bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Six-Gene-Based Prognostic Model Predicts Survival and Clinical Risk Score for Gastric Cancer
Authors: Li Juan , Pu Ke , Li Chunmei , Wang Yuping , Zhou Yongning
Published: February 2021

Background:Autophagy plays a vital role in cancer initiation, malignant progression, and resistance to treatment. However, autophagy-related genes (ARGs) have rarely been analyzed in gastric cancer (GC). The purpose of this study was to analyze ARGs in GC using bioinformatic analysis and to identify new biomarkers for predicting the overall survival (OS) of patients with GC.

Methods:The gene expression profiles and clinical data of patients with GC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, and ARGs were obtained from two other datasets (the Human Autophagy Database and Molecular Signatures Database). Lasso, univariate, and multivariate Cox regression analyses were performed to identify the OS-related ARGs. Finally, a six-ARG model was identified as a prognostic indicator using the risk-score model, and survival and prognostic performance were analyzed based on the Kaplan-Meier test and ROC curve. Estimate calculations were used to assess the immune status of this model, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed for investigating the functions and terms associated with the model-related genes in GC.

Results:The six ARGs,DYNLL1,PGK2,HPR,PLOD2,PHYHIP, andCXCR4, were identified using Lasso and Cox regression analyses. Survival analysis revealed that the OS of GC patients in the high-risk group was significantly lower than that of the low-risk group (p< 0.05). The ROC curves revealed that the risk score model exhibited better prognostic performance with respect to OS. Multivariate Cox regression analysis indicated that the model was an independent predictor of OS and was not affected by most of the clinical traits (p< 0.05). The model-related genes were associated with immune suppression and several biological process terms, such as extracellular structure organization and matrix organization. Moreover, the genes were associated with the P13K-Akt signaling pathway, focal adhesion, and MAPK signaling pathway.

Conclusions:This study presents potential prognostic biomarkers for GC patients that would aid in determining the best patient-specific course of treatment.
Genome-Scale Phylogenetic and Population Genetic Studies Provide Insight Into Introgression and Adaptive Evolution of Takifugu Species in East Asia
Authors: Liu Bo , Zhou Zhixiong , Bai Yulin , Yang Junyi , Shi Yue , Pu Fei , Xu Peng
Published: February 2021

As a typical marine adaptive radiation species, mostTakifuguspecies are widely distributed in East Asian offshore, which have diversified morphological characteristics and different ecological habits. The phylogenetic relationship and population structure of theTakifuguspecies was complicated because of incomplete lineage sorting, widespread hybridization and introgression. Therefore, to systematically clarify the phylogenetic relationships ofTakifugugenus, explore the introgression and natural hybridization between differentTakifuguspecies, and detect the selective signatures in the adaptive evolution of diversified traits, whole-genome resequencing was used in 122Takifugusamples from 10 species. Phylogenetic analysis showed solid sister-group relationships betweenTakifugu bimaculatusandTakifugu flavidus,Takifugu oblongus, andTakifugu niphobles,Takifugu rubripes, andTakifugu obscurus,Takifugu xanthoptreus, andTakifugu ocellatus. Further admixture analysis indicated the divergence ofT. obscuruspopulation and the bidirectional gene flow betweenT. bimaculatusandT. flavidus. Using species-specific homozygous genetic variance sites, we detected the asymmetric introgression betweenT. bimaculatusandT. flavidusat China East sea and southern Taiwan Strait. By genome-scale genetic diversity scanning, we detected two copies ofsyt1,zar1andtgfbr1related to the semilunar reproduction rhythm inT. niphobles, involved in memory formation, embryo maturation and female reproduction. Furthermore, we also found lots ofT. niphoblesspecific mutations in CDS region of circadian rhythm related genes and endocrine hormone genes. ForTakifuguspecies, our research provides reliable genetic resources and results for the phylogeny, introgression, hybridization and adaptive evolution, and could be used as a guide for the formulation of the protection and proliferation release policies.
Protein A Modulates Neutrophil and Keratinocyte Signaling and Survival in Response to Staphylococcus aureus
Authors: Ledo Camila , Gonzalez Cintia D. , Garofalo Ailin , Sabbione Florencia , Keitelman Irene A. , Giai Constanza , Stella Inés , Trevani Analía S. , Gómez Marisa I.
Published: February 2021

The type 1 TNF-α receptor (TNFR1) has a central role in initiating both pro-inflammatory and pro-apoptotic signaling cascades in neutrophils. Considering that TNFR1 signalsStaphylococcus aureusprotein A (SpA), the aim of this study was to explore the interaction of this bacterial surface protein with neutrophils and keratinocytes to underscore the signaling pathways that may determine the fate of these innate immune cells in the infected tissue during staphylococcal skin infections. Using human neutrophils culturedin vitroand isogenic staphylococcal strains expressing or not protein A, we demonstrated that SpA is a potent inducer of IL-8 in neutrophils and that the induction of this chemokine is dependent on the SpA-TNFR1 interaction and p38 activation. In addition to IL-8, protein A induced the expression of TNF-α and MIP-1α highlighting the importance of SpA in the amplification of the inflammatory response. Protein A contributed to reduce neutrophil mortality prolonging their lifespan upon the encounter withS. aureus. Signaling initiated by SpA modulated the type of neutrophil cell deathin vitroand during skin and soft tissue infections (SSTI)in vivotriggering the apoptotic pathway instead of necrosis. Moreover, SpA induced pro-inflammatory cytokines in keratinocytes, modulating their survivalin vitroand preventing the exacerbated necrosis and ulceration of the epithelium during SSTIin vivo. Taken together, these results highlight the importance of the inflammatory signaling induced by protein A in neutrophils and skin epithelial cells. The ability of protein A to modulate the neutrophil/epithelial cell death program in the skin is of clinical relevance considering that lysis of neutrophils and epithelial cells will promote an intense inflammatory response and contribute to tissue damage, a non-desirable feature of complicated SSTI.
Tenascin-W Is a Novel Stromal Marker in Biliary Tract Cancers
Authors: Hendaoui Ismaïl , Lahmar Ahlem , Campo Luca , Mebarki Sihem , Bichet Sandrine , Hess Daniel , Degen Martin , Kchir Nidhameddine , Charrada-Ben Farhat Leila , Hefaiedh Rania , Ruiz Christian , Terracciano Luigi M. , Tucker Richard P. , Hendaoui Lotfi , Chiquet-Ehrismann Ruth
Published: February 2021

