bluuebunny/crossref_metadata_2025 huggingface dataset:
Resveratrol-Loaded TPGS-Resveratrol-Solid Lipid Nanoparticles for Multidrug-Resistant Therapy of Breast Cancer: In Vivo and In Vitro Study
Authors: Wang Wenrui , Zhou Mengyang , Xu Yang , Peng Wei , Zhang Shiwen , Li Rongjie , Zhang Han , Zhang Hui , Cheng Shumin , Wang Youjing , Wei Xinyu , Yue Chengxu , Yang Qingling , Chen Changjie
Published: December 2021

Multidrug resistance (MDR) is a serious problem during cancer therapy. The purpose of the present study was to formulate D-α-Tocopheryl polyethylene glycol 1000 succinate-resveratrol-solid lipid nanoparticles (TPGS-Res-SLNs) to improve its therapeutic efficacy against breast cancer. In this study, the solvent injection method was used to prepare the TPGS-Res-SLNs. It was found that the TPGS-Res-SLNs exhibited zeta potential and drug-loading of −25.6 ± 1.3 mV and 32.4 ± 2.6%, respectively. Therefore, it was evident that the TPGS-Res-SLNs can increase cellular uptake of chemotherapeutic drugs, induce mitochondrial dysfunction, and augment tumor treatment efficiency by inducing apoptosis. Moreover, it was found that SKBR3/PR cells treated with TPGS-Res-SLNs exhibited significant inhibition of cell migration and invasion, as compared with free resveratrol. In addition, results from in vivo SKBR3/PR xenograft tumor models revealed that TPGS-Res-SLNs has better efficacy in promoting apoptosis of tumor cells owing to high therapeutic outcomes on tumors when compared with the efficacy of free resveratrol. In conclusion, the findings of the present study indicate significant potential for use of TPGS-Res-SLNs as an efficient drug delivery vehicle to overcome drug resistance in breast cancer therapy.
Multifunctional Coatings of Titanium Implants Toward Promoting Osseointegration and Preventing Infection: Recent Developments
Authors: Lu Xiaoxuan , Wu Zichen , Xu Kehui , Wang Xiaowei , Wang Shuang , Qiu Hua , Li Xiangyang , Chen Jialong
Published: December 2021

Titanium and its alloys are dominant material for orthopedic/dental implants due to their stable chemical properties and good biocompatibility. However, aseptic loosening and peri-implant infection remain problems that may lead to implant removal eventually. The ideal orthopedic implant should possess both osteogenic and antibacterial properties and do proper assistance to in situ inflammatory cells for anti-microbe and tissue repair. Recent advances in surface modification have provided various strategies to procure the harmonious relationship between implant and its microenvironment. In this review, we provide an overview of the latest strategies to endow titanium implants with bio-function and anti-infection properties. We state the methods they use to preparing these efficient surfaces and offer further insight into the interaction between these devices and the local biological environment. Finally, we discuss the unmet needs and current challenges in the development of ideal materials for bone implantation.
A Label-Free Immunosensor Based on Gold Nanoparticles/Thionine for Sensitive Detection of PAT Protein in Genetically Modified Crops
Authors: Yang Qianwen , Wang Yu , Liu Xiaofeng , Liu Hua , Bao Huifang , Wang Jinbin , Zeng Haijuan
Published: December 2021

Genetically modified (GM) crops containing phosphinothricin acetyltransferase (PAT) protein has been widely planted worldwide. The development of a rapid method for detecting PAT protein is of great importance to food supervision. In this study, a simple label-free electrochemical immunosensor for the ultrasensitive detection of PAT protein was constructed using thionine (Thi)/gold nanoparticles (AuNPs) as signal amplification molecules and electrochemically active substances. Under optimum conditions, the limits of detection of the sensor for soybean A2704-12 and maize BT-176 were 0.02% and 0.03%, respectively. The sensor could detect crops containing PAT protein and had no cross-reaction with other proteins. After storage at 4°C for 33 days, the sensor still retained 82.5% of the original signal, with a relative standard deviation (RSD) of 0.92%. The recoveries of the sensor for soybean A2704-12 and maize BT-176 were 85%–108% and 98%–113%, respectively. The developed PAT-target immunosensor with high sensitivity, specificity, and satisfactory reproducibility and accuracy will be a useful tool in the trace screening of GM crops. Moreover, this design concept can be extended to other proteins by simply changing the antibody.
Gut Microbiota Exceeds Cervical Microbiota for Early Diagnosis of Endometriosis
Authors: Huang Liujing , Liu Bingdong , Liu Zhihong , Feng Wanqin , Liu Minjuan , Wang Yifeng , Peng Dongxian , Fu Xiafei , Zhu Honglei , Cui Zongbin , Xie Liwei , Ma Ying
Published: December 2021

