified as the best models based on evaluation metrics used in each article. These results indicate that meteorological factors are important predictors that cannot be ignored and SVM and LSTM algorithms are the most commonly used models in dengue fever prediction with good predictive performance. This review will contribute to the development of more robust early dengue warning systems and promote the application of machine learning methods in predicting climate-related infectious diseases.

Isolation of three MiDi19-4 genes from mango, the ectopic expression of which confers early flowering and enhances stress tolerance in transgenic Arabidopsis.

MAIN CONCLUSION: Three Di19-4 genes were identified in mango. Overexpression of MiDi19-4B in A. thaliana promoted earlier flowering and enhanced drought, salt, and ABA resistance. Drought-induced protein 19 (Di19) is a drought-induced protein that is mainly involved in multiple stress responses. Here, three Di19-4 genes (MiDi19-4A/B/C) in mango (Mangifera indica L.) were identified, and the coding sequences (CDS) had lengths of 684, 666, and 672 bp and encoded proteins with 228, 222, and 224 amino acids, respectively. The promoters of the MiDi19-4 genes contained phytohormone-, light-, and abiotic stress-responsive elements. The MiDi19-4 genes were expressed in every tissue and highly expressed in leaves. Moreover, MiDi19-4 genes were highly correlated with the vegetative growth period and induced by polyethylene glycol (PEG) or salt stress. MiDi19-4B displayed the highest expression during the vegetative growth period and then showed decreased expression, and MiDi19-4B was highly expressed at both the late stage of the vegetative growth period and the initial stage of the flowering induction period. The 35S::GFP-MiDi19-4B fusion protein was located in the cell nucleus. The transgenic plants ectopically expressing MiDi19-4B exhibited earlier flowering and increased expression patterns of FRUITFULL (AtFUL), APETALA1 (AtAP1), and FLOWERING LOCUS T (AtFT). The drought and salt tolerance of MiDi19-4B transgenic plants was significantly increased, and these plants showed decreased sensitivity to abscisic acid (ABA) and considerably increased expression levels of drought- and salt-related genes and ABA signalling pathway genes. Additionally, bimolecular fluorescence complementation (BiFC) experiments revealed that the MiDi19-4B protein interacted with CAULIFLOWER (MiCAL1), MiCAL2, MiAP1-1, and MiAP1-2. Taken together, these results highlighted the important regulatory roles of MiDi19-4B in tolerance to multiple abiotic stresses and in flowering.

ATG4B and pS383/392-ATG4B serve as potential biomarkers and therapeutic targets of colorectal cancer.

BACKGROUND: Autophagy related protease 4B (ATG4B) is a protease required for autophagy processing, which is strongly implicated in cancer progression.  Phosphorylation of ATG4B is crucial for activation of its protease activity.  However, little is known about the relationship of ATG4B and its phosphorylated form at Ser 383 and 392 sites (pS383/392-ATG4B), with clinical outcomes, particularly in colorectal cancer (CRC). METHODS: The ATG4B gene expression in CRC patients was obtained from The Cancer Genome Atlas (TCGA) database to analyze its clinical relevance. Tissue microarrays composed of 118 CRC patient specimens were used to determine the associations of ATG4B and pS383/392-ATG4B protein levels with prognosis. The biological functions of ATG4B in CRC cells were inspected with cell proliferation, mobility and spheroid culture assays. RESULTS: ATG4B gene expression was elevated in tumor tissues of CRC patients compared to that in adjacent normal tissues and high level of ATG4B expression was associated with poor survival. Similarly, protein levels of ATG4B and pS383/392-ATG4B were highly correlated with worse overall survival and disease-free survival. Stratification analysis results showed that high level of ATG4B had significantly higher risk of mortality in males and elderly patients compared to those female patients and patients 60 years or younger. In contrast, multivariate Cox's regression analysis indicated that high level of pS383/392-ATG4B was significantly linked to unfavorable overall survival and disease-free survival of males and elderly patients, whereas, it had no correlation with female patients and patients 60 years or younger. Moreover, high level of ATG4B was positively associated with increased mortality risk in patients with advanced AJCC stages (III and IV) and lymph node invasion (N1 and N2) for both overall survival and disease-free survival. Nevertheless, high level of pS383/392-ATG4B was positively correlated with increased mortality risk in patients with early AJCC stages (I and II) and without lymph node invasion (N0). In addition, silencing ATG4B attenuated migration, invasion, and further enhanced the cytotoxic effects of chemotherapeutic drugs in two and three-dimensional cultures of CRC cells. CONCLUSIONS: Our results suggest that ATG4B and pS383/392-ATG4B might be suitable biomarkers and therapeutic targets for CRC.

