bluuebunny/crossref_metadata_2025 huggingface dataset:
New Insights Into the Function of Flavohemoglobin in Mycobacterium tuberculosis: Role as a NADPH-Dependent Disulfide Reductase and D-Lactate-Dependent Mycothione Reductase
Authors: Thakur Naveen , Sharma Amar Nath , Hade Mangesh Dattu , Chhaya Ajay , Kumar Ashwani , Jolly Ravinder Singh , Dikshit Kanak L.
Published: February 2022

Mycobacterium tuberculosis (Mtb) produces an unconventional flavohemoglobin (MtbFHb) that carries a FAD-binding site similar to D-lactate dehydrogenases (D-LDH) and oxidizes D-lactate into pyruvate. The molecular mechanism by which MtbFHb functions in Mtb remains unknown. We discovered that the D-LDH-type FAD-binding site in MtbFHb overlaps with another FAD-binding motif similar to thioredoxin reductases and reduces DTNB in the presence of NADPH similar to trxB of Mtb. These results suggested that MtbFHb is functioning as a disulfide oxidoreductase. Interestingly, D-lactate created a conformational change in MtbFHb and attenuated its ability to oxidize NADPH. Mass spectroscopy demonstrated that MtbFHb reduces des-myo-inositol mycothiol in the presence of D-lactate unlike NADPH, indicating that D-lactate changes the specificity of MtbFHb from di-thiol to di-mycothiol. When M. smegmatis carrying deletion in the fhbII gene (encoding a homolog of MtbFHb) was complemented with the fhb gene of Mtb, it exhibited four- to fivefold reductions in lipid peroxidation and significant enhancement in the cell survival under oxidative stress. These results were corroborated by reduced lipid peroxidation and enhanced cell survival of wild-type M. smegmatis after overexpression of the fhb gene of Mtb. Since D-lactate is a by-product of lipid peroxidation and MtbFHb is a membrane-associated protein, D-lactate-mediated reduction of mycothiol disulfide by MtbFHb may uniquely equip Mtb to relieve the toxicity of D-lactate accumulation and protect the cell from oxidative damage, simultaneously balancing the redox environment under oxidative stress that may be vital for the pathogenesis of Mtb.
The Dissolution of Olivine Added to Soil at 4°C: Implications for Enhanced Weathering in Cold Regions
Authors: Pogge von Strandmann Philip A. E. , Tooley Chloe , Mulders Josephina J. P. A. , Renforth Phil
Published: February 2022

Crushed olivine was added to a soil core to mimic enhanced weathering, and water was continually dripped through for ~6 months. Our experiments were conducted at 4°C, and are compared to previously run identical experiments at 19°C. Olivine dissolution rates in both experiments start out similar, likely due to fines and sharp crystal corners. However, after >100 days of reaction, the dissolution rate at 4°C was two orders of magnitude lower than at 19°C. The accumulation of heavy metals, such as Ni and Cd, was low in both experiments, but soil retention of these elements was proportionally higher at higher temperatures, likely due to enhanced sorption and formation of clays. Overall, this study suggests that olivine dissolution rates in experiments that mimic natural settings are orders of magnitude slower than in normal laboratory experiments, and that enhanced weathering may be a considerably less efficient method of carbon dioxide removal at low climatic temperatures. Both of these conclusions have implications for the application of enhanced weathering as a CO2 removal method.
Impacts of El Niño Diversity on Tropical Cyclone Activity in the Bay of Bengal
Authors: Lakshani W. A. E. , Zhou Wen , Cheung Paxson K. Y.
Published: February 2022

This study investigates the variation in large-scale parameters associated with two types of El Niño and their impact on tropical cyclone (TC) activity over the Bay of Bengal (BoB) from 1980 to 2019. The Genesis Potential Index (GPI)-based quantitative evaluation was conducted to compute the relative contribution of ENSO and El Niño flavor–associated large-scale parameters. Relationship between the GPI and ENSO in the primary TC peak season (October–November; OND) exhibits a distinct meridional pattern over southwestern to northeastern parts of the BoB. Moreover, the results show that ENSO-modulated vertical wind shear (VWS) term (relative humidity; RH term) contributes the most to enhancing (suppressing) the GPI over the southwestern (northeastern) BoB during the primary TC peak season. The GPI exhibits a significantly positive (negative) dipole pattern with EP El Niño in the southern (northern) BoB, while CP El Niño shows a southwestern (positive)–northeastern (negative) meridional pattern. The increased GPI in the southern BoB with EP El Niño is due mainly to the VWS term, while RH term makes a minimal contribution. Similarly, during CP El Niño, VWS term contributes the most to the enhancement of the GPI, while the smallest contribution is from potential intensity (PI) term. Moreover, this study reveals that the thermodynamic (RH) factor is crucial in reducing TC genesis during CP El Niño in the northeastern BoB. On the other hand, the dynamic (VWS) and thermodynamic (RH) terms are almost equally important for suppressing TCs over the northern BoB in EP El Niño.Analysis of the secondary TC peak season (April–June; AMJ) demonstrates that CP El Niño and EP El Niño induce an increase and decrease in the GPI in the southern BoB mainly due to the dynamic factor (VWS term) and thermodynamic factor (RH term), respectively. On the other hand, TCs in AMJ are more favorable to occur in the south of BoB during CP El Niño events. The two types of El Niño-associated physical mechanisms are consistent with the diagnosed GPI changes, emphasizing the vital role of both EP and CP El Niño in influencing thermodynamic and dynamic parameters related to TC genesis over the BoB. Thus, the association of CP and EP El Niño with the GPI provides a valuable platform for studying El Niño–generated TC impacts over the BoB.
Changes of Divergence and Confluence Relationship Between Dongting Lake and the Yangtze River After the Operation of the Three Gorges Project and Its Impact on the Waterway Depth
Authors: Yang Yunping , Liu Wanli , Zhang Jie , Yang Lijie , Jia Menglin , Zhu Lingling
Published: February 2022