Extrahepatic cancers of the biliary system are typically asymptomatic until after metastasis, which contributes to their poor prognosis. Here we examined intrahepatic cholangiocarcinomas (n = 8), carcinomas of perihilar bile ducts (n = 7), carcinomas of the gallbladder (n = 11) and hepatic metastasis from carcinomas of the gallbladder (n = 4) for the expression of the extracellular matrix glycoproteins tenascin-C and tenascin-W. Anti-tenascin-C and anti-tenascin-W immunoreactivity was found in all biliary tract tumors examined. Unlike tenascin-C, tenascin-W was not detected in normal hepatobiliary tissue. Tenascin-W was also expressed by the cholangiocarcinoma-derived cell line Huh-28. However, co-culture of Huh-28 cells with immortalized bone marrow-derived stromal cells was necessary for the formation and organization of tenascin-W fibrils in vitro. Our results indicate that tenascin-W may be a novel marker of hepatobiliary tumor stroma, and its absence from many normal tissues suggests that it may be a potential target for biotherapies.
Machine Learning Identifies Complicated Sepsis Course and Subsequent Mortality Based on 20 Genes in Peripheral Blood Immune Cells at 24 H Post-ICU Admission
Authors: Banerjee Shayantan , Mohammed Akram , Wong Hector R. , Palaniyar Nades , Kamaleswaran Rishikesan
Published: February 2021

A complicated clinical course for critically ill patients admitted to the intensive care unit (ICU) usually includes multiorgan dysfunction and subsequent death. Owing to the heterogeneity, complexity, and unpredictability of the disease progression, ICU patient care is challenging. Identifying the predictors of complicated courses and subsequent mortality at the early stages of the disease and recognizing the trajectory of the disease from the vast array of longitudinal quantitative clinical data is difficult. Therefore, we attempted to perform a meta-analysis of previously published gene expression datasets to identify novel early biomarkers and train the artificial intelligence systems to recognize the disease trajectories and subsequent clinical outcomes. Using the gene expression profile of peripheral blood cells obtained within 24 h of pediatric ICU (PICU) admission and numerous clinical data from 228 septic patients from pediatric ICU, we identified 20 differentially expressed genes predictive of complicated course outcomes and developed a new machine learning model. After 5-fold cross-validation with 10 iterations, the overall mean area under the curve reached 0.82. Using a subset of the same set of genes, we further achieved an overall area under the curve of 0.72, 0.96, 0.83, and 0.82, respectively, on four independent external validation sets. This model was highly effective in identifying the clinical trajectories of the patients and mortality. Artificial intelligence systems identified eight out of twenty novel genetic markers (SDC4, CLEC5A, TCN1, MS4A3, HCAR3, OLAH, PLCB1, and NLRP1) that help predict sepsis severity or mortality. While these genes have been previously associated with sepsis mortality, in this work, we show that these genes are also implicated in complex disease courses, even among survivors. The discovery of eight novel genetic biomarkers related to the overactive innate immune system, including neutrophil function, and a new predictive machine learning method provides options to effectively recognize sepsis trajectories, modify real-time treatment options, improve prognosis, and patient survival.
Phenotypic Characterization of CD4+ T Lymphocytes in Periportal Fibrosis Secondary to Schistosomiasis
Authors: Santana Jordana Batista , de Almeida Tarcísio Vila Verde Santana , Lopes Diego Mota , Page Brady , Oliveira Sergio Costa , Souza Irismá , Ribeiro Luís Eduardo Viana Silva , Gutiérrez Néstor Adrián Guerrero , Carvalho Edgar M. , Cardoso Luciana Santos
Published: February 2021