Interaction between home and community-based services and PM2.5 on cognition: A prospective cohort study of Chinese elderly.

PM2.5 and home and community-based services (HCBSs) had been shown to affect cognition, but the evidence on their joint effects was limited. Aimed to study the joint effects of HCBSs and PM2.5 on cognition, we utilized the follow-up data of participants in the Chinese Longitudinal Health Longevity Survey (CLHLS) who were 65 years of age or older and had normal cognitive function at baseline for the 2008-2018, 2011-2018, and 2014-2018 waves. 16,954, 9,765, and 7192 participants from each of these three waves were initially recruited, respectively. The PM2.5 concentration data of each province in China from 2008 to 2018 was obtained from the Atmospheric Composition Analysis Group. Participants were asked what kind of HCBSs were available in their community. The cognitive status of the participants was evaluated by the Chinese version of Mini-Mental State Examination (CMMSE). We applied the Cox proportional hazard regression model to investigate the joint effects of HCBSs and PM2.5 on cognition and further stratified the analysis according to HCBSs. Hazard ratio (HR) and 95% confidence interval (95% CI) were calculated based on Cox models. During a median follow-up period of 5.2 years, 911 (8.8%) participants with normal baseline cognitive function developed cognitive impairment. Compared to participants without HCBSs and exposed to the highest level of PM2.5, those with HCBSs and exposed to the lowest level of PM2.5 had a significantly reduced risk of developing cognitive impairment (HR = 0.428, 95% CI: 0.303-0.605). The results from the stratified analysis revealed that the detrimental effect of PM2.5 on cognition was more pronounced in participants without HCBSs (HR = 3.44, 95% CI: 2.18-5.41) compared with those with HCBSs (HR = 1.42, 95% CI: 0.77-2.61). HCBSs may attenuate the harmful impact of PM2.5 on cognitive status in the elderly Chinese and the government should further promote the application of HCBSs.

Free triiodothyronine predicts the risk of developing diabetic kidney disease.

BACKGROUND: Low levels of Free Triiodothyronine (FT3) are associated with poor survival in chronic kidney disease, and the aim of this study was to further assess the relationship between changes in FT3 levels and renal damage in patients with type 2 diabetes based on glomerular and tubular markers. METHODS: We retrospectively studied 452 type 2 diabetic patients, measured glomerular damage markers (UACR, eGFR) and tubular damage markers (NAG/Cr,ß2-MG), analyzed the relationship between FT3 and renal damage by logistic regression models, and plotted restrictive cubic splines. RESULTS: 41.6% of subjects had diabetic kidney disease (DKD), and the prevalence of DKD decreased progressively with increasing FT3 levels in the third quartile. Spearman correlation analysis showed that FT3 was negatively associated with UACR, NAG/Cr and ß2-MG, while eGFR was positively associated with FT3. Multifactorial analysis, after adjusting for relevant confounders, revealed that compared with the lowest quartile of FT3, the highest quartile reduced the risk of developing urinary albumin (OR = 0.499,95% CI:0.289-0.856), moderate to severe impairment of glomerular filtration rate (OR = 0.106,95% CI:0.032-0.354), renal tubular marker ß2 -MG positive (OR = 0.516,95% CI:0.299 to 0.883) and the risk of DKD occurrence (OR = 0.450,95% CI:0.260 to 0.774). In the sample model, FT3 levels below 4.39 pmol/L were associated with an increased risk of glomerular tubule injury and DKD occurrence. CONCLUSIONS: FT3 is closely associated with glomerular tubular injury and is a protective factor. As FT3 levels (< 4.39 pmol/L) decrease, the risk of developing DKD becomes higher, and FT3 can be used as an independent predictor of developing DKD.

Traffic-related air pollution, adherence to healthy lifestyles, and risk of cognitive impairment: A nationwide population-based study.

