bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive Analysis of Myeloid Signature Genes in Head and Neck Squamous Cell Carcinoma to Predict the Prognosis and Immune Infiltration
Authors: Liu Zhifeng , Zhang Diekuo , Liu Chao , Li Guo , Chen Huihong , Ling Hang , Zhang Fengyu , Huang Donghai , Wang Xingwei , Liu Yong , Zhang Xin
Published: April 2021

Myeloid cells are a major heterogeneous cell population in the tumor immune microenvironment (TIME). Imbalance of myeloid response remains a major obstacle to a favorable prognosis and successful immune therapy. Therefore, we aimed to construct a risk model to evaluate the myeloid contexture, which may facilitate the prediction of prognosis and immune infiltration in patients with head and neck squamous cell carcinoma (HNSCC). In our study, six myeloid signature genes (including CCL13, CCR7, CD276, IL1B, LYVE1 and VEGFC) analyzed from 52 differentially expressed myeloid signature genes were finally pooled to establish a prognostic risk model, termed as myeloid gene score (MGS) in a training cohort and validated in a test cohort and an independent external cohort. Furthermore, based on the MGS subgroups, we were able to effectively identify patients with a poor prognosis, aggressive clinical parameters, immune cell infiltration status and immunotherapy response. Thus, MGS may serve as an effective prognostic signature and predictive indicator for immunotherapy response in patients with HNSCC.
Microbial Phagocytic Receptors and Their Potential Involvement in Cytokine Induction in Macrophages
Authors: Fu Yan Lin , Harrison Rene E.
Published: April 2021

Phagocytosis is an essential process for the uptake of large (>0.5 µm) particulate matter including microbes and dying cells. Specialized cells in the body perform phagocytosis which is enabled by cell surface receptors that recognize and bind target cells. Professional phagocytes play a prominent role in innate immunity and include macrophages, neutrophils and dendritic cells. These cells display a repertoire of phagocytic receptors that engage the target cells directly, or indirectlyviaopsonins, to mediate binding and internalization of the target into a phagosome. Phagosome maturation then proceeds to cause destruction and recycling of the phagosome contents. Key subsequent events include antigen presentation and cytokine production to alert and recruit cells involved in the adaptive immune response. Bridging the innate and adaptive immunity, macrophages secrete a broad selection of inflammatory mediators to orchestrate the type and magnitude of an inflammatory response. This review will focus on cytokines produced by NF-κB signaling which is activated by extracellular ligands and serves a master regulator of the inflammatory response to microbes. Macrophages secrete pro-inflammatory cytokines including TNFα, IL1β, IL6, IL8 and IL12 which together increases vascular permeability and promotes recruitment of other immune cells. The major anti-inflammatory cytokines produced by macrophages include IL10 and TGFβ which act to suppress inflammatory gene expression in macrophages and other immune cells. Typically, macrophage cytokines are synthesized, trafficked intracellularly and released in response to activation of pattern recognition receptors (PRRs) or inflammasomes. Direct evidence linking the event of phagocytosis to cytokine production in macrophages is lacking. This review will focus on cytokine output after engagement of macrophage phagocytic receptors by particulate microbial targets. Microbial receptors include the PRRs: Toll-like receptors (TLRs), scavenger receptors (SRs), C-type lectin and the opsonic receptors. Our current understanding of how macrophage receptor stimulation impacts cytokine production is largely based on work utilizing soluble ligands that are destined for endocytosis. We will instead focus this review on research examining receptor ligation during uptake of particulate microbes and how this complex internalization process may influence inflammatory cytokine production in macrophages.
The Promiscuous Profile of Complement Receptor 3 in Ligand Binding, Immune Modulation, and Pathophysiology
Authors: Lamers Christina , Plüss Carla Johanna , Ricklin Daniel
Published: April 2021

The β2-integrin receptor family has a broad spectrum of physiological functions ranging from leukocyte adhesion, cell migration, activation, and communication to the phagocytic uptake of cells and particles. Among the members of this family, complement receptor 3 (CR3; CD11b/CD18, Mac-1, αMβ2) is particularly promiscuous in its functional profile and ligand selectivity. There are close to 100 reported structurally unrelated ligands for CR3, and while many ligands appear to cluster at the αMI domain, molecular details about binding modes remain largely elusive. The versatility of CR3 is reflected in its functional portfolio, which includes prominent roles in the removal of invaders and cell debris, induction of tolerance and synaptic pruning, and involvement in the pathogenesis of numerous autoimmune and chronic inflammatory pathologies. While CR3 is an interesting therapeutic target for immune modulation due to these known pathophysiological associations, drug development efforts are limited by concerns of potential interference with host defense functions and, most importantly, an insufficient molecular understanding of the interplay between ligand binding and functional impact. Here, we provide a systematic summary of the various interaction partners of CR3 with a focus on binding mechanisms and functional implications. We also discuss the roles of CR3 as an immune receptor in health and disease, as an activation marker in research and diagnostics, and as a therapeutic target.
PRV-1 Infected Macrophages in Melanized Focal Changes in White Muscle of Atlantic Salmon (Salmo salar) Correlates With a Pro-Inflammatory Environment
Authors: Malik Muhammad Salman , Bjørgen Håvard , Nyman Ingvild Berg , Wessel Øystein , Koppang Erling Olaf , Dahle Maria K. , Rimstad Espen
Published: April 2021

