bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying Local and Mesoscale Drivers of the Urban Heat Island of Moscow with Reference and Crowdsourced Observations
Authors: Varentsov Mikhail , Fenner Daniel , Meier Fred , Samsonov Timofey , Demuzere Matthias
Published: December 2021

Urban climate features, such as the urban heat island (UHI), are determined by various factors characterizing the modifications of the surface by the built environment and human activity. These factors are often attributed to the local spatial scale (hundreds of meters up to several kilometers). Nowadays, more and more urban climate studies utilize the concept of the local climate zones (LCZs) as a proxy for urban climate heterogeneity. However, for modern megacities that extend to dozens of kilometers, it is reasonable to suggest a significant contribution of the larger-scale factors to the temperature and UHI climatology. In this study, we investigate the contribution of local-scale and mesoscale driving factors of the nocturnal canopy layer UHI of the Moscow megacity in Russia. The study is based on air temperature observations from a dense network consisting of around 80 reference and more than 1,500 crowdsourced citizen weather stations for a summer and a winter season. For the crowdsourcing data, an advanced quality control algorithm is proposed. Based on both types of data, we show that the spatial patterns of the UHI are shaped both by local-scale and mesoscale driving factors. The local drivers represent the surface features in the vicinity of a few hundred meters and can be described by the LCZ concept. The mesoscale drivers represent the influence of the surrounding urban areas in the vicinity of 2–20 km around a station, transformed by diffusion, and advection in the atmospheric boundary layer. The contribution of the mesoscale drivers is reflected in air temperature differences between similar LCZs in different parts of the megacity and in a dependence between the UHI intensity and the distance from the city center. Using high-resolution city-descriptive parameters and different statistical analysis, we quantified the contributions of the local- and mesoscale driving factors. For selected cases with a pronounced nocturnal UHI, their respective contributions are of similar magnitude. Our findings highlight the importance of taking both local- and mesoscale effects in urban climate studies for megacities into account. Furthermore, they underscore a need for an extension of the LCZ concept to take mesoscale settings of the urban environment into account.
Increased Nitrogen Loading Boosts Summer Phytoplankton Growth by Alterations in Resource and Zooplankton Control: A Mesocosm Study
Authors: He Hu , Chen Kunquan , Du Yingxun , Li Kuanyi , Liu Zhengwen , Jeppesen Erik , Søndergaard Martin
Published: December 2021

The effectiveness of controlling nitrogen (N) to manage eutrophication of aquatic ecosystems remains debated. To understand the mechanisms behind phytoplankton growth in shallow lakes (resource and grazing effects) under contrasting N loading scenarios, we conducted a 70-days mesocosm experiment in summer. The mesocosms contain natural plankton communities deriving from a 10-cm layer of lake sediment and 450 L of lake water. We also added two juvenile crucian carp (Carassius carassius) in each mesocosm to simulate presence of the prevailing omni-benthivorous fish in subtropical lakes. Our results showed that N addition increased not only water N levels but also total phosphorus (TP) concentrations, which together elevated the phytoplankton biomass and caused strong dominance of cyanobacteria. Addition of N significantly lowered the herbivorous zooplankton to phytoplankton biomass ratio and promoted the phytoplankton yield per nutrient (Chl-a: TP or Chl-a: TN ratio), indicating that summer N addition likely also favored phytoplankton growth through reduced grazing by zooplankton. Accordingly, our study indicates that summer N loading may boost eutrophication via both changes in resource and grazing control in shallow lakes. Thus, alleviation of eutrophication in shallow eutrophic lakes requires a strategic approach to control both nutrients (N and P) appropriately.
A Movable Fog-Haze Boundary Layer Conceptual Model Over Jianghuai Area, China
Authors: Liu Duanyang , Yan Wenlian , Qian Junlong , Liu Mei , Wang Zida , Cheng Muning , Peng Huaqing
Published: December 2021

The Jianghuai area is an “important” region not only for its local pollutant accumulation but the belt for pollutant transportation between North China and the Yangtze River Delta during the winter half of the year (often from October to next February). In this study, a movable boundary layer conceptual model for the Jianghuai area in the winter half of the year is established based on the analyses of characteristics of atmospheric circulations and boundary layer dynamic conditions. This conceptual model can well explain the causes of air quality change and frequent fog-haze episodes. Variations of the intensity and range of the cold and warm fronts in the Jianghuai area in the winter half of the year lead to form a movable boundary in this area. When the southerly wind is strong, or affected by strong cold air mass, the air quality in the Jianghuai area may be excellent with a low air pollution index; Two atmospheric circulations provide favorable conditions for the fog-haze formation and maintenance in Jianghuai area: 1) When the shallow weak cold air mass is below the deep moist warm air mass, a stable temperature inversion occurs. The pollutants are transported to the Jianghuai area by the weak cold air mass, and local emissions also accumulate. As a result, a severe air pollution episode appears. 2) When the northerly cold air mass is as intense as the southerly moist warm air mass, the pollutants transported from North China as well as local emissions will continuously accumulate in the study area, which may lead to more severe air pollution. This conceptual model can help us analyze atmospheric diffusion capacity, and benefit the forecast and early warning of airflow stagnation area and fog-haze episode.
Infrasound as a Cue for Seabird Navigation
Authors: Patrick Samantha C. , Assink Jelle D. , Basille Mathieu , Clusella-Trullas Susana , Clay Thomas A. , den Ouden Olivier F. C. , Joo Rocío , Zeyl Jeffrey N. , Benhamou Simon , Christensen-Dalsgaard Jakob , Evers Läslo G. , Fayet Annette L. , Köppl Christine , Malkemper E. Pascal , Martín López Lucía Martina , Padget Oliver , Phillips Richard A. , Prior Mark K. , Smets Pieter S. M. , van Loon E. Emiel
Published: December 2021

