bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of Doublesex1 Expression for Environmental Sex Determination in the Cladoceran Crustacean Daphnia
Authors: Kato Yasuhiko , Watanabe Hajime
Published: April 2022

The cladoceran crustacean Daphnia produces only females by parthenogenesis in a healthy population. However, in response to environmental declines such as crowding and lack of foods, it produces eggs destined to become males that are genetically identical to females. During the development of the sexually committed eggs, DM domain-containing transcription factor Doublesex1 (Dsx1) orchestrates male trait formation globally both in somatic and gonadal tissues. Recent studies have revealed that Dsx1 expression is tightly controlled at transcriptional, post-transcriptional, and epigenetic levels to avoid sexual ambiguity. In this review, together with basic information on Dsx1 structure and expression, we introduce the multi-layered Dsx1 regulation and discuss how each regulation is interconnected for controlling male development in environmental sex-determining Daphnia.
Expression, Prognostic Value, and Functional Mechanism of the KDM5 Family in Pancreatic Cancer
Authors: Duan Yunjie , Du Yongxing , Gu Zongting , Zheng Xiaohao , Wang Chengfeng
Published: April 2022

Background: The histone lysine demethylase KDM5 family is an important epigenetic state-modifying enzyme family. Increasing evidence supports that epigenetic abnormalities in the KDM5 family are related to multiple cancers in humans. However, the role of the KDM5 family in pancreatic cancer is not clear, and related research is very scarce.

Methods: R software, Kaplan–Meier Plotter, cBioPortal, TIMER, LinkedOmics, STRING, Metascape, TISIDB, and the GSCA Lite online tool were utilized for bioinformatics analysis.

Results: KDM5A/B/C was significantly overexpressed in many kinds of tumor tissues, including pancreatic adenocarcinoma (PAAD), while the expression of KDM5D was significantly downregulated. The high expression of KDM5A/B/C was related to poor clinical features, such as worse treatment efficacy, higher tumor grade, and more advanced clinical stage. Patients with a family history of breast cancer and melanoma, history of drinking or history chronic pancreatitis were more likely to have KDM5A/B/C gene abnormalities, which were related to a variety of adverse clinical features. The results of gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) pathway analyses of the KDM5 family and its 800 co-expressed genes showed that many gene terms related to cell proliferation, migration and many carcinogenic pathways. Notably, we found that the expression level of KDM5A/B/C was positively correlated with the expression of multiple key driver genes such as KRAS, BRCA1, and BRCA2 etc. In addition, PPI network analysis showed KDM5 family proteins have strong interactions with histone deacetylase family 1 (HDAC1), which could modify the lysines of histone H3, and co-act on many pathways, including the “longevity-regulating pathway” and “Notch signaling pathway”. Moreover, the upregulation of KDM5A/B/C expression was associated with an increase in the infiltration of B cells, CD8+ T cells and other infiltrating immune lymphocytes and the expression levels of immune molecules such as NT5E and CD274. Interestingly, the overexpression of KDM5A/C was also corelated with reduced sensitivity of pancreatic cancer cells to many kinds of pancreatic cancer-targeting or chemotherapeutic drugs, including axitinib and gemcitabine.

Conclusion: KDM5 family members may be prognostic markers and new therapeutic targets for patients with pancreatic cancer.
Evaluation of Potential DnaK Modulating Proline-Rich Antimicrobial Peptides Identified by Computational Screening
Authors: Handley Thomas N. G. , Li Wenyi , Welch Nicholas G. , O’Brien-Simpson Neil M. , Hossain Mohammed Akhter , Wade John D.
Published: April 2022

The day is rapidly approaching where current antibiotic therapies will no longer be effective due to the development of multi-drug resistant bacteria. Antimicrobial peptides (AMPs) are a promising class of therapeutic agents which have the potential to help address this burgeoning problem. Proline-rich AMPs (PrAMPs) are a sub-class of AMPs, that have multiple modes of action including modulation of the bacterial protein folding chaperone, DnaK. They are highly effective against Gram-negative bacteria and have low toxicity to mammalian cells. Previously we used an in silico approach to identify new potential PrAMPs from the DRAMP database. Four of these peptides, antibacterial napin, attacin-C, P9, and PP30, were each chemically assembled and characterized. Together with synthetic oncocin as a reference, each peptide was then assessed for antibacterial activity against Gram-negative/Gram-positive bacteria and for in vitro DnaK modulation activity. We observed that these peptides directly modulate DnaK activity independently of eliciting or otherwise an antibiotic effect. Based on our findings, we propose a change to our previously established PrAMP definition to remove the requirement for antimicrobial activity in isolation, leaving the following classifiers: >25% proline, modulation of DnaK AND/OR the 70S ribosome, net charge of +1 or more, produced in response to bacterial infection AND/OR with pronounced antimicrobial activity.
Superalkali Coated Rydberg Molecules
Authors: Tkachenko Nikolay V. , Rublev Pavel , Boldyrev Alexander I. , Lehn Jean-Marie
Published: April 2022