The diagnosis of endometriosis is typically delayed by years for the unexclusive symptom and the traumatic diagnostic method. Several studies have demonstrated that gut microbiota and cervical mucus potentially can be used as auxiliary diagnostic biomarkers. However, none of the previous studies has compared the robustness of endometriosis classifiers based on microbiota of different body sites or demonstrated the correlation among microbiota of gut, cervical mucus, and peritoneal fluid of endometriosis, searching for alternative diagnostic approaches. Herein, we enrolled 41 women (control, n = 20; endometriosis, n = 21) and collected 122 well-matched samples, derived from feces, cervical mucus, and peritoneal fluid, to explore the nature of microbiome of endometriosis patients. Our results indicated that microbial composition is remarkably distinguished between three body sites, with 19 overlapped taxa. Moreover, endometriosis patients harbor distinct microbial communities versus control group especially in feces and peritoneal fluid, with increased abundance of pathogens in peritoneal fluid and depletion of protective microbes in feces. Particularly, genera of Ruminococcus and Pseudomonas were identified as potential biomarkers in gut and peritoneal fluid, respectively. Furthermore, novel endometriosis classifiers were constructed based on taxa selected by a robust machine learning method. These results demonstrated that gut microbiota exceeds cervical microbiota in diagnosing endometriosis. Collectively, this study reveals important insights into the microbial profiling in different body sites of endometriosis, which warrant future exploration into the role of microbiota in endometriosis and highlighted values on gut microbiota in early diagnosis of endometriosis.
Effect of Coronary Disease Characteristics on Prognostic Relevance of Residual Ischemia After Stent Implantation
Authors: Yang Seokhun , Zhang Jinlong , Hwang Doyeon , Lee Joo Myung , Nam Chang-Wook , Shin Eun-Seok , Doh Joon-Hyung , Hoshino Masahiro , Hamaya Rikuta , Kanaji Yoshihisa , Murai Tadashi , Zhang Jun-Jie , Ye Fei , Li Xiaobo , Ge Zhen , Chen Shao-Liang , Kakuta Tsunekazu , Koo Bon-Kwon
Published: December 2021

Objectives: We investigated the influence of coronary disease characteristics on prognostic implications of residual ischemia after coronary stent implantation.

Methods: This study included 1,476 patients with drug-eluting stent implantation and available pre- and post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) measurements. Residual ischemia was defined as post-PCI FFR ≤ 0.80. Coronary disease characteristics with significant interaction hazard ratios (HRs) for clinical outcomes with residual ischemia were defined as interaction characteristics with residual ischemia (ICwRI). The primary outcome was target vessel failure (TVF)—a composite of cardiac death, target vessel myocardial infarction, and target vessel revascularization—at 2 years.

Results: The mean pre- and post-PCI FFR were 0.68 ± 0.11 and 0.87 ± 0.07, respectively. During the median follow-up duration of 2.0 years, the cumulative incidence of TVF was 6.1%. The 203 vessels (13.8%) with residual ischemia had higher risks of TVF compared to that for post-PCI FFR >0.80 (P < 0.001). ICwRI with a significant interaction HR with residual ischemia included pre-PCI SYNTAX score >17 and pre-PCI FFR ≤ 0.62. Each ICwRI had a direct prognostic effect not mediated by residual ischemia. The association between an increased TVF risk and residual ischemia was significant in patients with 0 or 1 ICwRI [hazard ratio (HR) 3.25, 95% confidence interval (CI) 1.90–5.57, P < 0.001] but not in those with 2 ICwRI (HR 0.47, 95% CI 0.14–1.64, P = 0.24). Among patients with post-PCI FFR >0.80, those with 2 ICwRI showed similar TVF risks to those with residual ischemia (HR 1.55, 95% CI 0.79–3.02, P = 0.20).

Conclusions: Coronary disease characteristics including pre-PCI SYNTAX score and pre-PCI FFR affected the prognostic implications of residual ischemia. The prognostic relevance of residual ischemia was attenuated in patients with multiple interacting characteristics.
Histopathological Features and Protein Markers of Arrhythmogenic Cardiomyopathy
Authors: Bueno-Beti Carlos , Asimaki Angeliki
Published: December 2021

Arrhythmogenic cardiomyopathy (ACM) is a heritable heart muscle disease characterized by syncope, palpitations, ventricular arrhythmias and sudden cardiac death (SCD) especially in young individuals. It is estimated to affect 1:5,000 individuals in the general population, with >60% of patients bearing one or more mutations in genes coding for desmosomal proteins. Desmosomes are intercellular adhesion junctions, which in cardiac myocytes reside within the intercalated disks (IDs), the areas of mechanical and electrical cell-cell coupling. Histologically, ACM is characterized by fibrofatty replacement of cardiac myocytes predominantly in the right ventricular free wall though left ventricular and biventricular forms have also been described. The disease is characterized by age-related progression, vast phenotypic manifestation and incomplete penetrance, making proband diagnosis and risk stratification of family members particularly challenging. Key protein redistribution at the IDs may represent a specific diagnostic marker but its applicability is still limited by the need for a myocardial sample. Specific markers of ACM in surrogate tissues, such as the blood and the buccal epithelium, may represent a non-invasive, safe and inexpensive alternative for diagnosis and cascade screening. In this review, we shall cover the most relevant biomarkers so far reported and discuss their potential impact on the diagnosis, prognosis and management of ACM.
Photosynthetic Production Determines Bottom Water Oxygen Variations in the Upwelling Coastal South China Sea Over Recent Decades
Authors: Zhu Xiaowei , Jia Guodong , Tian Yuhang , Mo Aibin , Xu Weihai , Miao Li , Xu Shendong , Yan Wen
Published: December 2021

