bluuebunny/crossref_metadata_2025 huggingface dataset:
Preexisting Oral Anticoagulant Therapy Ameliorates Prognosis in Hospitalized COVID-19 Patients
Authors: Iaccarino Guido , Grassi Guido , Borghi Claudio , Grassi Davide , Mancusi Costantino , Muiesan Maria Lorenza , Salvetti Massimo , Volpe Massimo , Ferri Claudio
Published: May 2021

Objective: Altered coagulation parameters in COVID-19 patients is associated with a poor prognosis. We tested whether COVID-19 patients on chronic oral anticoagulants (cOACs) for thromboembolism prophylaxis could receive protection from developing more severe phenotypes of the disease.

Approach and Results: We searched the database of the SARS-RAS study (Clinicaltrials.gov: NCT04331574), a cross-sectional observational multicenter nationwide survey in Italy designed by the Italian Society of Hypertension. The database counts 2,377 charts of Italian COVID-19 patients in 26 hospitals. We calculated the Charlson comorbidity index (CCI), which is associated with death in COVID-19 patients. In our population (n = 2,377, age 68.2 ± 0.4 years, CCI: 3.04 ± 0.04), we confirm that CCI is associated with increased mortality [OR: 1.756 (1.628-1.894)], admission to intensive care units [ICU; OR: 1.074 (1.017-1.134)], and combined hard events [CHE; OR: 1.277 (1.215-1.342)]. One hundred twenty-five patients were on cOACs (age: 79.3 ± 0.9 years, CCI: 4.35 ± 0.13); despite the higher CCI, cOACs patients presented with a lower risk of admissions to the ICU [OR 0.469 (0.250-0.880)] but not of death [OR: 1.306 (0.78-2.188)] or CHE [OR: 0.843 (0.541-1.312)]. In multivariable logistic regression, cOACs confirmed their protective effect on ICU admission and CHE. The CCI remains the most important risk factor for ICU admission, death, and CHE.

Conclusions: Our data support a mechanism for the continuation of cOAC therapy after hospital admission for those patients who are on chronic treatment. Our preliminary results suggest the prophylactic use of direct cOACs in patients with elevated CCI score at the time of the COVID-19 pandemic even in absence of other risks of thromboembolism.
Machine Learning for Predicting Heart Failure Progression in Hypertrophic Cardiomyopathy
Authors: Fahmy Ahmed S. , Rowin Ethan J. , Manning Warren J. , Maron Martin S. , Nezafat Reza
Published: May 2021

Background: Development of advanced heart failure (HF) symptoms is the most common adverse pathway in hypertrophic cardiomyopathy (HCM) patients. Currently, there is a limited ability to identify HCM patients at risk of HF.

Objectives: In this study, we present a machine learning (ML)-based model to identify individual HCM patients who are at high risk of developing advanced HF symptoms.

Methods: From a consecutive cohort of HCM patients evaluated at the Tufts HCM Institute from 2001 to 2018, we extracted a set of 64 potential risk factors measured at baseline. Only patients with New York Heart Association (NYHA) functional class I/II and LV ejection fraction (LVEF) by echocardiography >35% were included. The study cohort (n = 1,427 patients) was split into three disjoint subsets: development (50%), model selection (10%), and independent validation (40%). The least absolute shrinkage and selection operator was used to select the most influential clinical variables. An ensemble of ML classifiers, including logistic regression, was used to identify patients with high risk of developing a HF outcome. Study outcomes were defined as progression to NYHA class III/IV, drop in LVEF below 35%, septal reduction procedure, and/or heart transplantation.

Results: During a mean follow-up of 4.7 ± 3.7 years, advanced HF occurred in 283 (20% out of 1,427) patients. The model features included patients' sex, NYHA class (I or II), HCM type (i.e., obstructive or not), LV wall thickness, LVEF, presence of HF symptoms (e.g., dyspnea, presyncope), comorbidities (atrial fibrillation, hypertension, mitral regurgitation, and systolic anterior motion), and type of cardiac medications. The developed risk stratification model showed strong differentiation power to identify patients at advanced HF risk in the testing dataset (c-statistics = 0.81; 95% confidence interval [CI]: 0.76, 0.86). The model allowed correct identification of high-risk patients with accuracy 74% (CI: 0.70, 0.78), sensitivity 80% (CI: 0.77, 0.83), and specificity 72% (CI: 0.68, 0.76). The model performance was comparable among different sex and age groups.