Melanized focal changes in white skeletal muscle of farmed Atlantic salmon, “black spots”, is a quality problem affecting on average 20% of slaughtered fish. The spots appear initially as “red spots” characterized by hemorrhages and acute inflammation and progress into black spots characterized by chronic inflammation and abundant pigmented cells. Piscine orthoreovirus 1 (PRV-1) was previously found to be associated with macrophages and melano-macrophages in red and black spots. Here we have addressed the inflammatory microenvironment of red and black spots by studying the polarization status of the macrophages and cell mediated immune responses in spots, in both PRV-1 infected and non-infected fish. Samples that had been collected at regular intervals through the seawater production phase in a commercial farm were analyzed by multiplex fluorescent in situ hybridization (FISH) and RT-qPCR methods. Detection of abundant inducible nitric oxide synthase (iNOS2) expressing M1-polarized macrophages in red spots demonstrated a pro-inflammatory microenvironment. There was an almost perfect co-localization with the iNOS2 expression and PRV-1 infection. Black spots, on the other side, had few iNOS2 expressing cells, but a relatively high number of arginase-2 expressing anti-inflammatory M2-polarized macrophages containing melanin. The numerous M2-polarized melano-macrophages in black spots indicate an ongoing healing phase. Co-localization of PRV-1 and cells expressing CD8+ and MHC-I suggests a targeted immune response taking place in the spots. Altogether, this study indicates that PRV-1 induces a pro-inflammatory environment that is important for the pathogenesis of the spots. We do not have indication that infection of PRV-1 is the initial causative agent of this condition.
Cold Agglutinins and Cryoglobulins Associate With Clinical and Laboratory Parameters of Cold Urticaria
Authors: Bizjak Mojca , Košnik Mitja , Terhorst-Molawi Dorothea , Dinevski Dejan , Maurer Marcus
Published: April 2021

Mast cell-activating signals in cold urticaria are not yet well defined and are likely to be heterogeneous. Cold agglutinins and cryoglobulins have been described as factors possibly associated with cold urticaria, but their relevance has not been explained. We performed a single-center prospective cohort study of 35 cold urticaria patients. Cold agglutinin and cryoglobulin test results, demographics, detailed history data, cold stimulation test results, complete blood count values, C-reactive protein, total immunoglobulin E levels, and basal serum tryptase levels were analyzed. Forty six percent (n = 16) of 35 tested patients had a positive cold agglutinin test and 27% (n = 9) of 33 tested patients had a positive cryoglobulin test. Cold agglutinin positive patients, when compared to cold agglutinin negative ones, were mainly female (P = 0.030). No gender-association was found for cryoglobulins. A positive cold agglutinin test, but not a positive cryoglobulin test, was associated with a higher rate of reactions triggered by cold ambient air (P = 0.009) or immersion in cold water (P = 0.041), and aggravated by increased summer humidity (P = 0.007). Additionally, patients with a positive cold agglutinin test had a higher frequency of angioedema triggered by ingestion of cold foods or drinks (P = 0.043), and lower disease control based on Urticaria Control Test (P = 0.023). Cold agglutinin levels correlated with erythrocyte counts (r = −0.372, P = 0.028) and monocyte counts (r = −0.425, P = 0.011). Cryoglobulin concentrations correlated with basal serum tryptase levels (r = 0.733, P = 0.025) and cold urticaria duration (r = 0.683, P = 0.042). Results of our study suggest that cold agglutinins and cryoglobulins, in a subpopulation of cold urticaria patients, are linked to the course and possibly the pathogenesis of their disease.
Plasma Lectin Pathway Complement Proteins in Patients With COVID-19 and Renal Disease
Authors: Medjeral-Thomas Nicholas R. , Troldborg Anne , Hansen Annette G. , Gisby Jack , Clarke Candice L. , Prendecki Maria , McAdoo Stephen P. , Sandhu Eleanor , Lightstone Liz , Thomas David C. , Willicombe Michelle , Botto Marina , Peters James E. , Pickering Matthew C. , Thiel Steffen
Published: April 2021

We do not understand why non-white ethnicity and chronic kidney disease increase susceptibility to COVID-19. The lectin pathway of complement activation is a key contributor to innate immunity and inflammation. Concentrations of plasma lectin pathway proteins influence pathway activity and vary with ethnicity. We measured circulating lectin proteins in a multi-ethnic cohort of chronic kidney disease patients with and without COVID19 infection to determine if lectin pathway activation was contributing to COVID19 severity. We measured 11 lectin proteins in serial samples from a cohort of 33 patients with chronic kidney impairment and COVID19. Controls were single plasma samples from 32 patients on dialysis and 32 healthy individuals. We demonstrated multiple associations between recognition molecules and associated proteases of the lectin pathway and COVID-19, including COVID-19 severity. Some of these associations were unique to patients of Asian and White ethnicity. Our novel findings demonstrate that COVID19 infection alters the concentration of plasma lectin proteins and some of these changes were linked to ethnicity. This suggests a role for the lectin pathway in the host response to COVID-19 and suggest that variability within this pathway may contribute to ethnicity-associated differences in susceptibility to severe COVID-19.
Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy
Authors: Lemarié Maud , Chatonnet Fabrice , Caron Gersende , Fest Thierry
Published: April 2021