Dissolved oxygen (DO) in seawater is fundamental to marine ecosystem health. How DO in coastal upwelling areas responds to upwelling intensity under climate change is of particular interest and vital importance, because these productive regions account for a large fraction of global fishery production and marine biodiversity. The Yuedong upwelling (YDU) in the coastal northern South China Sea can be served as a study case to explore long-term responses of DO to upwelling and climate due to minor influence of riverine input. Here, bottom water DO conditions were recovered by sedimentary C28Δ22/Δ5,22 ratios of steroids in three short cores, with lower ratio value indicating higher DO concentration. The ratio records showed oscillations in varying degrees and exhibited no clear trends before ∼1980s, after which, however, there occurred a persistent decreasing trend or basically remained at lower values. Thus, inferred DO variations by the C28Δ22/Δ5,22 ratio records are not compatible with regional YDU-involved physical processes under climate change, such as southwesterly wind-induced onshore advection of reduced-oxygenated source waters from outer shelf and oceanic warming that would rather lead to less oxygenation in bottom waters in recent decades. Intriguingly, the alcohol records of n-C20:1/C28Δ5,22 and br-C15/C28Δ5,22 ratios, indicative of the relative strengths between biogeochemical oxygen consumption (i.e., by zooplankton and microbes) and photosynthetic oxygen production (i.e., by phytoplankton), changed almost in parallel with the C28Δ22/Δ5,22 records in three cores. Accordingly, we propose that net photosynthetic oxygen production outweighs source water– and warming-induced increasing deoxygenation in the study area. This study may suggest an important biogeochemical mechanism in determining bottom water DO dynamics in shallow coastal upwelling regions with minor contribution of riverine input.
Analysis of N6-Methyladenosine Methylation Modification in Fructose-Induced Non-Alcoholic Fatty Liver Disease
Authors: Luo Yunchen , Zhang Zhijian , Xiang Liping , Zhou Bing , Wang Xuejiao , Lin Yi , Ding Xiaoying , Liu Fang , Lu Yan , Peng Yongde
Published: December 2021

Improvements in living standards have led to non-alcoholic fatty liver disease (NAFLD), one of the most common chronic liver diseases worldwide. Recent studies have shown that N6-methyladenosine (m6A), a type of RNA modification, is strongly associated with many important biological processes. However, the relationship between m6A methylation modifications and NAFLD remains poorly understood. In the present study, through methylated RNA immunoprecipitation sequencing and RNA transcriptome sequencing in high fructose diet-induced NAFLD mice, we found that hypermethylation-encoding genes were mainly enriched in lipid metabolism processes. We identified 266 overlapping and differentially expressed genes (DEGs) that changed at both the mRNA expression level and m6A modification level. Among them, 193 genes displayed increased expression and m6A modification, indicating that m6A RNA modifications tend to be positively correlated with NAFLD. We further compared the high fructose diet-induced NAFLD mouse model with leptin receptor-deficient mice and found that DEGs enriched in the lipid metabolism pathway were up-regulated in both groups. In contrast, DEGs associated with the immune inflammatory response were up-regulated in the high fructose diet group, but down-regulated in leptin receptor-deficient mice. Taken together, our results demonstrate that m6A methylation modifications may play an important role in the development of NAFLD.
Evaluating Consumer Acceptance of the Commercial Fleet of Methanol Vehicles in China
Authors: Li Chengjiang , Negnevitsky Michael , Wang Xiaolin , Wang Honglei , Hu Yujie
Published: December 2021

To enhance domestic energy security and reduce air pollution, China has accelerated the deployment of alternative fuel vehicles including methanol vehicles since the 2010s. Already completed pilot projects have demonstrated that methanol vehicles (commercial fleet) are economical, environmentally friendly, and technically mature. Therefore, the Chinese government aims to continually deploy methanol vehicles in coal-rich provinces. There are more than 20,000 methanol taxis in operation in China, it is important to evaluate the existing consumer acceptance of such commercial fleet before commercialization in a wider range. This paper proposes a conceptual model to identify consumer acceptance of methanol taxis. The model generates hypotheses that have been tested using surveys completed by taxi drivers of methanol vehicles in the cities of Xi’an (Shaanxi province) and Guiyang (Guizhou province). Results demonstrate that market, economic, and technological concerns strongly determine the consumer acceptance of the commercial fleet of methanol vehicles in China.
Urban Environments Aid Invasion of Brown Widows (Theridiidae: Latrodectus geometricus) in North America, Constraining Regions of Overlap and Mitigating Potential Impact on Native Widows
Authors: Sadir Melissa , Marske Katharine A.
Published: December 2021

Urbanization is a major cause of biotic homogenization and habitat fragmentation for native communities. However, the role of urbanization on the success of biological invasions on a continental scale has yet to be explored. Urbanization may facilitate the establishment success of invasive species by minimizing niche differentiation between native and invaded ranges. In such cases, we might expect anthropogenic variables to have stronger influence on the geographic distribution of invasive compared to native populations. In this study, we use ecological niche modeling to define the distribution of non-native brown widow spider (Latrodectus geometricus) and three native black widows (L. hespersus, L. mactans, L. variolus) in North America and gauge the importance of urbanization on the geographic ranges of widows at a continental scale. We also quantify the geographic overlap of L. geometricus with each native widow to assess potential species and regions at risk of ecological impact. Consistent with our hypothesis, we find that the distribution of L. geometricus is strongly constrained to urban environments, while native widow distributions are more strongly driven by climatic factors. These results show that urbanization plays a significant role in facilitating the success of invasion, weakening the significance of climate on the realized niche in its invaded range.
Beyond the Tree-Line: The C3-C4 “Grass-Line” Can Track Global Change in the World’s Grassy Mountain Systems
Authors: de Deus Vidal João , le Roux Peter C. , Johnson Steven D. , te Beest Mariska , Clark Vincent Ralph
Published: December 2021