Conclusions: A 5-year risk prediction of progressive HF in HCM patients can be accurately estimated using ML analysis of patients' clinical and imaging parameters. A set of 17 clinical and imaging variables were identified as the most important predictors of progressive HF in HCM.
Cardiovascular Impacts on COVID-19 Infected Patients
Authors: Raghavan Somasundaram , Gayathri R. , Kancharla Sudhakar , Kolli Prachetha , Ranjitha J. , Shankar Vijayalakshmi
Published: May 2021

The SARS-CoV-2 virus has taken more than 2 million lives on a global scale. Over 10 million people were confirmed with COVID-19 infection. The well-known spot of primary infection includes the lungs and the respiratory system. Recently it has been reported that the cardiovascular system and coagulation mechanisms were the second major targets of biological system affected due to the viral replication. The replication mechanism of SARS-CoV-2 involves the angiotensin-converting enzyme 2- (ACE2) surface receptors of endothelial cells belonging to various organs which act as the binding site for the viral spike (S) protein of SARS-CoV-2. The COVID-19 virus has been recently listed as a primary risk factor for the following cardiovascular conditions such as pericarditis, myocarditis, arrhythmias, myocardial injury, cardiac arrest, heart failure and coagulation abnormalities in the patients confirmed with COVID-19 viral infection. Direct and indirect type of tissue damage were the two major categories detected with cardiovascular abnormalities. Direct myocardial cell injury and indirect damage to the myocardial cell due to inflammation were clinically reported. Few drugs were clinically administered to regulate the vital biological mechanism along with symptomatic treatment and supportive therapy.
Effect of Stress Interactions on Effective Elasticity and Fracture Parameters in the Damage Zones
Authors: Cao Chenghao , Fu Li-Yun , Fu Bo-Ye , Guo Qiang
Published: May 2021

Elastic interactions between fractures will greatly affect the effective elasticity, which, in turn, will reshape the effective fracture parameters. The disturbance will be more complex in the fault zone due to the complicated fracture distributions. This problem is addressed by the comparison of two types of solutions: one containing the stress interaction while the other one excluding the stress interaction. The gap between the two solutions allows the quantitative estimation of stress interactions on elasticity. Furthermore, based on the orthorhombic assumption for fracture clustering in the damage zone, the effect of stress interaction on the equivalent fracture parameter is estimated. We first characterize the fracture parameters in the fault damage zone considering more realistic distributions of fractures. Then, a series of numerical simulations are conducted to study the effective parameters of the fractured model. Finally, assuming the orthorhombic system of the fracture clustering, we invert the crack density and validate the accuracy of the inversion through the incidence angle seismic velocities. Our numerical results suggest that the size of fractures will determine the dominant type of stress interactions, and thus significantly reshape the effective properties of the models regardless of the spatial distribution of the fracture. Furthermore, the stress interactions tend to underestimate the fracture density for models containing long fractures but generate a relatively satisfactory inverted fracture density for short fractures.
Thyroseq v3, Afirma GSC, and microRNA Panels Versus Previous Molecular Tests in the Preoperative Diagnosis of Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis
Authors: Silaghi Cristina Alina , Lozovanu Vera , Georgescu Carmen Emanuela , Georgescu Raluca Diana , Susman Sergiu , Năsui Bogdana Adriana , Dobrean Anca , Silaghi Horatiu
Published: May 2021

Background

Molecular tests are being used increasingly as an auxiliary diagnostic tool so as to avoid a diagnostic surgery approach for cytologically indeterminate thyroid nodules (ITNs). Previous test versions, Thyroseq v2 and Afirma Gene Expression Classifier (GEC), have proven shortcomings in malignancy detection performance.

Objective

This study aimed to evaluate the diagnostic performance of the established Thyroseq v3, Afirma Gene Sequencing Classifier (GSC), and microRNA-based assays versus prior iterations in ITNs, in light of “rule-in” and “rule-out” concepts. It further analyzed the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) reclassification and Bethesda cytological subtypes on the performance of molecular tests.

Methods

Pubmed, Scopus, and Web of Science were the databases used for the present research, a process that lasted until September 2020. A random-effects bivariate model was used to estimate the summary sensitivity, specificity, positive (PLR) and negative likelihood ratios (NLR), and area under the curve (AUC) for each panel. The conducted sensitivity analyses addressed different Bethesda categories and NIFTP thresholds.

Results

A total of 40 eligible studies were included with 7,831 ITNs from 7,565 patients. Thyroseq v3 showed the best overall performance (AUC 0.95; 95% confidence interval: 0.93–0.97), followed by Afirma GSC (AUC 0.90; 0.87–0.92) and Thyroseq v2 (AUC 0.88; 0.85–0.90). In terms of “rule-out” abilities Thyroseq v3 (NLR 0.02; 95%CI: 0.0–2.69) surpassed Afirma GEC (NLR 0.18; 95%CI: 0.10–0.33). Thyroseq v2 (PLR 3.5; 95%CI: 2.2–5.5) and Thyroseq v3 (PLR 2.8; 95%CI: 1.2–6.3) achieved superior “rule-in” properties compared to Afirma GSC (PLR 1.9; 95%CI: 1.3–2.8). Evidence for Thyroseq v3 seems to have higher quality, notwithstanding the paucity of studies. Both Afirma GEC and Thyroseq v2 performance have been affected by NIFTP reclassification. ThyGenNEXT/ThyraMIR and RosettaGX show prominent preliminary results.

Conclusion

The newly emerged tests, Thyroseq v3 and Afirma GSC, designed for a “rule-in” purpose, have been proved to outperform in abilities to rule out malignancy, thus surpassing previous tests no longer available, Thyroseq 2 and Afirma GEC. However, Thyroseq v2 still ranks as the best rule-in molecular test.