BACKGROUND: Traffic-related air pollution (TRAP) is a risk factor for cognitive function, whereas healthy lifestyles are associated with better cognition. We aimed to examine their joint effects on cognition among the Chinese elderly. METHODS: The data from the Chinese Longitudinal Healthy Longevity Survey was used. Participants' cognitive performance was assessed by the Chinese version of the mini-mental state examination. Residential proximity to major roadways was obtained through self-report and categorized into five categories: > 300 m, 201-300 m, 101-200 m, 50-100 m, and < 50 m, serving as a surrogate for TRAP. Six lifestyle behaviors (smoking, drinking, exercise, body mass index, sleep duration, and dietary diversity) were taken into account to calculate healthy lifestyle scores. The scores ranged from zero to six and were then divided into three groups: healthy (5-6), intermediate (2-4), and unhealthy (0-1). Logistic regression models were applied to investigate the joint effects of TRAP and healthy lifestyle scores on cognition. RESULTS: Compared to participants living < 50 m from major roadways and adopting an unhealthy lifestyle, those living > 300 m from major roadways and adopting a healthy lifestyle had a significantly decreased risk of cognitive impairment. Stratified analysis indicated that the associations between TRAP and cognitive impairment were more pronounced among participants adopting an unhealthy lifestyle compared to the participants adopting a healthy lifestyle. CONCLUSIONS: TRAP may impair cognitive function, and its detrimental impacts may be lessened by healthy lifestyles.

CT-based radiographic measurements and effectiveness estimates of full-endoscopic surgery in thoracic myelopathy caused by ossification of ligamentum flavum.

BACKGROUND: Evaluate the effectiveness of posterior percutaneous full-endoscopic technique for patients with thoracic myelopathy caused by ossification of ligamentum flavum (TOLF). METHODS: A prospective study was conducted for 16 patients with TOLF, who were treated with posterior endoscopic technique from 2017 to 2019. The sagittal and cross-sectional CT images are used to measure the area of ossified ligamentum and evaluate the decompression of surgery, respectively. The effectiveness was evaluated with visual analog scale (VAS), modified Japanese Orthopedic Association scale (mJOA), The Oswestry Disability Index (ODI), and Macnab efficacy evaluation. RESULTS: The average area of TOLF on sagittal and cross-sectional CT images in the 16 patients was (116.62 ± 32.72) mm2 and (141.59 ± 27.25) mm2 preoperatively, (15.99 ± 12.54) mm2 and (11.72 ± 8.64) mm2 at 3 days after the operation, (16.78 ± 11.49) mm2 and (10.82 ± 7.57) mm2 postoperative 1 year, respectively. The invasive proportion of spinal canal at preoperative sagittal and cross-sectional CT images was (48.10 ± 10.04) % and (57.58 ± 11.37) %, which decreased to (6.83 ± 4.48) % and (4.40 ± 3.01) % at the final follow-up. The average score of mJOA, VAS and ODI improved. The excellent and good rate was 87.50% according to Macnab evaluation. Compared with preoperative, differences in areas of TOLF, proportions of spinal canal, and clinical assessments of postoperative 3 days and 1 year were all statistically significant. Two cases of dural tear were observed. CONCLUSION: Endoscopic surgery has a good clinical effect on TOLF, which has the advantage of less trauma to the paraspinal muscles and no impact on the spinal structure. The CT-based radiographic measurements can quantitatively evaluate the degree of spinal canal stenosis in TOLF.

[Characterization and identification of chemical components in traditional Chinese medicine Psoraleae Fructus based on UHPLC-Q-TOF-MS].

This study was designed to comprehensively characterize and identify the chemical components in traditional Chinese medicine Psoraleae Fructus by establishing an ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) method in combination with in-house library. The chromatographic separation conditions(stationary phase, column temperature, mobile phase, and elution gradient) and key MS monitoring parameters(capillary voltage, nozzle voltage, and fragmentor) were sequentially optimized via single-factor experiments. A BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) was finally adopted, with the mobile phase consisting of 0.1% formic acid in water(A) and acetonitrile(B) at the flow rate of 0.4 mL·min~(-1) and column temperature of 30 ℃. Auto MS/MS was utilized for data acquisition in both positive and negative ion modes. By comparison with reference compounds, analysis of the MS~2 fragments, in-house library retrieval and literature research, 83 compounds were identified or tentatively characterized from Psoraleae Fructus, including 58 flavonoids, 11 coumarins, 4 terpenoid phenols, and 10 others. Sixteen of them were identified by comparison with reference compounds, and ten compounds may have not been reported from Psoraleae Fructus. This study achieved a rapid qualitative analysis on the chemical components in Psoraleae Fructus, which provided useful reference for elucidating its material basis and promoting the quality control.