von Humboldt’s tree-line concept has dominated mountain ecology for almost two hundred years, and is considered a key indicator for monitoring change in biome boundaries and biodiversity shifts under climate change. Even though the concept of life zones and elevation gradients are a globally observed phenomenon, they have not been thoroughly explored for many contexts. One such example is the tree-line ecotone, a widely used conceptual tool to track climate change in many regions, which has limited application in the widespread tree-sparse, grassy systems that comprise a third of the world’s mountain systems. Among grasses (Poaceae), temperature is linked to variation in photosynthetic performance and community dominance for C3 and C4 metabolic groups, due to its role in limiting photorespiration in the C3 photosynthesis process. Here, we investigate this community shift in grassland-dominated mountains to demonstrate the role of climate in driving this transition and discuss the potential applications of this tool to mountain ecosystem conservation worldwide. For identifying grass-dominated mountains worldwide, we measured the grass-cover using satellite data. We then compiled Poaceae distribution data for ten grass-dominated mountains spanning from 42°S to 41°N and determined the temperature intervals and elevation ranges at which each genus was found, testing for effects of temperature, precipitation, and latitudinal gradients on the dominance of C3-C4 grasses. Temperature was the main driver of C3 dominance, with the richness of C3 genera tending to surpass the taxonomic dominance of C4 plants along mountain temperature gradients where the annual mean temperature was colder than ca. 14.6°C. Similar patterns were observed in eight out of ten mountains, suggesting that this may constitute an isotherm-driven ecotone. Consequently, this C3-C4 transition offers a promising tool for monitoring climate change impacts in grassy mountains. C3-C4 grass community shifts in response to environmental change will likely have major implications for fire frequency and severity, rangeland productivity and livelihoods, food security, and water budgets in mountain systems. Given the severity of the implications of global change on these social-ecological systems, we propose that a “grass-line” monitoring protocol be developed for global application.
Selection Forces Driving Herding of Herbivorous Insect Larvae
Authors: Despland Emma
Published: December 2021

Herding behavior is widespread among herbivorous insect larvae across several orders. These larval societies represent one of several different forms of insect sociality that have historically received less attention than the well-known eusocial model but are showing us that social diversity in insects is broader than originally imagined. These alternative forms of sociality often focus attention on the ecology, rather than the genetics, of sociality. Indeed, mutually beneficial cooperation among individuals is increasingly recognized as important relative to relatedness in the evolution of sociality, and I will explore its role in larval insect herds. Larval herds vary in in the complexity of their social behavior but what they have in common includes exhibiting specialized social behaviors that are ineffective in isolated individuals but mutually beneficial in groups. They hence constitute cooperation with direct advantages that doesn’t require kinship between cooperators to be adaptive. Examples include: trail following, head-to-tail processions and other behaviors that keep groups together, huddling tightly to bask, synchronized biting and edge-feeding to overwhelm plant defenses, silk production for shelter building or covering plant trichomes and collective defensive behaviors like head-swaying. Various selective advantages to group living have been suggested and I propose that different benefits are at play in different taxa where herding has evolved independently. Proposed benefits include those relative to selection pressure from abiotic factors (e.g., thermoregulation), to bottom-up pressures from plants or to top-down pressures from natural enemies. The adaptive value of herding cooperation must be understood in the context of the organism’s niche and suite of traits. I propose several such suites in herbivorous larvae that occupy different niches. First, some herds aggregate to thermoregulate collectively, particularly in early spring feeders of the temperate zone. Second, other species aggregate to overwhelm host plant defenses, frequently observed in tropical species. Third, species that feed on toxic plants can aggregate to enhance the warning signal produced by aposematic coloration or stereotyped defensive behaviors. Finally, the combination of traits including gregariousness, conspicuous behavior and warning signals can be favored by a synergy between bottom-up and top-down selective forces. When larvae on toxic plants aggregate to overcome plant defenses, this grouping makes them conspicuous to predators and favors warning signals. I thus conclude that a single explanation is not sufficient for the broad range of herding behaviors that occurs in phylogenetically diverse insect larvae in different environments.
Genetic Factors Underlying Single Fiber Quality in A-Genome Donor Asian Cotton (Gossypium arboreum)
Authors: Iqbal Muhammad Shahid , Tang Shurong , Sarfraz Zareen , Iqbal Muhammad Sajid , Li Hongge , He Shoupu , Jia Yinhua , Sun Gaofei , Pan Zhaoe , Xiaoli Geng , Mahmood Abid , Ahmad Saghir , Nazir Mian Faisal , Chen Baojun , Wang Liru , Pang Baoyin , Wei Shoujun , Du Xiongming
Published: December 2021