Human activities and climate change have profoundly changed the hydrological and geomorphological evolutionary processes and trends of rivers and lakes, which, in turn, has affected the utilization of their waterway depth. This study chose the Dongting Lake–Jingjiang confluence of the Changjiang River (Yangtze Rvier), since the operation of the Three Gorges Project, the split ratio of water and the sediment distribution of the three outlets of Dongting Lake—that is, Songzikou, Taipigkou, and Ouchikou—have continued to decrease. Along with the decreasing flow of Dongting Lake, the relative increase in the runoff of the Jingjiang reach and the increase in riverbed erosion intensity have increased the relative height difference between Jingjiang and Dongting Lake, intensifying the reduction of the split ratio of water and the sediment distribution of the three outlets. The riverbed erosion of the Jingjiang reach has created a promising foundation for an increase in the waterway dimensions. However, the length of the reach not meeting the requirements of 4.5× 200 m (water depth × width) is 18.4 km, of which the length in the river-lake confluence is 12.6 km, accounting for 68.35% of the total length of obstructed navigation. Furthermore, at the reach (Zhicheng–Dabujie reach) affected by the first outlet (Songzikou), a 4.5-m flume has been formed, but its width is less than 200 m. Moreover, the “steep slope and rapid current” phenomenon is clear, and it affects the safety of ships. At the reach (Taipingkou reach) affected by the second outlet, the shrinkage of the bottomland, and the intersecting braided river channels make the low-flow routes unstable, the water depth being less than 4.5 m. At the reach (Tianxingzhou–Ouchikou reach) affected by the third outlet, the shoreline of the reach has collapsed and retreated significantly. Additionally, beach erosion and the downstream movement of cut banks have caused the downstream waterway width at the reach to be reduced to less than 200 m or formed shoals with a water depth of less than 4.5 m. Owing to the jacking effect of the lake’s outflow backwater, the flow rate of the reach (Xiongjiazhou–Chenglingji reach) affected by the confluence of Dongting Lake decreased, creating a shoal with a water depth of less than 4.5 m in the navigation waterway. The results of this study have guiding significance for understanding the changes of channel conditions and the improvement of channel scale in the intersection area of rivers and lakes.
Pre-Weaning Exposure to Maternal High-Fat Diet Is a Critical Developmental Window for Programming the Metabolic System of Offspring in Mice
Authors: Yang Hong , Chen Nan , Fan Lei , Lin Xiaojing , Liu Juncheng , You Yuehua , Zhong Ying , Chen Yan , Li Jibin , Xiao Xiaoqiu
Published: February 2022

Background

Maternal high-fat diet (HFD) during pregnancy and lactation exerts long-term effects on the health of offspring. However, the critical developmental window for metabolic programming of maternal exposure to HFD on pathogenesis of obesity in offspring needs further clarification.

Materials & Methods

Female ICR mice were fed low-fat diet (LFD) or HFD for 8 weeks until delivery. During lactation, half of LFD dams received HFD while the other half of LFD dams and HFD dams maintained the previous diet. Male offspring were weaned at postnatal day 21 (P21) and fed LFD or HFD for 7 weeks. Metabolic parameters, biochemical, and histological indicators of thermogenesis, rectal temperature, and sympathetic nerve tone were detected at P21 and 10 weeks old.

Results

At P21, LH (maternal LFD before delivery but HFD during lactation) and HH (maternal HFD before delivery and during lactation) offspring gained more body weight and showed higher serum glucose and triglyceride levels as compared with LL (maternal LFD before delivery and during lactation), and the metabolic characters were maintained until 10 weeks age when fed with LFD after weaning. However, LH offspring exhibited a greater degree of metabolic abnormalities compared to HH offspring, with increased body weight, as well as lower norepinephrine (NE)-stimulated rectal temperature rise when fed with HFD after weaning. The lower UCP1 levels and HSL phosphorylation in LH offspring further suggested that brown adipose tissue (BAT) thermogenic function was impaired.

Conclusion

Exposure to maternal HFD feeding during pre-weaning period alone showed similar detrimental effects on programming metabolic system of offspring as those of both prenatal and early postnatal HFD feeding. Early postnatal stage is a critical time window for metabolic programming and has profound and long-lasting effects on BAT development and function through sympathetic nerve-mediated thermogenesis.
Assessing Spatial and Temporal Distribution of Algal Blooms Using Gini Coefficient and Lorenz Asymmetry Coefficient
Authors: Zhou Ting , Ni Cheng , Zhang Ming , Xia Ping
Published: February 2022