Systematic Review Registration

http://www.crd.york.ac.uk/PROSPERO, identifier CRD42020212531.
Serum Uric Acid Is a Mediator of the Association Between Obesity and Incident Nonalcoholic Fatty Liver Disease: A Prospective Cohort Study
Authors: Zhang Qian , Ma Xiaoqian , Xing Jie , Shi Haiyun , Yang Runkuan , Jiao Yue , Chen Shuohua , Wu Shouling , Zhang Shutian , Sun Xiujing
Published: May 2021

Objective

Obesity has been demonstrated to show a consistent link with the increased possibility of nonalcoholic fatty liver disease (NAFLD). Since both serum uric acid (SUA) and obesity are essential components of metabolic syndrome (MetS), it is uncertain whether the incidence of NAFLD results from serum uric acid, obesity, or other potential factors based on previous studies.

Patients and methods

This study enrolled 16,839 participants with no history of alcohol consumption and no fatty liver disease in 2010. All participants completed a survey which included health and lifestyle questionnaires, and underwent physical examination, ultrasonography, and laboratory examinations of blood samples. After the four-year follow up, 5,104 (30.31%) participants were diagnosed with NAFLD. The associations between SUA, BMI or obesity, and incident NAFLD were assessed by multivariate linear regression, logistic regression analysis, and mediation analysis, respectively.

Results

By adjusting demographic and serum characteristics, linear correlation coefficients between obesity and SUA were 20.26 [95% confidence interval (CI)]: 15.74, 24.77), 13.31 (95% CI: 6.63, 19.99) and 22.21 (95% CI: 16.41, 28.02) in the total population, and in the female and male groups, respectively. The odds ratios were 2.49 (95% CI: 1.61, 3.87) in the total population, 5.71 (95% CI: 2.25, 14.45) in the female group and 1.99 (95% CI: 1.15, 3.45) in the male group for the correlation between obesity and incident NAFLD. The mediation analysis showed that SUA contributed to 10.03%, 0.58%, and 12.54% of obesity-related NAFLD development in the total population, females and males, respectively.

Conclusion

The findings showed mediation linkages of both obesity and SUA with the incident NAFLD. The role of SUA as a mediator constitutes clinical significance that should be recognized and considered.
Hippocampal Glycerol-3-Phosphate Acyltransferases 4 and BDNF in the Progress of Obesity-Induced Depression
Authors: Huang Yin-qiong , Wang Yaofeng , Hu Keyue , Lin Shu , Lin Xia-hong
Published: May 2021

Background

Obesity has been reported to lead to increased incidence of depression. Glycerol-3-phosphate acyltransferases 4 (GPAT4) is involved in triacylglycerol synthesis and plays an important role in the occurrence of obesity. GPAT4 is the only one of GPAT family expressed in the brain. The aim of this study is to investigate if central GPAT4 is associated with obesity-related depression and its underlying mechanism.

Results

A high-fat diet resulted in increased body weight and blood lipid. HFD induced depression like behavior in the force swimming test, tail suspension test and sucrose preference test. HFD significantly up-regulated the expression of GPAT4 in hippocampus, IL-1β, IL-6, TNF-α and NF-κB, accompanied with down-regulation of BDNF expression in hippocampus and ventromedical hypothalamus, which was attributed to AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB).

Conclusion

Our findings suggest that hippocampal GPAT4 may participate in HFD induced depression through AMPK/CREB/BDNF pathway, which provides insights into a clinical target for obesity-associated depression intervention.
Investigation on Rod Bundle CHF Mechanistic Model for DNB and DO Prediction Under Wide Parameter Range
Authors: Liu Wei , Peng Shinian , Jiang Guangming , Liu Yu
Published: May 2021

For a water cooled reactor, the key thermal-hydraulic parameters span a wide range corresponding to different CHF regimes. Under accident conditions, due to the flow regime transition and interchannel mixing effect, the corresponding CHF can transition from the DO to DNB regime. In order to continuously and accurately predict DNB and DO regime CHF under wide parameter range for rod bundle channel, a comprehensive CHF mechanistic model covering the DNB and DO regime CHF prediction is established based on the rod bundle CHF-regime criterion. The DNB regime CHF mechanistic model of superheated liquid layer depletion under turbulence fluctuation bubbles and the mature DO regime CHF mechanistic model are combined to form the comprehensive CHF model. Furthermore, the comprehensive CHF model is assessed by 5 × 5 rod bundle CHF experimental data independently obtained by the Nuclear Power Institute of China (NPIC). The statistical evaluation and parametric trend analysis show that the maximum mean error of P/M is within ±22%, and the local pressure, mass flux, and quality do not have any effects on the average deviations of the predicted flux P from the measured flux M. This indicates that the comprehensive CHF mechanistic model can accurately and continuously predict the DNB and DO regime CHF in the rod bundle channel.
Robust Scheduling for Networked Microgrids Under Uncertainty
Authors: Zhang Kai , Troitzsch Sebastian
Published: May 2021