Antibody therapy, where artificially-produced immunoglobulins (Ig) are used to treat pathological conditions such as auto-immune diseases and cancers, is a very innovative and competitive field. Although substantial efforts have been made in recent years to obtain specific and efficient antibodies, there is still room for improvement especially when considering a precise tissular targeting or increasing antigen affinity. A better understanding of the cellular and molecular steps of terminal B cell differentiation, in which an antigen-activated B cell becomes an antibody secreting cell, may improve antibody therapy. In this review, we use our recently published data about human B cell differentiation, to show that the mechanisms necessary to adapt a metamorphosing B cell to its new secretory function appear quite early in the differentiation process i.e., at the pre-plasmablast stage. After characterizing the molecular pathways appearing at this stage, we will focus on recent findings about two main processes involved in antibody production: unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We’ll show that many genes coding for factors involved in UPR and ER stress are induced at the pre-plasmablast stage, sustaining our hypothesis. Finally, we propose to use this recently acquired knowledge to improve productivity of industrialized therapeutic antibodies.
Mitochondria as Key Players in the Pathogenesis and Treatment of Rheumatoid Arthritis
Authors: Clayton Sally A. , MacDonald Lucy , Kurowska-Stolarska Mariola , Clark Andrew R.
Published: April 2021

Mitochondria are major energy-producing organelles that have central roles in cellular metabolism. They also act as important signalling hubs, and their dynamic regulation in response to stress signals helps to dictate the stress response of the cell. Rheumatoid arthritis is an inflammatory and autoimmune disease with high prevalence and complex aetiology. Mitochondrial activity affects differentiation, activation and survival of immune and non-immune cells that contribute to the pathogenesis of this disease. This review outlines what is known about the role of mitochondria in rheumatoid arthritis pathogenesis, and how current and future therapeutic strategies can function through modulation of mitochondrial activity. We also highlight areas of this topic that warrant further study. As producers of energy and of metabolites such as succinate and citrate, mitochondria help to shape the inflammatory phenotype of leukocytes during disease. Mitochondrial components can directly stimulate immune receptors by acting as damage-associated molecular patterns, which could represent an initiating factor for the development of sterile inflammation. Mitochondria are also an important source of intracellular reactive oxygen species, and facilitate the activation of the NLRP3 inflammasome, which produces cytokines linked to disease symptoms in rheumatoid arthritis. The fact that mitochondria contain their own genetic material renders them susceptible to mutation, which can propagate their dysfunction and immunostimulatory potential. Several drugs currently used for the treatment of rheumatoid arthritis regulate mitochondrial function either directly or indirectly. These actions contribute to their immunomodulatory functions, but can also lead to adverse effects. Metabolic and mitochondrial pathways are attractive targets for future anti-rheumatic drugs, however many questions still remain about the precise role of mitochondrial activity in different cell types in rheumatoid arthritis.
Research Trends of Development on Pearl Bivalve Mollusks Based on a Bibliometric Network Analysis in the Past 25 Years
Authors: Cheng Qichao , Hu Wanqing , Bai Zhiyi
Published: April 2021

Freshwater pearl mussels and marine pearl oysters are major producers of cultured pearls. With the development of pearl farming, pearl bivalve mollusks have attracted significant research attention over the past 25 years. To provide an overview of this research, we conducted a bibliometric analysis of publications from the Web of Science Core Collection database from 1995 to 2020. A network map generated by VOSviewer software was used to evaluate studies of pearl bivalve mollusks in terms of author, country, organization, journal, and keywords. A total of 2,288 publications were obtained, showing an annual increase in the number of papers. Researchers based in China were a major contributor to the field and there was active cooperation among authors. Research focused on mussel and oyster developmental biology, growth, culture mode, molecular biology, and ecological conservation. In recent years, hot topics, such as growth performance and traits, pearl formation and biomineralization, and immune response, have been widely discussed. Genomics, transcriptomics, proteomics, and metabonomics analyses were commonly used to analyze the regulatory mechanism of coding and non-coding genes. The interaction between the environment and farming activities showed the importance of sustainable development. Interdisciplinary research could solve some of the issues facing the pearl bivalve mollusk farming. In conclusion, our findings could serve as another way to understand research trends in pearl bivalve mollusks and contribute to future studies.
Prevalence of Venous Thromboembolism in Critically Ill Patients With Coronavirus Disease 2019: A Meta-Analysis
Authors: Wu Changgang , Liu Yunlong , Cai Xiangjing , Zhang Wenming , Li Yongjie , Fu Chunsheng
Published: April 2021

Background: Accumulating evidence suggests that coronavirus disease 2019 (COVID-19) is associated with hypercoagulative status, particularly for critically ill patients in the intensive care unit. However, the prevalence of venous thromboembolism (VTE) in these patients under routine prophylactic anticoagulation remains unknown. A meta-analysis was performed to evaluate the prevalence of VTE in these patients by pooling the results of these observational studies.