A series of complexes of Na, K, NH4, and H3O with [bpy.bpy.bpy]cryptand, [2.2.2]cryptand, and spherical cryptand were investigated via DFT and ab initio methods. We found that by coating Rydberg molecules with the “organic skin” one could further decrease their ionization potential energy, reaching the values of ∼1.5 eV and a new low record of 1.3 eV. The neutral cryptand complexes in this sense possess a weakly bounded electron and may be considered as very strong reducing agents. Moreover, the presence of an organic cage increases the thermodynamic stability of Rydberg molecules making them stable toward the proton detachment.
Recent Updates on Electrogenerated Hypervalent Iodine Derivatives and Their Applications as Mediators in Organic Electrosynthesis
Authors: Chen Chaoyue , Wang Xin , Yang Tinghai
Published: April 2022

With the renaissance of chemical electrosynthesis in the last decade, the electrochemistry of hypervalent iodine compounds has picked up the pace and achieved significant improvements. By employing traceless electrons instead of stoichiometric oxidants as the alternative clean “reagents”, many hypervalent iodine compounds were efficiently electro-synthesized via anodic oxidation methods and utilized as powerful redox mediators triggering valuable oxidative coupling reactions in a more sustainable way. This minireview gives an up-to-date overview of the recent advances during the past 3 years, encompassing enhanced electrosynthesis technologies, novel synthetic applications, and ideas for improving reaction sustainability.
The Potential Role of MicroRNA‐124‐3p in Growth, Development, and Reproduction of Schistosoma japonicum
Authors: Zhou Xue , Hong Yang , Shang Zheng , Abuzeid Asmaa M. I. , Lin Jiaojiao , Li Guoqing
Published: April 2022

The microRNA‐124‐3p plays an important role in regulating development and neurogenesis. Previous microRNA sequencing analyses of Schistosoma japonicum revealed sja-miR-124-3p differential expression patterns in schistosomes from different hosts and at different developmental stages. This study explores the regulatory role of sja-miR-124-3p in S. japonicum development and reproduction. Quantitative reverse-transcription PCR (qRT-PCR) showed that the expression level of sja-miR-124-3p in S. japonicum from resistant hosts, such as Microtus fortis, and unsuitable hosts, such as rats and water buffalo, was significantly higher than that in mice and yellow cattle at the same developmental stage. Overexpressing sja-miR-124-3p in infected mice led to a hepatic egg reduction rate of 36.97%, smaller egg granulomas in the livers, increased liver weight, subsided hepatocyte necrosis, and diminished inflammatory cell infiltration. The width of female worms increased but decreased in males. The vitelline cells were irregular, swollen, or fused. The teguments and ventral sucker of males and females were swollen and broken, but the morphological changes were particularly notable in males. qRT-PCR and dual-luciferase reporter assay system were used to confirm the in-silico-predicted target genes, S. japonicum DEAD-box ATP-dependent RNA helicase 1 (sjDDX1) and DNA polymerase II subunit 2 (sjPOLE2). Our results showed that RNA interference (RNAi)-mediated sjDDX1 silencing in mice provided a 24.55% worm reduction rate and an 18.36% egg reduction rate, but the difference was not significant (p > 0.05). Thus, our findings suggest that sja-miR-124-3p has an important role in growth, development, and reproduction in S. japonicum. All these results will greatly contribute toward providing important clues for searching vaccine candidates and new drug targets against schistosomiasis.
Meta-Analysis of Whole Blood Transcriptome Datasets Characterizes the Immune Response of Respiratory Syncytial Virus Infection in Children
Authors: Feng Qianyu , Lin Shujin , Liu Huifang , Yang Bin , Han Lifen , Han Xiao , Xu Lili , Xie Zhengde
Published: April 2022

Respiratory syncytial virus (RSV) is the most common and critical viral pathogen causing acute lower respiratory tract infection in infants and young children and has a huge disease burden worldwide. At present, there are many studies on RSV transcriptomics exploring the mechanism of disease, but different studies show different gene expression patterns and results due to different sample collection platforms and data analysis strategies. A meta-analysis was performed on eight whole blood transcriptome datasets containing 436 children with acute RSV infection and 241 healthy children. A total of 319 differentially expressed genes (DEGs) (P value <0.0001) were identified in a meta-analysis using a random effect model. Functional enrichment analysis showed that several pathways related to immunity were significantly altered, including the “chemokine signaling pathway”, “natural killer cell mediated cytotoxicity” and “cytokine–cytokine receptor interaction”. Immune cell type analysis showed that the proportion of neutrophils in most RSV-infected children was higher than that in healthy children. These immune characteristics may help to provide new insights into RSV infection in children.
Multimodal Gestalts and Post-pandemic Utopianism: Drum and Bass on the Bike
Authors: Rivers Damian J.
Published: April 2022

Framed within a society insidiously damaged by the novel coronavirus pandemic and associated lockdown restrictions, this article examines the drum and bass on the bike initiative of British DJ Dom Whiting. The initiative comprises of Dom riding a tricycle through various urban landscapes while broadcasting live to social media from on-board mixing decks. Since the first two solo rides in early 2021, thousands of individuals have accompanied him through twelve urban landscapes in addition to millions more participating across social media through views, comments, likes, and shares. Situating YouTube uploads as text, and positioning Dom as a harmonic navigator of change and reformation in the urban space, the article draws from a social semiotic multimodal approach to communication and details the development of three multimodal gestalts indicative of post-pandemic society. Against a soundtrack of thunderous drum and bass music, the three emergent gestalts communicate post-pandemic utopianism through the reformation of the relationship between motor vehicle drivers and cyclists, the reformation of urban road space use, and the reformation of diversity in organized cycling events.
The Volume and Geochemical Characteristics of Desorption Gases From Wufeng–Longmaxi (O3w-S1l) Shale in the Xishui Area, North Guizhou, China
Authors: Shi Shuyong , Wang Yunpeng , Sun Yu , Guo Huijuan
Published: April 2022