This paper proposes a framework that facilitates the energy exchange between networked microgrids (MGs) in the electricity market. An alternating direction method of multipliers (ADMM)-based robust optimization algorithm is proposed to derive the optimal energy exchange strategy for the networked MGs considering the uncertainties of the electrical load, intermittent generation, and electricity prices in the external market. The proposed method naturally lends itself to a classical market-clearing problem between two hierarchical levels comprising (i) main-grid-to-MG and (ii) MG-to-MG, aiding in the result interpretation and practical realization. Leveraging from the decentralized organization, the operational autonomy and information privacy of each MG is protected. The proposed framework is tested on a modified 144-node network with 3 MGs. The numerical experiments demonstrate the convergence of the proposed market clearing to the market equilibrium in different grid operational scenarios with different conservatism parameter settings for MG operators.
The Strategy for Constructing the Structure: Pt-O-Ce3+ Applied in Efficient NOx Removal
Authors: Liu Guoquan , Hao Zhifei , Mi Xueyue , Ma Nan , Zhang He , Li Yi , Zhan Sihui
Published: May 2021

Exploring a unique structure with superior catalytic performance has remained a severe challenge in many important catalytic reactions. Here, we reported a phenomenon that CeO2-based catalysts loaded with different Pt precursors showed a significant difference in the performance of the reduction of NO with H2. The supported platinum nitrate [PtCe(N)] exhibited a superior low-temperature catalytic performance than the supported chloroplatinic acid [PtCe(C)]. In a wide operating temperature (125–200°C), more than 80% NOx conversion was achieved over PtCe(N) as well as excellent thermal stability. Various characterizations were used to study the microstructure and chemical electronic states. Results showed the introduction of a low valence state of Pt species into the CeO2 resulted in the rearrangement of charges on the surface of CeO2, accompanied by increasing contents of oxygen vacancies and Ce3+ sites. Furthermore, the X-ray photoelectron spectroscopy (XPS) and Raman spectra confirmed that the divalent Pt atom could substitute Ce atom to form the Pt-O-Ce3+ structure, which was the base unit in the high-performance PtCe(N) catalyst. The tunable catalytic system of the Pt-O-Ce3+ structure provides a strategy for the design of supported metal catalysts and may as a model unit for future studies of many other reactions.
Variation in Community-Level Trophic Niches of Soil Microarthropods With Conversion of Tropical Rainforest Into Plantation Systems as Indicated by Stable Isotopes (15N, 13C)
Authors: Krause Alena , Sandmann Dorothee , Potapov Anton , Ermilov Sergey , Widyastuti Rahayu , Haneda Noor Farikhah , Scheu Stefan , Maraun Mark
Published: May 2021

Land-use change is threatening biodiversity worldwide and is predicted to increase in the next decades, especially in tropical regions. Most studies focused on the response of single or few species to land-use change, only few investigated the response of entire communities. In particular the response of belowground communities to changes in land use received little attention. Oribatid mites (Oribatida, Acari) are among the most abundant soil animals, involved in decomposition processes and nutrient cycling. Oribatid mite species span a wide range of trophic niches and are known to sensitively respond to changes in land use. Here, we investigated shifts in the community-level trophic niche of oribatid mites with the conversion of rainforest into rubber and oil palm plantations. Due to a wider range of resources in more natural ecosystems, we expected the community-level trophic niche to shrink with conversion of rainforest into plantations. As the conversion of rainforest into plantations is associated with reduced availability of litter resources, we expected the average trophic level (indicated by the15N/14N ratio) to be higher and basal resources (indicated by the13C/12C ratio) to shift toward living plant material in rubber and oil palm plantations. Our analysis showed that community-level trophic niches in rainforest and rubber agroforest (“jungle rubber”) were separated from those in monoculture plantation systems, indicating a trophic niche shift with land-use intensification. As hypothesized, oribatid mites shifted their diet toward predation and/or scavenging and toward the plant-based energy channel with transformation of rainforest into plantations. Exceptionally low minimum13C/12C ratios in rubber plantations suggest that certain oribatid mite species in this land-use system use resources not available in the other studied ecosystems. We detected high isotopic uniqueness in oil palm plantations suggesting a low trophic redundancy and thus high vulnerability of trophic functioning in this system in comparison to rainforest. Overall, the results suggest that the conversion of rainforest into plantations is associated with pronounced shifts in community-level trophic niches of mesofauna detritivores with potential major consequences for the functioning of the decomposer system.
Detection of Jaguar (Panthera onca) From Genetic Material in Drinking Water
Authors: Wilcox Taylor M. , Caragiulo Anthony , Dysthe Joseph C. , Franklin Thomas W. , Mason Daniel H. , McKelvey Kevin S. , Zarn Katherine E. , Schwartz Michael K.
Published: May 2021

Jaguar (Panthera onca) are of conservation concern and occur at very low densities in the northern portion of their range in northern Mexico and the southwestern United States. Environmental DNA sampling to detect genetic material from drinking water may be an effective approach for jaguar detection in these arid landscapes. Here we develop a qPCR assay for the detection of jaguar mitochondrial DNA, show that large quantities of DNA (mean 66,820 copies/L) can be found in the drinking water of captive animals, and observe detectable levels of DNA (80 copies/L) in a wild habitat with known jaguar populations. We suggest that environmental DNA sampling may represent a useful, complementary sampling tool for detection of rare jaguars, although effective application would require careful consideration of DNA persistence time in the environment.
Impact of COVID-19 Pandemic on Motorcycle Purchase in Dhaka, Bangladesh
Authors: Zafri Niaz Mahmud , Khan Asif , Jamal Shaila , Alam Bhuiyan Monwar
Published: May 2021