The study of A-genome Asian cotton as a potential fiber donor in Gossypium species may offer an enhanced understanding of complex genetics and novel players related to fiber quality traits. Assessment of individual fibers providing classified fiber quality information to the textile industry is Advanced Fiber Information System (AFIS) in the recent technological era. Keeping the scenario, a diverse collection of 215 Asiatic cotton accessions were evaluated across three agro-ecological zones of China. Genome-Wide Association Studies (GWAS) was performed to detect association signals related to 17 AFIS fiber quality traits grouped into four categories viz: NEPs, fiber length, maturity, and fineness. Significant correlations were found within as well as among different categories of various traits related to fiber quality. Fiber fineness has shown a strong correlation to all other categories, whereas these categories are shown interrelationshipsviafiber-fineness. A total of 7,429 SNPs were found in association with 17 investigated traits, of which 177 were selected as lead SNPs. In the vicinity of these lead SNPs, 56 differentially expressed genes in various tissues/development stages were identified as candidate genes. This compendium connecting trait-SNP-genes may allow further prioritization of genes in GWAS loci to enable mechanistic studies. These identified quantitative trait nucleotides (QTNs) may prove helpful in fiber quality improvement in Asian cotton through marker-assisted breeding as well as in reviving eroded genetic factors ofG.hirsutum viaintrogression breeding.
tascCODA: Bayesian Tree-Aggregated Analysis of Compositional Amplicon and Single-Cell Data
Authors: Ostner Johannes , Carcy Salomé , Müller Christian L.
Published: December 2021

Accurate generative statistical modeling of count data is of critical relevance for the analysis of biological datasets from high-throughput sequencing technologies. Important instances include the modeling of microbiome compositions from amplicon sequencing surveys and the analysis of cell type compositions derived from single-cell RNA sequencing. Microbial and cell type abundance data share remarkably similar statistical features, including their inherent compositionality and a natural hierarchical ordering of the individual components from taxonomic or cell lineage tree information, respectively. To this end, we introduce a Bayesian model fortree-aggregatedamplicon andsingle-cellcompositionaldataanalysis (tascCODA) that seamlessly integrates hierarchical information and experimental covariate data into the generative modeling of compositional count data. By combining latent parameters based on the tree structure with spike-and-slab Lasso penalization, tascCODA can determine covariate effects across different levels of the population hierarchy in a data-driven parsimonious way. In the context of differential abundance testing, we validate tascCODA’s excellent performance on a comprehensive set of synthetic benchmark scenarios. Our analyses on human single-cell RNA-seq data from ulcerative colitis patients and amplicon data from patients with irritable bowel syndrome, respectively, identified aggregated cell type and taxon compositional changes that were more predictive and parsimonious than those proposed by other schemes. We posit that tascCODA1constitutes a valuable addition to the growing statistical toolbox for generative modeling and analysis of compositional changes in microbial or cell population data.
miR-10c Facilitates White Spot Syndrome Virus Infection by Targeting Toll3 in Litopenaeus vannemei
Authors: Zuo Hongliang , Liu Xinxin , Luo Mengting , Yang Linwei , Zhu Zhiming , Weng Shaoping , He Jianguo , Xu Xiaopeng
Published: December 2021

Toll-like receptors (TLRs) are canonical cell membrane receptors functioning to recognize pathogens and transduce signals to activate immune responses. It has been known that Toll3 in Pacific white shrimp Litopenaeus vannamei (LvToll3) plays a critical role in antiviral immunity by inducing the transcription of interferon regulatory factor (IRF), which mediates a signaling axis that is similar to the interferon system of vertebrates. However, the regulatory mechanism of the Toll3-IRF signaling is still unclear. In this study, a novel microRNA (miRNA) of miR-10 family, temporarily named as miR-10c, was identified from L. vannamei. miR-10c may play a nonnegligible regulatory role in shrimp immune responses since it was constitutively expressed in all detected tissues and transcriptionally induced by immune stimulation. Functional analysis validated that miR-10c could target LvToll3 to inhibit its expression, through which miR-10c blocked the nuclear translocation of IRF and facilitated white spot syndrome virus (WSSV) infection. To our knowledge, the present study revealed the first report of a Toll targeted by miRNA in crustaceans and provided a solid evidence base for supporting the role of LvToll3 in antiviral defense by activating IRF signaling in L. vannamei. Identification of the miR-10c/Toll3/IRF regulatory axis in shrimp provides new insights into the participation of miRNA in the regulation of immune responses and contributes to in-depth understanding of the mechanisms of Toll-induced immune responses in L. vannamei.
Activation of the TCA Cycle to Provide Immune Protection in Zebrafish Immunized by High Magnesium-Prepared Vibrio alginolyticus Vaccine
Authors: Yang Jun , Yang Xiao-li , Su Yu-bin , Peng Xuan-xian , Li Hui
Published: December 2021

Vaccines are safe and efficient in controlling bacterial diseases in the aquaculture industry and are in line with green farming. The present study develops a previously unreported approach to prepare a live-attenuated V. alginolyticus vaccine by culturing bacteria in a high concentration of magnesium to attenuate bacterial virulence. Furthermore, metabolomes of zebrafish immunized with the live-attenuated vaccines were compared with those of survival and dying zebrafish infected by V. alginolyticus. The enhanced TCA cycle and increased fumarate were identified as the most key metabolic pathways and the crucial biomarker of vaccine-mediated and survival fish, respectively. Exogenous fumarate promoted expression of il1β, il8, il21, nf-κb, and lysozyme in a dose-dependent manner. Among the five innate immune genes, the elevated il1β, il8, and lysozyme are overlapped in the vaccine-immunized zebrafish and the survival from the infection. These findings highlight a way in development of vaccines and exploration of the underlying mechanisms.
Association Between Interleukin 35 Gene Single Nucleotide Polymorphisms and the Uveitis Immune Status in a Chinese Han Population
Authors: Feng Meng , Zhou Shuping , Liu Tong , Yu Yong , Su Qinghong , Li Xiaofan , Zhang Min , Xie Xiao , Liu Tingting , Lin Wei
Published: December 2021

