bluuebunny/crossref_metadata_2025 huggingface dataset:
Unraveling the Immunopathogenesis and Genetic Variants in Vasculitis Toward Development of Personalized Medicine
Authors: Yap Bryan Ju Min , Lai-Foenander Ashley Sean , Goh Bey Hing , Ong Yong Sze , Duangjai Acharaporn , Saokaew Surasak , Chua Caroline Lin Lin , Phisalprapa Pochamana , Yap Wei Hsum
Published: September 2021

Leukocytoclastic vasculitis (LCV) is a systemic autoimmune disease characterized by the inflammation of the vascular endothelium. Cutaneous small vessel vasculitis (CSVV) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are two examples of LCV. Advancements in genomic technologies have identified risk haplotypes, genetic variants, susceptibility loci and pathways that are associated with vasculitis immunopathogenesis. The discovery of these genetic factors and their corresponding cellular signaling aberrations have enabled the development and use of novel therapeutic strategies for vasculitis. Personalized medicine aims to provide targeted therapies to individuals who show poor response to conventional interventions. For example, monoclonal antibody therapies have shown remarkable efficacy in achieving disease remission. Here, we discuss pathways involved in disease pathogenesis and the underlying genetic associations in different populations worldwide. Understanding the immunopathogenic pathways in vasculitis and identifying associated genetic variations will facilitate the development of novel and targeted personalized therapies for patients.
Marine Natural Products and Coronary Artery Disease
Authors: Liang Bo , Cai Xin-Yi , Gu Ning
Published: September 2021

Coronary artery disease is the major cause of mortality worldwide, especially in low- and middle-income earners. To not only reduce angina symptoms and exercise-induced ischemia but also prevent cardiovascular events, pharmacological intervention strategies, including antiplatelet drugs, anticoagulant drugs, statins, and other lipid-lowering drugs, and renin–angiotensin–aldosterone system blockers, are conducted. However, the existing drugs for coronary artery disease are incomprehensive and have some adverse reactions. Thus, it is necessary to look for new drug research and development. Marine natural products have been considered a valuable source for drug discovery because of their chemical diversity and biological activities. The experiments and investigations indicated that several marine natural products, such as organic small molecules, polysaccharides, proteins, and bioactive peptides, and lipids were effective for treating coronary artery disease. Here, we particularly discussed the functions and mechanisms of active substances in coronary artery disease, including antiplatelet, anticoagulant, lipid-lowering, anti-inflammatory, and antioxidant activities.
Groundwater Drought and Cycles in Xuchang City, China
Authors: Huang Jia , Cao Lianhai , Yu Furong , Liu Xiaobo , Wang Lei
Published: September 2021

The urban groundwater system is complex and affected by the interaction of natural and human factors. Groundwater scarcity can no longer reflect this complex situation, and the concept of groundwater drought can better interpret this situation. The groundwater drought cycle is the time interval in which groundwater droughts occur repeatedly and twice in a row. The study of the groundwater drought cycle can more comprehensively grasp the development characteristics of the groundwater drought, which is of great importance for the development, utilization, and protection of groundwater. This study used monthly observation data from seven groundwater wells in Xuchang, China, in the period 1980–2018. We applied the Kolmogorov–Smirnov test to select the best fitting distribution function and constructed a Standardized Groundwater Index (SGI). We analyzed groundwater drought at different time scales and used Morlet’s continuous complex wavelet transform to analyze the groundwater drought cycles. The following results were obtained: 1) the maximum intensity of groundwater drought in the seven observation wells ranged from 104.40 to 187.10. Well-3# has the most severe groundwater drought; 2) the drought years of well-5# were concentrated in 1984–1987 and 2003–2012 and those in the other wells in 1994–1999 and 2014–2018; and 3) the groundwater drought cycles in the seven observation wells were 97–120 months, and the average period is about 110 months. The cycle length had the following order: well-7# > well-4# > well-5# > well-2# > well-1# > well-3# > well-6. Therefore, Morlet wavelet transform analysis can be used to study the groundwater drought cycles and can be more intuitive in understanding the development of regional groundwater droughts. In addition, through the study of the Xuchang groundwater drought and its cycle, the groundwater drought in Xuchang city has been revealed, which can help local relevant departments to provide technical support and a scientific basis for the development, utilization, and protection of groundwater in the region.
A Statistical Hydrological Model for Yangtze River Watershed Based on Stepwise Cluster Analysis
Authors: Wang Feng , Huang Guohe , Li Yongping , Xu Jinliang , Wang Guoqing , Zhang Jianyun , Duan Ruixin , Ren Jiayan
Published: September 2021