The Upper Ordovician–Lower Silurian Wufeng–Longmaxi (O3w-S1l) shale is widely distributed in the Xishui area, north Guizhou, China. However, the potential and characteristics of shale gases in the Xishui area are not well evaluated, which has limited the exploration of shale gas in this area. In this study, we collected 14 fresh core samples of Wufeng–Longmaxi Formations from Well XK-3 and conducted gas desorption experiments to evaluate the potential of shale gas resources in the Xishui area. After analyzing the chemical and isotopic composition of desorption gases, the origin and genesis of the shale gas were systematically studied. Our results show that the volume of desorption gases varies from 2.14 m3/t to 6.01 m3/t, with a mean value of 4.12 m3/t, showing great potential for shale gas in this area. The positive correlation between total organic carbon (TOC) and desorption gas volume indicates that organic matter provides the main pore volume for shale gas preservation. The desorption gases are very dry, which are mainly composed of methane (99.64‰–99.74%) with a very low content of ethane, and no nitrogen, carbon dioxide, and hydrogen sulfide are detected. Based on geochemical diagrams, the desorption gases are identified as oil-associated thermogenic gases. The carbon isotopic values of methane and ethane display reversal distribution, due to the mixing of primary gases from kerogen cracking and the secondary gases from retained oil cracking and further possible cracking of heavy gaseous hydrocarbons (C3H8—C5H12) at higher thermal maturity (Ro > 2.00%). After comparing with Jiaoshiba, Changning, Weiyuan, and Dingshan areas, the carbon isotopic values of shale gases of Wufeng–Longmaxi shale also show different features at different areas, which are mainly controlled by the thermal maturity levels of the shale.
Epistemic Beliefs and Pre-service Teachers’ Conceptions of History Instruction
Authors: Paricio Javier , García-Ceballos Silvia , Rubio-Navarro Alodia
Published: April 2022

This study investigates the difficulties pre-service history teachers face in understanding and implementing a history curriculum focused on historical reasoning. Based on the general hypothesis of beliefs exerting a direct influence on teachers’ actions, this phenomenographic study provides a qualitative analysis of the epistemic and learning/teaching conceptions on which pre-service teachers base their reflections and decisions when they have to produce a teaching plan for a specific situation, taking n = 72 pre-service teachers from the Master’s Degree in Teaching in Secondary Education at the University of Zaragoza (specialty Geography and History) as statistical sample. The outcome of the first phases of the analysis was a new theoretical reference framework that innovated by simultaneously analyzing epistemic and educational conceptions. On the one hand, the analysis results include a considerable number of pre-service teachers who use epistemic beliefs identifying history and the past when addressing the curriculum. On the other, none of them, not even those with advanced epistemic beliefs, think about the curriculum in terms of an inquiry-based approach to historical problems, and, therefore, they display a transmissive–reproductive conception of history instruction. Consequently, the main contribution is observation of a twofold threshold that pre-service teachers must cross to understand and accept an interpretive history curriculum: they must overcome the identification between past and history and instead immerse themselves in the necessarily interpretive nature of any history; and they must stop viewing learning as knowledge internalization and reproduction and, instead, embrace a conception of learning as inquiry and reasoning.
Correlation Between Circulating PCSK9 Levels and Gestational Diabetes Mellitus in a Chinese Population
Authors: Wu Yiming , Shi Jie , Su Qing , Yang Zhen , Qin Li
Published: April 2022

Background

Previous studies reported that proprotein convertase subtilisin/kexin type 9 (PCSK9) was a key player in the regulations of lipid metabolism and glucose homeostasis. The current study aimed to detect the expression of PCSK9 in pregnant women with gestational diabetes mellitus (GDM) and investigate the possible relationships between PCSK9 and related metabolic phenotypes in GDM.

Methods

Circulating PCSK9 levels were determined by ELISA kit in a cohort of subjects with GDM (n = 170) and normal glucose tolerance (NGT; n = 130). We collected blood samples from all participants for the biochemical index determinations. Diagnosis of GDM was made according to the International Association of the Diabetes and Pregnancy Study Groups Consensus Panel. Correlation analysis and logistic regression analysis were used to study the potential associations between PCSK9 and GDM.

Results

GDM women presented significantly higher circulating PCSK9 levels than those in NGT pregnant subjects (268.07 ± 77.17 vs. 254.24 ± 74.22 ng/ml, P < 0.05). In the GDM group, serum PCSK9 levels were positively correlated with fasting plasma glucose (FPG) (R = 0.251, P = 0.015), glycated hemoglobin (HbA1c) (R = 0.275, P = 0.009), total cholesterol (TC) (R = 0.273, P = 0.010), and low-density lipoprotein cholesterol (LDL-C) (R = 0.326, P = 0.002) after adjustment of age and gestational age. Logistic regression found that age [odds ratio (OR) = 5.412, P = 0.02] and serum PCSK9 levels (OR = 4.696, P = 0.03) were independently associated with GDM. Compared with the lowest serum PCSK9 level quartile group, the prevalence of GDM was significantly higher in the highest quartile group, the ORs of GDM were 3.485 (95% CI 1.408–8.627, P < 0.05 for the trend), after adjusting for potential confounders.