Schistosomiasis is a parasitic disease that affects about 166 million people around the world. It is estimated that 5%–10% of individuals with schistosomiasis develop severe forms of the disease, which are characterized by pulmonary hypertension, ascites, periportal fibrosis, and other significant complications. The chronic phase of the disease is associated with a Th2 type immune response, but evidence also suggests there are roles for Th1 and Th17 in the development of severe disease. The aim of this study was to evaluate the CD4+T lymphocyte profile of patients with different degrees of periportal fibrosis secondary to schistosomiasis. These individuals had been treated for schistosomiasis, but since they live in aS. mansoniendemic area, they are at risk of reinfection. They were evaluated in relation to the degree of periportal fibrosis and classified into three groups: without fibrosis or with incipient fibrosis (WF/IFNE), n=12, possible periportal fibrosis/periportal fibrosis, n=13, and advanced periportal fibrosis/advanced periportal fibrosis with portal hypertension, n=4. We observed in the group without fibrosis a balance between the low expression of Th2 cytokines and high expression of T reg cells. As has already been described in the literature, we found an increase of the Th2 cytokines IL-4, IL-5, and IL-13 in the group with periportal fibrosis. In addition, this group showed higher expression of IL-17 and IL-10 but lower IL-10/IL-13 ratio than patients in the WF/IFNE group. Cells from individuals who present any level of fibrosis expressed more TGF-β compared to the WF/IFNE group and a positive correlation with left lobe enlargement and portal vein wall thickness. There was a negative correlation between IL-17 and the thickness of the portal vein wall, but more studies are necessary in order to explore the possible protective role of this cytokine. Despite the fibrosis group having presented a higher expression of pro-fibrotic molecules compared to WF/IFNE patients, it seems there is a regulation through IL-10 and T reg cells that is able to maintain the low morbidity of this group.
Reduced Expression of Autophagy Markers and Expansion of Myeloid-Derived Suppressor Cells Correlate With Poor T Cell Response in Severe COVID-19 Patients
Authors: Tomić Sergej , Đokić Jelena , Stevanović Dejan , Ilić Nataša , Gruden-Movsesijan Alisa , Dinić Miroslav , Radojević Dušan , Bekić Marina , Mitrović Nebojša , Tomašević Ratko , Mikić Dragan , Stojanović Dragoš , Čolić Miodrag
Published: February 2021

Widespread coronavirus disease (COVID)-19 is causing pneumonia, respiratory and multiorgan failure in susceptible individuals. Dysregulated immune response marks severe COVID-19, but the immunological mechanisms driving COVID-19 pathogenesis are still largely unknown, which is hampering the development of efficient treatments. Here we analyzed ~140 parameters of cellular and humoral immune response in peripheral blood of 41 COVID-19 patients and 16 age/gender-matched healthy donors by flow-cytometry, quantitative PCR, western blot and ELISA, followed by integrated correlation analyses with ~30 common clinical and laboratory parameters. We found that lymphocytopenia in severe COVID-19 patients (n=20) strongly affects T, NK and NKT cells, but not B cells and antibody production. Unlike increased activation of ICOS-1+ CD4+ T cells in mild COVID-19 patients (n=21), T cells in severe patients showed impaired activation, low IFN-γ production and high functional exhaustion, which correlated with significantly down-regulated HLA-DR expression in monocytes, dendritic cells and B cells. The latter phenomenon was followed by lower interferon responsive factor (IRF)-8 and autophagy-related genes expressions, and the expansion of myeloid derived suppressor cells (MDSC). Intriguingly, PD-L1-, ILT-3-, and IDO-1-expressing monocytic MDSC were the dominant producers of IL-6 and IL-10, which correlated with the increased inflammation and accumulation of regulatory B and T cell subsets in severe COVID-19 patients. Overall, down-regulated IRF-8 and autophagy-related genes expression, and the expansion of MDSC subsets could play critical roles in dysregulating T cell response in COVID-19, which could have large implications in diagnostics and design of novel therapeutics for this disease.
An Antibody-Drug Conjugate That Selectively Targets Human Monocyte Progenitors for Anti-Cancer Therapy
Authors: Izumi Yuta , Kanayama Masashi , Shen Zhongchuzi , Kai Masayuki , Kawamura Shunsuke , Akiyama Megumi , Yamamoto Masahide , Nagao Toshikage , Okada Keigo , Kawamata Norihiko , Toyota Shigeo , Ohteki Toshiaki
Published: February 2021

As hematopoietic progenitors supply a large number of blood cells, therapeutic strategies targeting hematopoietic progenitors are potentially beneficial to eliminate unwanted blood cells, such as leukemic cells and immune cells causing diseases. However, due to their pluripotency, targeting those cells may impair the production of multiple cell lineages, leading to serious side effects such as anemia and increased susceptibility to infection. To minimize those side effects, it is important to identify monopotent progenitors that give rise to a particular cell lineage. Monocytes and monocyte-derived macrophages play important roles in the development of inflammatory diseases and tumors. Recently, we identified human monocyte-restricted progenitors, namely, common monocyte progenitors and pre-monocytes, both of which express high levels of CD64, a well-known monocyte marker. Here, we introduce a dimeric pyrrolobenzodiazepine (dPBD)-conjugated anti-CD64 antibody (anti-CD64-dPBD) that selectively induces the apoptosis of proliferating human monocyte-restricted progenitors but not non-proliferating mature monocytes. Treatment with anti-CD64-dPBD did not affect other types of hematopoietic cells including hematopoietic stem and progenitor cells, neutrophils, lymphocytes and platelets, suggesting that its off-target effects are negligible. In line with these findings, treatment with anti-CD64-dPBD directly killed proliferating monocytic leukemia cells and prevented monocytic leukemia cell generation from bone marrow progenitors of chronic myelomonocytic leukemia patients in a patient-derived xenograft model. Furthermore, by depleting the source of monocytes, treatment with anti-CD64-dPBD ultimately eliminated tumor-associated macrophages and significantly reduced tumor size in humanized mice bearing solid tumors. Given the selective action of anti-CD64-dPBD on proliferating monocyte progenitors and monocytic leukemia cells, it should be a promising tool to target cancers and other monocyte-related inflammatory disorders with minimal side effects on other cell lineages.
Schistosome Infection and Schistosome-Derived Products as Modulators for the Prevention and Alleviation of Immunological Disorders
Authors: Mu Yi , McManus Donald P. , Hou Nan , Cai Pengfei
Published: February 2021