Autoimmune uveitis is characterized by immune disorders of the eyes and the whole body and is often recurrent in young adults, but its pathogenesis is still unclear. IL-35 is an essential regulatory factor in many autoimmune diseases, which is produced by Breg cells and can induce Breg cells to regulate the immune response. The relationship between the expression and gene polymorphism of IL-35 and the immune status of patients with autoimmune uveitis has not been reported. The peripheral blood of the subjects was collected from patients with Behçet’s Disease (BD) and those with Vogt–Koyanagi–Harada (VKH) syndrome. The percentage of immune cell subsets including B cells, DC, and T cells, and the expression of IL-35 in serum of these two kinds of disease were analyzed. And then, the associations between seven IL-35 single nucleotide polymorphism (SNP) sites and disease susceptibility, the immune status, the clinical characteristics, and the serum IL-35 levels were analyzed. Our results showed that the percentage of Breg cells was significantly decreased in the blood of patients with VKH syndrome compared to that of healthy controls. The levels of IL-35 in the serum of patients with VKH syndrome or BD patients were not changed significantly, compared to that of healthy controls. Furthermore, the associations between two subunits of IL-35 (IL-12p35 and EBI3) and BD or VKH patients were analyzed. We found that there was an association between the EBI3 rs428253 and the occurrence of BD. There was an association between the IL-12p35 rs2243131 and the low level of Breg cell of VKH patients. In addition, there were associations between the polymorphisms of EBI3 rs4740 and the occurrence of headache and tinnitus of VKH patients, respectively. And the genotype frequency of IL-12p35 rs2243115 was related to the concentration of serum IL-35 in patients with VKH syndrome. Thus, the specific SNP sites change of IL-35 were correlated to the immune disorders in uveitis. And they may also play a guiding role in the occurrence of clinical symptoms in patients with uveitis, especially for VKH syndrome.
Multiple Tolerization Subtractive Immunization (MTSI) Protocol: Effects on Mice and Monoclonal Antibody Specificity
Authors: de Lima Fontes Marina , Neves Franciny Mara de Lima , Santos Kelvin Sousa , Fusco-Almeida Ana Marisa , Giannini Maria José Soares Mendes , Felisbino Sergio Luis , Deffune Elenice , Moroz Andrei
Published: December 2021

Monoclonal antibodies (mAbs) have been a valuable tool to elucidate several biological processes, such as stem cell differentiation and cancer, and contributed to virtually all areas of biomedical sciences. Yet, it remains a challenge to obtain mAbs specific to poorly expressed epitopes, or to epitopes that are actually involved in important biological phenomena, such as cell differentiation and metastasis. Drug-induced subtractive immunization, and recently the multiple tolerization subtractive immunization (MTSI) technique, reported by our group, have the potential to level up the field, as they direct the host´s immune response towards these epitopes. However, due to cyclophosphamide (CY) treatment, high mice mortality can be observed, and only a few data are available on how these techniques affect the immune system of mice. Tolerogen and immunogen cells, RWPE-1 and PC-3 cells, respectively, were individually seeded at 2 × 104 cells/cm2, and then adjusted to 2 × 106 cells per mouse before immunization, which was conducted in a subtractive approach (MTSI) with CY. Immunosuppression of mice was recorded via total white blood counting, as well the reactivity of circulating polyclonal antibodies (pAbs). General parameters, including weight, physical appearance, and behavior on mice subjected to three different concentrations of CY were recorded. mAbs were obtained using classical hybridoma techniques, using the spleen of immunized mice. After purification, antibodies were characterized by Western blotting, and Indirect immunofluorescence. In conclusion, all CY dosage were efficient in creating an immunosuppression state, but only the 100 mg/kg body weight was feasible, as the others resulted in extensive mice mortality. pAbs obtained in the peripheral blood of mice showed more reactivity towards tumor cells. MAbs 2-7A50 and 2-5C11 recognized antigens from tumor cells, but not from their non-tumor counterparts, as shown in western blotting and immunofluorescence assays. MTSI technique was successful in generating mAbs that recognize tumor-specific antigens.
Polarized Macrophages in Periodontitis: Characteristics, Function, and Molecular Signaling
Authors: Sun Xiaoyu , Gao Jike , Meng Xiang , Lu Xiaoxuan , Zhang Lei , Chen Ran
Published: December 2021

Periodontitis (PD) is a common chronic infectious disease. The local inflammatory response in the host may cause the destruction of supporting periodontal tissue. Macrophages play a variety of roles in PD, including regulatory and phagocytosis. Moreover, under the induction of different factors, macrophages polarize and form different functional phenotypes. Among them, M1-type macrophages with proinflammatory functions and M2-type macrophages with anti-inflammatory functions are the most representative, and both of them can regulate the tendency of the immune system to exert proinflammatory or anti-inflammatory functions. M1 and M2 macrophages are involved in the destructive and reparative stages of PD. Due to the complex microenvironment of PD, the dynamic development of PD, and various local mediators, increasing attention has been given to the study of macrophage polarization in PD. This review summarizes the role of macrophage polarization in the development of PD and its research progress.
Protein Diversity and Immune Specificity of Hemocyanin From Shrimp Litopenaeus vannamei
Authors: Zhao Xianliang , Qiao Jie , Zhang Pei , Zhang Zehui , Aweya Jude Juventus , Chen Xiaohan , Zhao Yongzhen , Zhang Yueling
Published: December 2021