Conclusions

Circulating PCSK9 levels were associated with dyslipidemia, pathoglycemia, and the risk of incident GDM, indicating a potential link between PCSK9 and GDM.
A New Grounding Resistance Reduction Method for Wind Turbines by Grounding Grid Connection in Limited Areas
Authors: Hu Yuanchao , Liu Zhixiang , Huang Tao , An Yunzhu , Shen Wentao , Hu Shangmao , Ma Chenghui , An Bingchen , Chen Dan
Published: April 2022

Restricted by cultivated land vegetation, road construction, and land acquisition compensation costs, the grounding electrode extension method is not applicable for grounding resistance reduction of some wind turbines in limited areas. A new grounding resistance reduction method is proposed and verified for wind turbines by connecting nearby wind turbine grounding grids. To study the efficiency of the proposed method, the grounding characteristics of connected grounding grids are calculated. Simulation results indicate that the grounding resistance of connected grounding grids is smaller than that of box extension grounding grids. The grounding characteristics of the grounding grid connection are affected by grounding current frequency and material parameters. The grounding grid connection increases the current dispersion area and reduces the ground potential rise of the grounding conductor.
Intelligent Optimization Method for Core Flow Zoning of Long-Cycle Lead-Bismuth-Cooled Reactor
Authors: Yu Qingyuan , Dai Shengqi , Zhao Pengcheng , Zhao Yanan , Xiao Yingjie , Peng Liangxing , Yu Tao
Published: April 2022

Flow zoning is an important way to achieve core outlet temperature flattening. Appropriate zoning can improve safety and economy. This study combines an artificial intelligence optimization algorithm with a parallel multi-channel model to develop a model for calculating reactor core flow zoning based on the modern optimization theory, convergence analysis of a genetic algorithm, differential evolution algorithm, and quantum genetic algorithm is carried out for long-life reactor flow partitioning. Using the optimized algorithm, two flow rates are determined using power distribution at the beginning of the core life as the sample data and the maximum power of each fuel assembly during the entire life as the sample data. Comparative analysis of two different flow zoning schemes is implemented on a small long-life natural circulation lead-bismuth fast reactor, SPALLER-100. The findings of this study show that the quantum genetic algorithm has the best convergence for the long-life reactor among the three intelligent optimization algorithms, and it can quickly provide optimal results. In flow zoning scheme calculations based on the core power distribution at the beginning of reactor life, the maximum outlet temperature of the fuel assembly exceeds the thermal safety limit of the reactor, and in the flow zoning scheme calculations based on the average core power distribution during the whole reactor life, the maximum outlet temperature of the fuel assembly is 140 K lower than the maximum outlet temperature obtained in the previous scheme, remaining below the thermal safety limit. The optimal number of partitions for the SPALLER-100 reactor is determined to be 5, and increasing the number of zones only slightly improved the thermal safety performance of the reactor.
Investigation of Nodal Numerical Adjoints From CMFD-Based Acceleration Methods
Authors: Oh Taesuk , Kim Yonghee
Published: April 2022

In this work, the attribute of mathematical adjoints acquired from various CMFD (coarse-mesh finite difference) accelerated nodal methods based on the nodal expansion method (NEM) is presented. The direct transposition is implemented to the NEM-CMFD system matrix that includes correction factors to acquire the adjoint flux. Three different acceleration schemes are considered in this paper, which are, namely, CMFD, pCMFD, and one-node CMFD methods, and the self-adjoint attribute of migration operator for each acceleration scheme is studied. With regard to the one-node CMFD acceleration, a mathematical description for encountering negative adjoint flux values is given alongside an adjusted one-node CMFD scheme that stifles such an occurrence. The overall features of the aforementioned acceleration methods are recognized through analyses of 2D reactor problems including the KWU PWR 2D benchmark problem. Further systematic assessment is conducted based on the first-order perturbation theory, where the obtained adjoint fluxes are applied as weighting functions. It is clearly shown that the adjusted one-node CMFD scheme results in an improved reactivity estimation by excluding the presence of negative adjoint flux values.
Does Forest Resource Protection Under the Carbon Neutrality Target Inhibit Economic Growth? Evidence of Poverty-Stricken County From China
Authors: Qi Huibo , Sun Lei , Long Fei , Gao Xiaowei , Hu Leifang
Published: April 2022

Given the overlapping characteristics of poverty-stricken counties within key ecological function zones and ecologically fragile areas in China, this study takes the sample of 393 state-designated poverty-stricken counties from 2011 to 2018 and uses the differences-in-differences model to test the influence of forest resource protection on economic growth and its mechanism under the carbon neutrality target. The empirical research proves how to break the “green paradox” and “poverty curse” in the process of Chinese ecological civilization construction and targeted poverty alleviation and how policy tools integrate emission reductions with carbon-sequestration increase and achieve sustainable development. The results show that 1) the economic growth of poverty-stricken counties cannot be separated from industrialization, urbanization, and financial system; 2) China’s poverty-stricken counties have achieved an initial decoupling of carbon emissions from economic growth; 3) forest resource protection represented by forest coverage and stock changes the carbon emissions through emission reductions with carbon-sequestration increase and affect the economic growth of poverty-stricken counties; and 4) the reduction of total carbon emissions in poverty-stricken counties further enhances the role of forest resource protection in promoting county economic growth. Taking the 13th Five-Year Plan for eco-environment protection as the starting point, this research reveals different paths and impacts selected by Chinese local governments in poverty alleviation.
The Eco-Environmental Changes in Typical Coastal Zones of Southern China From 1987 to 2020: A Case Study of Guangdong Coastal Counties
Authors: Li Yuchen , Abbas Zaheer , Chen Danying , Zhu Ziyang , Guo Haijing , Zhao Yaolong
Published: April 2022