Changing trends in the disease burden of non-melanoma skin cancer globally from 1990 to 2019 and its predicted level in 25 years.

BACKGROUND: The disease burden of non-melanoma skin cancer (NMSC) has become a significant public health threat. We aimed to conduct a comprehensive analysis to mitigate the health hazards of NMSC. METHODS: This study had three objectives. First, we reported the NMSC-related disease burden globally and for different subgroups (sex, socio-demographic index (SDI), etiology, and countries) in 2019. Second, we examined the temporal trend of the disease burden from 1990 to 2019. Finally, we used the Bayesian age-period-cohort (BAPC) model integrated nested Laplacian approximation to predict the disease burden in the coming 25 years. The Norpred age-period-cohort (APC) model and the Autoregressive Integrated Moving Average (ARIMA) model were used for sensitivity analysis. RESULTS: The disease burden was significantly higher in males than in females in 2019. The results showed significant differences in disease burden in different SDI regions. The better the socio-economic development, the heavier the disease burden of NMSC. The number of new cases and the ASIR of basal cell carcinoma (BCC) were higher than that of squamous cell carcinoma (SCC) in 2019 globally. However, the number of DALYs and the age-standardized DALYs rate were the opposite. There were statistically significant differences among different countries. The age-standardized incidence rate (ASIR) of NMSC increased from 54.08/100,000 (95% uncertainty interval (UI): 46.97, 62.08) in 1990 to 79.10/100,000 (95% UI: 72.29, 86.63) in 2019, with an estimated annual percentage change (EAPC) of 1.78. Other indicators (the number of new cases, the number of deaths, the number of disability-adjusted life years (DALYs), the age-standardized mortality rate (ASMR), and the age-standardized DALYs rate) showed the same trend. Our predictions suggested that the number of new cases, deaths, and DALYs attributable to NMSC would increase by at least 1.5 times from 2020 to 2044. CONCLUSIONS: The disease burden attributable to NMSC will continue to increase or remain stable at high levels. Therefore, relevant policies should be developed to manage NMSC, and measures should be taken to target risk factors and high-risk groups.

Associations of RPEL1 and miR-1307 gene polymorphisms with disease susceptibility, glucocorticoid efficacy, anxiety, depression, and health-related quality of life in Chinese systemic lupus erythematosus patients.

OBJECTIVE: Our present study intended to examine the associations of RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) with susceptibility, glucocorticoids (GCs) efficacy, anxiety, depression, and health-related quality of life (HRQoL) in Chinese systemic lupus erythematosus (SLE) patients. METHODS: Initially, 1000 participants (500 SLE cases and 500 controls) were recruited for the case-control study. Then, 429 cases who received GCs were followed through 12 weeks to explore GCs efficacy, depression, anxiety, and HRQoL. We selected the iMLDR technique for genotyping: RPEL1: rs4917385 (G/T) and miR-1307: rs7911488 (A/G). RESULTS: The minor G allele of rs7911488 reduced the risk of SLE (p = .024). Four haplotypes consisting of rs4917385 and rs7911488 were associated with SLE susceptibility (p < .025). Both rs4917385 and rs7911488 were associated with anxiety symptoms and physical function (PF) in SLE patients (p < .025). The rs4917385 was associated with depression and its improvement. No statistical significance was found between RPEL1 and miR-1307 gene polymorphisms with GCs efficacy. Meanwhile, additive interaction analysis showed a significant association between RPEL1 and miR-1307 gene polymorphisms with tea consumption in anxiety. CONCLUSION: RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) might be related to SLE susceptibility in Chinese population. Additionally, the two polymorphisms were possibly associated with depression, anxiety, and HRQoL in Chinese SLE population.