Hemocyanin is an important non-specific innate immune defense molecule with phenoloxidase, antiviral, antibacterial, hemolytic, and antitumor activities. To better understand the mechanism of functional diversity, proteomics approach was applied to characterize hemocyanin (HMC) expression profiles from Litopenaeus vannamei. At first, hemocyanin was purified by Sephadex G-100 and DEAE-cellulose (DE-52) columns from shrimp serum, and 34 protein spots were identified as HMC on the 2-DE gels. Furthermore, we found that 9 HMC spots about 75 or 77 kDa were regulated by Streptococcus agalactiae and Vibrio parahaemolyticus infection at 6, 12, and 24 h. In addition, 6 different pathogen-binding HMC fractions, viz., HMC-Mix, HMC-Vp, HMC-Va, HMC-Vf, HMC-Ec, and HMC-Sa, showed different agglutinative and antibacterial activities. Moreover, lectin-blotting analysis showed significant differences in glycosylation level among HMC isomers and bacteria-binding HMC fractions. Particularly, the agglutinative activities of the HMC fractions were almost completely abolished when HMC was deglycosylated by O-glycosidase, which suggest that O-linked sugar chains of HMC played important roles in the innate immune recognition. Our findings demonstrated for the first time that L. vannamei HMC had molecular diversity in protein level, which is closely associated with its ability to recognize diverse pathogens, whereas glycan modification probably contributed to HMC’s diversity and multiple immune activities.
The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer
Authors: Qi Lina , Ye Chenyang , Zhang Ding , Bai Rui , Zheng Shu , Hu Wangxiong , Yuan Ying
Published: December 2021

Background

The homeobox (HOX) gene family encodes highly conserved transcription factors, that play important roles in the morphogenesis and embryonic development of vertebrates. Mammals have four similar HOX gene clusters, HOXA, HOXB, HOXC, and HOXD, which are located on chromosomes 7, 17,12 and 2 and consist of 38 genes. Some of these genes were found to be significantly related to a variety of tumors; however, it remains unknown whether abnormal expression of the HOX gene family affects prognosis and the tumor microenvironment (TME) reshaping in colorectal cancer (CRC). Therefore, we conducted this systematic exploration to provide additional information for the above questions.

Methods

RNA sequencing data from The Cancer Genome Atlas (TCGA) and mRNA expression data from Gene Expression Omnibus (GEO) combined with online tumor analysis databases (UALCAN, TIMER, PrognoScan) were utilized to explore the relationship among abnormal expression of HOX family genes, prognosis and the tumor immune microenvironment in CRC.

Results

1. Differential expression and prognosis analysis: 24 genes were significantly differentially expressed in CRC compared to adjacent normal tissues, and seven upregulated genes were significantly associated with poor survival. Among these seven genes, univariate and multivariate Cox regression analysis revealed that only high expression of HOXC6 significantly contributed to poor prognosis; 2. The influence of overexpressed HOXC6 on the pathway and TME: High HOXC6 expression was significantly related to the cytokine pathway and expression of T cell attraction chemokines, the infiltration ratio of immune cells, expression of immune checkpoint markers, tumor mutation burden (TMB) scores and microsatellite instability-high (MSI-H) scores; 3. Stratified analysis based on stages: In stage IV, HOXC6 overexpression had no significant impact on TMB, MSI-H, infiltration ratio of immune cells and response prediction of immune checkpoint blockers (ICBs), which contributed to significantly poor overall survival (OS).

Conclusion

Seven differentially expressed HOX family genes had significantly worse prognoses. Among them, overexpressed HOXC6 contributed the most to poor OS. High expression of HOXC6 was significantly associated with high immunogenicity in nonmetastatic CRC. Further research on HOXC6 is therefore worthwhile to provide potential alternatives in CRC immunotherapy.
Case Report: Mevalonic Aciduria Complicated by Acute Myeloid Leukemia After Hematopoietic Stem Cell Transplantation
Authors: Kim Hyery , Lee Beom Hee , Do Hyo-Sang , Kim Gu-Hwan , Kang Sunghan , Koh Kyung-Nam , Im Ho Joon
Published: December 2021

Mevalonic aciduria (MA) is the most severe clinical subtype of mevalonate kinase deficiency (MKD) caused by an inherited defect in the mevalonate pathway. The treatment of MKD focuses on the suppression of recurrent hyperinflammatory attacks using anti-inflammatory drugs. Recently, allogeneic hematopoietic stem cell transplantation (HCT) was shown to successfully ameliorate autoinflammatory attacks in patients with MKD. Here, we report a case of an infant who showed severe recurrent systemic inflammation and was diagnosed with MA. Although she responded to steroids, her symptoms relapsed after the dose was tapered, and organ deterioration occurred. Therefore, at the age of 11 months, HCT from a matched, unrelated donor was performed for curative treatment. However, at 50 days after transplantation, acute myeloid leukemia was diagnosed, which was chemo-refractory. A second HCT from her haploidentical father was performed to treat the acute myeloid leukemia, but the patient died of sepsis on day 4 after transplantation. This is the first report of malignancy following HCT for MA. Our findings suggest that normalizing the mevalonate pathway after HCT in patients with MKD impacts patients differently depending on the clinical spectrum and severity of disease.
The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)
Authors: Barca Cristina , Foray Claudia , Hermann Sven , Herrlinger Ulrich , Remory Isabel , Laoui Damya , Schäfers Michael , Grauer Oliver M. , Zinnhardt Bastian , Jacobs Andreas H.
Published: December 2021

