bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Treatment Regimens on Antibody Response to the SARS-CoV-2 Coronavirus
Authors: Shang Yufeng , Liu Tao , Li Jingfeng , Kaweme Natasha Mupeta , Wang Xinghuan , Zhou Fuling
Published: April 2021

The coronavirus disease 2019 (COVID-19) is widely spread and remains a global pandemic. Limited evidence on the systematic evaluation of the impact of treatment regimens on antibody responses exists. Our study aimed to analyze the role of antibody response on prognosis and determine factors influencing the IgG antibodies’ seroconversion. A total of 1,111 patients with mild to moderate COVID-19 symptoms admitted to Leishenshan Hospital in Wuhan were retrospectively analyzed. A serologic SARS-CoV-2 IgM/IgG antibody test was performed on all the patients 21 days after the onset of symptoms. Patient clinical characteristics were compared. In the study, 42 patients progressed to critical illness, with 6 mortalities reported while 1,069 patients reported mild to moderate disease. Advanced age (P = 0.028), gasping (P < 0.001), dyspnea (P = 0.024), and IgG negativity (P = 0.006) were associated with progression to critical illness. The mortality rate in critically ill patients with IgG antibody was 6.45% (95% CI 1.12–22.84%) and 36.36% (95% CI 12.36–68.38%) in patients with no IgG antibody (P = 0.003). Symptomatic patients were more likely to develop IgG antibody responses than asymptomatic patients. Using univariable analysis, fever (P < 0.001), gasping (P = 0.048), cancer (P < 0.001), cephalosporin (P = 0.015), and chloroquine/hydroxychloroquine (P = 0.021) were associated with IgG response. In the multivariable analysis, fever, cancer, cephalosporins, and chloroquine/hydroxychloroquine correlated independently with IgG response. We determined that the absence of SARS-CoV-2 antibody IgG in the convalescent stage had a specific predictive role in critical illness progression. Importantly, risk factors affecting seropositivity were identified, and the effect of antimalarial drugs on antibody response was determined.
PRAK Promotes the Pathogen Clearance by Macrophage Through Regulating Autophagy and Inflammasome Activation
Authors: Mi Ligu , Wang Yan , Xu Hui , Wang Yu , Wu Jia , Dai Hui , Zhang Yu
Published: April 2021

The p38 regulated/activated protein kinase (PRAK) is a protein kinase downstream of p38MAPK. The present study investigated its function in the macrophage. Myeloid-specific deletion of Prak resulted in a significant reduction in F4/80+CD11b+ peritoneal macrophages with decreased expression of MHC-II and CD80. Upon infection with Listeria monocytogenes, Prak-deficient mice demonstrated an increased mortality, which was accompanied by a higher bacterial load in multiple tissues and elevated levels of proinflammatory cytokines in the serum. While the Prak-deficient macrophage showed similar potency in phagocytosis assays, its bactericidal activity was severely impaired. Moreover, Prak deficiency was associated with defects in ROS production, inflammasome activation as well as autophagy induction. Therefore, PRAK critically contributes to the clearance of intracellular pathogens by affecting multiple aspects of the macrophage function.
Variant to Gene Mapping to Discover New Targets for Immune Tolerance
Authors: Mehra Parul , Wells Andrew D.
Published: April 2021

The breakdown of immunological tolerance leads to autoimmune disease, and the mechanisms that maintain self-tolerance, especially in humans, are not fully understood. Genome-wide association studies (GWAS) have identified hundreds of human genetic loci statistically linked to autoimmune disease risk, and epigenetic modifications of DNA and chromatin at these loci have been associated with autoimmune disease risk. Because the vast majority of these signals are located far from genes, identifying causal variants, and their functional consequences on the correct effector genes, has been challenging. These limitations have hampered the translation of GWAS findings into novel drug targets and clinical interventions, but recent advances in understanding the spatial organization of the genome in the nucleus have offered mechanistic insights into gene regulation and answers to questions left open by GWAS. Here we discuss the potential for ‘variant-to-gene mapping’ approaches that integrate GWAS with 3D functional genomic data to identify human genes involved in the maintenance of tolerance.
Revisit of Optimal Donor Number Estimation in the Hong Kong Bone Marrow Donor Registry
Authors: Ho Jenny Chung Yee , Cheung Stephen Kwok Fan , Lui Zhongyi , Tang Ivan Wing Hong , Yang Wanling , Ip Patrick , Lee Cheuk Kwong , Middleton Derek , Kwok Janette Siu Yin
Published: April 2021