Streamflow prediction is one of the most important topics in operational hydrology. The responses of runoffs are different among watersheds due to the diversity of climatic conditions as well as watershed characteristics. In this study, a stepwise cluster analysis hydrological (SCAH) model is developed to reveal the nonlinear and dynamic rainfall-runoff relationship. The proposed approach is applied to predict the runoffs with regional climatic conditions in Yichang station, Hankou station, and Datong station over the Yangtze River Watershed, China. The main conclusions are: 1) the performances of SCAH in both deterministic and probabilistic modeling are notable.; 2) the SCAH is insensitive to the parameter p in SCAH with robust cluster-tree structure; 3) in terms of the case study in the Yangtze River watershed, it can be inferred that the water resource in the lower reaches of the Yangtze River is seriously affected by incoming water from the upper reaches according to the strong correlations. This study has indicated that the developed statistical hydrological model SCAH approach can characterize such hydrological processes complicated with nonlinear and dynamic relationships, and provide satisfactory predictions. Flexible data requirements, quick calibration, and reliable performances make SCAH an appealing tool in revealing rainfall-runoff relationships.
Waveform Decontamination for Improving Satellite Radar Altimeter Data Over Nearshore Area: Upgraded Algorithm and Validation
Authors: Wang Haihong , Huang Zhengkai
Published: September 2021

One of the thorniest problems in altimetry community is retrieving accurate coastal sea surface height, especially in the last several kilometers offshore. It is confirmed in previous studies that decontaminating waveforms is beneficial to improve the quality of coastal SSHs. In this article, we proposed an upgraded strategy for waveform decontamination, including a novel realignment algorithm and gate-wise outlier detector. We validated the new strategy in four test regions using Jason-2 altimeter data. In the validation process, we compared retracked SSHs by 16 retrackers, which include retrackers provided in SGDR (Sensor Geophysical Data Record), ALES (Adaptive Leading Edge Subwaveform), and PISTACH (Prototype Innovant de Système de Traitement pour les Applications Côtières et l’Hydrologie) products. Comparison results verified that retracking the waveforms decontaminated using our new method can greatly improve the SSHs in the coastal region. The 20% threshold retracker (DW-TR20) and the ICE1 retracker (DW-ICE1) based on the decontaminated waveforms outperform other retrackers, especially in 0–4 km zone offshore. DW-TR20 and DW-ICE1 can provide robust SSHs with a consistent accuracy in 0–20 km coastal band and a high correlation (>0.9) with nearby gauge data. To conclude, the upgraded waveform decontamination strategy provides a promising solution for coastal altimetry, which makes it possible to extend reliable observations to the last several kilometers offshore.
Electrical Modelling of In-Vivo Impedance Spectroscopy of Nicotiana tabacum Plants
Authors: Bar-On Lee , Garlando Umberto , Sophocleous Marios , Jog Aakash , Motto Ros Paolo , Sade Nir , Avni Adi , Shacham-Diamand Yosi , Demarchi Danilo
Published: September 2021

Electrical impedance spectroscopy has been suggested as a sensing method for plants. Here, a theoretical approach for electrical conduction via the plant stem is presented and validated, linking its living electrical characteristics to its internal structure. An electrical model for the alternating current conduction and the associated impedance in a live plant stem is presented. The model accounts for biological and geometrical attributes. It uses the electrically prevalent coupled transmission line model approach for a simplified description of the complicated vessel structure. It considers the electrode coupling to the plant stem (either Galvanic or Faradic), and accounts for the different interactions of the setup. Then the model is simplified using the lumped element approach. The model is then validated using a four-point probe impedance spectroscopy method, where the probes are galvanically coupled to the stem of Nicotiana tabacum plants. The electrical impedance data was collected continuously and the results exhibit an excellent fitting to the theoretical model, with a fitting error of less than 1.5% for data collected on various days and plants. A parametric evaluation of the fitting corresponds to the proposed physically based model, therefore providing a baseline for future plant sensor design.
Identification of mRNA Prognostic Markers for TGCT by Integration of Co-Expression and CeRNA Network
Authors: Zhu Fang , Liu Zhizhong , Zhou Qianyin , Fan Jingyu , Zhou Dai , Xing Liu , Bo Hao , Tang Le , Fan Liqing
Published: September 2021

Testicular germ cell tumor (TGCT) is the most common malignant tumor in young men and is associated with poor prognosis. We assessed the RNA expression profiles of 13 TGCT tissues and 4 adjacent normal tissues by transcriptome sequencing to identify novel prognostic biomarkers. We detected several differentially expressed mRNAs in TGCT that were functionally annotated by GO and KEGG enrichment analyses to tumorigenesis-related processes such as immunity and chemotherapeutic resistance. An mRNA-lncRNA-miRNA regulatory network was constructed using RNA-Seq data and public databases, and integrated with TCGA database to develop a prediction model for metastasis and recurrence. Finally, GRK4, PCYT2 and RGSL1 were identified as predictive markers of survival and therapeutic response. In conclusion, we found several potential predictors for TGCT prognosis and immunotherapeutic response by ceRNA network analysis.
Modeling the Relationship Between Economic Complexity and Environmental Degradation: Evidence From Top Seven Economic Complexity Countries
Authors: Martins José Moleiro , Adebayo Tomiwa Sunday , Mata Mário Nuno , Oladipupo Seun Damola , Adeshola Ibrahim , Ahmed Zahoor , Correia Anabela Batista
Published: September 2021