Algal bloom in an inland lake is characterized by significant spatial and temporal dynamics. Accurate assessment of algal bloom distribution and dynamics is highly required for tracing the causes of and creating countermeasures for algal bloom. Satellite remote sensing provides a fast and efficient way to capture algal bloom distribution at a large scale, but it is difficult to directly derive accurate and quantitative assessment based on satellite images. In this study, the Gini coefficient and Lorenz asymmetry coefficient were introduced to examine the spatio-temporal algal bloom distribution of Chaohu Lake, the fifth largest inland lake in China. A total of 61 remote sensing images from three satellite sensors, Landsat, Gaofen, and Sentinel were selected to obtain algal bloom distributions. By dividing remote sensing images into 0.01°*0.01° grid cells, the normalized difference vegetation index (NDVI) for each grid cell was derived, forming a spatial and time series database for quantitative analysis. Two coefficients, Gini coefficient and Lorenz asymmetry coefficient, were used to evaluate the overall intensity, unevenness, and attribution of algal bloom in Chaohu Lake from 2011 to 2020. The Gini coefficient results show a large variety of algal bloom in the spatial and temporal scales of Chaohu lake. The lake edge and northwestern part had longer lasting and more severe algal bloom than the lake center, which was mainly due to nutrient import, especially from three northwestern tributaries that flow through the upstream city. The Lorenz asymmetry coefficient revealed the exact source of the unevenness. Spatial uncertainties were mostly caused by the tiny areas with high NDVI values, accounting for 53 cases out of 61 cases. Temporal unevenness in northwestern and northeastern parts of the lake was due to the most severe breakout occurrences, while unevenness in the lake center was mainly due to the large number of light occurrences. Finally, the advantage of Gini coefficient and Lorenz asymmetry coefficient are discussed by comparison with traditional statistical coefficients. By incorporating the two coefficients, this paper provides a quantitative and comprehensive assessment method for the spatial and temporal distribution of algal bloom.
The Impact of the Voluntary Environmental Agreements on Green Technology Innovation: Evidence From the Prefectural-Level Data in China
Authors: Ren Kai , Kong Yu-Sheng , Imran Muhammad , Bangash Arshad Khan
Published: February 2022

“Porter Hypothesis” believes that moderate environmental regulation can promote the growth of green technology innovation. Voluntary environmental agreements are a typical type of environmental regulation and theoretically promote green technology innovation. In 1964, Japan was the first country in the world to implement a voluntary environmental agreement, with good results. Subsequently, European Union countries began to implement the “fifth Environmental Action Plan” on 1 January 1993, which effectively combined voluntary environmental agreements with corporate self-regulation. The prior empirical work assists the idea that environmental regulation has diverse impacts on the environment. However, China’s voluntary environmental agreements have a short implementation time and lack of experience and need to be further explored in terms of policy proposal and technology implementation. The existing literature is based on a sample of units at the provincial level or national level are studied, utilizing multiple regression analysis methods, this study in China prefecture-level administrative units as investigation object, and choose the government environmental protection education, the government agreement propaganda, enterprise ecological ethics, information disclosure, market efficiency, and information technology support six elements as the key independent variables. This paper empirically examines the promotion effect of the voluntary environmental agreement on green technology innovation, finds the shortcomings of China’s voluntary environmental agreement regulation, and puts forward specific improvement strategies to promote the growth of green technology innovation more effectively. It is found that government environmental protection education, enterprise ecological ethics construction, market effectiveness, and information technology support have obvious promoting effects on green product innovation, green process innovation, and end management innovation. Government agreement publicity has no promotion function for green product innovation, green process innovation, and terminal governance innovation. The disclosure of protocol information has a promotion effect on green product innovation, but it lacks the promotion function on green process innovation, and end management innovation. The research believes that the deepening of the implementation of voluntary environmental agreements in China should give full play to the leading role of the government, implement progressive policies, deepen the internal coordination of environmental regulations, give play to the supervision role of the public and the media, learn from the experience of western countries, and promote green credit. The finding of the study opens up new insight for appropriate policymaking.
Effects of Three Widely Used Antibiotics and Their Mixture on the Haemocytes of the Clam Ruditapes philippinarum
Authors: Nicolussi Greta , Fabrello Jacopo , Asnicar Davide , Ciscato Maria , Matozzo Valerio , Marin Maria Gabriella
Published: February 2022

Although the presence of pharmaceutical and personal care products in aquatic ecosystems is well documented, little information is available about their sublethal effects, on aquatic invertebrates. From an ecotoxicological point of view, the use of in vitro approaches has been recommended as a tool to assess adverse effects and to understand the mechanisms of action of chemicals at the cellular level. In the present in vitro study, the effects of Amoxicillin (AMX), Trimethoprim (TMP) and Ciprofloxacin (CIP) (1 µg/L, each) were tested alone and—for the first time—as a mixture (MIX) on haemocytes of the clam Ruditapes philippinarum. After the exposure, a battery of cellular parameters was evaluated, such as haemocyte viability, lysosomal membrane stability, superoxide anion production, acid phosphatase activity, the frequency of micronuclei and chromosomal aberrations. The results demonstrated that AMX, TMP, CIP and MIX affected lysosomal membrane stability, as well as superoxide anion and acid phosphatase production, and promoted chromosomal aberrations. This study highlighted that Manila clam haemocytes are a sensitive cell model to assess the effects of exposure to pharmaceutical products on non-target species. Our study demonstrated that the effects of pharmaceutical mixtures on marine species should be experimentally evaluated because they are not predictable from single exposures as the compounds can interact in different ways on the various biological endpoints considered.
Zooplankton Size Structure in Relation to Environmental Factors in the Xiangxi Bay of Three Gorges Reservoir, China
Authors: Li Haoran , Gu Yuan , Cai Qinghua , Dong Xiaowei , Ye Lin
Published: February 2022