The emerging role of miRNAs in the pathogenesis of COVID-19: Protective effects of nutraceutical polyphenolic compounds against SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause immunosuppression and cytokine storm, leading to lung damage and death. The clinical efficacy of anti-SARS-CoV-2 drugs in preventing viral entry into host cells and suppressing viral replication remains inadequate. MicroRNAs (miRNAs) are crucial to the immune response to and pathogenesis of coronaviruses, such as SARS-CoV-2. However, the specific roles of miRNAs in the life cycle of SARS-CoV-2 remain unclear. miRNAs can participate in SARS-CoV-2 infection and pathogenesis through at least four possible mechanisms: 1. host cell miRNA expression interfering with SARS-CoV-2 cell entry, 2. SARS-CoV-2-derived RNA transcripts acting as competitive endogenous RNAs (ceRNAs) that may attenuate host cell miRNA expression, 3. host cell miRNA expression modulating SARS-CoV-2 replication, and 4. SARS-CoV-2-encoded miRNAs silencing the expression of host protein-coding genes. SARS-CoV-2-related miRNAs may be used as diagnostic or prognostic biomarkers for predicting outcomes among patients with SARS-CoV-2 infection. Furthermore, accumulating evidence suggests that dietary polyphenolic compounds may protect against SARS-CoV-2 infection by modulating host cell miRNA expression. These findings have major implications for the future diagnosis and treatment of COVID-19.

Dedicator of cytokinesis protein 2 knockdown ameliorates LPS-induced acute lung injury by modulating Rac1/2 activity.

Dedicator of cytokinesis protein 2 (DOCK2) is a member of the cytoskeletal dynamics protein family, and is ubiquitously expressed in hematopoietic cells according to previous studies. This paper was intended to explore the underlying mechanism that DOCK2 might involve in the progression of acute lung injury (ALI). Following lipopolysaccharide (LPS) induction in the purchased A549 cells, the expression level of DOCK2 was determined and its knockdown was performed by transfection. Subsequently, the viability, inflammation, oxidative stress barrier, and apoptosis of transfected A549 cells were measured to observe the alterations. Inflammation-related and apoptosis-related proteins were measured by western blot analysis. Finally, 8-Chlorophenylthio-cyclic monophosphate (8-CPT), ras-related C3 botulinum toxin substrate (Rac) 1 agonist, was applied to treat cells for investigating the underlying mechanism regarding the role of DOCK2. According to the results, DOCK2 was upregulated in LPS-induced A549 cells. Following the knockdown of DOCK2, the release of inflammatory cytokines was alleviated, accompanied by attenuated oxidative stress, barrier injury, and apoptosis of LPS-induced A549 cells. Nonetheless, this trend was reversed by further treatment of 8-CPT. In summary, DOCK2 knockdown alleviates inflammation, oxidative stress, barrier injury, and apoptosis of LPS-induced A549 cells by associating with Rac1/Rac2. These findings highlighted the therapeutic potential of DOCK2 for the treatment of ALI.

The Perspective of Vitamin D on suPAR-Related AKI in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has claimed the lives of millions of people around the world. Severe vitamin D deficiency can increase the risk of death in people with COVID-19. There is growing evidence that acute kidney injury (AKI) is common in COVID-19 patients and is associated with poorer clinical outcomes. The kidney effects of SARS-CoV-2 are directly mediated by angiotensin 2-converting enzyme (ACE2) receptors. AKI is also caused by indirect causes such as the hypercoagulable state and microvascular thrombosis. The increased release of soluble urokinase-type plasminogen activator receptor (suPAR) from immature myeloid cells reduces plasminogen activation by the competitive inhibition of urokinase-type plasminogen activator, which results in low plasmin levels and a fibrinolytic state in COVID-19. Frequent hypercoagulability in critically ill patients with COVID-19 may exacerbate the severity of thrombosis. Versican expression in proximal tubular cells leads to the proliferation of interstitial fibroblasts through the C3a and suPAR pathways. Vitamin D attenuates the local expression of podocyte uPAR and decreases elevated circulating suPAR levels caused by systemic inflammation. This decrease preserves the function and structure of the glomerular barrier, thereby maintaining renal function. The attenuated hyperinflammatory state reduces complement activation, resulting in lower serum C3a levels. Vitamin D can also protect against COVID-19 by modulating innate and adaptive immunity, increasing ACE2 expression, and inhibiting the renin-angiotensin-aldosterone system. We hypothesized that by reducing suPAR levels, appropriate vitamin D supplementation could prevent the progression and reduce the severity of AKI in COVID-19 patients, although the data available require further elucidation.

Reliability of Sonography-based Volume Computer Aided Diagnosis in the Normal Fetal Heart.