Seabirds are amongst the most mobile of all animal species and spend large amounts of their lives at sea. They cross vast areas of ocean that appear superficially featureless, and our understanding of the mechanisms that they use for navigation remains incomplete, especially in terms of available cues. In particular, several large-scale navigational tasks, such as homing across thousands of kilometers to breeding sites, are not fully explained by visual, olfactory or magnetic stimuli. Low-frequency inaudible sound, i.e., infrasound, is ubiquitous in the marine environment. The spatio-temporal consistency of some components of the infrasonic wavefield, and the sensitivity of certain bird species to infrasonic stimuli, suggests that infrasound may provide additional cues for seabirds to navigate, but this remains untested. Here, we propose a framework to explore the importance of infrasound for navigation. We present key concepts regarding the physics of infrasound and review the physiological mechanisms through which infrasound may be detected and used. Next, we propose three hypotheses detailing how seabirds could use information provided by different infrasound sources for navigation as an acoustic beacon, landmark, or gradient. Finally, we reflect on strengths and limitations of our proposed hypotheses, and discuss several directions for future work. In particular, we suggest that hypotheses may be best tested by combining conceptual models of navigation with empirical data on seabird movements and in-situ infrasound measurements.
The Impact of Haze on Healthcare Utilizations for Acute Respiratory Diseases: Evidence From Malaysia
Authors: Jaafar Hafiz , Azzeri Amirah , Isahak Marzuki , Dahlui Maznah
Published: December 2021

Haze imposes a substantial disease burden on the human population especially in the Southeast Asia region due to the high frequency of haze episodes. The reduction of air quality levels by haze has resulted in a substantial disease burden and an increase in healthcare utilization (HU). This study aims to determine the association between haze and HU of haze-related respiratory illnesses with a focus given on the acute exacerbation of bronchial asthma (AEBA) and chronic obstructive pulmonary disease (AECOPD). A cross-sectional study was conducted through secondary data collection of haze/non-haze episodes as the study exposures and HU related to the exacerbation of bronchial asthma and COPD as the study outcomes. Data on haze/non-haze episodes and HU for four consecutive years (2012–2015) were retrieved from the Department of Environment and Ministry of Health Malaysia, respectively. In the four consecutive years, the percentage of haze episodes recorded in all stations was higher (67%) as compared to non-haze (33%) episodes. Means (SD) of patients diagnosed with AEBA and AECOPD were also significantly higher (p < 0.05) for inpatient 74 (62.1) and outpatient 320 (650.1) cases during haze episodes as compared to inpatient 34 (16.5) and outpatient 146 (170.5) cases during non-haze episodes. Findings from this study indicated that haze episodes incurred a significant healthcare burden due to an increase in HU. The evidence from this study will help the policymakers to prepare and allocate resources to control future implications of haze-related illnesses.
Brazil’s Cattle Sector Played Large Role in Fires During 2020 Moratorium
Authors: Schelly Ian H. , Rausch Lisa L. , Gibbs Holly K.
Published: December 2021

In response to global concern about recent fires, Brazil placed a 120-day moratorium on burning in the Amazon in 2020. We assessed how the cattle sector was linked to these fires by estimating the number of cattle properties involved with fires despite the moratorium, and their roles in cattle supply chains. We examined the land cover prior to the fire to identify instances of fires associated with recent deforestation. Our results show that the cattle sector contributed disproportionately to the fires in 2020, in terms of both the number of properties involved and the area burned. Improvements in both supply chain policies and overall environmental governance in the Amazon are likely needed to avoid recurrences of the catastrophic scale of fires during the 2020 season.
Prime Editing for Inherited Retinal Diseases
Authors: Costa Bruna Lopes da , Levi Sarah R. , Eulau Eric , Tsai Yi-Ting , Quinn Peter M. J.
Published: December 2021

Inherited retinal diseases (IRDs) are chronic, hereditary disorders that lead to progressive degeneration of the retina. Disease etiology originates from a genetic mutation—inherited or de novo—with a majority of IRDs resulting from point mutations. Given the plethora of IRDs, to date, mutations that cause these dystrophies have been found in approximately 280 genes. However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP). Although clinical trials for other genes are underway, these techniques typically involve gene augmentation rather than genome surgery. While gene augmentation therapy delivers a healthy copy of DNA to the cells of the retina, genome surgery uses clustered regularly interspaced short palindromic repeats (CRISPR)-based technology to correct a specific genetic mutation within the endogenous genome sequence. A new technique known as prime editing (PE) applies a CRISPR-based technology that possesses the potential to correct all twelve possible transition and transversion mutations as well as small insertions and deletions. EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene. Preferably, PE does not cause double-strand breaks nor does it require any donor DNA repair template, highlighting its unparalleled efficiency. Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment.
Targeted Knockout of Eukaryotic Translation Initiation Factor 4E Confers Bymovirus Resistance in Winter Barley
Authors: Hoffie Robert Eric , Otto Ingrid , Perovic Dragan , Budhagatapalli Nagaveni , Habekuß Antje , Ordon Frank , Kumlehn Jochen
Published: December 2021