Body size is sensitive to environmental changes and one of the fundamental traits linking ecological functions. Size structure has been suggested as a useful indicator for environmental monitoring and assessment in aquatic ecosystems. However, the organisms’ size structure and the relationship with environmental factors remain seldom addressed in reservoir ecosystems. In this study, we investigated the size spectrum, size diversity of the zooplankton and their relationships with environmental conditions across nitrogen and phosphorus gradients in the Xiangxi Bay of Three Gorges Reservoir, China. We further tested the hypotheses that how nutrient and water temperature affect zooplankton size structure: nutrients indirectly affect zooplankton size spectrum and size diversity via phytoplankton (H1); increasing water temperature will reduce size diversity and result in a steeper size spectrum (H2); size diversity is a more robust metric indicating environment changes than the size spectrum in high dynamic ecosystems (H3). We found that both the size spectrum and size diversity showed high spatiotemporal dynamics. The size spectrum ranged from −3.373 to −0.984. The size diversity ranged from 0.631 to 3.291. Spatially, the lowest values of the size spectrum and size diversity were observed in the upstream areas of Xiangxi Bay, where nitrogen and phosphorus concentrations are high and low, respectively. And in temporal dynamics, lower values of the size spectrum and size diversity were generally observed in March and April. Further analyses based on the structural equation model (SEM) found a clear pathway revealing that nutrient variables affect the zooplankton abundance and size structure, supporting hypothesis H1. That is, dissolved inorganic nitrogen had an indirect effect on the zooplankton abundance, size spectrum, and size diversity by influencing the concentration of phytoplankton chlorophyll a. In addition, results of SEM suggested that increased water temperature had a significant negative effect on the size diversity but had non-significant effects on zooplankton abundance and size spectrum. This finding suggests that size diversity is a reliable and useful index in measuring the zooplankton size structure in reservoir ecosystems with high dynamics, which may have a wide application in environmental monitoring and assessment, especially for complex and dynamic aquatic ecosystems.
Set of 15 SNP-SNP Markers for Detection of Unbalanced Degraded DNA Mixtures and Noninvasive Prenatal Paternity Testing
Authors: Zhang Ranran , Tan Yu , Wang Li , Jian Hui , Zhu Jing , Xiao Yuanyuan , Tan Mengyu , Xue Jiaming , Yang Fan , Liang Weibo
Published: February 2022

Unbalanced and degraded mixtures (UDM) are very common in forensic DNA analysis. For example, DNA signals from criminal suspects are masked by a large amount of DNA from victims, or cell-free fetal DNA (cffDNA) in maternal plasma is masked by a high background of maternal DNA. Currently, detecting minor DNA in these mixtures is complex and challenging. We developed a new set of SNP-SNP microhaplotypes with short amplicons, and we successfully genotyped them using the new method of amplification-refractory mutation system PCR (ARMS-PCR) combined with SNaPshot technology based on a capillary electrophoresis (CE) platform. This panel reflects a high polymorphism in the Southwest Chinese Han population and thus has excellent potential for mixture studies. We evaluated the feasibility of this panel for UDM detection and noninvasive prenatal paternity testing (NIPPT). Fifteen SNP-SNPs detected minor DNA of homemade DNA mixtures, with a sensitivity of 0.025–0.05 ng and a specificity of 1:1,000. In addition, the panel successfully genotyped degraded DNA from single and mixed samples. Finally, 15 SNP-SNPs were applied to 26 trios. All samples displayed positive results with at least one marker to detect cffDNA. Besides, all fetal alleles in maternal plasma were confirmed by genotyping fetal genomic DNA from amniocentesis and paternal genomic DNA from peripheral blood. The results indicated that the SNP-SNP strategy based on the CE platform was useful for UDM detection and NIPPT.
Weighted Co-Expression Network Analysis Identifies RNF181 as a Causal Gene of Coronary Artery Disease
Authors: Dang Ruoyu , Qu Bojian , Guo Kaimin , Zhou Shuiping , Sun He , Wang Wenjia , Han Jihong , Feng Ke , Lin Jianping , Hu Yunhui
Published: February 2022

Background: Coronary artery disease (CAD) exerts a global challenge to public health. Genetic heritability is one of the most vital contributing factors in the pathophysiology of CAD. Co-expression network analysis is an applicable and robust method for the interpretation of biological interaction from microarray data. Previous CAD studies have focused on peripheral blood samples since the processes of CAD may vary from tissue to blood. It is therefore necessary to find biomarkers for CAD in heart tissues; their association also requires further illustration.

Materials and Methods: To filter for causal genes, an analysis of microarray expression profiles, GSE12504 and GSE22253, was performed with weighted gene co-expression network analysis (WGCNA). Co-expression modules were constructed after batch effect removal and data normalization. The results showed that 7 co-expression modules with 8,525 genes and 1,210 differentially expressed genes (DEGs) were identified. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Four major pathways in CAD tissue and hub genes were addressed in the Hybrid Mouse Diversity Panel (HMDP) and Human Protein Atlas (HPA), and isoproterenol (ISO)/doxycycline (DOX)-induced heart toxicity models were used to validate the hub genes. Lastly, the hub genes and risk variants were verified in the CAD cohort and in genome-wide association studies (GWAS).

Results: The results showed that RNF181 and eight other hub genes are perturbed during CAD in heart tissues. Additionally, the expression of RNF181 was validated using RT-PCR and immunohistochemistry (IHC) staining in two cardiotoxicity mouse models. The association was further verified in the CAD patient cohort and in GWAS.