The continuous growth in CO2 emissions of nations around the globe has made achieving the aim of sustainable development extremely challenging. Therefore, the current research assesses the connection between CO2 emissions and economic complexity in the top 7 economic complexity countries while taking into account the role of economic growth, renewable energy consumption, and globalization for the period between 1993 and 2018. The research aims to answer the following questions: 1) What is the association between CO2 and the regressors in the long-run? 2) What are the effects of renewable energy consumption, economic growth, economic complexity, and globalization on CO2 emissions? The research utilized the CS-ARDL, CCEMG and panel causality approaches to investigate these interconnections. The empirical outcomes revealed that economic growth and economic complexity increase CO2 emissions while renewable energy consumption and globalization mitigate CO2 emissions. The outcomes of the causality test revealed a feedback causal connection between economic growth and CO2, while a unidirectional causality was established from economic complexity, globalization and renewable energy consumption to CO2 emissions in the top 7 economic complexity countries.
In a Neotropical Periurban Park, Fruit Consumption by Birds Seems to Be a Random Process
Authors: Teodosio-Faustino Issaac Azrrael , Chávez-González Edgar , Ruelas Inzunza Ernesto
Published: September 2021

Frugivory interactions between birds and fruit-bearing plants are shaped by the abundance of its interacting species, their temporal overlap, the matching of their morphologies, as well as fruit and seed characteristics. Our study evaluates the role of seven factors of fruits and plants in determining the frequency of whole-fruit consumption by birds. We studied the frugivory network of a Neotropical periurban park in Xalapa, Veracruz, Mexico, and quantified relative abundance and phenology of birds and fruit, as well as fruit morphology, chromatic and achromatic contrast, and nutritional content. Using a maximum likelihood approach, we compared the observed interaction network with 62 single- and multiple-variable probabilistic models. Our network is composed of 11 plants and 17 birds involved in 81 frugivory interactions. This network is nested, modular, and relatively specialized. However, the frequency of pairwise interactions is not explained by the variables examined in our probabilistic models and found the null model has the best performance. This indicates that no single predictor or combination of them is better at explaining the observed frequency of pairwise interactions than the null model. The subsequent four top-ranking models, with ΔAIC values < 100, are single-variable ones: carbohydrate content, lipid content, chromatic contrast, and morphology. Two- and three-variable models show the poorest fit to observed data. The lack of a deterministic pattern does not support any of our predictions nor neutral- or niche-based processes shaping the observed pattern of fruit consumption in our interaction network. It may also mean that fruit consumption by birds in this periurban park is a random process. Although our study failed to find a pattern, our work exemplifies how investigations done in urban settings, poor in species and interactions, can help us understand the role of disturbance in the organization of frugivory networks and the processes governing their structure.
Unraveling the Hidden Diversity of the Native White Claw Crayfish in the Iberian Peninsula
Authors: Martín-Torrijos Laura , Buckley David , Doadrio Ignacio , Machordom Annie , Diéguez-Uribeondo Javier
Published: September 2021

Several European freshwater crayfish species are currently included in one of the IUCN Red list categories. In the Iberian Peninsula, the native Austropotamobius pallipes species complex (the white clawed crayfish, WCC) has experienced a drastic decline since 1973. Implementing conservation management strategies for this species requires a better understanding of the patterns and structure of its genetic diversity. In this study, we assessed the levels and patterns of genetic variation in 71 populations along the whole distributional range of the WCC in the Iberian Peninsula. The two mitochondrial markers analyzed (Cytochrome Oxidase subunit I and 16S rRNA genes) indicated high levels of genetic diversity, which are significantly geographically structured in three main genetic groups, two corresponding to Northern and one to Central-Eastern and the westernmost Iberian Peninsula. The diversity found included new private haplotypes, and revealed the potential effect of paleogeographic barriers and last glaciations in the population structure observed. Current conservation and management programs for the WCC in the Iberian Peninsula should consider these three phylogeographic groups as essential management units in order to preserve the remaining genetic diversity in the species.
Genetic Link Determining the Maternal-Fetal Circulation of Vitamin D
Authors: Sampathkumar Aparna , Tan Karen M. , Chen Li , Chong Mary F. F. , Yap Fabian , Godfrey Keith M. , Chong Yap Seng , Gluckman Peter D. , Ramasamy Adaikalavan , Karnani Neerja
Published: September 2021

Vitamin D is an essential micronutrient whose demand is heightened during pregnancy to support the growth of the fetus. Furthermore, the fetus does not produce vitamin D and hence relies exclusively on the supply of maternal vitamin D through the placenta. Vitamin D inadequacy is linked with pregnancy complications and adverse infant outcomes. Hence, early predictive markers of vitamin D inadequacy such as genetic vulnerability are important to both mother and offspring. In this multi-ethnic Asian birth cohort study, we report the first genome-wide association analysis (GWAS) of maternal and fetal vitamin D in circulation. For this, 25-hydroxyvitamin D (25OHD) was measured in the antenatal blood of mothers during mid gestation (n=942), and the cord blood of their offspring at birth (n=812). Around ~7 million single nucleotide polymorphisms (SNPs) were regressed against 25OHD concentrations to identify genetic risk variants. About 41% of mothers had inadequate 25OHD (≤75nmol/L) during pregnancy. Antenatal 25OHD was associated with ethnicity [Malay (Β=−22.32nmol/L, p=2.3×10−26); Indian (Β=−21.85, p=3.1×10−21); reference Chinese], age (Β=0.47/year, p=0.0058), and supplement intake (Β=16.47, p=2.4×10−13). Cord blood 25OHD highly correlated with antenatal vitamin D (r=0.75) and was associated with ethnicity [Malay (Β=−4.44, p=2.2×10−7); Indian (Β=−1.99, p=0.038); reference Chinese]. GWAS analysis identified rs4588, a missense variant in the group-specific component (GC) gene encoding vitamin D binding protein (VDBP), and its defining haplotype, as a risk factor for low antenatal (Β=−8.56/T-allele, p=1.0×10−9) and cord blood vitamin D (Β=−3.22/T-allele, p=1.0×10−8) in all three ethnicities. We also discovered a novel association in a SNP downstream of CYP2J2 (rs10789082), a gene involved in 25-hydroxylation of vitamin D, with vitamin D in pregnant women (Β=−7.68/G-allele, p=1.5×10−8), but not their offspring. As the prevention and early detection of suboptimal vitamin D levels are of profound importance to both mother and offspring’s health, the genetic risk variants identified in this study allow risk assessment and precision in early intervention of vitamin D deficiency.
Novel Hemizygous Mutations of TEX11 Cause Meiotic Arrest and Non-obstructive Azoospermia in Chinese Han Population
Authors: Ji Zhiyong , Yao Chencheng , Yang Chao , Huang Chuan , Zhao Liangyu , Han Xia , Zhu Zijue , Zhi Erlei , Liu Nachuan , Zhou Zhi , Li Zheng
Published: September 2021