The impacts of COVID-19 on the transportation system have received attention from researchers all over the world. Initial findings reveal that patronage of public transport has gone down, while the use of active transport has increased in general. To the best of our knowledge, no study has focused on the pandemic’s effects on motorcycle mode, let alone in the context of an Asian city. We attempted to fill this void in literature by investigating if COVID-19 has influenced people to purchase motorcycles and determining the factors driving their intentions. The study is based on an online survey of 368 people in Dhaka, the capital of Bangladesh. The study found that around 46% of the respondents were expected to increase travel by motorcycle during the post-lockdown period. About 21% of the respondents were also expected to do the opposite. Around 31% of the respondents planned to purchase a motorcycle by August 2021, and the results indicated that the pandemic has influenced more people to purchase motorcycles compared to the pre-pandemic period. The study further identified factors that influenced the respondents’ plan for purchasing a motorcycle during the post-lockdown period applying the binary logistic regression. Based on the findings of the study, policy measures were proposed for controlling the growth of motorcycle numbers and increasing the use of active transport modes as its alternative, and consequently, helping to achieve sustainable transportation outcomes.
A Genome-Wide Association Study of Novel Genetic Variants Associated With Anthropometric Traits in Koreans
Authors: Cho Hye-Won , Jin Hyun-Seok , Eom Yong-Bin
Published: May 2021

Most previous genome-wide association studies (GWAS) have identified genetic variants associated with anthropometric traits. However, most of the evidence were reported in European populations. Anthropometric traits such as height and body fat distribution are significantly affected by gender and genetic factors. Here we performed GWAS involving 64,193 Koreans to identify the genetic factors associated with anthropometric phenotypes including height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip ratio. We found nine novel single-nucleotide polymorphisms (SNPs) and 59 independent genetic signals in genomic regions that were reported previously. Of the 19 SNPs reported previously, eight genetic variants at RP11-513I15.6 and one genetic variant at the RP11-977G19.10 region and six Asian-specific genetic variants were newly found. We compared our findings with those of previous studies in other populations. Five overlapping genetic regions (PAN2, ANKRD52, RNF41, HGMA1, and C6orf106) had been reported previously but none of the SNPs were independently identified in the current study. Seven of the nine newly found novel loci associated with height in women revealed a statistically significant skeletal expression of quantitative trait loci. Our study provides additional insight into the genetic effects of anthropometric phenotypes in East Asians.
Identification of a Prognostic Signature for Ovarian Cancer Based on the Microenvironment Genes
Authors: Huo Xiao , Sun Hengzi , Liu Shuangwu , Liang Bing , Bai Huimin , Wang Shuzhen , Li Shuhong
Published: May 2021

Background: Ovarian cancer is highly malignant and has a poor prognosis in the advanced stage. Studies have shown that infiltration of tumor microenvironment cells, immune cells and stromal cells has an important impact on the prognosis of cancers. However, the relationship between tumor microenvironment genes and the prognosis of ovarian cancer has not been studied.

Methods: Gene expression profiles and SNP data of ovarian cancer were downloaded from the TCGA database. Cluster analysis, WGCNA analysis and univariate survival analysis were used to identify immune microenvironment genes as prognostic signatures for predicting the survival of ovarian cancer patients. External data were used to evaluate the signature. Moreover, the top five significantly correlated genes were evaluated by immunohistochemical staining of ovarian cancer tissues.

Results: We systematically analyzed the relationship between ovarian cancer and immune metagenes. Immune metagenes expression were associated with prognosis. In total, we identified 10 genes related to both immunity and prognosis in ovarian cancer according to the expression of immune metagenes. These data reveal that high expression of ETV7 (OS, HR = 1.540, 95% CI 1.023–2.390, p = 0.041), GBP4 (OS, HR = 1.834, 95% CI 1.242–3.055, p = 0.004), CXCL9 (OS, HR = 1.613, 95% CI 1.080 –2.471, p = 0.021), CD3E (OS, HR = 1.590, 95% CI 1.049 –2.459, p = 0.031), and TAP1 (OS, HR = 1.766, 95% CI 1.163 –2.723, p = 0.009) are associated with better prognosis in patients with ovarian cancer.