OBJECTIVES: To explore the inter- and intra-observer reliability of Sonography-based Volume Computer Aided Diagnosis (SonoVCAD) in the display of 8 diagnostic planes of fetal echocardiography and to evaluate its efficiency. METHODS: Three-dimensional volume data sets of the 56 normal singleton fetuses were acquired from a 4-chamber view by using a volume probe. After processing the data sets by using SonoVCAD, 8 cardiac diagnostic planes were displayed automatically. Three doctors with different experiences of performing fetal echocardiography evaluated each diagnostic plane and the success rates of 8 diagnostic planes were calculated. Inter-observer and intra-observer reliabilities were estimated by Cohen's kappa statistics. RESULTS: A total of 276 volume data sets acquired from the 56 normal fetuses were used for SonoVCAD analysis and display. The success rate of each diagnostic section was more than 90%, ranging from 90.6% to 99.6%. Among 276 volumes, 81.5% (225/276) of volumes were able to generate all 8 diagnostic views successfully. Moderate to substantial agreement (kappa, 0.509-0.794) was found between 2 less experienced operators. Moderate to near-perfect agreement (kappa, 0.439-0.933) was found between an expert and 2 less experienced sonographers. Intra-observer reliability was substantial to near-perfect (kappa, 0.602-0.903). The efficiency of SonoVCAD was assessed. The expert spent less time than 2 less experienced examiners (P < 0.001) but no significant difference was found between 2 less experienced examiners (P = 0.176). Besides, SonoVCAD consumed significantly less time than 2-dimensional ultrasound (P < 0.001). CONCLUSIONS: SonoVCAD can significantly improve the success rates of 8 diagnostic planes in fetal echocardiography with low operator dependency, good reproducibility and high efficiency.

The Framework for Human Host Immune Responses to Four Types of Parasitic Infections and Relevant Key JAK/STAT Signaling.

The human host immune responses to parasitic infections are complex. They can be categorized into four immunological pathways mounted against four types of parasitic infections. For intracellular protozoa, the eradicable host immunological pathway is TH1 immunity involving macrophages (M1), interferon gamma (IFNγ) CD4 T cells, innate lymphoid cells 1 (NKp44+ ILC1), CD8 T cells (Effector-Memory4, EM4), invariant natural killer T cells 1 (iNKT1) cells, and immunoglobulin G3 (IgG3) B cells. For intracellular protozoa, the tolerable host immunological pathway is TH1-like immunity involving macrophages (M2), interferon gamma (IFNγ)/TGFß CD4 T cells, innate lymphoid cells 1 (NKp44- ILC1), CD8 T cells (EM3), invariant natural killer T 1 (iNKT1) cells, and immunoglobulin A1 (IgA1) B cells. For free-living extracellular protozoa, the eradicable host immunological pathway is TH22 immunity involving neutrophils (N1), interleukin-22 CD4 T cells, innate lymphoid cells 3 (NCR+ ILC3), iNKT17 cells, and IgG2 B cells. For free-living extracellular protozoa, the tolerable host immunological pathway is TH17 immunity involving neutrophils (N2), interleukin-17 CD4 T cells, innate lymphoid cells 3 (NCR- ILC3), iNKT17 cells, and IgA2 B cells. For endoparasites (helminths), the eradicable host immunological pathway is TH2a immunity with inflammatory eosinophils (iEOS), interleukin-5/interleukin-4 CD4 T cells, interleukin-25 induced inflammatory innate lymphoid cells 2 (iILC2), tryptase-positive mast cells (MCt), iNKT2 cells, and IgG4 B cells. For ectoparasites (parasitic insects and arachnids), the eradicable host immunological pathway is TH2b immunity with inflammatory basophils, chymase- and tryptase-positive mast cells (MCct), interleukin-3/interleukin-4 CD4 T cells, interleukin-33 induced nature innate lymphoid cells 2 (nILC2), iNKT2 cells, and immunoglobulin E (IgE) B cells. The tolerable host immunity against ectoparasites and endoparasites is TH9 immunity with regulatory eosinophils, regulatory basophils, interleukin-9 mast cells (MMC9), thymic stromal lymphopoietin induced innate lymphoid cells 2, interleukin-9 CD4 T cells, iNKT2 cells, and IgA2 B cells. In addition, specific transcription factors important for specific immune responses were listed. This JAK/STAT signaling is key to controlling or inducing different immunological pathways. In sum, Tfh is related to STAT5ß, and BCL6 expression. Treg is related to STAT5α, STAT5ß, and FOXP3. TH1 immunity is related to STAT1α, STAT4, and T-bet. TH2a immunity is related to STAT6, STAT1α, GATA1, and GATA3. TH2b immunity is related to STAT6, STAT3, GATA2, and GATA3. TH22 immunity is associated with both STAT3α and AHR. THαß immunity is related to STAT1α, STAT1ß, STAT2, STAT3ß, and ISGF. TH1-like immunity is related to STAT1α, STAT4, STAT5α, and STAT5ß. TH9 immunity is related to STAT6, STAT5α, STAT5ß, and PU.1. TH17 immunity is related to STAT3α, STAT5α, STAT5ß, and RORG. TH3 immunity is related to STAT1α, STAT1ß, STAT2, STAT3ß, STAT5α, STAT5ß, and ISGF. This categorization provides a complete framework of immunological pathways against four types of parasitic infections. This framework as well as relevant JAK/STAT signaling can provide useful knowledge to control allergic hypersensitivities and parasitic infections via development of vaccines or drugs in the near future.