The Eukaryotic Translation Initiation Factor 4E (EIF4E) is a well-known susceptibility factor for potyvirus infections in many plant species. The barley yellow mosaic virus disease, caused by the bymoviruses Barley yellow mosaic virus (BaYMV) and Barley mild mosaic virus (BaMMV), can lead to yield losses of up to 50% in winter barley. In autumn, the roots of young barley plants are infected by the soil-borne plasmodiophoraceous parasite Polymyxa graminis L. that serves as viral vector. Upon viral establishment and systemic spreading into the upper parts of the plants, yellow mosaics occur as first symptoms on leaves. In the further course of plant development, the disease entails leaf necrosis and increased susceptibility to frost damage. Thanks to the rym4 and rym5 allelic variants of the HvEIF4E gene, more than two thirds of current European winter barley cultivars are resistant to BaYMV and BaMMV. However, several strains of BaYMV and BaMMV have already overcome rym4- and rym5-mediated resistance. Accordingly, new resistance-conferring alleles are needed for barley breeding. Therefore, we performed targeted mutagenesis of the EIF4E gene by Cas9 endonuclease in BaMMV/BaYMV-susceptible winter barley cv. “Igri”. Small insertions were generated, resulting in a shift of the translational reading frame, thereby causing the loss-of-function of EIF4E. The mutations occurred in the homozygous state already in the primary mutants. Their progeny proved invariably homozygous and fully resistant to mechanical inoculation with BaMMV. EIF4E knockout plants showed normal growth habit and produced grains, yet exhibited a yield penalty.
POLR2A Promotes the Proliferation of Gastric Cancer Cells by Advancing the Overall Cell Cycle Progression
Authors: Jiang Qiuyu , Zhang Jinyuan , Li Fang , Ma Xiaoping , Wu Fei , Miao Jiyu , Li Qian , Wang Xiaofei , Sun Ruifang , Yang Yang , Zhao Lingyu , Huang Chen
Published: December 2021

RNA polymerase II subunit A (POLR2A) is the largest subunit encoding RNA polymerase II and closely related to cancer progression. However, the biological role and underlying molecular mechanism of POLR2A in gastric cancer (GC) are still unclear. Our study demonstrated that POLR2A was highly expressed in GC tissue and promoted the proliferation of GC in vitro and in vivo. We also found that POLR2A participated in the transcriptional regulation of cyclins and cyclin-dependent kinases (CDKs) at each stage and promoted their expression, indicated POLR2A’s overall promotion of cell cycle progression. Moreover, POLR2A inhibited GC cell apoptosis and promoted GC cell migration. Our results indicate that POLR2A play an oncogene role in GC, which may be an important factor involved in the occurrence and development of GC.
Genome-Wide Identification and Expression Analysis of the Plant U-Box Protein Gene Family in Phyllostachys edulis
Authors: Zhou Jie , Hu Yaping , Li Jiajia , Yu Zhaoyan , Guo Qirong
Published: December 2021

The U-box gene encodes a ubiquitin ligase that contains a U-box domain. The plant U-box (PUB) protein plays an important role in the plant stress response; however, very few studies have investigated the role of these proteins in Moso bamboo (Phyllostachys edulis). Thus, more research on PUB proteins is necessary to understand the mechanisms of stress tolerance in P. edulis. In this study, we identified 121 members of the PUB family in P. edulis (PePUB), using bioinformatics based on the P. edulis V2 genome build. The U-box genes of P. edulis showed an uneven distribution among the chromosomes. Phylogenetic analysis of the U-box genes between P. edulis and Arabidopsis thaliana suggested that these genes can be classified into eight subgroups (Groups I–VIII) based on their structural and phylogenetic features. All U-box genes and the structure of their encoded proteins were identified in P. edulis. We further investigated the expression pattern of PePUB genes in different tissues, including the leaves, panicles, rhizomes, roots, and shoots. The qRT-PCR results showed that expression of three genes, PePUB15, PePUB92, and PePUB120, was upregulated at low temperatures compared to that at 25°C. The expression levels of two PePUBs, PePUB60 and PePUB120, were upregulated under drought stress. These results suggest that the PePUB genes play an important role in resistance to low temperatures and drought in P. edulis. This research provides new insight into the function, diversity, and characterization of PUB genes in P. edulis and provides a basis for understanding their biological roles and molecular mechanisms.
Identification of Candidate Variants Associated With Bone Weight Using Whole Genome Sequence in Beef Cattle
Authors: Niu Qunhao , Zhang Tianliu , Xu Ling , Wang Tianzhen , Wang Zezhao , Zhu Bo , Gao Xue , Chen Yan , Zhang Lupei , Gao Huijiang , Li Junya , Xu Lingyang
Published: December 2021