Parasitic helminths, comprising the flatworms (tapeworms and flukes) and nematodes (roundworms), have plagued humans persistently over a considerable period of time. It is now known that the degree of exposure to these and other pathogens inversely correlates with the incidence of both T helper 1 (Th1)-mediated autoimmunity and Th2-mediated allergy. Accordingly, there has been recent increased interest in utilizing active helminth worm infections and helminth-derived products for the treatment of human autoimmune and inflammatory diseases and to alleviate disease severity. Indeed, there is an accumulating list of novel helminth derived molecules, including proteins, peptides, and microRNAs, that have been shown to exhibit therapeutic potential in a variety of disease models. Here we consider the blood-dwelling schistosome flukes, which have evolved subtle immune regulatory mechanisms that promote parasite survival but at the same time minimize host tissue immunopathology. We review and discuss the recent advances in using schistosome infection and schistosome-derived products as therapeutics to treat or mitigate human immune-related disorders, including allergic asthma, arthritis, colitis, diabetes, sepsis, cystitis, and cancer.
T Cell Protein Tyrosine Phosphatase in Osteoimmunology
Authors: Wang Ya-nan , Liu Shiyue , Jia Tingting , Feng Yao , Zhang Wenjing , Xu Xin , Zhang Dongjiao
Published: February 2021

Osteoimmunology highlights the two-way communication between bone and immune cells. T cell protein tyrosine phosphatase (TCPTP), also known as protein-tyrosine phosphatase non-receptor 2 (PTPN2), is an intracellular protein tyrosine phosphatase (PTP) essential in regulating immune responses and bone metabolism via dephosphorylating target proteins. Tcptp knockout in systemic or specific immune cells can seriously damage the immune function, resulting in bone metabolism disorders. This review provided fresh insights into the potential role of TCPTP in osteoimmunology. Overall, the regulation of osteoimmunology by TCPTP is extremely complicated. TCPTP negatively regulates macrophages activation and inflammatory factors secretion to inhibit bone resorption. TCPTP regulates T lymphocytes differentiation and T lymphocytes-related cytokines signaling to maintain bone homeostasis. TCPTP is also expected to regulate bone metabolism by targeting B lymphocytes under certain time and conditions. This review offers a comprehensive update on the roles of TCPTP in osteoimmunology, which can be a promising target for the prevention and treatment of inflammatory bone loss.
From Melanoma Development to RNA-Modified Dendritic Cell Vaccines: Highlighting the Lessons From the Past
Authors: Shadbad Mahdi Abdoli , Hajiasgharzadeh Khalil , Derakhshani Afshin , Silvestris Nicola , Baghbanzadeh Amir , Racanelli Vito , Baradaran Behzad
Published: February 2021

Although melanoma remains the deadliest skin cancer, the current treatment has not resulted in the desired outcomes. Unlike chemotherapy, immunotherapy has provided more tolerable approaches and revolutionized cancer therapy. Although dendritic cell-based vaccines have minor side effects, the undesirable response rates of traditional approaches have posed questions about their clinical translation. The immunosuppressive tumor microenvironment can be the underlying reason for their low response rates. Immune checkpoints and indoleamine 2,3-dioxygenase have been implicated in the induction of immunosuppressive tumor microenvironment. Growing evidence indicates that the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Protein kinase B (PKB) (PI3K/AKT) pathways, as the main oncogenic pathways of melanoma, can upregulate the tumoral immune checkpoints, like programmed death-ligand 1. This study briefly represents the main oncogenic pathways of melanoma and highlights the cross-talk between these oncogenic pathways with indoleamine 2,3-dioxygenase, tumoral immune checkpoints, and myeloid-derived suppressor cells. Moreover, this study sheds light on a novel tumor antigen on melanoma, which has substantial roles in tumoral immune checkpoints expression, indoleamine 2,3-dioxygenase secretion, and stimulating the oncogenic pathways. Finally, this review collects the lessons from the previous unsuccessful trials and integrates their lessons with new approaches in RNA-modified dendritic cell vaccines. Unlike traditional approaches, the advances in single-cell RNA-sequencing techniques and RNA-modified dendritic cell vaccines along with combined therapy of the immune checkpoint inhibitors, indoleamine 2,3-dioxygenase inhibitor, and RNA-modified dendritic cell-based vaccine can overcome these auto-inductive loops and pave the way for developing robust dendritic cell-based vaccines with the most favorable response rate and the least side effects.
Immunomodulatory Role of Tenascin-C in Myocarditis and Inflammatory Cardiomyopathy
Authors: Tajiri Kazuko , Yonebayashi Saori , Li Siqi , Ieda Masaki
Published: February 2021