Testis-expressed gene 11 (TEX11) mutation has been associated with non-obstructive azoospermia (NOA) and meiotic arrest. An analogous mutation of TEX11 in the mouse impairs meiosis and can be rescued by in vitro expansion of SSCs and gene therapy. However, a lack of genetic screening of a large cohort of Asian patients (including pedigree analysis) and proper functional evaluation limit the clinical application of TEX11 mutation screening. Thus, we performed whole-exome sequencing (WES) in 479 patients with NOA and identified three novel mutations (two splicing mutations and one missense mutation) in TEX11 in three pairs of siblings from three families and four novel pathogenic mutations (three frameshift mutations and a non-sense mutation) of TEX11 in four sporadic NOA-affected cases. Novel variants among family members were segregated by disease phenotype, and all the seven mutations were predicted to be pathogenic. Histological analysis showed that three patients with TEX11 mutations underwent meiotic arrest. The four mutations that resulted in protein truncations and defective meiosis-specific sporulation domain SPO22 were validated by Western blot. In total, we find seven of 479 patients of NOA (1.5%) carrying TEX11 mutations. Our study expands the knowledge of mutations of TEX11 gene in Asian patients with NOA. The high prevalence and X-linked inherited mode indicated that TEX11 might be included in genetic screening panels for the clinical evaluation of patients with NOA.
Cohesin Core Complex Gene Dosage Contributes to Germinal Center Derived Lymphoma Phenotypes and Outcomes
Authors: Rivas Martin A. , Durmaz Ceyda , Kloetgen Andreas , Chin Cristopher R. , Chen Zhengming , Bhinder Bhavneet , Koren Amnon , Viny Aaron D. , Scharer Christopher D. , Boss Jeremy M. , Elemento Olivier , Mason Christopher E. , Melnick Ari M.
Published: September 2021

The cohesin complex plays critical roles in genomic stability and gene expression through effects on 3D architecture. Cohesin core subunit genes are mutated across a wide cross-section of cancers, but not in germinal center (GC) derived lymphomas. In spite of this, haploinsufficiency of cohesin ATPase subunit Smc3 was shown to contribute to malignant transformation of GC B-cells in mice. Herein we explored potential mechanisms and clinical relevance of Smc3 deficiency in GC lymphomagenesis. Transcriptional profiling of Smc3 haploinsufficient murine lymphomas revealed downregulation of genes repressed by loss of epigenetic tumor suppressors Tet2 and Kmt2d. Profiling 3D chromosomal interactions in lymphomas revealed impaired enhancer-promoter interactions affecting genes like Tet2, which was aberrantly downregulated in Smc3 deficient lymphomas. Tet2 plays important roles in B-cell exit from the GC reaction, and single cell RNA-seq profiles and phenotypic trajectory analysis in Smc3 mutant mice revealed a specific defect in commitment to the final steps of plasma cell differentiation. Although Smc3 deficiency resulted in structural abnormalities in GC B-cells, there was no increase of somatic mutations or structural variants in Smc3 haploinsufficient lymphomas, suggesting that cohesin deficiency largely induces lymphomas through disruption of enhancer-promoter interactions of terminal differentiation and tumor suppressor genes. Strikingly, the presence of the Smc3 haploinsufficient GC B-cell transcriptional signature in human patients with GC-derived diffuse large B-cell lymphoma (DLBCL) was linked to inferior clinical outcome and low expression of cohesin core subunits. Reciprocally, reduced expression of cohesin subunits was an independent risk factor for worse survival int DLBCL patient cohorts. Collectively, the data suggest that Smc3 functions as a bona fide tumor suppressor for lymphomas through non-genetic mechanisms, and drives disease by disrupting the commitment of GC B-cells to the plasma cell fate.
Alpk1 Sensitizes Pancreatic Beta Cells to Cytokine-Induced Apoptosis via Upregulating TNF-α Signaling Pathway
Authors: Ding Fei , Luo Xi , Tu Yiting , Duan Xianlan , Liu Jia , Jia Lijing , Zheng Peilin
Published: September 2021