Methods: Observational studies that reported the prevalence of VTE in critically ill patients with COVID-19 were identified by searching the PubMed and Embase databases. A random-effect model was used to pool the results by incorporating the potential heterogeneity.

Results: A total of 19 studies with 1,599 patients were included. The pooled results revealed that the prevalence of VTE, deep venous thrombosis (DVT), and pulmonary embolism (PE) in critically ill patients with COVID-19 was 28.4% [95% confidence interval (CI): 20.0–36.8%], 25.6% (95% CI: 17.8–33.4%), and 16.4% (95% CI: 10.1–22.7%), respectively. Limited to studies, in which all patients received routine prophylactic anticoagulation, and the prevalence for VTE, DVT, and PE was 30.1% (95% CI: 19.4–40.8%), 27.2% (95% CI: 16.5–37.9%), and 18.3% (95% CI: 9.8%−26.7%), respectively. The prevalence of DVT was higher in studies with routine screening for all patients, when compared to studies with screening only in clinically suspected patients (47.5% vs. 15.1%, P < 0.001).

Conclusion: Critically ill patients with COVID-19 have a high prevalence of VTE, despite the use of present routine prophylactic anticoagulation.
Investigation of Macular Choroidal Thickness and Blood Flow Change by Optical Coherence Tomography Angiography After Posterior Scleral Reinforcement
Authors: Zhang Zheng , Qi Yue , Wei Wenbin , Jin Zi-Bing , Wang Wen , Duan Anli , Liu Wu
Published: April 2021

Purpose: This work aimed to study the effect of posterior scleral reinforcement (PSR) on choroidal thickness (CT) and blood flow.

Methods: This study included 25 eyes of 24 patients with high myopia ( ≤ -6.0 dioptres or axial length ≥ 26.0 mm) who underwent PSR surgery. All patients completed the 1-month follow-up visit. Myopic macular degeneration (MMD) was graded according to the International Meta-Analysis for Pathologic Myopia (META-PM) classification based on color fundus photographs. Swept-source optical coherence tomography angiography (SSOCTA) was performed to investigate CT, choroidal perfusion area (CPA), and choriocapillaris perfusion area (CCPA) change following PSR surgery.

Results: The distribution of MMD categories was 9 (36.0%) in category 1, 10 (40.0%) in category 2, and 6 (24.0%) in category 3 or 4. MMD severity was strongly correlated with CT (all P < 0.01) and CPA (all P < 0.04). Postoperative CT at each sector increased significantly at 1 week's follow-up, compared to preoperative measures (all P < 0.05). Postoperative CPA at subfoveal, superior, inferior, and nasal sectors also increased significantly 1 week after PSR surgery (all P < 0.05). Moreover, the increased CT, CPA, and CCPA remain after PSR surgery at 1 month's follow-up, but the difference was not statistically significant.

Conclusions: We demonstrated that the CT and choroidal blood flow increased significantly in patients with high myopia who underwent PSR surgery in a short period of time. In addition, the CT and CPA were independently associated with MMD. However, whether the transient improvement of the choroidal circulation could prevent long-term progression of high myopia warrants further study in the future.
Natural Fermentation Quality and Bacterial Community of 12 Pennisetum sinese Varieties in Southern China
Authors: Zi Xuejuan , Li Mao , Yu Daogeng , Tang Jun , Zhou Hanlin , Chen Yeyuan
Published: April 2021

This study investigated the fermentation quality of 12 varieties of Pennisetum sinese grown in different regions of Southern China. Following the production of silage from the natural fermentation of P. sinese, the interplay between the chemical composition, fermentation characteristics, environmental factors, and microbiome was examined to understand the influence of these factors on the fermentation quality of silage. The silage quality produced by most of the P. sinese was low; the pH value of the silage was high (4.26–4.86), whilst the lactic acid content was low (10.7–24.1 g/kg DM), with V-scores between 57.9 and 78.3. The bacterial alpha diversities of the 12 P. sinese silages were distinct. There was a predominance of undesirable bacteria (Pseudomonas, Massilia, and Raoultella), which likely caused the poor fermentation quality. The chemical composition and fermentation characteristics of the silage were closely correlated with the composition of the bacterial community. Furthermore, environmental factors (precipitation, temperature, humidity, location) were found to significantly influence the microbiome of the silage. The results confirmed that silage produced from the natural fermentation of 12 different P. sinese varieties had significant variation in their bacterial communities. The difference in environmental factors, due to the P. sinese being grown in various locations across south china, greatly affected the bacterial community found in the silage and thus the fermentation quality. The specific cultivar used for the silage and the environment in which the cultivar is grown must therefore be considered before the initiation of production of silage in order to ensure a higher quality product.
Global Trends of Benthic Bacterial Diversity and Community Composition Along Organic Enrichment Gradients of Salmon Farms
Authors: Frühe Larissa , Dully Verena , Forster Dominik , Keeley Nigel B. , Laroche Olivier , Pochon Xavier , Robinson Shawn , Wilding Thomas A. , Stoeck Thorsten
Published: April 2021