Bone weight is critical to affect body conformation and stature in cattle. In this study, we conducted a genome-wide association study for bone weight in Chinese Simmental beef cattle based on the imputed sequence variants. We identified 364 variants associated with bone weight, while 350 of them were not included in the Illumina BovineHD SNP array, and several candidate genes and GO terms were captured to be associated with bone weight. Remarkably, we identified four potential variants in a candidate region on BTA6 using Bayesian fine-mapping. Several important candidate genes were captured, including LAP3, MED28, NCAPG, LCORL, SLIT2, and IBSP, which have been previously reported to be associated with carcass traits, body measurements, and growth traits. Notably, we found that the transcription factors related to MED28 and LCORL showed high conservation across multiple species. Our findings provide some valuable information for understanding the genetic basis of body stature in beef cattle.
Identification of an Autophagy-Related Gene Signature for the Prediction of Prognosis in Early-Stage Colorectal Cancer
Authors: Lin Xu-tao , Wu Qiu-ning , Qin Si , Fan De-jun , Lv Min-yi , Chen Xi , Cai Jia-wei , Weng Jing-rong , Zou Yi-feng , Rong Yu-ming , Gao Feng
Published: December 2021

Purpose: A certain number of early-stage colorectal cancer (CRC) patients suffer tumor recurrence after initial curative resection. In this context, an effective prognostic biomarker model is constantly in need. Autophagy exhibits a dual role in tumorigenesis. Our study aims to develop an autophagy-related gene (ATG) signature-based on high-throughput data analysis for disease-free survival (DFS) prognosis of patients with stage I/II CRC.

Methods: Gene expression profiles and clinical information of CRC patients extracted from four public datasets were distributed to discovery and training cohort (GSE39582), validation cohort (TCGA CRC, n = 624), and meta-validation cohort (GSE37892 and GSE14333, n = 420). Autophagy genes significantly associated with prognosis were identified.

Results: Among 655 autophagy-related genes, a 10-gene ATG signature, which was significantly associated with DFS in the training cohort (HR, 2.76[1.56–4.82]; p = 2.06 × 10–4), was constructed. The ATG signature, stratifying patients into high and low autophagy risk groups, was validated in the validation (HR, 2.29[1.15–4.55]; p = 1.5 × 10–2) and meta-validation cohorts (HR, 2.5[1.03–6.06]; p = 3.63 × 10–2) and proved to be prognostic in a multivariate analysis. Functional analysis revealed enrichment of several immune/inflammatory pathways in the high autophagy risk group, where increased infiltration of T regulatory cells (Tregs) and decreased infiltration of M1 macrophages were observed.

Conclusion: Our study established a prognostic ATG signature that effectively predicted DFS for early-stage CRC patients. Meanwhile, the study also revealed the possible relationship among autophagy process, immune/inflammatory response, and tumorigenesis.
Identifying Biomarkers to Predict the Prognosis of Biliary Atresia by Weighted Gene Co-Expression Network Analysis
Authors: Kong Meng , Xiang Bo
Published: December 2021

The prognosis of children with biliary atresia (BA) after Kasai operation remains difficult to predict, and liver fibrosis is closely related to the prognosis of children with BA. We aimed to find biomarkers for native liver survival (NLS) prediction by weighted gene co-expression network analysis (WGCNA). The biological processes and signal pathways that biomarkers involved in were further analyzed by bioinformatics. Quantitative Real-time PCR, Western blot and immunohistochemistry was performed to detect biomarkers expression. The relationship of biomarkers with clinicopathological characteristics of BA was also investigated. LECT2 was overexpressed or knockdown in LX-2 cells, and the expression of fibrogenic genes such as a-SMA and COL1A1 was quantified. We found that LECT2 mRNA expression was higher in BA liver tissues compared with normal liver tissues. Bioinformatics showed that LECT2 mainly played a fibrosis-promoting role in the development in BA by regulating bile acid metabolism and promoting inflammatory response. LECT2 immunohistochemistry scores of BA children were higher than control group (p = 0.001). Survival analysis revealed that LECT2 high expression is an unfavorable prognostic factor for native liver survival in BA patients. Additionally, the high LECT2 expression was an independent prognostic factor affecting native liver survival (HR 3.702, 95%CI:2.085–6.575, p = 0.001). LECT2 modulates TGF-β mediated a-SMA and COL1A1 expression in LX-2 cells. siRNA-LECT2 inhibits the expression of a-SMA and COL1A1 in LX-2 cells. Overexpression of LECT2 resulted in an increase in a-SMA and COL1A1 expression. Knockdown of LECT2 inhibits the proliferation and increase apoptosis in activated LX-2 cells. LECT2 may act as a new prognostic biomarker for native liver survival in BA patients.
Biological Network Inference With GRASP: A Bayesian Network Structure Learning Method Using Adaptive Sequential Monte Carlo
Authors: Yu Kaixian , Cui Zihan , Sui Xin , Qiu Xing , Zhang Jinfeng
Published: December 2021