Population growth, socioeconomic development, and rapid urbanization have exacerbated the deterioration of coastal ecosystems, particularly in the coastal region of southern China, which has experienced significant urbanization. A precise and timely insight into the ecological changes is indicative of economic and environmental harmonization in southern coast of China and other regions of the world. This study applied 731 Landsat images to assess quantitatively the spatial and temporal evolution of ecological environment quality in the coastal zone of South China during 1987─2020 based on the remote sensing ecological index (RSEI). The results show that 1) the correlation between the RSEI calculated using Landsat data and the parameters is more than 75%, and the results were significant when applied to assess the ecological environment of the coastal zone in South China. ​2) The ecological quality of the coastal zone in South China as a whole showed a slight initial degradation during 1987─2020, followed by a gradual improvement trend and then a slight degradation; the area with good ecological quality decreased from 38.96 to 7.97%, and then gradually recovered to 56.61% in 2010. Subsequently, the regions with good ecological quality showed a significant decline, reducing to 1.72%, and then increasing to 38.46% until 2020. In addition, regional differences persisting during the study period are caused by the impact of human activities on the land use types of different landscapes. 3) Good and moderate ecological quality classes occupy most of the coastal zones in South China, but the pressure on the coastal zone is still not optimistic due to the sensitivity of the coastal zone and the accelerated urbanization in South China. As a large-scale, long time series of coastal zone ecological monitoring, this study can provide support for planning, ecological monitoring, environmental protection policy formulation, and integrated regional management of coastal zones and similar areas in South China.
Beneficial Effects of Warming Temperatures on Embryonic and Hatchling Development in a Low-Latitude Margin Population of the High-Latitude Lizard Lacerta agilis
Authors: Cui Luoxin , Yang Cheng , Zhang Decheng , Lin Shu , Zhao Wenge , Liu Peng
Published: April 2022

The effects of warming temperatures on embryonic and hatchling development are critical for determining the vulnerability of species to climate warming. However, these effects have rarely been investigated in high-latitude oviparous species, particularly in their low-latitude margin populations. This study investigated the embryonic and hatchling development and fitness-related traits of a low-latitude margin population of a high-latitude lizard (Lacerta agilis). These traits were examined under present (24°C), moderate warming (27 and 30°C), and severe warming scenarios (33°C). Based on embryonic and hatchling responses to thermal variation, this study aimed to predict the vulnerability of the early life stages of low-latitude margin population of Lacerta agilis to climate warming. The incubation period of the low-latitude margin population of Lacerta agilis decreased as the temperature increased from 24 to 33°C. Hatching success was similar at 24, 27, and 30°C but decreased significantly at 33°C. No differences with temperature were observed for hatchling snout-vent length and hatchling body mass. The sprint speed was higher for hatchlings from temperatures of 24 and 33°C. The growth rate of hatchlings was highest at 30°C; however, the survival rate of hatchlings was not affected by the thermal environment. This study demonstrated that even for a low-latitude margin population of the high-latitude lizard, Lacerta agilis, moderate warming (i.e., 27 and 30°C) would benefit embryonic and hatchling development. This was indicated by the results showing higher hatching success, growth rate, and survival rate. However, if temperatures increase above 33°C, development and survival would be depressed significantly. Thus, low-latitude margin population of high-latitude species Lacerta agilis would benefit from climate warming in the near future but would be under stress if the nest temperature exceeded 30°C.
The Impact of Anthropogenic Disturbance to the Canopy Microclimate of Tropical Forests in the Southern Western Ghats, India
Authors: Sagar Rubin , Devy M. Soubadra
Published: April 2022

Anthropogenic disturbances are a pressing driver of forest degradation and are known to affect the microclimate within forests. Most organisms experience the microclimate and hence, associated changes may drive species communities in rainforests. However, such knowledge remains limited in the case of forest canopies, especially in south Asia. We aimed to identify differences in the temperature and light intensity, and beetles and vascular epiphytes in the canopy between old-growth and secondary forests. Using sensors, we recorded two key microclimatic variables, the air temperature, and light intensity, in the crowns of 36 Cullenia exarillata A. Robyns trees. We sampled beetles (morphospecies) and vascular epiphytes (genera) in the crowns. We provide evidence that canopies of secondary forest stands (intensively logged 60 years ago) (1) continue to show higher canopy air temperatures and light intensity, and (2) have higher beetle abundance (individuals), richness (morphospecies), and diversity but lower vascular epiphyte abundance (individuals), richness (genera), and diversity as compared to primary forest stands. We also show that the beetle communities differ (with greater beta diversity in the primary forest), but the vascular epiphyte communities were similar between the two forest types. We hope that this information begins to bridge the gap in understanding the role of microclimate in driving species communities and the ecology of human-modified forests.
CD154 Expression Indicates T Cell Activation Following Tetanus Toxoid Vaccination of Horses
Authors: Schnabel Christiane L. , Fletemeyer Babette , Lübke Sabrina , Marti Eliane , Wagner Bettina , Alber Gottfried
Published: April 2022