Conclusion: Our findings illustrated for the first time that the E3 ubiquitination ligase protein RNF181 may serve as a potential biomarker in CAD, but further in vivo validation is warranted.
Regulation of DNA Methylation During Plant Endosperm Development
Authors: Lu Dongdong , Zhai Jixian , Xi Mengli
Published: February 2022

The endosperm is a vital storage tissue in plant seeds. It provides nutrients to the embryos or the seedlings during seed development and germination. Although the genetic information in the endosperm cannot be passed directly to the next generation, its inherited epigenetic marks affect gene expression and its development and, consequently, embryo and seed growth. DNA methylation is a major form of epigenetic modification that can be investigated to understand the epigenome changes during reproductive development. Therefore, it is of great significance to explore the effects of endosperm DNA methylation on crop yield and traits. In this review, we discuss the changes in DNA methylation and the resulting imprinted gene expression levels during plant endosperm development, as well as their effects on seed development.
Effective Identification of Maternal Malignancies in Pregnancies Undergoing Noninvasive Prenatal Testing
Authors: Li Jia , Ju Jia , Zhao Qiang , Liu Weiqiang , Yuan Yuying , Liu Qiang , Zhou Lijun , Han Yuan , Yuan Wen , Huang Yonghua , Xie Yingjun , Li Zhihua , Chen Jingsi , Huang Shuyu , Chen Rufang , Li Wei , Tan Meihua , Wang Danchen , Zhou Si , Zhang Jian , Zeng Fanwei , Yu Nan , Su Fengxia , Chen Min , Ge Yunsheng , Huang Yanming , Jin Xin
Published: February 2022

Background: The existence of maternal malignancy may cause false-positive results or failed tests of NIPT. Though recent studies have shown multiple chromosomal aneuploidies (MCA) are associated with malignancy, there is still no effective solution to identify maternal cancer patients from pregnant women with MCA results using NIPT. We aimed to develop a new method to effectively detect maternal cancer in pregnant women with MCA results using NIPT and a random forest classifier to identify the tissue origin of common maternal cancer types.

Methods: For examination, 496 participants with MCA results via NIPT were enrolled from January 2016 to June 2019 at BGI. Cancer and non-cancer participants were confirmed through the clinical follow-up. The cohort comprising 42 maternal cancer cases and 294 non-cancer cases enrolled from January 2016 to December 2017 was utilized to develop a method named mean of the top five chromosome z scores (MTOP5Zscores). The remaining 160 participants enrolled from January 2018 to June 2019 were used to validate the performance of MTOP5Zscores. We established a random forest model to classify three common cancer types using normalized Pearson correlation coefficient (NPCC) values, z scores of 22 chromosomes, and seven plasma tumor markers (PTMs) as predictor variables.

Results: 62 maternal cancer cases were confirmed with breast cancer, liver cancer, and lymphoma, the most common cancer types. MTOP5Zscores showed a sensitivity of 85% (95% confidence interval (CI), 62.11–96.79%) and specificity of 80% (95% CI, 72.41–88.28%) in the detection of maternal cancer among pregnant women with MCA results. The sensitivity of the classifier was 93.33, 66.67, and 50%, while specificity was 66.67, 90, and 97.06%, and positive predictive value (PPV) was 60.87, 72.73, and 80% for the prediction of breast cancer, liver cancer, and lymphoma, respectively.

Conclusion: This study presents a solution to identify maternal cancer patients from pregnant women with MCA results using NIPT, indicating it as a value-added application of NIPT in the detection of maternal malignancies in addition to screening for fetal aneuploidies with no extra cost.
Guanylate-Binding Protein 1 as a Potential Predictor of Immunotherapy: A Pan-Cancer Analysis
Authors: Zhao Yaqi , Wu Jie , Li Lan , Zhang Huibo , Zhang Haohan , Li Jing , Zhong Hao , Lei Tianyu , Jin Yan , Xu Bin , Song Qibin
Published: February 2022

Background: Mainstream application of cancer immunotherapy is hampered by the low response rate of most cancer patients. A novel immunotherapeutic target or a biomarker predicting response to immunotherapy needs to be developed. Guanylate-binding protein 1 (GBP1) is an interferon (IFN)-inducible guanosine triphosphatases (GTPases) involving inflammation and infection. However, the immunological effects of GBP1 in pan-cancer patients are still obscure.

Methods: Using large-scale public data, we delineated the landscape of GBP1 across 33 cancer types. The correlation between GBP1 expression or mutation and immune cell infiltration was estimated by ESTIMATE, TIMER, xCell, and quanTIseq algorithms. GBP1-related genes and proteins were subjected to function enrichment analysis. Clustering analysis explored the relationship between GBP1 expression and anti-tumor immune phenotypes. We assessed the patient’s response to immunotherapy using the tumor immune dysfunction and exclusion (TIDE) score and immunophenoscore (IPS). Furthermore, we validated the predictive power of GBP1 expression in four independent immunotherapy cohorts.

Results: GBP1 was differentially expressed in tumors and normal tissues in multiple cancer types. Distinct correlations existed between GBP1 expression and prognosis in cancer patients. GBP1 expression and mutation were positively associated with immune cell infiltration. Function enrichment analysis showed that GBP1-related genes were enriched in immune-related pathways. Positive correlations were also observed between GBP1 expression and the expression of immune checkpoints, as well as tumor mutation burden (TMB). Pan-cancer patients with higher GBP1 expression were more inclined to display “hot” anti-tumor immune phenotypes and had lower TIDE scores and higher immunophenoscore, suggesting that these patients had better responses to immunotherapy. Patients with higher GBP1 expression exhibited improved overall survival and clinical benefits in immunotherapy cohorts, including the Gide et al. cohort [area under the curve (AUC): 0.813], the IMvigor210 cohort (AUC: 0.607), the Lauss et al. cohort (AUC: 0.740), and the Kim et al. cohort (AUC: 0.793).