Bayesian networks (BNs) provide a probabilistic, graphical framework for modeling high-dimensional joint distributions with complex correlation structures. BNs have wide applications in many disciplines, including biology, social science, finance and biomedical science. Despite extensive studies in the past, network structure learning from data is still a challenging open question in BN research. In this study, we present a sequential Monte Carlo (SMC)-based three-stage approach, GRowth-based Approach with Staged Pruning (GRASP). A double filtering strategy was first used for discovering the overall skeleton of the target BN. To search for the optimal network structures we designed an adaptive SMC (adSMC) algorithm to increase the quality and diversity of sampled networks which were further improved by a third stage to reclaim edges missed in the skeleton discovery step. GRASP gave very satisfactory results when tested on benchmark networks. Finally, BN structure learning using multiple types of genomics data illustrates GRASP’s potential in discovering novel biological relationships in integrative genomic studies.
Comparison of Gene Expression Between Resistant and Susceptible Families Against VPAHPND and Identification of Biomarkers Used for Resistance Evaluation in Litopenaeus vannamei
Authors: Zhang Qian , Yu Yang , Luo Zheng , Xiang Jianhai , Li Fuhua
Published: December 2021

Acute hepatopancreatic necrosis disease (AHPND) has caused a heavy loss to shrimp aquaculture since its outbreak. Vibrio parahaemolyticus (VPAHPND) is regarded as one of the main pathogens that caused AHPND in the Pacific white shrimp Litopenaeus vannamei. In order to learn more about the mechanism of resistance to AHPND, the resistant and susceptible shrimp families were obtained through genetic breeding, and comparative transcriptome approach was used to analyze the gene expression patterns between resistant and susceptible families. A total of 95 families were subjected to VPAHPND challenge test, and significant variations in the resistance of these families were observed. Three pairs of resistant and susceptible families were selected for transcriptome sequencing. A total of 489 differentially expressed genes (DEGs) that presented in at least two pairwise comparisons were screened, including 196 DEGs highly expressed in the susceptible families and 293 DEGs in the resistant families. Among these DEGs, 16 genes demonstrated significant difference in all three pairwise comparisons. Gene set enrichment analysis (GSEA) of all 27,331 expressed genes indicated that some energy metabolism processes were enriched in the resistant families, while signal transduction and immune system were enriched in the susceptible families. A total of 32 DEGs were further confirmed in the offspring of the detected families, among which 19 genes were successfully verified. The identified genes in this study will be useful for clarifying the genetic mechanism of shrimp resistance against Vibrio and will further provide molecular markers for evaluating the disease resistance of shrimp in the breeding program.
Current HLA Investigations on SARS-CoV-2 and Perspectives
Authors: Douillard Venceslas , Castelli Erick C. , Mack Steven J. , Hollenbach Jill A. , Gourraud Pierre-Antoine , Vince Nicolas , Limou Sophie ,   for the Covid-19|HLA & Immunogenetics Consortium and the SNP-HLA Reference Consortium
Published: December 2021

The rapid, global spread of the SARS-CoV-2 virus during the current pandemic has triggered numerous efforts in clinical and research settings to better understand the host genetics’ interactions and the severity of COVID-19. Due to the established major role played by MHC/HLA polymorphism in infectious disease course and susceptibility, immunologists and geneticists have teamed up to investigate its contribution to the SARS-CoV-2 infection and COVID-19 progression. A major goal of the Covid-19|HLA & Immunogenetics Consortium is to support and unify these efforts. Here, we present a review ofHLAimmunogenomics studies in the SARS-CoV-2 pandemic and reflect on the role of various HLA data, their limitation and future perspectives.
Divergent Expression of SPARC, SPARC-L, and SCPP Genes During Jawed Vertebrate Cartilage Mineralization
Authors: Romero Adrian , Leurs Nicolas , Muñoz David , Debiais-Thibaud Mélanie , Marcellini Sylvain
Published: December 2021

While cartilage is an ancient tissue found both in protostomes and deuterostomes, its mineralization evolved more recently, within the vertebrate lineage. SPARC, SPARC-L, and the SCPP members (Secretory Calcium-binding PhosphoProtein genes which evolved from SPARC-L) are major players of dentine and bone mineralization, but their involvement in the emergence of the vertebrate mineralized cartilage remains unclear. We performed in situ hybridization on mineralizing cartilaginous skeletal elements of the frog Xenopus tropicalis (Xt) and the shark Scyliorhinus canicula (Sc) to examine the expression of SPARC (present in both species), SPARC-L (present in Sc only) and the SCPP members (present in Xt only). We show that while mineralizing cartilage expresses SPARC (but not SPARC-L) in Sc, it expresses the SCPP genes (but not SPARC) in Xt, and propose two possible evolutionary scenarios to explain these opposite expression patterns. In spite of these genetic divergences, our data draw the attention on an overlooked and evolutionarily conserved peripheral cartilage subdomain expressing SPARC or the SCPP genes and exhibiting a high propensity to mineralize.
Interleukin-5 (IL-5) Therapy Prevents Allograft Rejection by Promoting CD4+CD25+ Ts2 Regulatory Cells That Are Antigen-Specific and Express IL-5 Receptor
Authors: Hall Bruce M. , Hall Rachael M. , Tran Giang T. , Robinson Catherine M. , Wilcox Paul L. , Rakesh Prateek K. , Wang Chuanmin , Sharland Alexandra F. , Verma Nirupama D. , Hodgkinson Suzanne J.
Published: December 2021

CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25-T cells’ activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressedfoxp3, irf4, gata3andil5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts’ CD4+CD25+cells expressed moreIl5raand responded to specific donor Lewis but not self. Enriched CD4+CD25+cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3andIl5.These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.
Progesterone Aggravates Lung Fibrosis in a Mouse Model of Systemic Sclerosis
Authors: Vafashoar Fatemeh , Mousavizadeh Kazem , Poormoghim Hadi , Haghighi Amir , Pashangzadeh Salar , Mojtabavi Nazanin
Published: December 2021

Background

Gender-related factors have explained the higher prevalence of autoimmune diseases in women. Sex hormones play a key role in the immune system and parenchymal cells function; therefore, these hormones can be important in the pathogenesis of autoimmune diseases as a risk or beneficial factor. Lung fibrosis is the main cause of mortality in systemic sclerosis, a female predominant autoimmune disease. The objective of this study was to examine the effect of progesterone on lung fibrosis in a mouse model of systemic sclerosis.

Methods

Mice with bleomycin-induced lung fibrosis treated with progesterone subcutaneously for 21 and 28 days. Blood was collected for hormone and cytokine measurement at the end of treatment then, skin and lung tissues were harvested for histological assessment, gene expression, cytokine, hydroxyproline, and gelatinase measurement.

Results

Trichrome staining and hydroxyproline measurements showed that progesterone treatment increased the content of collagen in fibrotic and normal lung tissues. Progesterone increased α-SMA (P < 0.01), TGF- β (P < 0.05) and decreased MMP9 (P < 0.05) in fibrotic lung tissues. Also progesterone treatment decreased the gene expression of Col1a2 (P <0.05), Ctgf (P <01), End1 (0.001) in bleomycin- injured lung tissues. The serum level of TNF-α was decreased, but the serum level of cortisol was increased by progesterone treatment in fibrotic mice (P< 0.05).

Conclusion

Our results showed that progesterone aggravates lung fibrosis in a mouse model of systemic sclerosis.
Type I Interferon and the Spectrum of Susceptibility to Viral Infection and Autoimmune Disease: A Shared Genomic Signature
Authors: Sugrue Jamie A. , Bourke Nollaig M. , O’Farrelly Cliona
Published: December 2021

Type I interferons (IFN-I) and their cognate receptor, the IFNAR1/2 heterodimer, are critical components of the innate immune system in humans. They have been widely explored in the context of viral infection and autoimmune disease where they play key roles in protection against infection or shaping disease pathogenesis. A false dichotomy has emerged in the study of IFN-I where interferons are thought of as either beneficial or pathogenic. This ‘good or bad’ viewpoint excludes more nuanced interpretations of IFN-I biology - for example, it is known that IFN-I is associated with the development of systemic lupus erythematosus, yet is also protective in the context of infectious diseases and contributes to resistance to viral infection. Studies have suggested that a shared transcriptomic signature underpins both potential resistance to viral infection and susceptibility to autoimmune disease. This seems to be particularly evident in females, who exhibit increased viral resistance and increased susceptibility to autoimmune disease. The molecular mechanisms behind such a signature and the role of sex in its determination have yet to be precisely defined. From a genomic perspective, several single nucleotide polymorphisms (SNPs) in the IFN-I pathway have been associated with both infectious and autoimmune disease. While overlap between infection and autoimmunity has been described in the incidence of these SNPs, it has been overlooked in work and discussion to date. Here, we discuss the possible contributions of IFN-Is to the pathogenesis of infectious and autoimmune diseases. We comment on genetic associations between common SNPs in IFN-I or their signalling molecules that point towards roles in protection against viral infection and susceptibility to autoimmunity and propose that a shared transcriptomic and genomic immunological signature may underlie resistance to viral infection and susceptibility to autoimmunity in humans. We believe that defining shared transcriptomic and genomic immunological signatures underlying resistance to viral infection and autoimmunity in humans will reveal new therapeutic targets and improved vaccine strategies, particularly in females.
An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition
Authors: Ebonwu Joy , Lassaunière Ria , Paximadis Maria , Goosen Mark , Strehlau Renate , Gray Glenda E. , Kuhn Louise , Tiemessen Caroline T.
Published: December 2021