Despite the relevance of adaptive immunity against equine pathogens antigen-specific T cell responses of horses are not well characterized and the lack of insight into T cell responses hampers the understanding of the pathogeneses of important diseases. In this study we used tetanus toxoid (TT) as a well-defined antigen to characterize antigen-reactive T cells. Six healthy adult horses received a routine booster against tetanus with an immune stimulating complex (ISCOM)-based vaccine and were followed for 28 days. TT-specific serum antibodies were quantified by ELISA and increased in all horses by day 7 after vaccination. CD154 is an established indicator of antigen-reactive T helper cells in other species, but has not been characterized in horses. CD154 detection in equine PBMC by an anti-human CD154 antibody (clone 5C8) was confirmed by Western blots and then applied for flow cytometry. As a common indicator of equine T cell activation, cytokine induction was studied in parallel. T cells were analyzed by multicolor flow cytometry of PBMC after re-stimulation with TTin vitro. Reactive T helper (Th) cells were characterized by increased frequencies of CD4+CD154+lymphocytes inin vitroTT-re-stimulated PBMC on day 14 after vaccination of the horses compared to pre-vaccination. The majority of all CD154+cells after TT re-stimulation were CD4+Th cells, but CD154 was also induced on CD4-cells albeit in lower frequencies. CD154+CD4+Th cells were enriched in cytokine-expressing cells compared to CD154-CD4+Th cells. Similar to the CD4+CD154+frequencies, CD4+IL-4+, CD4+IFN-γ+and CD4+TNF-α+were increased after vaccination, but IL-4+increased later than IFN-γ+and CD4+TNF-α+, which already exceeded pre-vaccination frequencies on day 7. CD4+CD154+frequencies correlated positively with those of CD4+IL-4+(Th2) on day 14, and negatively with CD4+IFN-γ+induction on day 7, but did not correlate with CD4+TNF-α+frequencies or TT-specific antibody concentrations. CD154 appears to be a useful marker of antigen-reactive equine Th cells in combination with cytokine expression. The T cell analyses established here with TT can be applied to other antigens relevant for infections or allergies of horses and in horse models for translational research.
Association Between Baseline Therapy and Flare Reduction in Mepolizumab-Treated Patients With Hypereosinophilic Syndrome
Authors: Reiter Andreas , Lefevre Guillaume , Cid Maria C. , Kwon Namhee , Mavropolou Eleni , Yancey Steven W. , Steinfeld Jonathan
Published: April 2022

Background

Current standard-of-care treatments for hypereosinophilic syndrome (HES) include oral corticosteroids (OCS) and immunosuppressive/cytotoxic (IS/CT) therapies. The anti-IL-5 monoclonal antibody mepolizumab has also recently been approved for patients with this disease. The objective of this analysis was to assess the relationship between baseline therapy and flare reduction in patients with HES treated with mepolizumab, using data from the Phase III 200622 study (NCT02836496).

Methods

In the double-blind, parallel-group 200622 study, eligible patients were ≥12 years old and had HES for ≥6 months, ≥2 flares in the previous 12 months, blood eosinophils ≥1000 cells/μL at screening and ≥4 weeks’ stable HES therapy. Patients were randomised (1:1) to receive mepolizumab 300 mg subcutaneously or placebo every 4 weeks for 32 weeks plus their existing HES therapy. This post hoc, descriptive analysis assessed the effect of baseline HES therapy [IS/CT (± OCS), OCS No IS/CT, and No IS/CT/OCS] on the proportion of patients with ≥1 flare during the study period, the annualised rate of flares, time to first flare, and the proportion of patients with ≥1 flare during Weeks 20─32, with mepolizumab versus placebo.

Results

Mepolizumab treatment was associated with a decrease in the proportion of patients who experienced ≥1 flare during the study period in all baseline therapy groups versus placebo (32–96% reduction). Similarly, the probability of a flare was lower with mepolizumab (14.3–31.4%) than placebo (35.7–74.1%) in all baseline therapy groups, as was the annualised flare rate (0.22–0.68 vs 1.14–1.62). The proportion of patients who experienced ≥1 flare during Weeks 20–32 was reduced with mepolizumab versus placebo for all baseline therapy groups (55–85% reduction). For all endpoints, the greatest effect of mepolizumab treatment was seen in the IS/CT (± OCS) group.

Conclusions

Patients with poorly controlled HES are likely to achieve clinical benefit with mepolizumab in terms of flare reduction, regardless of their baseline therapy.

Clinical Trial Registration

(https://clinicaltrials.gov/ct2/show/NCT02836496).
Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney
Authors: Tiller Gesa , Lammerts Rosa G. M. , Karijosemito Jessy J. , Alkaff Firas F. , Diepstra Arjan , Pol Robert A. , Meter-Arkema Anita H. , Seelen Marc. A. , van den Heuvel Marius C. , Hepkema Bouke G. , Daha Mohamed R. , van den Born Jacob , Berger Stefan P.
Published: April 2022

Background

The role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined in vitro complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies.

Methods

We included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15).

Results

Complement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings in vitro using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells in vitro.