Pancreatic beta cell failure is the hallmark of type 1 diabetes (T1D). Recent studies have suggested that pathogen recognizing receptors (PRRs) are involved in the survival, proliferation and function of pancreatic beta cells. So far, little is known about the role of alpha-protein kinase 1 (ALPK1), a newly identified cytosolic PRR specific for ADP-β-D-manno-heptose (ADP-heptose), in beta cell survival. In current study we aimed to fill the knowledge gap by investigating the role of Alpk1 in the apoptosis of MIN6 cells, a murine pancreatic beta cell line. We found that the expression of Alpk1 was significantly elevated in MIN6 cells exposed to pro-inflammatory cytokines, but not to streptozotocin, low-dose or high-dose glucose. Activation of Alpk1 by ADP heptose alone was insufficient to induce beta cell apoptosis. However, it significantly exacerbated cytokine-induced apoptosis in MIN6 cells. Mechanistic investigations showed that Alpk1 activation was potent to further induce the expression of tumor necrosis factor (TNF)-α and Fas after cytokine stimulation, possibly due to enhanced activation of the TIFA/TAK1/NF-κB signaling axis. Treatment of GLP-1 receptor agonist decreased the expression of TNF-α and Fas and improved the survival of beta cells exposed to pro-inflammatory cytokines and ADP heptose. In summary, our data suggest that Alpk1 sensitizes beta cells to cytokine-induced apoptosis by potentiating TNF-α signaling pathway, which may provide novel insight into beta cell failure and T1D development.
The Combination of Radiotherapy With Immunotherapy and Potential Predictive Biomarkers for Treatment of Non-Small Cell Lung Cancer Patients
Authors: Meng Lu , Xu Jianfang , Ye Ying , Wang Yingying , Luo Shilan , Gong Xiaomei
Published: September 2021

Radiotherapy is an effective local treatment modality of NSCLC. Its capabilities of eliminating tumor cells by inducing double strand DNA (dsDNA) damage and modulating anti-tumor immune response in irradiated and nonirradiated sites have been elucidated. The novel ICIs therapy has brought hope to patients resistant to traditional treatment methods, including radiotherapy. The integration of radiotherapy with immunotherapy has shown improved efficacy to control tumor progression and prolong survival in NSCLC. In this context, biomarkers that help choose the most effective treatment modality for individuals and avoid unnecessary toxicities caused by ineffective treatment are urgently needed. This article summarized the effects of radiation in the tumor immune microenvironment and the mechanisms involved. Outcomes of multiple clinical trials investigating immuno-radiotherapy were also discussed here. Furthermore, we outlined the emerging biomarkers for the efficacy of PD-1/PD-L1 blockades and radiation therapy and discussed their predictive value in NSCLC.
Antiphospholipid Antibody Assays in 2021: Looking for a Predictive Value in Addition to a Diagnostic One
Authors: Meroni Pier Luigi , Borghi Maria Orietta
Published: September 2021

Antiphospholipid antibodies (aPL) are mandatory for the diagnosis but are also a risk factor for the antiphospholipid syndrome (APS) clinical manifestations. Lupus anticoagulant (LA), anticardiolipin (aCL), and anti-beta2 glycoprotein I (β2GPI) assays are the formal laboratory classification/diagnostic criteria. Additional nonclassification assays have been suggested; among them, antiphosphatidylserine-prothrombin (aPS/PT) and antidomain 1 β2GPI antibodies are the most promising ones although not yet formally accepted. aPL represent the example of a laboratory test that moved from dichotomous to quantitative results consistent with the idea that reporting quantitative data offers more diagnostic/prognostic information for both vascular and obstetric manifestations. Although the general rule is that the higher the aPL titer, the higher the test likelihood ratio, there is growing evidence that this is not the case for persistent low titers and obstetric events. LA displays the highest diagnostic/prognostic power, although some isolated LAs are apparently not associated with APS manifestations. Moreover, isotype characterization is also critical since IgG aPL are more diagnostic/prognostic than IgA or IgM. aPL are directed against two main autoantigens: β2GPI and PT. However, anti-β2GPI antibodies are more associated with the APS clinical spectrum. In addition, there is evidence that anti-β2GPI domain 1 antibodies display a stronger diagnostic/prognostic value. This finding supports the view that antigen and even epitope characterization represents a further step for improving the assay value. The strategy to improve aPL laboratory characterization is a lesson that can be translated to other autoantibody assays in order to improve our diagnostic and prognostic power.
Silent SARS-CoV-2 Infections, Waning Immunity, Serology Testing, and COVID-19 Vaccination: A Perspective
Authors: Narasimhan Madhusudhanan , Mahimainathan Lenin , Noh Jungsik , Muthukumar Alagarraju
Published: September 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes a spectrum of clinical manifestations, ranging from asymptomatic to mild, moderate, or severe illness with multi-organ failure and death. Using a new machine learning algorithm developed by us, we have reported a significantly higher number of predicted COVID-19 cases than the documented counts across the world. The sole reliance on confirmed symptomatic cases overlooking the symptomless COVID-19 infections and the dynamics of waning immunity may not provide ‘true’ spectrum of infection proportion, a key element for an effective planning and implementation of protection and prevention strategies. We and others have previously shown that strategic orthogonal testing and leveraging systematic data-driven modeling approach to account for asymptomatics and waning cases may situationally have a compelling role in informing efficient vaccination strategies beyond prevalence reporting. However, currently Centers for Disease Control and Prevention (CDC) does not recommend serological testing either before or after vaccination to assess immune status. Given the 27% occurrence of breakthrough infections in fully vaccinated (FV) group with many being asymptomatics and still a larger fraction of the general mass remaining unvaccinated, the relaxed mask mandate and distancing by CDC can drive resurgence. Thus, we believe it is a key time to focus on asymptomatics (no symptoms) and oligosymptomatics (so mild that the symptoms remain unrecognized) as they can be silent reservoirs to propagate the infection. This perspective thus highlights the need for proactive efforts to reevaluate the current variables/strategies in accounting for symptomless and waning fractions.
Ex Vivo Evaluation of Egg Yolk IgY Degradation in Chicken Gastrointestinal Tract
Authors: Wang Huiwen , Zeng Ximin , Lin Jun
Published: September 2021