In the Thai RV144 HIV-1 vaccine trial, a three-variant haplotype within the Fc gamma receptor 2C gene (FCGR2C) reduced the risk of HIV-1 acquisition. A follow-on trial, HVTN702, of a similar vaccine candidate found no efficacy in South Africa, where the predominant population is polymorphic for only a single variant in the haplotype, c.134-96C>T (rs114945036). To investigate a role for this variant in HIV-1 acquisition in South Africans, we used the model of maternal-infant HIV-1 transmission. A nested case-control study was conducted of infants born to mothers living with HIV-1, comparing children with perinatally-acquired HIV-1 (cases, n = 176) to HIV-1-exposed uninfected children (controls, n = 349). All had received nevirapine for prevention of mother-to-child transmission. The FCGR2C copy number and expression variants (c.−386G>C, c.−120A>T c.169T>C, and c.798+1A>G) were determined using a multiplex ligation-dependent probe amplification assay and the c.134-96C>T genotype with Sanger sequencing. The copy number, genotype and allele carriage were compared between groups using univariate and multivariate logistic regression. The FCGR2C c.134-96C>T genotype distribution and copy number differed significantly between HIV-1 cases and exposed-uninfected controls (P = 0.002, PBonf = 0.032 and P = 0.010, PBonf = > 0.05, respectively). The FCGR2C c.134-96T allele was overrepresented in the cases compared to the controls (58% vs 42%; P = 0.001, PBonf = 0.016). Adjusting for birthweight and FCGR2C copy number, perinatal HIV-1 acquisition was associated with the c.134-96C>T (AOR = 1.89; 95% CI 1.25-2.87; P = 0.003, PBonf = 0.048) and c.169C>T (AOR = 2.39; 95% CI 1.45-3.95; P = 0.001, PBonf = 0.016) minor alleles but not the promoter variant at position c.−386G>C. The c.134-96C>T variant was in strong linkage disequilibrium with the c.169C>T variant, but remained significantly associated with perinatal acquisition when adjusted for c.169C>T in multivariate analysis. In contrast to the protective effect observed in the Thai RV144 trial, we found the FCGR2C variant c.134-96T-allele associated with increased odds of perinatal HIV-1 acquisition in South African children. These findings, taken together with a similar deleterious association found with HIV-1 disease progression in South African adults, highlight the importance of elucidating the functional relevance of this variant in different populations and vaccination/disease contexts.
Impact of Cryopreservation on Viability, Phenotype, and Functionality of Porcine PBMC
Authors: Li Yanli , Mateu Enric , Díaz Ivan
Published: December 2021

The use of frozen peripheral blood mononuclear cells (PBMC) is common in immunological studies. The impact of freezing PBMC has been assessed using human and mice cells, but little information is available regarding domestic animals. In the present study, the phenotype and functionality of frozen porcine PBMC were examined. In a preliminary experiment, three freezing media: fetal bovine serum plus 10% dimethyl sulfoxide, PSC cryopreservation kit, and Cryostor CS10, were compared regarding the preservation of cell viability and the response of PBMC to mitogens after thawing. After being stored one month in liquid nitrogen, cell viability was above 89% for all freezing media. The ELISPOT IFN-gamma (IFN-γ) results in response to PHA and of IgG ELISPOT in response to R848+IL-2 were similar to those obtained using fresh PBMC. In the second set of experiments, PBMC were obtained from five pigs vaccinated against Porcine reproductive and respiratory syndrome virus (PRRSV) and then frozen using Cryostor CS10. Recovered cells were phenotyped by flow cytometry using anti-CD3, CD4, CD8, and CD21 antibodies and were used to assess the PRRSV-specific responses in a proliferation experiment, an IFN-γ ELISPOT, and an IgG ELISPOT, and compared to the results obtained with fresh cells. The antigen-specific responses of frozen cells were significantly (p<0.05) impaired in the proliferation assay, particularly for CD4/CD8 double-positive T-cells and for CD21+ cells. Freezing resulted in decreased proliferation when Con A, but not PHA, was used. In ELISPOT, cryopreservation resulted in a decreased frequency of IFN-γ-secreting cells in response to PRRSV (p<0.05) but the response to PHA was not affected. No differences were observed in the IgG ELISPOT after polyclonal activation. Taken together, cryopreservation of porcine PBMC had a significant impact on the magnitude of recall antigen responses and therefore, it may affect the response of effector/memory cells but seems not to have a major impact on naïve T-cells. These results may help to the better use of frozen porcine PBMC, and to the interpretation of the results obtained from them.
Pediococcus pentosaceus Enhances Host Resistance Against Pathogen by Increasing IL-1β Production: Understanding Probiotic Effectiveness and Administration Duration
Authors: Shan Chengjie , Li Miao , Liu Zhu , Xu Rong , Qiao Fang , Du Zhen-Yu , Zhang Mei-Ling
Published: December 2021