The analysis of benthic bacterial community structure has emerged as a powerful alternative to traditional microscopy-based taxonomic approaches to monitor aquaculture disturbance in coastal environments. However, local bacterial diversity and community composition vary with season, biogeographic region, hydrology, sediment texture, and aquafarm-specific parameters. Therefore, without an understanding of the inherent variation contained within community complexes, bacterial diversity surveys conducted at individual farms, countries, or specific seasons may not be able to infer global universal pictures of bacterial community diversity and composition at different degrees of aquaculture disturbance. We have analyzed environmental DNA (eDNA) metabarcodes (V3–V4 region of the hypervariable SSU rRNA gene) of 138 samples of different farms located in different major salmon-producing countries. For these samples, we identified universal bacterial core taxa that indicate high, moderate, and low aquaculture impact, regardless of sampling season, sampled country, seafloor substrate type, or local farming and environmental conditions. We also discuss bacterial taxon groups that are specific for individual local conditions. We then link the metabolic properties of the identified bacterial taxon groups to benthic processes, which provides a better understanding of universal benthic ecosystem function(ing) of coastal aquaculture sites. Our results may further guide the continuing development of a practical and generic bacterial eDNA-based environmental monitoring approach.
In vitro Fermentation Reveals Changes in Butyrate Production Dependent on Resistant Starch Source and Microbiome Composition
Authors: Teichmann June , Cockburn Darrell W.
Published: April 2021

One of the primary benefits associated with dietary resistant starch (RS) is the production of butyrate by the gut microbiome during fermentation of this fiber in the large intestine. The ability to degrade RS is a relatively rare trait among microbes in the gut, seemingly confined to only a few species, none of which are butyrate producing organisms. Thus, production of butyrate during RS fermentation requires a network of interactions between RS degraders and butyrate producers. This is further complicated by the fact that there are multiple types of RS that differ in their structural properties and impacts on the microbiome. Human dietary intervention trials with RS have shown increases in fecal butyrate levels at the population level but with individual to individual differences. This suggests that interindividual differences in microbiome composition dictate butyrate response, but the factors driving this are still unknown. Furthermore, it is unknown whether a lack of increase in butyrate production upon supplementation with one RS is indicative of a lack of butyrate production with any RS. To shed some light on these issues we have undertaken anin vitrofermentation approach in an attempt to mimic RS fermentation in the colon. Fecal samples from 10 individuals were used as the inoculum for fermentation with 10 different starch sources. Butyrate production was heterogeneous across both fecal inocula and starch source, suggesting that a given microbiome is best suited to produce butyrate only from a subset of RS sources that differs between individuals. Interestingly, neither the total amount of RS degraders nor butyrate producers seemed to be limiting for any individual, rather the membership of these sub-populations was more important. While none of the RS degrading organisms were correlated with butyrate levels,Ruminococcus bromiiwas strongly positively correlated with many of the most important butyrate producers in the gut, though total butyrate production was strongly influenced by factors such as pH and lactate levels. Together these results suggest that the membership of the RS degrader and butyrate producer communities rather than their abundances determine the RS sources that will increase butyrate levels for a given microbiome.
Molecular Epidemiology of Citrus Leprosis Virus C: A New Viral Lineage and Phylodynamic of the Main Viral Subpopulations in the Americas
Authors: Chabi-Jesus Camila , Ramos-González Pedro L. , Postclam-Barro Matheus , Fontenele Rafaela Salgado , Harakava Ricardo , Bassanezi Renato B. , Moreira Alecio S. , Kitajima Elliot W. , Varsani Arvind , Freitas-Astúa Juliana
Published: April 2021

Despite the importance of viral strains/variants as agents of emerging diseases, genetic and evolutionary processes affecting their ecology are not fully understood. To get insight into this topic, we assessed the population and spatial dynamic parameters of citrus leprosis virus C (CiLV-C, genus Cilevirus, family Kitaviridae). CiLV-C is the etiological agent of citrus leprosis disease, a non-systemic infection considered the main viral disorder affecting citrus orchards in Brazil. Overall, we obtained 18 complete or near-complete viral genomes, 123 complete nucleotide sequences of the open reading frame (ORF) encoding the putative coat protein, and 204 partial nucleotide sequences of the ORF encoding the movement protein, from 430 infected Citrus spp. samples collected between 1932 and 2020. A thorough examination of the collected dataset suggested that the CiLV-C population consists of the major lineages CRD and SJP, unevenly distributed, plus a third one called ASU identified in this work, which is represented by a single isolate found in an herbarium sample collected in Asuncion, Paraguay, in 1937. Viruses from the three lineages share about 85% nucleotide sequence identity and show signs of inter-clade recombination events. Members of the lineage CRD were identified both in commercial and non-commercial citrus orchards. However, those of the lineages SJP were exclusively detected in samples collected in the citrus belt of São Paulo and Minas Gerais, the leading Brazilian citrus production region, after 2015. The most recent common ancestor of viruses of the three lineages dates back to, at least, ∼1500 years ago. Since citrus plants were introduced in the Americas by the Portuguese around the 1520s, the Bayesian phylodynamic analysis suggested that the ancestors of the main CiLV-C lineages likely originated in contact with native vegetation of South America. The intensive expansion of CRD and SJP lineages in Brazil started probably linked to the beginning of the local citrus industry. The high prevalence of CiLV-C in the citrus belt of Brazil likely ensues from the intensive connectivity between orchards, which represents a potential risk toward pathogen saturation across the region.
Cucumber Ribosomal Protein CsRPS21 Interacts With P22 Protein of Cucurbit Chlorotic Yellows Virus
Authors: Yang Xue , Wei Ying , Shi Yajuan , Han Xiaoyu , Chen Siyu , Yang Lingling , Li Honglian , Sun Bingjian , Shi Yan
Published: April 2021