Conclusion: This study provides comprehensive insights into the role of GBP1 in a pan-cancer manner. We identify GBP1 expression as a predictive biomarker for immunotherapy, potentially enabling more precise and personalized immunotherapeutic strategies in the future.
Anti-Mouse CD83 Monoclonal Antibody Targeting Mature Dendritic Cells Provides Protection Against Collagen Induced Arthritis
Authors: Silveira Pablo A. , Kupresanin Fiona , Romano Adelina , Hsu Wei-Hsun , Lo Tsun-Ho , Ju Xinsheng , Chen Hsiao-Ting , Roberts Helen , Baker Daniel G. , Clark Georgina J.
Published: February 2022

Antibodies targeting the activation marker CD83 can achieve immune suppression by targeting antigen-presenting mature dendritic cells (DC). This study investigated the immunosuppressive mechanisms of anti-CD83 antibody treatment in mice and tested its efficacy in a model of autoimmune rheumatoid arthritis. A rat anti-mouse CD83 IgG2a monoclonal antibody, DCR-5, was developed and functionally tested in mixed leukocyte reactions, demonstrating depletion of CD83+conventional (c)DC, induction of regulatory DC (DCreg), and suppression of allogeneic T cell proliferation. DCR-5 injection into mice caused partial splenic cDC depletion for 2–4 days (mostly CD8+and CD83+cDC affected) with a concomitant increase in DCreg and regulatory T cells (Treg). Mice with collagen induced arthritis (CIA) treated with 2 or 6 mg/kg DCR-5 at baseline and every three days thereafter until euthanasia at day 36 exhibited significantly reduced arthritic paw scores and joint pathology compared to isotype control or untreated mice. While both doses reduced anti-collagen antibodies, only 6 mg/kg achieved significance. Treatment with 10 mg/kg DCR-5 was ineffective. Immunohistological staining of spleens at the end of CIA model with CD11c, CD83, and FoxP3 showed greater DC depletion and Treg induction in 6 mg/kg compared to 10 mg/kg DCR-5 treated mice. In conclusion, DCR-5 conferred protection from arthritis by targeting CD83, resulting in selective depletion of mature cDC and subsequent increases in DCreg and Treg. This highlights the potential for anti-CD83 antibodies as a targeted therapy for autoimmune diseases.
Neuroimmunology of Common Parasitic Infections in Africa
Authors: Idro Richard , Ogwang Rodney , Barragan Antonio , Raimondo Joseph Valentino , Masocha Willias
Published: February 2022

Parasitic infections of the central nervous system are an important cause of morbidity and mortality in Africa. The neurological, cognitive, and psychiatric sequelae of these infections result from a complex interplay between the parasites and the host inflammatory response. Here we review some of the diseases caused by selected parasitic organisms known to infect the nervous system includingPlasmodium falciparum,Toxoplasma gondii,Trypanosoma bruceispp., andTaenia soliumspecies. For each parasite, we describe the geographical distribution, prevalence, life cycle, and typical clinical symptoms of infection and pathogenesis. We pay particular attention to how the parasites infect the brain and the interaction between each organism and the host immune system. We describe how an understanding of these processes may guide optimal diagnostic and therapeutic strategies to treat these disorders. Finally, we highlight current gaps in our understanding of disease pathophysiology and call for increased interrogation of these often-neglected disorders of the nervous system.
A DNA-Methylation-Driven Genes Based Prognostic Signature Reveals Immune Microenvironment in Pancreatic Cancer
Authors: Xiao Mingjia , Liang Xiangjing , Yan Zhengming , Chen Jingyang , Zhu Yaru , Xie Yuan , Li Yang , Li Xinming , Gao Qingxiang , Feng Feiling , Fu Gongbo , Gao Yi
Published: February 2022

Pancreatic cancer (PACA), which is characterized by an immunosuppressive nature, remains one of the deadliest malignancies worldwide. Aberrant DNA methylation (DNAm) reportedly influences tumor immune microenvironment. Here, we evaluated the role of DNA methylation driven genes (MDGs) in PACA through integrative analyses of epigenomic, transcriptomic, genomic and clinicopathological data obtained from TCGA, ICGC, ArrayExpress and GEO databases. Thereafter, we established a four-MDG signature, comprising GPRC5A, SOWAHC, S100A14, and ARNTL2. High signature risk-scores were associated with poor histologic grades and late TNM stages. Survival analyses showed the signature had a significant predictive effect on OS. WGCNA revealed that the signature may be associated with immune system, while high risk-scores might reflect immune dysregulation. Furthermore, GSEA and GSVA revealed significant enrichment of p53 pathway and mismatch repair pathways in high risk-score subgroups. Immune infiltration analysis showed that CD8+ T cells were more abundant in low score subgroups, while M0 macrophages exhibited an opposite trend. Moreover, negative regulatory genes of cancer-immunity cycle (CIC) illustrated that immunosuppressors TGFB1, VEGFA, and CD274 (PDL1) were all positively correlated with risk-scores. Furthermore, the four signature genes were negatively correlated with CD8+ lymphocytes, but positively associated with myeloid derived suppressor cells (MDSC). Conversely, specimens with high risk-scores exhibited heavier tumor mutation burdens (TMB) and might show better responses to some chemotherapy and targeted drugs, which would benefit stratification of PACA patients. On the other hand, we investigated the corresponding proteins of the four MDGs using paraffin-embedded PACA samples collected from patients who underwent radical surgery in our center and found that all these four proteins were elevated in cancerous tissues and might serve as prognostic markers for PACA patients, high expression levels indicated poor prognosis. In conclusion, we successfully established a four-MDG-based prognostic signature for PACA patients. We envisage that this signature will help in evaluation of intratumoral immune texture and enable identification of novel stratification biomarkers for precision therapies.
Establishment of Chimerism and Organ Transplant Tolerance in Laboratory Animals: Safety and Efficacy of Adaptation to Humans
Authors: Lowsky Robert , Strober Samuel
Published: February 2022