Egg yolk antibody (immunoglobulin Y, IgY), due to its unique features (e.g., cost-effectiveness for mass production), is emerging as a promising passive immune agent and alternative to antibiotics to combat infectious diseases, particularly in livestock. Oral administration of egg yolk IgY is the most common and convenient route that has been extensively investigated for controlling enteric pathogens. However, the in vivo stability of egg yolk IgY in the gastrointestinal (GI) tract, a critical issue for the success of this approach, still has not been clearly elucidated. Our recent study showed instability of orally administered egg yolk IgY in chicken GI tract, as demonstrated by both in vivo and ex vivo evidence. To better understand the magnitude and dynamics of instability of egg yolk IgY in vivo, in this study, we conducted comprehensive ex vivo analyses by spiking hyperimmune egg yolk IgY in fresh GI contents collected from five broilers at each sampling age (2, 4, or 6 weeks). The pH in gizzard slightly increased with age from 2.4 to 3.0, while the pH in the small intestine was around 5.8. ELISA analysis indicated that a short time of treatment (30 or 60 min) of IgY with the gizzard contents from the chickens at 2, 4, and 6 weeks of age greatly reduced specific IgY titer by over 8, 6, and 5 log2 units, respectively, when compared with saline control. However, small intestine content only had a mild effect on egg yolk IgY, leading to 1 log2 unit of reduction in IgY titer upon 30 min of treatment. Consistent with these findings, SDS-PAGE and immunoblotting analyses provided direct evidence demonstrating that egg yolk IgY could be drastically degraded to undetectable level in gizzard content upon as short as 5 min of treatment; however, the IgY was only slightly degraded in small intestine content. Immunoblotting also showed that treatment of IgY with HCl (pH 3.0) for 60 min did not affect its integrity at all, further supporting the enzymatic degradation of IgY in gizzard. Collectively, egg yolk IgY could be substantially degraded in chicken gizzard, highly warranting the development of effective approaches, such as encapsulation, for the controlled release and protection of orally administered egg yolk IgY in livestock.
Meta-Analysis of Interleukin-2 Receptor Antagonists as the Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease
Authors: Shen Meng-Zhu , Li Jing-Xia , Zhang Xiao-Hui , Xu Lan-Ping , Wang Yu , Liu Kai-Yan , Huang Xiao-Jun , Hong Shen-Da , Mo Xiao-Dong
Published: September 2021

Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Corticosteroid is the first-line treatment for aGVHD, but its response rate is only approximately 50%. At present, no uniformly accepted treatment for steroid-refractory aGVHD (SR-aGVHD) is available. Blocking interleukin-2 receptors (IL-2Rs) on donor T cells using pharmaceutical antagonists alleviates SR-aGVHD. This meta-analysis aimed to compare the efficacy and safety of four commercially available IL-2R antagonists (IL-2RAs) in SR-aGVHD treatment. A total of 31 studies met the following inclusion criteria (1): patients of any race, any sex, and all ages (2); those diagnosed with SR-aGVHD after HSCT; and (3) those using IL-2RA-based therapy as the treatment for SR-aGVHD. The overall response rate (ORR) at any time after treatment with basiliximab and daclizumab was 0.81 [95% confidence interval (CI): 0.74–0.87)] and 0.71 (95% CI: 0.56–0.82), respectively, which was better than that of inolimomab 0.54 (95% CI: 0.39–0.68) and denileukin diftitox 0.56 (95% CI: 0.35–0.76). The complete response rate (CRR) at any time after treatment with basiliximab and daclizumab was 0.55 (95% CI: 0.42–0.68) and 0.42 (95%CI: 0.29–0.56), respectively, which was better than that of inolimomab 0.30 (95% CI: 0.16–0.51) and denileukin diftitox 0.37 (95% CI: 0.24–0.52). The ORR and CRR were better after 1-month treatment with basiliximab and daclizumab than after treatment with inolimomab and denileukin diftitox. The incidence of the infection was higher after inolimomab treatment than after treatment with the other IL-2RAs. In conclusion, the efficacy and safety of different IL-2RAs varied. The response rate of basiliximab was the highest, followed by that of daclizumab. Prospective, randomized controlled trials are needed to compare the efficacy and safety of different IL-2RAs.
Circulating Fibroblast Activation Protein as Potential Biomarker in Patients With Inflammatory Bowel Disease
Authors: Corsi Fabio , Sorrentino Luca , Albasini Sara , Colombo Francesco , Cigognini Maria , Massari Alessandro , Morasso Carlo , Mazzucchelli Serena , Piccotti Francesca , Ardizzone Sandro , Sampietro Gianluca M. , Truffi Marta
Published: September 2021