Conclusion: Our study identified 10 immune microenvironment genes related to the prognosis of ovarian cancer. The list of tumor microenvironment-related genes provides new insights into the underlying biological mechanisms driving the tumorigenesis of ovarian cancer.
The Antibody Receptor Fc Gamma Receptor IIIb Induces Calcium Entry via Transient Receptor Potential Melastatin 2 in Human Neutrophils
Authors: Alemán Omar Rafael , Mora Nancy , Rosales Carlos
Published: May 2021

Human neutrophils express two unique antibody receptors for IgG, the FcγRIIa and the FcγRIIIb. FcγRIIa contains an immunoreceptor tyrosine-based activation motif (ITAM) sequence within its cytoplasmic tail, which is important for initiating signaling. In contrast, FcγRIIIb is a glycosylphosphatidylinositol (GPI)-linked receptor with no cytoplasmic tail. Although, the initial signaling mechanism for FcγRIIIb remains unknown, it is clear that both receptors are capable of initiating distinct neutrophil cellular functions. For example, FcγRIIa is known to induce an increase in L-selectin expression and efficient phagocytosis, while FcγRIIIb does not promote these responses. In contrast, FcγRIIIb has been reported to induce actin polymerization, activation of β1 integrins, and formation of neutrophils extracellular traps (NET) much more efficiently than FcγRIIa. Another function where these receptors seem to act differently is the increase of cytoplasmic calcium concentration. It has been known for a long time that FcγRIIa induces production of inositol triphosphate (IP3) to release calcium from intracellular stores, while FcγRIIIb does not use this phospholipid. Thus, the mechanism for FcγRIIIb-mediated calcium rise remains unknown. Transient Receptor Potential Melastatin 2 (TRPM2) is a calcium permeable channel expressed in many cell types including vascular smooth cells, endothelial cells and leukocytes. TRPM2 can be activated by protein kinase C (PKC) and by oxidative stress. Because we previously found that FcγRIIIb stimulation leading to NET formation involves PKC activation and reactive oxygen species (ROS) production, in this report we explored whether TRPM2 is activatedviaFcγRIIIb and mediates calcium rise in human neutrophils. Calcium rise was monitored after Fcγ receptors were stimulated by specific monoclonal antibodies in Fura-2-loaded neutrophils. The bacterial peptide fMLF and FcγRIIa induced a calcium rise coming initially from internal pools. In contrast, FcγRIIIb caused a calcium rise by inducing calcium entry from the extracellular medium. In addition, in the presence of 2-aminoethoxydiphenyl borate (2-APB) or of clotrimazole, two inhibitors of TRPM2, FcγRIIIb-induced calcium rise was blocked. fMLF- or FcγRIIa-induced calcium rise was not affected by these inhibitors. These data suggest for the first time that FcγRIIIb aggregation activates TRPM2, to induce an increase in cytoplasmic calcium concentration through calcium internalization in human neutrophils.
A 10-Day-Old Murine Model of Coxsackievirus A6 Infection for the Evaluation of Vaccines and Antiviral Drugs
Authors: Jiang Zaixue , Zhang Yaozhong , Lin Huayuan , Cheng Qingqiu , Lu Xiaomei , Liu Wenkuan , Zhou Rong , Zhong Baimao , Tian Xingui
Published: May 2021

Coxsackievirus A6 (CVA6) is recognized as a major enterovirus type that can cause severe hand, foot, and mouth disease and spread widely among children. Vaccines and antiviral drugs may be developed more effectively based on a stable and easy-to-operate CVA6 mouse infection model. In this study, a wild CVA6-W strain was sub-cultured in newborn mice of different ages (in days), for adaptation. Therefore, a CVA6-A mouse-adapted strain capable of stably infecting the mice was generated, and a fatal model was built. As the result indicated, CVA6-A could infect the 10-day-old mice to generate higher levels of IFN-γ, IL-6, and IL-10. The mice infected with CVA6-A were treated with IFN-α1b at a higher dose, with complete protection. Based on this strain, an animal model with active immunization was built to evaluate antiviral protection by active immunization. The three-day-old mice were pre-immunized with inactivated CVA6 thereby generating IgM and IgG antibodies within 7 days that enabled complete protection of the pre-immunized mice following the CVA6 virus challenge. There were eight mutations in the genome of CVA6-A than in that of CVA6-W, possibly attributed to the virulence of CVA6 in mice. Briefly, the CVA6 infection model of the 10-day-old mice built herein, may serve as an applicable preclinical evaluation model for CVA6 antiviral drugs and vaccine study.
A Comprehensive Review on Crustaceans’ Immune System With a Focus on Freshwater Crayfish in Relation to Crayfish Plague Disease
Authors: Bouallegui Younes
Published: May 2021

Freshwater crayfish immunity has received great attention due to the need for urgent conservation. This concern has increased the understanding of the cellular and humoral defense systems, although the regulatory mechanisms involved in these processes need updating. There are, however, aspects of the immune response that require clarification and integration. The particular issues addressed in this review include an overall description of the oomycete Aphanomyces astaci, the causative agent of the pandemic plague disease, which affects freshwater crayfish, and an overview of crustaceans’ immunity with a focus on freshwater crayfish. It includes a classification system of hemocyte sub-types, the molecular factors involved in hematopoiesis and the differential role of the hemocyte subpopulations in cell-mediated responses, including hemocyte infiltration, inflammation, encapsulation and the link with the extracellular trap cell death pathway (ETosis). In addition, other topics discussed include the identity and functions of hyaline cells, the generation of neoplasia, and the emerging topic of the role of sessile hemocytes in peripheral immunity. Finally, attention is paid to the molecular execution of the immune response, from recognition by the pattern recognition receptors (PRRs), the role of the signaling network in propagating and maintaining the immune signals, to the effector elements such as the putative function of the Down syndrome adhesion molecules (Dscam) in innate immune memory.
A Thioester-Containing Protein Controls Dengue Virus Infection in Aedes aegypti Through Modulating Immune Response
Authors: Weng Shih-Che , Li Hsing-Han , Li Jian-Chiuan , Liu Wei-Liang , Chen Chun-Hong , Shiao Shin-Hong
Published: May 2021