The definition of immune tolerance to allogeneic tissue and organ transplants in laboratory animals and humans continues to be the acceptance of the donor graft, rejection of third-party grafts, and specific unresponsiveness of recipient immune cells to the donor alloantigens in the absence of immunosuppressive treatments. Actively acquired tolerance was achieved in mice more than 60 years ago by the establishment of mixed chimerism in neonatal mice. Once established, mixed chimerism was self-perpetuating and allowed for acceptance of tissue transplants in adults. Successful establishment of tolerance in humans has now been reported in several clinical trials based on the development of chimerism after combined transplantation of hematopoietic cells and an organ from the same donor. This review examines the mechanisms of organ graft acceptance after establishment of mixed chimerism (allo-tolerance) or complete chimerism (self-tolerance), and compares the development of graft versus host disease (GVHD) and graft versus tumor (GVT) activity in complete and mixed chimerism. GVHD, GVT activity, and complete chimerism are also discussed in the context of bone marrow transplantation to treat hematologic malignancies. The roles of transient versus persistent mixed chimerism in the induction and maintenance of tolerance and organ graft acceptance in animal models and clinical studies are compared. Key differences in the stability of mixed chimeras and tolerance induction in MHC matched and mismatched rodents, large laboratory animals, and humans are examined to provide insights into the safety and efficacy of translation of results of animal models to clinical trials.
CD39/CD73 Dysregulation of Adenosine Metabolism Increases Decidual Natural Killer Cell Cytotoxicity: Implications in Unexplained Recurrent Spontaneous Abortion
Authors: Zhu Jianan , Song Guangmin , Zhou Xiaobo , Han Ting-Li , Yu Xinyang , Chen Hao , Mansell Toby , Novakovic Boris , Baker Philip N. , Cannon Richard D. , Saffery Richard , Chen Chang , Zhang Hua
Published: February 2022

Unexplained recurrent spontaneous abortion (URSA) is believed to be associated with impaired immunosuppression at the maternal-fetal interface, but the detailed molecular mechanism remains unclear. The ATP-adenosine metabolic pathway regulated by CD39/CD73 has recently been recognized to be important in immunosuppression. This study aimed to investigate the regulation of decidual natural killer (dNK) cells and fetal extravillous trophoblast (EVT) cells by CD39 and CD73 in URSA, as well as the possible regulatory mechanism of CD39/CD73 via the TGF-β-mTOR-HIF-1α pathway using clinical samples and cell models. Fewer CD39+ and CD73+ cells were found in the URSA decidual and villous tissue, respectively. Inhibition of CD39 on dNK cells transformed the cells to an activated state with increased toxicity and decreased apoptosis, and changed their cytokine secretion, leading to impaired invasion and proliferation of the co-cultured HTR8/SVneo cells. Similarly, inhibition of CD73 on HTR8/SVneo cells decreased the adenosine concentration in the cell culture media, increased the proportion of CD107a+ dNK cells, and decreased the invasion and proliferation capabilities of the HTR8/SVneo cells. In addition, transforming growth factor-β (TGF-β) triggered phosphorylation of mammalian target of rapamycin (mTOR) and Smad2/Smad3, which subsequently activated hypoxia-inducible factor-1α (HIF-1α) to induce the CD73 expression on the HTR8/SVneo cells. In summary, reduced numbers of CD39+ and CD73+ cells at the maternal-fetal interface, which may be due to downregulated TGF-β-mTOR-HIF-1α pathway, results in reduced ATP-adenosine metabolism and increased dNK cytotoxicity, and potentially contributes to URSA occurrences.
CD3+CD4-CD8- (Double-Negative) T Cells in Inflammation, Immune Disorders and Cancer
Authors: Wu Zhiheng , Zheng Yu , Sheng Jin , Han Yicheng , Yang Yanyan , Pan Hongming , Yao Junlin
Published: February 2022

The crucial role of CD4+ and CD8+ T cells in shaping and controlling immune responses during immune disease and cancer development has been well established and used to achieve marked clinical benefits. CD3+CD4-CD8- double-negative (DN) T cells, although constituting a rare subset of peripheral T cells, are gaining interest for their roles in inflammation, immune disease and cancer. Herein, we comprehensively review the origin, distribution and functions of this unique T cell subgroup. First, we focused on characterizing multifunctional DN T cells in various immune responses. DN regulatory T cells have the capacity to prevent graft-versus-host disease and have therapeutic value for autoimmune disease. T helper-like DN T cells protect against or promote inflammation and virus infection depending on the specific settings and promote certain autoimmune disease. Notably, we clarified the role of DN tumor-infiltrating lymphocytes and outlined the potential for malignant proliferation of DN T cells. Finally, we reviewed the recent advances in the applications of DN T cell-based therapy for cancer. In conclusion, a better understanding of the heterogeneity and functions of DN T cells may help to develop DN T cells as a potential therapeutic tool for inflammation, immune disorders and cancer.
Sulforaphane Exerts Beneficial Immunomodulatory Effects on Liver Tissue via a Nrf2 Pathway-Related Mechanism in a Murine Model of Hemorrhagic Shock and Resuscitation
Authors: Liang Weiqiang , Greven Johannes , Qin Kang , Fragoulis Athanassios , Horst Klemens , Bläsius Felix , Wruck Christoph , Pufe Thomas , Kobbe Philipp , Hildebrand Frank , Lichte Philipp
Published: February 2022