High resolution typing of the HLA-DPB1 locus for patient who requested for hematopoietic stem cell transplantation (HSCT) workup has recently become mandatory by the National Marrow Donor Program (NMDP) in order to facilitate matching between donors and recipients for better outcomes. The likelihood of identifying HLA matched donors in Hong Kong, on top of the existing HLA-A, -B, -C, and -DRB1 loci, is revisited in this study. HLA-A, -B, -C, -DRB1 and -DPB1 genotypes of 5,266 volunteer unrelated Chinese donors from the Hong Kong Bone Marrow Donor Registry (HKBMDR), were included in this study. Matching models were employed to determine the matching probabilities for 10/10(DPB1) and 9/10(DPB1) HLA match. The matching probabilities are 20% at 10/10(DPB1) HLA match and 55% at 9/10(DPB1) match, based on the existing 130,000 donors in the HKBMDR. The likelihoods of match become 27% and 65% respectively, by increasing the registry to 250,000. However, if DPB T-cell-epitope (TCE) model is considered in the matching, the probability will increase to 46% at 10/10 DPB1 permissive mismatching. Our findings provide vital information about the future planning on the targeted recruitment size, HLA typing and search strategies of the donor registry and arose the transplant physicians’ acceptability to 9/10(DBP1) or 10/10(DBP1) HLA match. Nevertheless, the marrow donor registry has planned for increasing the registry size and bringing down the age of recruited donors which will ultimately enhance patient outcome.
Bile Acids Impair Vaccine Response in Children With Biliary Atresia
Authors: Liu Jinchuan , Fei Yi , Zhou Tao , Ji Hao , Wu Ji , Gu Xiangqian , Luo Yi , Zhu Jianjun , Feng Mingxuan , Wan Ping , Qiu Bijun , Lu Yefeng , Yang Tian , Deng Pengfei , Zhou Cuiping , Gong Dongcheng , Deng Jun , Xue Feng , Xia Qiang
Published: April 2021

Background

Vaccination is the best way to protect children under 5 years from death or disability. Children with biliary atresia (BA), which is the most common pediatric cholestatic end-stage liver disease (PELD), are more vulnerable to infectious diseases. However, the vaccination coverage and factors modulating vaccine responses in children with BA are largely unknown.

Methods

In this study, 288 children (median age: 7 months) diagnosed with BA before liver transplantation were enrolled for the evaluation of vaccination status and the factors affecting the immune response to the hepatitis B (HBV) vaccine. Moreover, 49 BA children (median age: 4 months) were enrolled for flow cytometric analysis of CD4+ T cells and CD19+ B cell subsets and correlations with serum bile acid levels.

Results

Generally, these children had very low routine vaccination rates for the meningococcal serogroup AC (Men AC) (41.2%), measles-mumps-rubella (MMR) (31.3%), poliomyelitis (Polio) (25.3%), hepatitis A (HAV) (25.0%), Japanese encephalitis (JE) (15.0%), diphtheria-tetanus-pertussis (DTP) (14.2%), meningococcal serogroup A (Men A) (13.5%) and varicella (VAR) (10.8%) vaccines, but not for the HBV (96.2%) and bacillus Calmette-Guérin (BCG) (84.7%) vaccines. Remarkably, 19.8% (57/288) of the patients had HBV infection. Out of 220 patients vaccinated for HBV, 113 (51.4%), 85 (38.6%) and 22 (10%) had one, two or three doses of the HBV vaccine, respectively. Furthermore, logistic regression analysis revealed that the bile acid level was an independent factor associated with poor HBV vaccine response (p = 0.03; OR = 0.394; 95% CI = 0.170-0.969). Immunophenotyping showed that bile acids were only negatively correlated with the CD19+CD27+IgG+ post-class-switched memory B cell ratio (p = 0.01).

Conclusion

This study reveals the overall vaccination rates of routine vaccines in Chinese BA children are very low and the poor HBV vaccine responses are associated with bile acids, possibly via the inhibition of CD19+CD27+IgG+ post-class-switched memory B cell response.