Cucurbit chlorotic yellows virus (CCYV) is a cucurbit-infecting crinivirus. RNA silencing can be initiated as a plant defense against viruses. Viruses encode various RNA silencing suppressors to counteract antiviral silencing. P22 protein encoded by RNA1 of CCYV is a silencing suppressor, but its mechanism of action remains unclear. In this study, the cucumber ribosomal-like protein CsRPS21 was found to interact with P22 protein in vitro and in vivo. A conserved CsRPS21 domain was indispensable for its nuclear localization and interaction with P22. Transient expression of CsRPS21 in Nicotiana benthamiana leaves interfered with P22 accumulation and inhibited P22 silencing suppressor activity. CsRPS21 expression in N. benthamiana protoplasts inhibited CCYV accumulation. Increasing numbers of ribosomal proteins are being found to be involved in viral infections of plants. We identified a P22-interacting ribosomal protein, CsRPS21, and uncovered its role in early viral replication and silencing suppressor activity. Our study increases knowledge of the function of ribosomal proteins during viral infection.
Staphylococcus aureus Floating Biofilm Formation and Phenotype in Synovial Fluid Depends on Albumin, Fibrinogen, and Hyaluronic Acid
Authors: Knott Samantha , Curry Dylan , Zhao Neil , Metgud Pallavi , Dastgheyb Sana S. , Purtill Caroline , Harwood Marc , Chen Antonia F. , Schaer Thomas P. , Otto Michael , Hickok Noreen J.
Published: April 2021

Biofilms are typically studied in bacterial media that allow the study of important properties such as bacterial growth. However, the results obtained in such media cannot take into account the bacterial localization/clustering caused by bacteria–protein interactions in vivo and the accompanying alterations in phenotype, virulence factor production, and ultimately antibiotic tolerance. We and others have reported that methicillin-resistant or methicillin-susceptible Staphylococcus aureus (MRSA or MSSA, respectively) and other pathogens assemble a proteinaceous matrix in synovial fluid. This proteinaceous bacterial aggregate is coated by a polysaccharide matrix as is characteristic of biofilms. In this study, we identify proteins important for this aggregation and determine the concentration ranges of these proteins that can reproduce bacterial aggregation. We then test this protein combination for its ability to cause marked aggregation, antibacterial tolerance, preservation of morphology, and expression of the phenol-soluble modulin (PSM) virulence factors. In the process, we create a viscous fluid that models bacterial behavior in synovial fluid. We suggest that our findings and, by extension, use of this fluid can help to better model bacterial behavior of new antimicrobial therapies, as well as serve as a starting point to study host protein–bacteria interactions characteristic of physiological fluids.
Regional Diets Targeting Gut Microbial Dynamics to Support Prolonged Healthspan
Authors: Low Dorrain Yanwen , Hejndorf Sophia , Tharmabalan Rachel Thomas , Poppema Sibrandes , Pettersson Sven
Published: April 2021

In the last 150 years, we have seen a significant increase in average life expectancy, associated with a shift from infectious to non-communicable diseases. The rising incidence of these diseases, for which age is often the largest risk factor, highlights the need for contemporary societies to improve healthy ageing for their growing silver generations. As ageing is an inevitable, non-reversing and highly individualised process, we need to better understand how non-genetic factors like diet choices and commensal gut microbes can modulate the biology of ageing. In this review, we discuss how geographical and ethnic variations influence habitual dietary patterns, nutrient structure, and gut microbial profiles with potential impact on the human healthspan. Several gut microbial genera have been associated with healthy elderly populations but are highly variable across populations. It seems unlikely that a universal pro-longevity gut microbiome exists. Rather, the optimal microbiome appears to be conditional on the microbial functionality acting on regional- and ethnicity-specific trends driven by cultural food context. We also highlight dietary and microbial factors that have been observed to elicit individual and clustered biological responses. Finally, we identify next generation avenues to modify otherwise fixed host functions and the individual ageing trajectory by manipulating the malleable gut microbiome with regionally adapted, personalised food intervention regimens targeted at prolonging human healthspan.
Coupling of Transcription and Translation in Archaea: Cues From the Bacterial World
Authors: Weixlbaumer Albert , Grünberger Felix , Werner Finn , Grohmann Dina
Published: April 2021