Accumulating evidence suggests that the breakdown of immune tolerance plays an important role in the development of myocarditis triggered by cardiotropic microbial infections. Genetic deletion of immune checkpoint molecules that are crucial for maintaining self-tolerance causes spontaneous myocarditis in mice, and cancer treatment with immune checkpoint inhibitors can induce myocarditis in humans. These results suggest that the loss of immune tolerance results in myocarditis. The tissue microenvironment influences the local immune dysregulation in autoimmunity. Recently, tenascin-C (TN-C) has been found to play a role as a local regulator of inflammation through various molecular mechanisms. TN-C is a nonstructural extracellular matrix glycoprotein expressed in the heart during early embryonic development, as well as during tissue injury or active tissue remodeling, in a spatiotemporally restricted manner. In a mouse model of autoimmune myocarditis, TN-C was detectable before inflammatory cell infiltration and myocytolysis became histologically evident; it was strongly expressed during active inflammation and disappeared with healing. TN-C activates dendritic cells to generate pathogenic autoreactive T cells and forms an important link between innate and acquired immunity.
Immune Responses to Pseudomonas aeruginosa Biofilm Infections
Authors: Moser Claus , Jensen Peter Østrup , Thomsen Kim , Kolpen Mette , Rybtke Morten , Lauland Anne Sofie , Trøstrup Hannah , Tolker-Nielsen Tim
Published: February 2021

Pseudomonas aeruginosais a key pathogen of chronic infections in the lungs of cystic fibrosis patients and in patients suffering from chronic wounds of diverse etiology. In these infections the bacteria congregate in biofilms and cannot be eradicated by standard antibiotic treatment or host immune responses. The persistent biofilms induce a hyper inflammatory state that results in collateral damage of the adjacent host tissue. The host fails to eradicate the biofilm infection, resulting in hindered remodeling and healing. In the present review we describe our current understanding of innate and adaptive immune responses elicited byP. aeruginosabiofilms in cystic fibrosis lung infections and chronic wounds. This includes the mechanisms that are involved in the activation of the immune responses, as well as the effector functions, the antimicrobial components and the associated tissue destruction. The mechanisms by which the biofilms evade immune responses, and potential treatment targets of the immune response are also discussed.
Role of the IL-23/IL-17 Pathway in Rheumatic Diseases: An Overview
Authors: Schinocca Claudia , Rizzo Chiara , Fasano Serena , Grasso Giulia , La Barbera Lidia , Ciccia Francesco , Guggino Giuliana
Published: February 2021

Interleukin-23 (IL-23) is a pro-inflammatory cytokine composed of two subunits, IL-23A (p19) and IL-12/23B (p40), the latter shared with Interleukin-12 (IL-12). IL-23 is mainly produced by macrophages and dendritic cells, in response to exogenous or endogenous signals, and drives the differentiation and activation of T helper 17 (Th17) cells with subsequent production of IL-17A, IL-17F, IL-6, IL-22, and tumor necrosis factor α (TNF-α). Although IL-23 plays a pivotal role in the protective immune response to bacterial and fungal infections, its dysregulation has been shown to exacerbate chronic immune-mediated inflammation. Well-established experimental data support the concept that IL-23/IL-17 axis activation contributes to the development of several inflammatory diseases, such as PsA, Psoriasis, Psoriatic Arthritis; AS, Ankylosing Spondylitis; IBD, Inflammatory Bowel Disease; RA, Rheumatoid Arthritis; SS, Sjogren Syndrome; MS, Multiple Sclerosis. As a result, emerging clinical studies have focused on the blockade of this pathogenic axis as a promising therapeutic target in several autoimmune disorders; nevertheless, a greater understanding of its contribution still requires further investigation. This review aims to elucidate the most recent studies and literature data on the pathogenetic role of IL-23 and Th17 cells in inflammatory rheumatic diseases.
Isolation of Porcine Reproductive and Respiratory Syndrome Virus GP5-Specific, Neutralizing Monoclonal Antibodies From Hyperimmune Sows
Authors: Young Jordan E. , Dvorak Cheryl M. T. , Graham Simon P. , Murtaugh Michael P.
Published: February 2021

Porcine reproductive and respiratory syndrome (PRRS) is a devastating disease which impacts the pig industry worldwide. The disease is caused by PRRS viruses (PRRSV-1 and -2) which leads to abortions and other forms of reproductive failure in sows and severe respiratory disease in growing pigs. Current PRRSV vaccines provide limited protection; only providing complete protection against closely related strains. The development of improved PRRSV vaccines would benefit from an increased understanding of epitopes relevant to protection, including those recognized by antibodies which possess the ability to neutralize distantly related strains. In this work, a reverse vaccinology approach was taken; starting first with pigs known to have a broadly neutralizing antibody response and then investigating the responsible B cells/antibodies through the isolation of PRRSV neutralizing monoclonal antibodies (mAbs). PBMCs were harvested from pigs sequentially exposed to a modified-live PRRSV-2 vaccine as well as divergent PRRSV-2 field isolates. Memory B cells were immortalized and a total of 5 PRRSV-specific B-cell populations were isolated. All identified PRRSV-specific antibodies were found to be broadly binding to all PRRSV-2 isolates tested, but not PRRSV-1 isolates. Antibodies against GP5 protein, commonly thought to possess a dominant PRRSV neutralizing epitope, were found to be highly abundant, as four out of five B cells populations were GP5 specific. One of the GP5-specific mAbs was shown to be neutralizing but this was only observed against homologous and not heterologous PRRSV strains. Further investigation of these antibodies, and others, may lead to the elucidation of conserved neutralizing epitopes that can be exploited for improved vaccine design and lays the groundwork for the study of broadly neutralizing antibodies against other porcine pathogens.
Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels
Authors: Gill Erin E. , Smith Maren L. , Gibson Kristen M. , Morishita Kimberly A. , Lee Amy H. Y. , Falsafi Reza , Graham Jinko , Foell Dirk , Benseler Susanne M. , Ross Colin J. , Luqmani Raashid A. , Cabral David A. , Hancock Robert E. W. , Brown Kelly L. ,   The PedVas Initiative Investigators
Published: February 2021

Objectives: Chronic primary vasculitis describes a group of complex and rare diseases that are characterized by blood vessel inflammation. Classification of vasculitis subtypes is based predominantly on the size of the involved vessels and clinical phenotype. There is a recognized need to improve classification, especially for small-to-medium sized vessel vasculitides, that, ideally, is based on the underlying biology with a view to informing treatment.