Our research explores the immunomodulatory effects of sulforaphane (SFN), a well-known nuclear factor erythroid 2-related factor 2 (Nrf2) pathway agonist, on the sterile inflammation of and ischemia-reperfusion injuries to the liver after hemorrhagic shock (HS) followed by resuscitation (R). Male C57/BL6 wild-type and transgenic ARE-luc mice were exposed to mean arterial pressure-controlled HS. Fluid resuscitation was performed after 90 min of HS, and SFN was administrated intraperitoneally after that. The animals were sacrificed at 6 h, 24 h, and 72 h after resuscitation, and their livers were extracted to perform H&E staining and myeloperoxidase (MPO) activity analysis. The Kupffer cells were isolated for cytokines profile measurements and Nrf2 immunofluorescence staining. Further, the ARE-luc mice were used to assess hepatic Nrf2 activity in vivo. We identified that SFN-activated Kupffer cells’ Nrf2 pathway and modulated its cytokines expression, including TNF-α, MCP-1, KC/CXCL1, IL-6, and IL-10. Furthermore, SFN mitigated liver ischemia-reperfusion injury, as evidenced by the downregulation of the Suzuki score and the enhanced hepatic Nrf2 activity. The in vivo SFN treatment decreased neutrophils infiltration, as shown by the decreased MPO levels. Our study shows that SFN can decrease HS/R-induced hepatic ischemia-reperfusion injury and modulate the activity of Kupffer cells via an Nrf2-dependent pathway.
High TRGV 9 Subfamily Expression Marks an Improved Overall Survival in Patients With Acute Myeloid Leukemia
Authors: Kong Xueting , Zheng Jiamian , Liu Xiaxin , Wang Wandi , Jiang Xuan , Chen Jie , Lai Jing , Jin Zhenyi , Wu Xiuli
Published: February 2022

Background

Heterogeneous T cells in acute myeloid leukemia (AML) have the combinatorial variety generated by different T cell receptors (TCRs). γδ T cells are a distinct subgroup of T cells containing TCRγ (TRGV) and TCRδ (TRDV) subfamilies with diverse structural and functional heterogeneity. Our previous study showed that clonally expanded TRDV T cells might benefit the immune response directed against AML. However, the features of the TRGV repertoire in AML remain unknown. To fully characterize the features of γδ T cells, we analyzed the distribution and clonality of TRGV I-III subfamilies (TRGV II is also termed TRVG 9), the proportions of γδ T cell subsets, and their effects on the overall survival (OS) of patients with AML.

Methods

In this study, the complementarity-determining region 3 (CDR3) size of TRGV subfamilies in γδ T cells of peripheral blood (PB) from de novo AML patients were analyzed by Genescan analysis. Expression levels of TRGV subfamilies were performed by real-time quantitative PCR. The proportions of total γδ T cells and their Vγ9+ Vδ2+ T cells subsets were detected by multicolor flow cytometry assay. We further compared the correlation among the TRGV gene expression levels, the proportion of Vγ9+ Vδ2+ T cells, and OS in AML.

Results

We first found that the distribution pattern and clonality of TRGV subfamilies were changed. The expression frequencies and gene expression levels of three TRGV subfamilies in AML samples were significantly lower than those in healthy individuals (HIs). Compared with HIs, the proportions of total γδ T cells and Vγ9+ Vδ2+ T cells were also significantly decreased in patients with AML. In addition, patients with AML who had higher expression levels of the TRGV gene and higher proportion of Vγ9+ Vδ2+ T cells showed better OS than their counterparts. Furthermore, high expression levels of TRGV 9 and proportion of Vγ9+ Vδ2+ T cells were identified as independent protective factors for complete remission in patients with AML.

Conclusions

The restriction of TRGV usage might be related to the preference of usage of γδ T cells. Higher expression of TRGV subfamilies might be associated with better OS in AML. Higher TRGV 9 expression and increased Vγ9+ Vδ2+ T cells subfamilies might indicate a better prognosis in patients with AML.
Comprehensive Transcriptomic and Metabolomic Analysis of the Litopenaeus vannamei Hepatopancreas After WSSV Challenge
Authors: Yu Dianjiang , Zhai Yufeng , He Peimin , Jia Rui
Published: February 2022

Litopenaeus vannamei is the major farmed shrimp species worldwide. White spot disease due to white spot syndrome virus (WSSV) is severely affecting shrimp worldwide, causing extensive economic losses in L. vannamei culture. This is the first study that applied combined transcriptomic and metabolomic analysis to study the effects on the L. vannamei hepatopancreas after WSSV challenge. Our transcriptomic data revealed differentially expressed genes (DEGs) associated with immunity, apoptosis, the cytoskeleton and the antioxidant system in the hepatopancreas of L. vannamei. Metabolomic results showed that WSSV disrupts metabolic processes including amino acid metabolism, lipid metabolism and nucleotide metabolism. After challenged by WSSV, immune-related DEGs and differential metabolites (DMs) were detected in the hepatopancreas of L. vannamei, indicating that WSSV may damage the immune system and cause metabolic disorder in the shrimp. In summary, these results provide new insights into the molecular mechanisms underlying L. vannamei’s response to WSSV.