A major concern in the management of Inflammatory Bowel Disease (IBD) is the absence of accurate and specific biomarkers to drive diagnosis and monitor disease status timely and non-invasively. Fibroblast activation protein (FAP) represents a hallmark of IBD bowel strictures, being overexpressed in stenotic intestinal myofibroblasts. The present study aimed at evaluating the potential of circulating FAP (cFAP) as an accessible blood biomarker of IBD. Quantitative determination of cFAP was performed by enzyme-linked immunosorbent assay on plasma samples prospectively collected from patients with IBD and control subjects. A discrimination model was established on a training set of 50% patients and validated on independent samples. Results showed that cFAP concentration was reduced in patients with IBD when compared to controls (p < 0.0001). Age, sex, smoking, disease location and behavior, disease duration and therapy were not associated with cFAP. The sensitivity and specificity of cFAP in discriminating IBD from controls were 70 and 84%, respectively, based on the optimal cutoff (57.6 ng mL−1, AUC = 0.78). Predictions on the test set had 57% sensitivity, 65% specificity, and 61% accuracy. There was no strong correlation between cFAP and routine inflammatory markers in the patients' population. A subgroup analysis was performed on patients with Crohn's disease undergoing surgery and revealed that cFAP correlates with endoscopic mucosal healing. In conclusion, cFAP deserves attention as a promising blood biomarker to triage patients with suspected IBD. Moreover, it might function as a biomarker of post-operative remission in patients with Crohn's disease.
The Effect of Loop Diuretics on 28-Day Mortality in Patients With Acute Respiratory Distress Syndrome
Authors: Zhang Rui , Chen Hui , Gao Zhiwei , Liang Meihao , Qiu Haibo , Yang Yi , Liu Ling
Published: September 2021

Background: Diuretics have been widely used in critically ill patients while it remains uncertain whether they can reduce mortality in patients with acute respiratory distress syndrome (ARDS). This study aimed to investigate the associations between diuretics and 28-day mortality in patients with ARDS.

Methods: This is a secondary analysis of the ARDS Network Fluid and Catheter Treatment Trial (FACTT) of National Heart, Lung, and Blood Institute. Those patients who did not receive renal replacement therapy within the first 48 h after enrollment in the FACTT were included in the analysis. A marginal structural Cox model (MSCM) was used to investigate the associations between diuretics and 28-day mortality after correction of both the baseline and time-varying variables. The latent class analysis (LCA) and subgroup analysis were performed to identify the kind of patients that could be benefited from diuretics.

Results: A total of 932 patients were enrolled, i.e., 558 patients in the diuretics group and 374 patients in the no diuretics group within the first 48 h. The 28-day mortality was lower in the diuretics group (15.1 vs. 28.1%, p < 0.001). In MSCM, diuretics use was related to the improved 28-day mortality (HR 0.78; 95% CI 0.62–0.99; p = 0.04). LCA identified three subtypes, and diuretics were associated with reduced mortality in subtype 3, which was characterized by worse renal function and higher central venous pressure (CVP). A subgroup analysis indicated survival advantage among the female patients, sepsis induced ARDS, and those with the ratio of partial pressure of oxygen to the fractional concentration of inspired oxygen (PaO2/FiO2) ≤ 150 mmHg, and mean arterial pressure (MAP) ≥ 65 mmHg.

Conclusion: Loop diuretics were associated with the reduced 28-day mortality in the patients with ARDS, after controlling for time-varying confounders. Randomized trials are required to verify the association.
Adaptation of Staphylococcus aureus to the Human Skin Environment Identified Using an ex vivo Tissue Model
Authors: Burian Marc , Plange Johanna , Schmitt Laurenz , Kaschke Anke , Marquardt Yvonne , Huth Laura , Baron Jens M. , Hornef Mathias W. , Wolz Christiane , Yazdi Amir S.
Published: September 2021

The healthy human epidermis provides physical protection and is impenetrable for pathogenic microbes. Nevertheless, commensal and pathogen bacteria such as Staphylococcus aureus are able to colonize the skin surface, which may subsequently lead to infection. To identify and characterize regulatory elements facilitating adaptation of S. aureus to the human skin environment we used ex vivo tissue explants and quantified S. aureus gene transcription during co-culture. This analysis provided evidence for a significant downregulation of the global virulence regulator agr upon initial contact with skin, regardless of the growth phase of S. aureus prior to co-culture. In contrast, the alternative sigma factor B (sigB) and the antimicrobial peptide-sensing system (graRS) were expressed during early colonization. Consistently, sigB target genes such as the clumping factor A (clfA) and fibrinogen and fibronectin binding protein A (fnbA) were strongly upregulated upon skin contact. At later timepoints of the adhesion process, wall teichoic acid (WTA) synthesis was induced. Besides the expression of adhesive molecules, transcription of molecules involved in immune evasion were increased during late colonization (staphylococcal complement inhibitor and staphylokinase). Similar to nasal colonization, enzymes involved in cell wall metabolism (sceD and atlA) were highly transcribed. Finally, we detected a strong expression of proteases from all three catalytic classes during the entire colonization process. Taken together, we here present an ex vivo skin colonization model that allows the detailed characterization of the bacterial adaptation to the skin environment.
Identification of Tick-Borne Pathogens and Genotyping of Coxiella burnetii in Rhipicephalus microplus in Yunnan Province, China
Authors: Jiao Jun , Zhang Jianing , He Peisheng , OuYang Xuan , Yu Yonghui , Wen Bohai , Sun Yi , Yuan Qinghong , Xiong Xiaolu
Published: September 2021