The lack of a nucleus is the defining cellular feature of bacteria and archaea. Consequently, transcription and translation are occurring in the same compartment, proceed simultaneously and likely in a coupled fashion. Recent cryo-electron microscopy (cryo-EM) and tomography data, also combined with crosslinking-mass spectrometry experiments, have uncovered detailed structural features of the coupling between a transcribing bacterial RNA polymerase (RNAP) and the trailing translating ribosome in Escherichia coli and Mycoplasma pneumoniae. Formation of this supercomplex, called expressome, is mediated by physical interactions between the RNAP-bound transcription elongation factors NusG and/or NusA and the ribosomal proteins including uS10. Based on the structural conservation of the RNAP core enzyme, the ribosome, and the universally conserved elongation factors Spt5 (NusG) and NusA, we discuss requirements and functional implications of transcription-translation coupling in archaea. We furthermore consider additional RNA-mediated and co-transcriptional processes that potentially influence expressome formation in archaea.
Connection Between Chromosomal Location and Function of CtrA Phosphorelay Genes in Alphaproteobacteria
Authors: Tomasch Jürgen , Koppenhöfer Sonja , Lang Andrew S.
Published: April 2021

Most bacterial chromosomes are circular, with replication starting at one origin (ori) and proceeding on both replichores toward the terminus (ter). Several studies have shown that the location of genes relative to ori and ter can have profound effects on regulatory networks and physiological processes. The CtrA phosphorelay is a gene regulatory system conserved in most alphaproteobacteria. It was first discovered in Caulobacter crescentus where it controls replication and division into a stalked and a motile cell in coordination with other factors. The locations of the ctrA gene and targets of this response regulator on the chromosome affect their expression through replication-induced DNA hemi-methylation and specific positioning along a CtrA activity gradient in the dividing cell, respectively. Here we asked to what extent the location of CtrA regulatory network genes might be conserved in the alphaproteobacteria. We determined the locations of the CtrA phosphorelay and associated genes in closed genomes with unambiguously identifiable ori from members of five alphaproteobacterial orders. The location of the phosphorelay genes was the least conserved in the Rhodospirillales followed by the Sphingomonadales. In the Rhizobiales a trend toward certain chromosomal positions could be observed. Compared to the other orders, the CtrA phosphorelay genes were conserved closer to ori in the Caulobacterales. In contrast, the genes were highly conserved closer to ter in the Rhodobacterales. Our data suggest selection pressure results in differential positioning of CtrA phosphorelay and associated genes in alphaproteobacteria, particularly in the orders Rhodobacterales, Caulobacterales and Rhizobiales that is worth deeper investigation.
The Complexity of Blood Pressure Fluctuation Mediated the Effects of Hypertension on Walking Speed in Older Adults
Authors: Jiang Xin , Cai Yurun , Zhao Yue , Gao Xia , Peng Dan , Zhang Hui , Deng Wuhong , Fu Wen , Qin Na , Chang Ruizhen , Manor Brad , Zhou Junhong
Published: April 2021

Background:Older adults with hypertension often had diminished walking performance. The underlying mechanism through which hypertension affects walking performance, however, has not been fully understood. We here measured the complexity of the continuous systolic (SBP) and diastolic (DBP) blood pressure fluctuation, grade of white matter lesions (WMLs), and cognitive function and used structural equation modeling (SEM) to examine the interrelationships between hypertension, BP complexity, WMLs, cognitive function, and walking speed in single- and dual-task conditions.

Methods:A total of 152 older adults with age > 60 years (90 hypertensive and 62 normotensive participants) completed one MRI scan of brain structure, a finger BP assessment of at least 10 min, Mini-Mental State Examination (MMSE) to assess cognitive function, and 10-meter walking tests in single (i.e., normal walking) and dual tasks (i.e., walking while performing a serial subtraction of three from a random three-digit number). The grade of WMLs was assessed using the total score of Fazekas scale; the complexity of SBP and DBP was measured using multiscale entropy (MSE), and the walking performance was assessed by walking speed in single- and dual-task conditions.

Results:As compared to normotensives, hypertensive older adults had significantly slower walking speed, lower complexity of SBP and DBP, greater grade of WMLs, and poorer cognitive function (p< 0.03). Those with lower BP complexity (β > 0.31,p< 0.003), greater WML grade (β < −0.39,p< 0.0002), and/or poorer cognitive function (β < −0.39,p< 0.0001) had slower walking speed in single- and/or dual-task conditions. The SEM model demonstrated significant total effects of hypertension on walking speed, and such effects were mediated by BP complexity only, or BP complexity, WML grade, and cognitive function together.

Conclusion:This study demonstrates the cross-sectional association between the complexity of continuous beat-to-beat BP fluctuation, WML grade, cognitive function, and walking speed in hypertensive and normotensive older adults, revealing a potential mechanism that hypertension may affect walking performance in older adults through diminished BP complexity, increased WML grade, and decreased cognitive function, and BP complexity is an important factor for such effects. Future longitudinal studies are warranted to confirm the findings in this study.
Transplantation of Human Cortically-Specified Neuroepithelial Progenitor Cells Leads to Improved Functional Outcomes in a Mouse Model of Stroke
Authors: Islam Rehnuma , Drecun Stasja , Varga Balazs V. , Vonderwalde Ilan , Siu Ricky , Nagy Andras , Morshead Cindi M.
Published: April 2021