Probiotic administration is a potential strategy against enteric pathogen infection in either clinical treatment or animal nutrition industry, but the administration duration of probiotics varied and the underlying mechanisms remain unclear. A strain (YC) affiliated to Pediococcus pentosaceus, a commonly used probiotic, was isolated from fish gut and the potential role of YC against Aeromonas hydrophila was detected in zebrafish. We found that 3- or 4-week YC administration (YC3W or YC4W) increased the resistance against A. hydrophila while 1- or 2-week treatment (YC1W or YC2W) did not. To determine the possible reason, intestinal microbiota analysis and RNAseq were conducted. The results showed that compared with CON and YC1W, YC4W significantly increased the abundance of short-chain fatty acids (SCFAs) producing bacteria and elevated the gene expression of nlrp3. Higher butyrate content and enhanced expression of IL1β were subsequently found in YC4W. To identify the causal relationship between butyrate and the higher pathogen resistance, different concentrations of sodium butyrate (SB) were supplemented. The results suggested that 10 mmol/kg SB addition mirrored the protective effect of YC4W by increasing the production of IL-1β. Furthermore, the increased IL-1β raised the percentage of intestinal neutrophils, which endued the zebrafish with A. hydrophila resistance. In vivo knockdown of intestinal il1b eliminated the anti-infection effect. Collectively, our data suggested that the molecular mechanism of probiotics determined the administration duration, which is vital for the efficiency of probiotics. Promoting host inflammation by probiotic pretreatment is one potential way for probiotics to provide their protective effects against pathogens.
High BTLA Expression Likely Contributes to Contraction of the Regulatory T Cell Subset in Lupus Disease
Authors: Aubergeon Lucie , Sawaf Matthieu , Felten Renaud , Gottenberg Jacques-Eric , Dumortier Hélène , Monneaux Fanny
Published: December 2021

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor that is expressed by lymphoid cells and regulates the immune response. Consistent with an inhibitory role for BTLA, the disease is exacerbated in BTLA-deficient lupus mice. We recently demonstrated that the BTLA pathway is altered in CD4+ T cells from lupus patients. In the present work, we aimed at delineating the expression pattern of BTLA on CD4+ T cell subsets suspected to play a key role in lupus pathogenesis, such as circulating follicular helper T cells (cTFH) and regulatory T cells (Tregs). We did not detect significant ex vivo variations of BTLA expression on total CD4+ T cells (naive and memory), cTFH or TFH subsets between lupus patients and healthy controls. However, we interestingly observed that BTLA expression is significantly increased on activated Tregs, but not resting Tregs, from lupus patients, especially those displaying an active disease. Moreover, it correlates with the diminution of the Tregs frequency observed in these patients. We also showed that both BTLA mRNA and protein expression remain low after TCR stimulation of activated Tregs sorted from healthy donors and evidenced a similar dynamic of BTLA and HVEM expression profile by human Tregs and effector CD4+ T cells upon T cell activation than the one previously described in mice. Finally, we observed that the HVEM/BTLA ratio is significantly lower in Tregs from lupus patients compared to healthy controls, whereas ex vivo effector CD4+ T cells express higher BTLA levels. Our data suggest that an altered expression of BTLA and HVEM could be involved in an impaired regulation of autoreactive T cells in lupus. These results provide a better understanding of the BTLA involvement in lupus pathogenesis and confirm that BTLA should be considered as an interesting target for the development of new therapeutic strategies.
The Emerging Role of Non-Coding RNAs in Osteoarthritis
Authors: Ghafouri-Fard Soudeh , Poulet Christophe , Malaise Michel , Abak Atefe , Mahmud Hussen Bashdar , Taheriazam Afshin , Taheri Mohammad , Hallajnejad Mohammad
Published: December 2021

Osteoarthritis (OS) is the most frequent degenerative condition in the joints, disabling many adults. Several abnormalities in the articular cartilage, subchondral bone, synovial tissue, and meniscus have been detected in the course of OA. Destruction of articular cartilage, the formation of osteophytes, subchondral sclerosis, and hyperplasia of synovial tissue are hallmarks of OA. More recently, several investigations have underscored the regulatory roles of non-coding RNAs (ncRNAs) in OA development. Different classes of non-coding RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been reported to affect the development of OA. The expression level of these transcripts has also been used as diagnostic tools in OA. In the present article, we aimed at reporting the role of these transcripts in this process. We need to give a specific angle on the pathology to provide meaningful thoughts on it.
Quercetin Preserves Oral Cavity Health by Mitigating Inflammation and Microbial Dysbiosis
Authors: Mooney Erin C. , Holden Sara E. , Xia Xia-Juan , Li Yajie , Jiang Min , Banson Camille N. , Zhu Bin , Sahingur Sinem Esra
Published: December 2021

Failure to attenuate inflammation coupled with consequent microbiota changes drives the development of bone-destructive periodontitis. Quercetin, a plant-derived polyphenolic flavonoid, has been linked with health benefits in both humans and animals. Using a systematic approach, we investigated the effect of orally delivered Quercetin on host inflammatory response, oral microbial composition and periodontal disease phenotype. In vivo, quercetin supplementation diminished gingival cytokine expression, inflammatory cell infiltrate and alveolar bone loss. Microbiome analyses revealed a healthier oral microbial composition in Quercetin-treated versus vehicle-treated group characterized by reduction in the number of pathogenic species including Enterococcus, Neisseria and Pseudomonas and increase in the number of non-pathogenic Streptococcus sp. and bacterial diversity. In vitro, Quercetin diminished inflammatory cytokine production through modulating NF-κB:A20 axis in human macrophages following challenge with oral bacteria and TLR agonists. Collectively, our findings reveal that Quercetin supplement instigates a balanced periodontal tissue homeostasis through limiting inflammation and fostering an oral cavity microenvironment conducive of symbiotic microbiota associated with health. This proof of concept study provides key evidence for translational studies to improve overall health.