Clinical Trial Registration

http://www.chictr.org.cn, identifier ChiCTR1800019165.
Diagnostic and Predictive Value of Immune-Related Genes in Crohn’s Disease
Authors: Yu Bing , Yin Yi-xin , Tang Yan-ping , Wei Kang-lai , Pan Zhi-gang , Li Ke-Zhi , Guo Xian-wen , Hu Bang-li
Published: April 2021

Abnormal immune cell infiltration is associated with the pathogenesis of Crohn’s disease (CD). This study aimed to determine the diagnostic and predictive value of immune-related genes in CD. Seven Gene Expression Omnibus datasets that analyzed the gene expression in CD tissues were downloaded. Single-sample gene set enrichment analysis (ssGSEA) was used to estimate the infiltration of the immune cells in CD tissues. Immune-related genes were screened by overlapping the immune-related genes with differentially expressed genes (DEGs). The protein-protein interaction (PPI) network was used to identify key immune-related DEGs. Diagnostic value of CD and predictive value of anti-TNFα therapy were analyzed. Immunohistochemical (IHC) assay was used to verify gene expression in CD tissues. There were significant differences among CD tissues, paired CD tissues, and normal intestinal tissues regarding the infiltration of immune cells. AQP9, CD27, and HVCN1 were identified as the key genes of the three sub-clusters in the PPI network. AQP9, CD27, and HVCN1 had mild to moderate diagnostic value in CD, and the diagnostic value of AQP9 was better than that of CD27 and HVCN1. AQP9 expression was decreased in CD after patients underwent anti-TNFα therapy, but no obvious changes were observed in non-responders. AQP9 had a moderate predictive value in patients who had undergone treatment. IHC assay confirmed that the expression of AQP9, CD27, and HVCN1 in CD tissues was higher than that in normal intestinal tissues, and AQP9, CD27 was correlated with the activity of CD. Immune-related genes, AQP9, CD27, and HVCN1 may act as auxiliary diagnostic indicators for CD, and AQP9 could serve as a promising predictive indicator in patients who underwent anti-TNF therapy.
Large-Scale Gene Expression Signatures Reveal a Microbicidal Pattern of Activation in Mycobacterium leprae-Infected Monocyte-Derived Macrophages With Low Multiplicity of Infection
Authors: Leal-Calvo Thyago , Martins Bruna Leticia , Bertoluci Daniele Ferreira , Rosa Patricia Sammarco , Camargo Rodrigo Mendes de , Germano Giovanna Vale , Brito de Souza Vania Nieto , Pereira Latini Ana Carla , Moraes Milton Ozório
Published: April 2021

Leprosy is a disease with a clinical spectrum of presentations that is also manifested in diverse histological features. At one pole, lepromatous lesions (L-pole) have phagocytic foamy macrophages heavily parasitized with freely multiplying intracellular Mycobacterium leprae. At the other pole, the presence of epithelioid giant cells and granulomatous formation in tuberculoid lesions (T-pole) lead to the control of M. leprae replication and the containment of its spread. The mechanism that triggers this polarization is unknown, but macrophages are central in this process. Over the past few years, leprosy has been studied using large scale techniques to shed light on the basic pathways that, upon infection, rewire the host cellular metabolism and gene expression. M. leprae is particularly peculiar as it invades Schwann cells in the nerves, reprogramming their gene expression leading to a stem-like cell phenotype. This modulatory behavior exerted by M. leprae is also observed in skin macrophages. Here, we used live M. leprae to infect (10:1 multiplicity of infection) monocyte-derived macrophages (MDMs) for 48 h and analyzed the whole gene expression profile using microarrays. In this model, we observe an intense upregulation of genes consistent with a cellular immune response, with enriched pathways including peptide and protein secretion, leukocyte activation, inflammation, and cellular divalent inorganic cation homeostasis. Among the most differentially expressed genes (DEGs) are CCL5/RANTES and CYP27B1, and several members of the metallothionein and metalloproteinase families. This is consistent with a proinflammatory state that would resemble macrophage rewiring toward granulomatous formation observed at the T-pole. Furthermore, a comparison with a dataset retrieved from the Gene Expression Omnibus of M. leprae-infected Schwann cells (MOI 100:1) showed that the patterns among the DEGs are highly distinct, as the Schwann cells under these conditions had a scavenging and phagocytic gene profile similar to M2-like macrophages, with enriched pathways rearrangements in the cytoskeleton, lipid and cholesterol metabolism and upregulated genes including MVK, MSMO1, and LACC1/FAMIN. In summary, macrophages may have a central role in defining the paradigmatic cellular (T-pole) vs. humoral (L-pole) responses and it is likely that the multiplicity of infection and genetic polymorphisms in key genes are gearing this polarization.
Listening to the Whispers in Neuroimmune Crosstalk: A Comprehensive Workflow to Investigate Neurotrophin Receptor p75NTR Under Endogenous, Low Abundance Conditions
Authors: Dorschner Benjamin W. , Wiedemuth Ralf , Funke Ann-Christin , Gentzel Marc , Rogers Mary-Louise , Brenner Sebastian , Thieme Sebastian
Published: April 2021