Methods: We performed RNA-Seq on blood samples from children (n = 41) and from adults (n = 11) with small-to-medium sized vessel vasculitis, and used unsupervised hierarchical clustering of gene expression patterns in combination with clinical metadata to define disease subtypes.

Results: Differential gene expression at the time of diagnosis separated patients into two primary endotypes that differed in the expression of ~3,800 genes in children, and ~1,600 genes in adults. These endotypes were also present during disease flares, and both adult and pediatric endotypes could be discriminated based on the expression of just 20 differentially expressed genes. Endotypes were associated with distinct biological processes, namely neutrophil degranulation and T cell receptor signaling.

Conclusions: Phenotypically similar subsets of small-to-medium sized vessel vasculitis may have different mechanistic drivers involving innate vs. adaptive immune processes. Discovery of these differentiating immune features provides a mechanistic-based alternative for subclassification of vasculitis.
End-to-End Modeling Reveals Species-Specific Effects of Large-Scale Coastal Restoration on Living Resources Facing Climate Change
Authors: de Mutsert Kim , Lewis Kristy A. , White Eric D. , Buszowski Joe
Published: February 2021

Coastal erosion and wetland loss are affecting Louisiana to such an extent that the loss of land between 1932 and 2016 was close to 5,000 km2. To mitigate this decline, coastal protection and restoration projects are being planned and implemented by the State of Louisiana, United States. The Louisiana Coastal Master Plan (CMP) is an adaptive management approach that provides a suite of projects that are predicted to build or maintain land and protect coastal communities. Restoring the coast with this 50-year large-scale restoration and risk reduction plan has the potential to change the biomass and distribution of economically and ecologically important fisheries species in this region. However, not restoring the coast may have negative impacts on these species due to the loss of habitat. This research uses an ecosystem model to evaluate the effects of plan implementation versus a future without action (FWOA) on the biomass and distribution of fisheries species in the estuaries over 50 years of model simulations. By simulating effects using a spatially-explicit ecosystem model, not only can the changes in biomass in response to plan implementation be evaluated, but also the distribution of species in response to the planned restoration and risk reduction projects. Simulations are performed under two relative sea level rise (SLR) scenarios to understand the effects of climate change on project performance and subsequent fisheries species biomass and distribution. Simulation output of eight economically important fisheries species shows that the plan mostly results in increases in species biomass, but that the outcomes are species-specific and basin-specific. The SLR scenario highly affects the amount of wetland habitat maintained after 50 years (with higher levels of wetland loss under increased SLR) and, subsequently, the biomass of species depending on that habitat. Species distribution results can be used to identify expected changes for specific species on a regional basis. By making this type of information available to resource managers, precautionary measures of ecosystem management and adaptation can be implemented.
Accelerometry of Seabream in a Sea-Cage: Is Acceleration a Good Proxy for Activity?
Authors: Palstra Arjan P. , Arechavala-Lopez Pablo , Xue Yuanxu , Roque Ana
Published: February 2021

Activity assessment of individual fish in a sea-cage could provide valuable insights into the behavior, but also physiological well-being and resilience, of the fish population in the cage. Acceleration can be monitored continuously with internal acoustic transmitter tags and is generally applied as a real-time proxy for activity. The objective of this study was to investigate the activity patterns of Gilthead seabream (Sparus aurata) by transmitter tags in a sea-cage and analyze correlations with water temperature, fish size and tissue weights. Experimental fish (N= 300) were transferred to an experimental sea-cage of which thirty fish (Standard Length SL = 18.3 ± 1.7 cm; Body Weight BW = 174 ± 39 g) were implanted with accelerometer tags. Accelerations were monitored for a period of 6 weeks (Nov.–Dec.) and were analyzed over the 6 weeks and 24 h of the day. At the end of the experimental period, tagged fish were again measured, weighed and dissected for tissue and filet weights, and correlations with accelerations were analyzed. Daily rhythms in accelerations under the experimental conditions were characterized by more active periods from 6 to 14 h and 18 to 0 h and less active periods from 0 to 6 h and 14 to 18 h. This W-shaped pattern remained over the experimental weeks, even with diurnal accelerations decreasing which was correlated to the dropping temperature. The increase in activity was not during, but just before feeding indicating food-anticipatory activity. Activity patterning can be useful for timing feeding events at the start of active periods, in this study between 6 and 11 h, and between 18 and 22 h. Acceleration was negatively correlated to heart and mesenteric fat mass, which was the exact contrary of our expectations for sustainedly swimming seabream. These results suggest that acceleration is a proxy for unsteady swimming activity only and research is required into the accelerations occurring during sustained swimming of seabream at various speeds.
Crystal Plasticity Modeling of Creep in Alloys with Lamellar Microstructures at the Example of Fully Lamellar TiAl
Authors: Schnabel Jan E. , Scheider Ingo
Published: February 2021