Conclusion

Our results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR.
dbPepNeo2.0: A Database for Human Tumor Neoantigen Peptides From Mass Spectrometry and TCR Recognition
Authors: Lu Manman , Xu Linfeng , Jian Xingxing , Tan Xiaoxiu , Zhao Jingjing , Liu Zhenhao , Zhang Yu , Liu Chunyu , Chen Lanming , Lin Yong , Xie Lu
Published: April 2022

Neoantigens are widely reported to induce T-cell response and lead to tumor regression, indicating a promising potential to immunotherapy. Previously, we constructed an open-access database, i.e., dbPepNeo, providing a systematic resource for human tumor neoantigens to storage and query. In order to expand data volume and application scope, we updated dbPepNeo to version 2.0 (http://www.biostatistics.online/dbPepNeo2). Here, we provide about 801 high-confidence (HC) neoantigens (increased by 170%) and 842,289 low-confidence (LC) HLA immunopeptidomes (increased by 107%). Notably, 55 class II HC neoantigens and 630 neoantigen-reactive T-cell receptor-β (TCRβ) sequences were firstly included. Besides, two new analytical tools are developed, DeepCNN-Ineo and BLASTdb. DeepCNN-Ineo predicts the immunogenicity of class I neoantigens, and BLASTdb performs local alignments to look for sequence similarities in dbPepNeo2.0. Meanwhile, the web features and interface have been greatly improved and enhanced.
Pregnancy and Tumour: The Parallels and Differences in Regulatory T Cells
Authors: Muralidhara Prerana , Sood Vanshika , Vinayak Ashok Vishnu , Bansal Kushagra
Published: April 2022

Immunological tolerance plays a critical role during pregnancy as semi-allogeneic fetus must be protected from immune responses during the gestational period. Regulatory T cells (Tregs), a subpopulation of CD4+T cells that express transcription factor Foxp3, are central to the maintenance of immunological tolerance and prevention of autoimmunity. Tregs are also known to accumulate at placenta in uterus during pregnancy, and they confer immunological tolerance at maternal-fetal interface by controlling the immune responses against alloantigens. Thus, uterine Tregs help in maintaining an environment conducive for survival of the fetus during gestation, and low frequency or dysfunction of Tregs is associated with recurrent spontaneous abortions and other pregnancy-related complications such as preeclampsia. Interestingly, there are many parallels in the development of placenta and solid tumours, and the tumour microenvironment is considered to be somewhat similar to that at maternal-fetal interface. Moreover, Tregs play a largely similar role in tumour immunity as they do at placenta- they create a tolerogenic system and suppress the immune responses against the cells within tumour and at maternal-fetal interface. In this review, we discuss the role of Tregs in supporting the proper growth of the embryo during pregnancy. We also highlight the similarities and differences between Tregs at maternal-fetal interface and tumour Tregs, in an attempt to draw a comparison between their roles in these two physiologic and pathologic states.
Serum Soluble B Cell-Activating Factor Is a Non-Invasive Biomarker of Antibody-Mediated Rejection in Kidney Allograft With Satisfactory Risk Stratification Performance But Negligible Diagnostic Value
Authors: Wu Shenghui , Su Xiaojun , Ye Qianyu , Wei Yongcheng , Gao Yifang , Huang Mingchuan , Chen Yanxu , Wang Jiali , Zhang Qiang , Fu Qian , Li Jun , Wu Chenglin , Huang Huiting , Xu Bowen , Zhang Huanxi , Liu Longshan , Wang Changxi
Published: April 2022

Objectives

B cell-activating factor (BAFF), which is critical in the activation and differentiation of B cells, is a candidate diagnostic and predictive biomarker for antibody-mediated rejection (ABMR). We aimed to investigate the value of serum soluble BAFF (sBAFF) for the diagnosis and risk stratification of ABMR after kidney transplantation.

Methods

In the diagnostic study, sBAFF level among ABMR (n = 25), T cell-mediated rejection (TCMR) (n = 14), 4 other pathological lesions (n = 21), and stable allograft function group (n = 15) were compared. In the nested case-control study, kidney allograft recipients with de novo donor-specific antibody (DSA) or ABMR (n = 16) vs. stable allograft function (n = 7) were enrolled, and sBAFF was measured preoperatively, at D7, M1, M3, M6, M9, M12, M18 posttransplant and at allograft biopsy.

Results

There was no significant difference in sBAFF level at biopsy between ABMR and non-ABMR groups. Longitudinal study showed that the sBAFF levels decreased dramatically at D7 in both groups. The sBAFF level in the DSA group started to increase within M1, while in the stable group, it maintained a low level until M3 and M6. The sBAFF levels of the DSA group were significantly higher than that of the stable group at M1 [1,013.23 (633.97, 1,277.38) pg/ml vs. 462.69 (438.77, 586.48) pg/ml, P = 0.005], M3 [1,472.07 (912.79, 1,922.08) pg/ml vs. 561.63 (489.77, 630.00) pg/ml, P = 0.002], and M6 [1,217.95 (965.25, 1,321.43) pg/ml vs. 726.93 (604.77, 924.60) pg/ml, P = 0.027]. sBAFF levels at M3 had the best predictive value for the DSA/ABMR with the area under the receiver operating characteristic (AUROC) curve value of 0.908. The predictive performance of the maximum (max) change rate from D7 to the peak within M3 was also excellent (AUROC 0.949, P = 0.580).