Inflammatory conditions are critically influenced by neuroimmune crosstalk. Cytokines and neurotrophic factors shape the responses of both nervous and immune systems. Although much progress has been made, most findings to date are based on expression of recombinant (tagged) proteins. The examination of receptor interactions by immunoprecipitation (IP) at endogenous levels provides further insight into the more subtle regulations of immune responses. Here, we present a comprehensive workflow and an optimized IP protocol that provide step-by-step instructions to investigate neurotrophin receptor p75NTR at endogenous, low abundance levels: from lysate preparation and confirmation of receptor expression to antibody validation and successful detection of protein-protein interactions. We employ human melanoma cell line A375 to validate specific antibodies and IP conditions, and apply these methods to explore p75NTR interactions in human leukemic plasmacytoid dendritic cell line PMDC05 detecting 14-3-3ϵ:p75NTR interaction in this cell type. With p75NTR as an exemplary protein, our approach provides a strategy to detect specific interaction partners even under endogenous, low abundance expression conditions.
SLAM Associated Protein Signaling in T Cells: Tilting the Balance Toward Autoimmunity
Authors: Gartshteyn Yevgeniya , Askanase Anca D. , Mor Adam
Published: April 2021

T cell activation is the result of the integration of signals across the T cell receptor and adjacent co-receptors. The signaling lymphocyte activation molecules (SLAM) family are transmembrane co-receptors that modulate antigen driven T cell responses. Signal transduction downstream of the SLAM receptor is mediated by the adaptor protein SLAM Associated Protein (SAP), a small intracellular protein with a single SH2 binding domain that can recruit tyrosine kinases as well as shield phosphorylated sites from dephosphorylation. Balanced SLAM-SAP signaling within T cells is required for healthy immunity, with deficiency or overexpression prompting autoimmune diseases. Better understanding of the molecular pathways involved in the intracellular signaling downstream of SLAM could provide treatment targets for these autoimmune diseases.
Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4+ T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression
Authors: Ponnan Sivasankaran Munusamy , Vidyavijayan K.K. , Thiruvengadam Kannan , Hilda J Nancy , Mathayan Manikannan , Murugavel Kailapuri Gangatharan , Hanna Luke Elizabeth
Published: April 2021

CD4+ T cells are critical players in the host adaptive immune response. Emerging evidence suggests that certain CD4+ T cell subsets contribute significantly to the production of neutralizing antibodies and help in the control of virus replication. Circulating T follicular helper cells (Tfh) constitute a key T cell subset that triggers the adaptive immune response and stimulates the production of neutralizing antibodies (NAbs). T cells having stem cell-like property, called stem-like memory T cells (Tscm), constitute another important subset of T cells that play a critical role in slowing the rate of disease progression through the differentiation and expansion of different types of memory cell subsets. However, the role of these immune cell subsets in T cell homeostasis, CD4+ T cell proliferation, and progression of disease, particularly in HIV-2 infection, has not yet been elucidated. The present study involved a detailed evaluation of the different CD4+ T cell subsets in HIV-2 infected persons with a view to understanding the role of these immune cell subsets in the better control of virus replication and delayed disease progression that is characteristic of HIV-2 infection. We observed elevated levels of CD4+ Tfh and CD4+ Tscm cells along with memory and effector T cell abundance in HIV-2 infected individuals. We also found increased frequencies of CXCR5+ CD8+ T cells and CD8+ Tscm cells, as well as memory B cells that are responsible for NAb development in HIV-2 infected persons. Interestingly, we found that the frequency of memory CD4+ T cells as well as memory B cells correlated significantly with neutralizing antibody titers in HIV-2 infected persons. These observations point to a more robust CD4+ T cell response that supports B cell differentiation, antibody production, and CD8+ T cell development in HIV-2 infected persons and contributes to better control of the virus and slower rate of disease progression in these individuals.
Designing Multi-Antigen Vaccines Against Acinetobacter baumannii Using Systemic Approaches
Authors: McConnell Michael J. , Martín-Galiano Antonio J.
Published: April 2021