A crystal plasticity model of the creep behavior of alloys with lamellar microstructures is presented. The model is based on the additive decomposition of the plastic strain into a part that describes the instantaneous (i.e., high strain rate) plastic response due to loading above the yield point, and a part that captures the viscoplastic deformation at elevated temperatures. In order to reproduce the transition from the primary to the secondary creep stage in a physically meaningful way, the competition between work hardening and recovery is modeled in terms of the evolving dislocation density. The evolution model for the dislocation density is designed to account for the significantly different free path lengths of slip systems in lamellar microstructures depending on their orientation with respect to the lamella interface. The established model is applied to reproduce and critically discuss experimental findings on the creep behavior of polysynthetically twinned TiAl crystals. Although the presented crystal plasticity model is designed with the creep behavior of fully lamellar TiAl in mind, it is by no means limited to these specific alloys. The constitutive model and many of the discussed assumptions also apply to the creep behavior of other crystalline materials with lamellar microstructures.
Crank-Angle Resolved Flow Measurements in the Intake Duct of a Research Engine Using Novel and Fast Response Aerodynamic Probes
Authors: Großmann Fabian , Mühlpfordt Torsten , Rambacher Patrick , Bikas Georgios
Published: February 2021

Despite the public debate nowadays on the future of Internal Combustion Engines (ICE), which is impeding their development, one limitation towards further optimization of ICE in terms of fuel consumption and emissions can be seen in the current approach and more specifically in the transient engine operation and its control. The main drawbacks in the current approach source from: 1) complex structure of mechanization including sensors and actuators, 2) low time resolution and accuracy of sensing (cost driven), 3) complex Electronic Control Unit (ECU)-software architecture associated with huge calibration effort and 4) recently, funded research due to unsecure business model of ICE is becoming less. To overcome these difficulties unexploited potential should be utilized. Some of this potential lies in cycle-by-cycle and cylinder-by-cylinder accurate fuel and air control, and in the development of physical based virtual sensors with high time resolution and accuracy. One of the main motivations for this study was to develop a measurement technique that enables crank-angle resolved air mass flow rate measurements during engine operation in a dynamometer test cell. The measurement principle is quite simple and is based on gauging the dynamic pressure in both the intake and exhaust duct at the closest possible positions to the valves. To fulfill these requirements aerodynamic probes have been developed and manufactured utilizing 3D printing. The probes have been integrated in special developed flanges, which correspond exactly to the shape of the air channels in the cylinder head of the engine. Hence, they can be mounted either in front of the valves at the intake or behind the valves at the exhaust duct. Results at different engine operating conditions have been obtained, analyzed and correlated to other sensors like air-flow meter. Those post-processed results can be further used to validate 1-D gas exchange models, or 3-D Computational Fluid Dynamics (CFD) port flow models. The ultimate scope of these measurements is to calibrate fast physical-based gas exchange models that can be directly used in the engine control framework on an embedded system.
Effect of High-Flow Oxygen on Exercise Performance in COPD Patients. Randomized Trial
Authors: Bitos Konstantinos , Furian Michael , Mayer Laura , Schneider Simon R. , Buenzli Simone , Mademilov Maamed Z. , Sheraliev Ulan U. , Marazhapov Nuridin H. , Abdraeva Ainura K. , Aidaralieva Shoira D. , Muratbekova Aybermet M. , Sooronbaev Talant M. , Ulrich Silvia , Bloch Konrad E.
Published: February 2021

Background: High-flow oxygen therapy (HFOT) provides oxygen-enriched, humidified, and heated air at high flow rates via nasal cannula. It could be an alternative to low-flow oxygen therapy (LFOT) which is commonly used by patients with chronic obstructive pulmonary disease (COPD) during exercise training.

Research Question: We evaluated the hypothesis that HFOT improves exercise endurance in COPD patients compared to LFOT.

Methods: Patients with stable COPD, FEV1 40–80% predicted, resting pulse oximetry (SpO2) ≥92%, performed two constant-load cycling exercise tests to exhaustion at 75% of maximal work rate on two different days, using LFOT (3 L/min) and HFOT (60 L/min, FiO2 0.45) in randomized order according to a crossover design. Primary outcome was exercise endurance time, further outcomes were SpO2, breath rate and dyspnea.

Results: In 79 randomized patients, mean ± SD age 58 ± 9 y, FEV1 63 ± 9% predicted, GOLD grades 2-3, resting PaO2 9.4 ± 1.0 kPa, intention-to-treat analysis revealed an endurance time of 688 ± 463 s with LFOT and 773 ± 471 s with HFOT, mean difference 85 s (95% CI: 7 to 164, P = 0.034), relative increase of 13% (95% CI: 1 to 28). At isotime, patients had lower respiratory rate and higher SpO2 with HFOT. At end-exercise, SpO2 was higher by 2% (95% CI: 2 to 2), and Borg CR10 dyspnea scores were lower by 0.8 points (95% CI: 0.3 to 1.2) compared to LFOT.