Rhipicephalus microplus, a vector that can transmit many pathogens to humans and domestic animals, is widely distributed in Yunnan province, China. However, few reports on the prevalence of tick-borne pathogens (TBPs) in Rh. microplus in Yunnan are available. The aim of this study was to detect TBPs in Rh. microplus in Yunnan and to analyze the phylogenetic characterization of TBPs detected in these ticks. The adult Rh. microplus (n = 516) feeding on cattle were collected. The pooled DNA samples of these ticks were evaluated using metagenomic next-generation sequencing (mNGS) and then TBPs in individual ticks were identified using genus- or group-specific nested polymerase chain reaction (PCR) combined with DNA sequencing assay. As a result, Candidatus Rickettsia jingxinensis (24.61%, 127/516), Anaplasma marginale (13.18%, 68/516), Coxiella burnetii (3.10%, 16/516), and Coxiella-like endosymbiont (CLE) (8.33%, 43/516) were detected. The dual coinfection with Ca. R. jingxinensis and A. marginale and the triple coinfection with Ca. R. jingxinensis, A. marginale, and CLE were most frequent and detected in 3.68% (19/516) and 3.10% (16/516) of these ticks, respectively. The results provide insight into the diversity of TBPs and their coinfections in Rh. microplus in Yunnan province of China, reporting for the first time that C. burnetii had been found in Rh. microplus in China. Multilocus variable number tandem repeat analysis with 6 loci (MLVA-6) discriminated the C. burnetii detected in Rh. microplus in Yunnan into MLVA genotype 1, which is closely related to previously described genotypes found primarily in tick and human samples from different regions of the globe, indicating a potential public health threat posed by C. burnetii in Rh. microplus in Yunnan.
Development of a Toll-Like Receptor-Based Gene Signature That Can Predict Prognosis, Tumor Microenvironment, and Chemotherapy Response for Hepatocellular Carcinoma
Authors: Liu Lixia , Liu Bin , Yu Jie , Zhang Dongyun , Shi Jianhong , Liang Ping
Published: September 2021

Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC.

Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined.

Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells.

Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.
Engineering of a Spider Peptide via Conserved Structure-Function Traits Optimizes Sodium Channel Inhibition In Vitro and Anti-Nociception In Vivo
Authors: Hu H. , Mawlawi S. E. , Zhao T. , Deuis J. R. , Jami S. , Vetter I. , Lewis R. J. , Cardoso F. C.
Published: September 2021

Venom peptides are potent and selective modulators of voltage-gated ion channels that regulate neuronal function both in health and in disease. We previously identified the spider venom peptide Tap1a from the Venezuelan tarantula Theraphosa apophysis that targeted multiple voltage-gated sodium and calcium channels in visceral pain pathways and inhibited visceral mechano-sensing neurons contributing to irritable bowel syndrome. In this work, alanine scanning and domain activity analysis revealed Tap1a inhibited sodium channels by binding with nanomolar affinity to the voltage-sensor domain II utilising conserved structure-function features characteristic of spider peptides belonging to family NaSpTx1. In order to speed up the development of optimized NaV-targeting peptides with greater inhibitory potency and enhanced in vivo activity, we tested the hypothesis that incorporating residues identified from other optimized NaSpTx1 peptides into Tap1a could also optimize its potency for NaVs. Applying this approach, we designed the peptides Tap1a-OPT1 and Tap1a-OPT2 exhibiting significant increased potency for NaV1.1, NaV1.2, NaV1.3, NaV1.6 and NaV1.7 involved in several neurological disorders including acute and chronic pain, motor neuron disease and epilepsy. Tap1a-OPT1 showed increased potency for the off-target NaV1.4, while this off-target activity was absent in Tap1a-OPT2. This enhanced potency arose through a slowed off-rate mechanism. Optimized inhibition of NaV channels observed in vitro translated in vivo, with reversal of nocifensive behaviours in a murine model of NaV-mediated pain also enhanced by Tap1a-OPT. Molecular docking studies suggested that improved interactions within loops 3 and 4, and C-terminal of Tap1a-OPT and the NaV channel voltage-sensor domain II were the main drivers of potency optimization. Overall, the rationally designed peptide Tap1a-OPT displayed new and refined structure-function features which are likely the major contributors to its enhanced bioactive properties observed in vivo. This work contributes to the rapid engineering and optimization of potent spider peptides multi-targeting NaV channels, and the research into novel drugs to treat neurological diseases.