Immunomodulatory therapies have fueled interest in targeting microglial cells as part of the innate immune response after infection or injury. In this context, the colony-stimulating factor 1 (CSF-1) and its receptor (CSF-1R) have gained attention in various neurological conditions to deplete and reprogram the microglia/macrophages compartment. Published data in physiological conditions support the use of small-molecule inhibitors to study microglia/macrophages dynamics under inflammatory conditions and as a therapeutic strategy in pathologies where those cells support disease progression. However, preclinical and clinical data highlighted that the complexity of the spatiotemporal inflammatory response could limit their efficiency due to compensatory mechanisms, ultimately leading to therapy resistance. We review the current state-of-art in the field of CSF-1R inhibition in glioma and stroke and provide an overview of the fundamentals, ongoing research, potential developments of this promising therapeutic strategy and further application toward molecular imaging.
CD19+IgD+CD27- Naïve B Cells as Predictors of Humoral Response to COVID 19 mRNA Vaccination in Immunocompromised Patients
Authors: Schulz Eduard , Hodl Isabel , Forstner Patrick , Hatzl Stefan , Sareban Nazanin , Moritz Martina , Fessler Johannes , Dreo Barbara , Uhl Barbara , Url Claudia , Grisold Andrea J. , Khalil Michael , Kleinhappl Barbara , Enzinger Christian , Stradner Martin H. , Greinix Hildegard T. , Schlenke Peter , Steinmetz Ivo
Published: December 2021

Immunocompromised patients are considered high-risk and prioritized for vaccination against COVID-19. We aimed to analyze B-cell subsets in these patients to identify potential predictors of humoral vaccination response. Patients (n=120) suffering from hematologic malignancies or other causes of immunodeficiency and healthy controls (n=79) received a full vaccination series with an mRNA vaccine. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Seroconversion occurred in 100% of healthy controls, in contrast to 67% (RBD) and 82% (TSP) of immunocompromised patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating CD19+IgD+CD27- naïve B cells was strongly associated with antibody levels (ρ=0.761, P<0.001) and the only independent predictor for achieving antibody levels comparable to healthy controls (OR 1.07 per 10-µL increase, 95%CI 1.02–1.12, P=0.009). Receiver operating characteristic analysis identified a cut-off at ≥61 naïve B cells per µl to discriminate between patients with and without an optimal antibody response. Consequently, measuring of naïve B cells in immunocompromised hematologic patients could be useful in predicting their humoral vaccination response.
Species Composition and Assemblages of Ichthyoplankton in Sansha Bay, Fujian Province, China
Authors: Jiang Yan , Lin Bai-an , He Hao-yang , Ding Guang-mao , Yan Li-ting , Zhang Ge , Liu Min , Zheng Lian-ming
Published: December 2021

Sansha Bay (26.40−27.00°N, 119.50−120.20°E) is a typical semi-enclosed bay, located in northern Fujian Province, China, and adjacent to the East China Sea. The ichthyoplankton species composition and assemblage structure were investigated based on monthly sampling at 25 stations in April−September 2019, covering the important spring and summer spawning seasons in the region. Sampling was conducted in the first 3−5 days of the full moon or new moon phases using a standard plankton net through horizontal and vertical tows during daytime. In total, 25,819 ichthyoplankton samples were collected, of which 25,449 samples (i.e., 24,757 eggs and 692 larvae) were from horizontal tows. For horizontal tow samples, the ichthyoplankton were classified into 58 taxa in 15 orders and 23 families with a combination of external morphology and DNA barcoding analyses, from pelagic to demersal and benthic species. The dominant order was the Gobiiformes, including 23 species (39.7% of all species). The dominant taxa, in terms of relative abundance and frequency of occurrence, consisted of commercially important fishes, such as Setipinna tenuifilis (Valenciennes, 1848) (Engraulidae), Epinephelus akaara (Temminck and Schlegel, 1842) (Serraenidae), Collichthys lucidus (Richardson, 1844), Nibea albiflora (Richardson, 1846) (Sciaenidae), Acanthopagrus schlegelii (Bleeker, 1854), and Pagrus major (Temminck and Schlegel, 1843) (Sparidae), accounting for 78.9% of the horizontal tow samples. Low-valued and small-sized fishes, such as Stolephorus commersonnii Lacepède, 1803 (Engraulidae), Solea ovata Richardson, 1846 (Soleidae), Nuchequula nuchalis (Temminck and Schlegel, 1845), and Photopectoralis bindus (Valenciennes, 1835) (Leiognathidae), were also dominant species, accounting for 11.4% of the horizontal tow samples. The ichthyoplankton assemblage was categorized into five different temporal assemblages based on the cluster and nonmetric multidimensional scaling analysis, namely, April, May, June, July, and August−September (ANOSIM, Global R = 0.656, p < 0.01) with the highest density and richness of ichthyoplankton occurred in May. The spatial distribution pattern showed that the high density (ind./m3) of ichthyoplankton occurred mainly in S12–S25 in Guanjingyang and along the Dongchong Peninsula coastline into Dongwuyang, while low density occurred mainly in S01–S11 in the northwest waters of Sandu Island (ANOVA, F = 8.270, p < 0.05). Temperature, salinity, and chlorophyll a were key factors structuring the ichthyoplankton assemblages in Sansha Bay. In addition, this study revealed the changes of the ichthyoplankton composition, density, and spatial distribution in Sansha Bay over the past three decades.