Interpretation: In mildly hypoxemic patients with COPD, HFOT improved endurance time in association with higher arterial oxygen saturation, reduced respiratory rate and less dyspnea compared to LFOT. Therefore, HFOT is promising for enhancing exercise performance in COPD.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03955770.
High-Frequency Ultrasonography—Possibilities and Perspectives of the Use of 20 MHz in Teledermatology
Authors: Polańska Adriana , Jenerowicz Dorota , Paszyńska Elżbieta , Żaba Ryszard , Adamski Zygmunt , Dańczak-Pazdrowska Aleksandra
Published: February 2021

High-frequency ultrasonography (HF-USG) is a non-invasive andin vivomethod of visualization of the skin and upper part of subcutaneous tissue based on ultrasounds above 20 MHz. Although initially HF-USG was introduced to measure skin thickness, it currently gained widespread acceptance in dermato-oncology, primarily when used to determine skin tumor margins. Moreover, its application in different dermatology fields is known, particularly as a rapidly evolving method in the objective evaluation of the severity of various chronic skin diseases. Among different specialties, teledermatology belongs to leading and continually developing areas of successful telemedicine applications. Various skin conditions are visible to the human eye, which makes them particularly suitable for telemedicine. However, HF-USG enables specialists to look into deeper skin layers, thus extending diagnostic options. On the other hand, teledermatology creates the possibility of sending images for consultation and facilitates the therapeutic decision as HF-USG can be used in an asynchronous store and forward manner. It seems that HF-USG and teledermatology may be regarded as a truly matched pair. The aim of this work is to present current applications of 20-MHz ultrasonography in dermatology, including skin neoplasms and chronic skin diseases. Moreover, the authors aimed to analyze the possibilities of HF-USG use as a valuable tool in teledermatology, especially in diagnosing and monitoring patients suffering from long-lasting skin conditions.
Assessment of Image Quality and Lesion Detectability With Digital PET/CT System
Authors: Delcroix Olivier , Bourhis David , Keromnes Nathalie , Robin Philippe , Le Roux Pierre-Yves , Abgral Ronan , Salaun Pierre-Yves , Querellou Solène
Published: February 2021

Purpose: The aim of this study was to assess image quality and lesion detectability acquired with a digital Positron Emission Tomography/Computed Tomography (PET/CT) Siemens Biograph Vision 600 system.

Material and Methods: Consecutive patients who underwent a FDG PET/CT during the first week of use of a digital PET/CT (Siemens Biograph Vision 600) at the nuclear medicine department of the university hospital of Brest were analyzed. PET were realized using list mode acquisition. For all patients, 4 datasets were reconstructed. We determined, according to phantom measurements, an equivalent time acquisition/reconstruction parameters pair of the digital PET/CT corresponding to an analog PET/CT image quality (“analog-like”) as reference dataset. We compared the reference dataset with 3 others digital PET/CT reconstruction parameters, allowing a decrease of emission duration: 60, 90, and 120 s per bed position. Three nuclear medicine physicians evaluated independently, for each dataset, overall image quality [Maximal Intensity Projection (MIP), noise, sharpness] using a 4-point scale. Physicians assessed also lesion detection capability by reporting new visible lesions on each digital datasets with their confidence level in comparison with analog-like dataset.

Results: Ninety-eight patients were analyzed. Image quality of MIP (IQMIP), sharpness (IQSHARPNESS), and noise (IQNOISE) of all digital datasets (60, 90, and 120 s) were better than those evaluated with analog-like reconstruction. Moreover, digital PET/CT system improved IQMIP, IQNOISE, and IQSHARPNESS whatever the BMI. Lesion detection capability and confidence level were higher for 60, 90, 120 s per bed position, respectively, than for analog-like images.

Conclusion: Our study demonstrated an improvement of image quality and lesion detectability with a digital PET/CT system.
Case Report: Metagenomics Next-Generation Sequencing Can Help Define the Best Therapeutic Strategy for Brain Abscesses Caused by Oral Pathogens
Authors: Ma Zhonghui , Yan Su , Dong Haoxin , Wang Huifen , Luo Yonggang , Wang Xi
Published: February 2021

Brain abscesses are associated with an increased long-term risk of new seizures and increased mortality within several years after infection. Common microorganisms that cause brain abscesses include bacteria, fungi, and mycoplasma. We report a 75-year-old man with a brain abscess caused by Prevotella denticola, an oral pathogen. Based on the clinical condition, we suspected that the patient had a blood-borne brain abscess, and he received antibiotics and systemic supportive treatment. The patient developed shock for the second time after negative Gram-staining results. Metagenomics next-generation sequencing showed one strain from the oral microbiome, confirming our hypothesis, and targeted antibiotic treatment was administered quickly. Thus, we report a case in which genomic analysis was the critical factor in determining the best antimicrobial therapy for administration.
Tree Species Richness and Neighborhood Effects on Ectomycorrhizal Fungal Richness and Community Structure in Boreal Forest
Authors: Otsing Eveli , Anslan Sten , Ambrosio Elia , Koricheva Julia , Tedersoo Leho
Published: February 2021

Tree species identity is one of the key factors driving ectomycorrhizal (EcM) fungal richness and community composition in boreal and temperate forest ecosystems, but little is known about the influence of tree species combinations and their neighborhood effects on EcM communities. To advance our understanding of host plant effects on EcM fungi, the roots of silver birch, Scots pine, and Norway spruce were analyzed using high-throughput sequencing across mature boreal forest exploratory plots of monocultures and two- and three-species mixtures in Finland. Our analyses revealed that tree species identity was an important determinant of EcM fungal community composition, but tree species richness had no significant influence on EcM fungal richness and community composition. We found that EcM fungal community composition associated with spruce depends on neighboring tree species. Our study suggests that at a regional-scale tree species identity is the primary factor determining community composition of root-associated EcM fungi alongside with tree species composition effects on EcM fungal community of spruce in mixed stands.