Complement-like proteins in arthropods defend against invading pathogens in the early phases of infection. Thioester-containing proteins (TEPs), which exhibit high similarity to mammalian complement C3, are thought to play a key role in the innate immunity of arthropods. We identified and characterized anti-dengue virus (DENV) host factors, in particular complement-like proteins, in the mosquito Aedes aegypti. Our results indicate that TEP1 limits DENV infection in Ae. aegypti. We showed that TEP1 transcription is highly induced in mosquitoes following DENV infection. Silencing TEP1 resulted in the up-regulation of viral RNA and proteins. In addition, the production of infectious virus particles increased in the absence of TEP1. We generated a transgenic mosquito line with a TEP1 loss-of-function phenotype under a blood meal-inducible promoter. We showed that viral protein and titers increased in transgenic mosquitoes after an infectious blood meal. Interestingly, expression of transcription factor Rel2 and certain anti-microbial peptides (AMPs) were inhibited in transgenic mosquitoes. Overall, our results suggest that TEP1 regulates the immune response and consequently controls the replication of dengue virus in mosquitoes. This finding provides new insight into the molecular mechanisms of mosquito host factors in the regulation of DENV replication.
Sildenafil Alleviates Murine Experimental Autoimmune Encephalomyelitis by Triggering Autophagy in the Spinal Cord
Authors: Duarte-Silva Eduardo , Meiry da Rocha Araújo Shyrlene , Oliveira Wilma Helena , Lós Deniele Bezerra , Bonfanti Amanda Pires , Peron Gabriela , de Lima Thomaz Livia , Verinaud Liana , Peixoto Christina Alves
Published: May 2021

Multiple Sclerosis (MS) is a neuroinflammatory and chronic Central Nervous System (CNS) disease that affects millions of people worldwide. The search for more promising drugs for the treatment of MS has led to studies on Sildenafil, a phosphodiesterase type 5 Inhibitor (PDE5I) that has been shown to possess neuroprotective effects in the Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. We have previously shown that Sildenafil improves the clinical score of EAE mice via modulation of apoptotic pathways, but other signaling pathways were not previously covered. Therefore, the aim of the present study was to further investigate the effects of Sildenafil treatment on autophagy and nitrosative stress signaling pathways in EAE. 24 female C57BL/6 mice were divided into the following groups: (A) Control - received only water; (B) EAE - EAE untreated mice; (C) SILD - EAE mice treated with 25mg/kg of Sildenafil s.c. The results showed that EAE mice presented a pro-nitrosative profile characterized by high tissue nitrite levels, lowered levels of p-eNOS and high levels of iNOS. Furthermore, decreased levels of LC3, beclin-1 and ATG5, suggests impaired autophagy, and decreased levels of AMPK in the spinal cord were also detected in EAE mice. Surprisingly, treatment with Sildenafil inhibited nitrosative stress and augmented the levels of LC3, beclin-1, ATG5, p-CREB and BDNF and decreased mTOR levels, as well as augmented p-AMPK. In conclusion, we propose that Sildenafil alleviates EAE by activating autophagy via the eNOS-NO-AMPK-mTOR-LC3-beclin1-ATG5 and eNOS-NO-AMPK-mTOR-CREB-BDNF pathways in the spinal cord.
Gender May Influence the Immunosuppressive Actions of Prednisone in Young Patients With Inflammatory Bowel Disease
Authors: Lucafò Marianna , Bramuzzo Matteo , Selvestrel Davide , Da Lozzo Prisca , Decorti Giuliana , Stocco Gabriele
Published: May 2021