Stroke is a leading cause of death and long-term disability worldwide. Current therapeutic options are limited in terms of their time for implementation and efficacy in promoting recovery. Cell transplantation has been shown to have promise in several animal models however significant challenges remain, including the optimal source of cells to promote neural repair. Here, we report on the use of a population of human ESC derived, cortically specified, neuroepithelial precursor cells (cNEPs) that are neurally restricted in their lineage potential. CNEPs have the potential to give rise to mature neural cell types following transplantation, including neurons, astrocytes and oligodendrocytes. With a view towards translation, we sought to determine whether this human cell source was effective in promoting improved functional outcomes following stroke. Undifferentiated cNEPs were transplanted in a pre-clinical endothelin-1 (ET-1) model of ischemic motor cortical stroke in immunocompromised SCID-beige mice and cellular and functional outcomes were assessed. We demonstrate that cNEP transplantation in the acute phase (4 days post-stroke) improves motor function as early as 20 days post-stroke, compared to stroke-injured, non-transplanted mice. At the time of recovery, a small fraction (<6%) of the transplanted cNEPs are observed within the stroke injury site. The surviving cells expressed the immature neuronal marker, doublecortin, with no differentiation into mature neural phenotypes. At longer survival times (40 days), the majority of recovered, transplanted mice had a complete absence of surviving cNEPS. Hence, human cNEPs grafted at early times post-stroke support the observed functional recovery following ET-1 stroke but their persistence is not required, thereby supporting a by-stander effect rather than cell replacement.
Fluid and White Matter Suppression Imaging and Voxel-Based Morphometric Analysis in Conventional Magnetic Resonance Imaging-Negative Epilepsy
Authors: Sun Ke , Yu Tao , Yang Dongju , Ren Zhiwei , Qiao Liang , Ni Duanyu , Wang Xueyuan , Zhao Yongxiang , Chen Xin , Xiang Jing , Chen Nan , Gao Runshi , Yang Kun , Lin Yicong , Kober Tobias , Zhang Guojun
Published: April 2021

Purpose: Delineation of subtle lesions in magnetic resonance imaging (MRI)-negative patients is of great importance in preoperative epilepsy evaluation. The aim of our study was to explore the diagnostic value of the novel fluid and white matter suppression (FLAWS) sequence in comparison with a voxel-based MRI postprocessing morphometric analysis program (MAP) in a consecutive cohort of non-lesional patients.

Methods: Surgical candidates with a negative finding on an official neuroradiology report were enrolled. High-resolution FLAWS image and MAP maps generated based on high-resolution three-dimensional (3D) T1 image were visually inspected for each patient. The findings of FLAWS or MAP-positive (FLAWS/MAP+) regions were compared with the surgical resection cavity in correlation with surgical outcome and pathology.

Results: Forty-five patients were enrolled; the pathological examination revealed focal cortical dysplasia (FCD) in 32 patients and other findings in 13 patients. The positive rate, sensitivity, and specificity were 48.9%, 0.43, and 0.87, respectively, for FLAWS and 64.4%, 0.57, and 0.8, respectively, for MAP. Concordance between surgical resection and FLAWS+ or MAP+ regions was significantly associated with a seizure-free outcome (FLAWS: p = 0.002; MAP: p = 0.0003). A positive finding in FLAWS and MAP together with abnormalities in the same gyrus (FLAWS–MAP gyral+) was detected in 31.1% of patients. FLAWS+ only and MAP+ only were found in 7 (15.5%) and 14 (31.1%) patients, respectively.

Conclusions: FLAWS showed a promising value for identifying subtle epileptogenic lesions and can be used as a complement to current MAP in patients with MRI-negative epilepsy.
Evidence That Pupil Size and Reactivity Are Determined More by Your Parents Than by Your Environment
Authors: Ansari Abdus Samad , Vehof Jelle , Hammond Christopher J. , Bremner Fion D. , Williams Katie M.
Published: April 2021

Purpose: A classic twin study to evaluate the relative contributions of genetic and environmental factors to resting pupil size and reactivity.

Methods: Pupillometry was performed on 326 female twins (mean age 64 years) from the TwinsUK Adult Twin Registry, assessing resting pupil diameter in darkness and increasing levels of ambient light, alongside dynamic pupillary characteristics. Maximum-likelihood structural equation models estimated the proportion of trait variance attributable to genetic factors.

Results: Mean (SD) pupil diameter in darkness was 5.29 mm (0.81), decreasing to 3.24 mm (0.57) in bright light. Pupil light reaction (PLR) had a mean (SD) amplitude of 1.38 mm (0.27) and latency of 250.34 milliseconds (28.58). Pupil size and PLR were not associated with iris colour, intraocular pressure or refractive error, but were associated with age (diameter β = −0.02, p = 0.016, constriction amplitude β = −0.01, p < 0.001, velocity β = 0.03, p < 0.001, and latency β = 0.98, p < 0.001). In darkness the resting pupil size showed a MZ intraclass correlation coefficient of 0.85, almost double that of DZ (0.44), suggesting strong additive genetic effects, with the most parsimonious model estimating a heritability of 86% [95% confidence interval (CI) 79–90%] with 14% (95% CI 10–21%) explained by unique environmental factors. PLR amplitude, latency and constriction velocity had estimated heritabilities of 69% (95% CI 54–79%), 40% (95% CI 21–56%), and 64% (95% CI 48–75%), respectively.

Conclusion: Genetic effects are key determinants of resting pupil size and reactivity. Future studies to identify these genetic factors could improve our understanding of variation in pupil size and pupillary reactions in health and disease.