Putative Role of Vitamin D for COVID-19 Vaccination.

Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy.

Analysing Sr isotopes in low-Sr samples such as single insects with inductively coupled plasma tandem mass spectrometry using N2 O as a reaction gas for in-line Rb separation.

RATIONALE: Strontium isotopes are valuable markers of provenance in a range of disciplines. Limited amounts of Sr in low-mass samples such as insects mean that conventional Sr isotope analysis precludes their use for geographic origins in many ecological studies or in applications such as biosecurity. Here we test the viability of using inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) with N2 O as a reaction gas for accurately determining Sr isotopes in insects with Sr < 100 ng. METHODS: Strontium isotopes were determined in solution mode using ICP-MS/MS with 0.14 L/min N2 O as a reaction gas to convert Sr+ into SrO+ for in-line separation of 87 Sr from 87 Rb. The Sr isotope reference standards NIST SRM 987, NIST SRM 1570a and NIST SRM 1547 were used to assess accuracy and reproducibility. Ten insect species collected from the wild as a proof-of-principle application were analysed for Sr concentration and Sr isotopes. RESULTS: Using ICP-MS/MS we show for the first time that internal mass bias correction of 87 Sr16 O/86 Sr16 O based on 88 Sr16 O/86 Sr16 O works to give for NIST SRM 987 a 87 Sr/86 Sr ratio of 0.7101 ± 0.012 (RSD = 0.17%) and for NIST SRM 1570a a 87 Sr/86 Sr ratio of 0.7100 ± 0.009 (RSD = 0.12%), which are within error of the accepted values. The first 87 Sr/86 Sr ratio of NIST SRM 1547 is 0.7596 ± 0.0014. Strontium analyses were run on 0.8 mL of 0.25-0.5 ppb Sr, which equates to 2-4 ng of Sr. Strontium isotope analysis with a precision of >99.8% can be achieved with in-line separation of 87 Sr from 87 Rb at least up to solutions with 25 ppb Rb. CONCLUSIONS: A minimum of 5 mg of insect tissue is required for Sr isotope analysis. This new ICP-MS/MS method enables Sr isotope analysis in single insects, allowing population-scale studies to be feasible and making possible applications with time-critical uses such as biosecurity.

Emerging Role of TRIM Family Proteins in Cardiovascular Disease.

Ubiquitination is one of the basic mechanisms of cell protein homeostasis and degradation and is accomplished by 3 enzymes, E1, E2, and E3. Tripartite motif-containing proteins (TRIMs) constitute the largest subfamily of RING E3 ligases, with >70 current members in humans and mice. These members are involved in multiple biological processes, including growth, differentiation, and apoptosis as well as disease and tumorigenesis. Accumulating evidence has shown that many TRIM proteins are associated with various cardiac processes and pathologies, such as heart development, signal transduction, protein degradation, autophagy mediation, ion channel regulation, congenital heart disease, and cardiomyopathies. In this review, we provide an overview of the TRIM family and discuss its involvement in the regulation of cardiac proteostasis and pathophysiology and its potential therapeutic implications.