Although the use of glucocorticoids (GC) is well established, the therapeutic response to these agents often shows important interindividual differences, in particular among young patients with inflammatory bowel diseases (IBD). Currently, GC resistance or dependence cannot be predicted by clinical or laboratory findings. The aim of this study was to investigate the association of gender and age with GC efficacy and with the expression of Glucocorticoid-Induced Leucine Zipper (GILZ). One hundred thirty patients (mean age at enrolment 12.6 years, 53 Crohn’s disease, 70 males) were enrolled in this retrospective study. IBD patients with active disease despite prednisone at a daily dose of up to 2 mg/kg over a period of 4 weeks were defined as steroid resistant. Patients who initially responded but relapsed upon dose reduction were considered steroid-dependent. Total RNA was extracted from biopsies of 14 patients (9 males) and the levels of GILZ mRNA were evaluated by real-time PCR. Association between clinical response to prednisone and the considered demographic variables was evaluated using logistic regression models. After 4 weeks of treatment, 112 patients were responders to prednisone and 18 were resistant; at this time-point, resistant patients were older than responders (p=0.032). After 12 weeks, 42, 71 and 12 patients were sensitive, dependent and resistant respectively; at this time-point, females were more prone than males to develop prednisone dependence vs a good response (p=0.028) while age had no effect. Age was associated with response both at 4 and 12 weeks in the subgroups of females: resistant patients were older than sensitive ones at 4 weeks (p=0.02). Likewise, at 12 weeks of therapy, dependent patients resulted older than sensitive ones (p=0.05). No association of age with prednisone response was found in males. In a subgroup of 14 patients (5 females), GILZ mRNA expression in intestinal biopsies was higher in males (p=0.0031). Patients with unfavorable response (7) presented lower GILZ expression at disease onset in comparison to the responder group (p=0.017). Older females with IBD have a higher incidence of prednisone unfavorable response and reduced intestinal expression of the GC pharmacodynamic marker GILZ.
Immunotherapy for Glioblastoma: Current Progress and Challenges
Authors: Yu Miranda W. , Quail Daniela F.
Published: May 2021

Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.
Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer
Authors: Chen Qiong-Yuan , Chen Yu-Xin , Han Qiu-Yue , Zhang Jiang-Gang , Zhou Wen-Jun , Zhang Xia , Ye Yao-Han , Yan Wei-Hua , Lin Aifen
Published: May 2021

Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.
STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development
Authors: Filderman Jessica N. , Appleman Mark , Chelvanambi Manoj , Taylor Jennifer L. , Storkus Walter J.
Published: May 2021

Tertiary lymphoid structures (TLS), also known as ectopic lymphoid structures (ELS) or tertiary lymphoid organs (TLO), represent a unique subset of lymphoid tissues noted for their architectural similarity to lymph nodes, but which conditionally form in peripheral tissues in a milieu of sustained inflammation. TLS serve as regional sites for induction and expansion of the host B and T cell repertoires via an operational paradigm involving mature dendritic cells (DC) and specialized endothelial cells (i.e. high endothelial venules; HEV) in a process directed by TLS-associated cytokines and chemokines. Recent clinical correlations have been reported for the presence of TLS within tumor biopsies with overall patient survival and responsiveness to interventional immunotherapy. Hence, therapeutic strategies to conditionally reinforce TLS formation within the tumor microenvironment (TME) via the targeting of DC, vascular endothelial cells (VEC) and local cytokine/chemokine profiles are actively being developed and tested in translational tumor models and early phase clinical trials. In this regard, a subset of agents that promote tumor vascular normalization (VN) have been observed to coordinately support the development of a pro-inflammatory TME, maturation of DC and VEC, local production of TLS-inducing cytokines and chemokines, and therapeutic TLS formation. This mini-review will focus on STING agonists, which were originally developed as anti-angiogenic agents, but which have recently been shown to be effective in promoting VN and TLS formation within the therapeutic TME. Future application of these drugs in combination immunotherapy approaches for greater therapeutic efficacy is further discussed.
Sediment Provenance in the Baker-Martínez Fjord System (Chile, 48°S) Indicated by Magnetic Susceptibility and Inorganic Geochemistry
Authors: Troch Matthias , Bertrand Sebastien , Amann Benjamin , Liu Dawei , Placencia Juan A. , Lange Carina B.
Published: May 2021

Fjord sediments are increasingly used as high-resolution archives of climate and environmental change, including variations in glacier mass balance and terrestrial hydrology. To accurately interpret such sediment records, it is crucial to comprehend sediment transport processes and determine sediment provenance. With this in mind, our main objective is to identify cost-effective parameters that can be used to reconstruct relative variations in the origin of sediments deposited in the Baker-Martínez fjord system, which is located between the Northern (NPI) and Southern (SPI) Patagonian Icefields. We focus on estimating the proportions of sediment derived from each icefield, taking advantage of the clearly distinct lithologies that underlie NPI (Patagonian Batholith) and SPI (Eastern Andean Metamorphic Complex) glaciers. The magnetic susceptibility and inorganic geochemistry of 21 surface sediment samples collected along the fjord system and that of suspended sediment samples from the four main rivers that discharge at its heads were investigated. Results indicate that sediments derived from the NPI are characterized by higher magnetic susceptibility and log(Ti/Al) values than those from the SPI, reflecting the mafic nature of the batholith. In fjords that receive contributions from both the NPI and SPI, magnetic susceptibility and log(Ti/Al) primarily reflect sediment provenance. In fjords receiving sediment from only one icefield, however, these parameters are positively correlated with grain size and reflect the progressive settling of particles from the surficial plume. Our results suggest that magnetic susceptibility and log(Ti/Al) can be used to reconstruct sediment provenance within the Baker-Martínez fjord system, but that only log(Ti/Al) can provide quantitative estimates of the proportions of sediment derived from each icefield. Ultimately, applying these provenance indicators to long sediment cores from the Baker-Martínez fjord system could allow reconstructing relative variations in sediment input from each icefield, which may in turn be interpreted as changes in river discharge and/or glacier mass balance.