Conclusion

We clarified by a diagnostic study that sBAFF is not a diagnostic biomarker for ABMR in kidney transplantation and revealed by a nested case-control study that sBAFF values at M3 posttransplant and dynamic changes in sBAFF within M3 posttransplant have a good predictive value for the DSA/ABMR. It provides a useful tool for early screening of low-risk patients with negative preoperative DSA for the risk of developing postoperative DSA in kidney allograft recipients.
Impact of Manufacturing Procedures on CAR T Cell Functionality
Authors: Watanabe Norihiro , Mo Feiyan , McKenna Mary Kathryn
Published: April 2022

The field of chimeric antigen receptor (CAR) modified T cell therapy has rapidly expanded in the past few decades. As of today, there are six CAR T cell products that have been approved by the FDA: KYMRIAH (tisagenlecleucel, CD19 CAR T cells), YESCARTA (axicabtagene ciloleucel, CD19 CAR T cells), TECARTUS (brexucabtagene autoleucel, CD19 CAR T cells), BREYANZI (lisocabtagene maraleucel, CD19 CAR T cells), ABECMA (idecabtagene vicleucel, BCMA CAR T cells) and CARVYKTI (ciltacabtagene autoleucel, BCMA CAR T cells). With this clinical success, CAR T cell therapy has become one of the most promising treatment options to combat cancers. Current research efforts focus on further potentiating its efficacy in non-responding patients and solid tumor settings. To achieve this, recent evidence suggested that, apart from developing next-generation CAR T cells with additional genetic modifications, ex vivo culture conditions could significantly impact CAR T cell functionality – an often overlooked aspect during clinical translation. In this review, we focus on the ex vivo manufacturing process for CAR T cells and discuss how it impacts CAR T cell function.
Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model
Authors: Jiang Wenwen , Wang Xiaoyu , Su Yuhao , Cai Lukui , Li Jingyan , Liang Jiangli , Gu Qin , Sun Mingbo , Shi Li
Published: April 2022

Pertussis, caused by the gram-negative bacterium Bordetella pertussis, is a highly contagious respiratory disease. Intranasal vaccination is an ideal strategy to prevent pertussis, as the nasal mucosa represents the first-line barrier to B. pertussis infection. The current intramuscular acellular pertussis (aP) vaccines elicit strong antibody and Th2-biased responses but not necessary cellular and mucosal immunity. Here, we formulated two cyclic dinucleotide (CDN)-adjuvanted aP subunit vaccines, a mammalian 2’,3’-cGAMP-adjuvanted aP vaccine and a bacterial-derived c-di-GMP-adjuvanted aP vaccine, and evaluated their immunogenicity in a mouse model. We found that the aP vaccine alone delivered intranasally (IN) induced moderate systemic and mucosal humoral immunity but weak cellular immunity, whereas the alum-adjuvanted aP vaccine administered intraperitoneally elicited higher Th2 and systemic humoral immune responses but weaker Th1 and Th17 and mucosal immune responses. In contrast, both CDN-adjuvanted aP vaccines administered via the IN route induced robust humoral and cellular immunity systemically and mucosally. Furthermore, the c-di-GMP-adjuvanted aP vaccine generated better antibody production and stronger Th1 and Th17 responses than the 2′,3′-cGAMP-adjuvanted aP vaccine. In addition, following B. pertussis challenge, the group of mice that received IN immunization with the c-di-GMP-adjuvanted aP vaccine showed better protection than all other groups of vaccinated mice, with decreased inflammatory cell infiltration in the lung and reduced bacterial burden in both the upper and lower respiratory tracts. In summary, the c-di-GMP-adjuvanted aP vaccine can elicit a multifaceted potent immune response resulting in robust bacterial clearance in the respiratory tract, which indicates that c-di-GMP can serve as a potential mucosal adjuvant for the pertussis vaccine.
A Short Peptide of Autotransporter Ata Is a Promising Protective Antigen for Vaccination Against Acinetobacter baumannii
Authors: Sun Peng , Li Xin , Pan Chao , Liu Zhicheng , Wu Jun , Wang Hengliang , Zhu Li
Published: April 2022

With the emergence of multidrug-resistant strains,Acinetobacter baumanniiinfection is becoming a thorny health problem in hospitals. However, there are no licensed vaccines againstA. baumannii.Acinetobactertrimeric autotransporter (Ata) is an important known virulence factor located on the outer membrane of bacteria. Herein, we carried out a series of experiments to test the immunogenicity of a short C-terminal extracellular region of Ata (Ataα, only containing 39 amino acids) in a murine model. The short peptide Ataαwas fused with the cholera toxin B subunit (CTB), which has been reported to have immunoadjuvant activity. The fusion protein showed no inflammation and organ damages, and have the ability to elicit both Th1 and Th2 immune responses in mice. The bactericidal activities againstA. baumanniiand prophylactic effects of the fusion protein were further evidenced by a significant reduction in the bacterial load in the organs and blood. In addition, the candidate vaccine could provide broad protection against lethal challenges with a variety ofA. baumanniistrains. Moreover, when CpG was added on the basis of aluminum adjuvant, the immune response, especially cellular immunity, could be further strengthened. Overall, these results revealed that the Ataαis a promising vaccine target againstA. baumanniiinfection.