Vaccines and monoclonal antibodies are promising approaches for preventing and treating infections caused by multidrug resistant Acinetobacter baumannii. However, only partial protection has been achieved with many previously tested protein antigens, which suggests that vaccines incorporating multiple antigens may be necessary in order to obtain high levels of protection. Several aspects that use the wealth of omic data available for A. baumannii have not been fully exploited for antigen identification. In this study, the use of fractionated proteomic and computational data from ~4,200 genomes increased the number of proteins potentially accessible to the humoral response to 8,824 non-redundant proteins in the A. baumannii panproteome. Among them, 59% carried predicted B-cell epitopes and T-cell epitopes recognized by two or more alleles of the HLA class II DP supertype. Potential cross-reactivity with human proteins was detected for 8.9% of antigens at the protein level and 2.7% at the B-cell epitope level. Individual antigens were associated with different infection types by genomic, transcriptomic or functional analyses. High intra-clonal genome density permitted the identification of international clone II as a “vaccitype”, in which 20% of identified antigens were specific to this clone. Network-based centrality measurements were used to identify multiple immunologic nodes. Data were formatted, unified and stored in a data warehouse database, which was subsequently used to identify synergistic antigen combinations for different vaccination strategies. This study supports the idea that integration of multi-omic data and fundamental knowledge of the pathobiology of drug-resistant bacteria can facilitate the development of effective multi-antigen vaccines against these challenging infections.
Neoantigen: A New Breakthrough in Tumor Immunotherapy
Authors: Zhang Zheying , Lu Manman , Qin Yu , Gao Wuji , Tao Li , Su Wei , Zhong Jiateng
Published: April 2021

Cancer immunotherapy works by stimulating and strengthening the body’s anti-tumor immune response to eliminate cancer cells. Over the past few decades, immunotherapy has shown remarkable efficacy in the treatment of cancer, particularly the success of immune checkpoint blockade targeting CTLA-4, PD-1 and PDL1, which has led to a breakthrough in tumor immunotherapy. Tumor neoantigens, a new approach to tumor immunotherapy, include antigens produced by tumor viruses integrated into the genome and antigens produced by mutant proteins, which are abundantly expressed only in tumor cells and have strong immunogenicity and tumor heterogeneity. A growing number of studies have highlighted the relationship between neoantigens and T cells’ recognition of cancer cells. Vaccines developed against neoantigens are now being used in clinical trials in various solid tumors. In this review, we summarized the latest advances in the classification of immunotherapy and the process of classification, identification and synthesis of tumor-specific neoantigens, as well as their role in current cancer immunotherapy. Finally, the application prospects and existing problems of neoantigens were discussed.
Case Report: Hypomorphic Function and Somatic Reversion in DOCK8 Deficiency in One Patient With Two Novel Variants and Sclerosing Cholangitis
Authors: Saettini Francesco , Fazio Grazia , Moratto Daniele , Galbiati Marta , Zucchini Nicola , Ippolito Davide , Dinelli Marco Emilio , Imberti Luisa , Mauri Mario , Melzi Maria Luisa , Bonanomi Sonia , Gerussi Alessio , Pinelli Marinella , Barisani Chiara , Bugarin Cristina , Chiarini Marco , Giacomelli Mauro , Piazza Rocco , Cazzaniga Giovanni , Invernizzi Pietro , Giliani Silvia Clara , Badolato Raffaele , Biondi Andrea
Published: April 2021

DOCK8 deficiency is a combined immunodeficiency due to biallelic variants in dedicator of cytokinesis 8 (DOCK8) gene. The disease has a wide clinical spectrum encompassing recurrent infections (candidiasis, viral and bacterial infections), virally driven malignancies and immune dysregulatory features, including autoimmune (cytopenia and vasculitis) as well as allergic disorders (eczema, asthma, and food allergy). Hypomorphic function and somatic reversion of DOCK8 has been reported to result in incomplete phenotype without IgE overproduction. Here we describe a case of DOCK8 deficiency in a 8-year-old Caucasian girl. The patient’s disease was initially classified as autoimmune thrombocytopenia, which then evolved toward a combined immunodeficiency phenotype with recurrent infections, persistent EBV infection and lymphoproliferation. Two novel variants (one deletion and one premature stop codon) were characterized, resulting in markedly reduced, but not absent, DOCK8 expression. Somatic reversion of the DOCK8 deletion was identified in T cells. Hypomorphic function and somatic reversion were associated with restricted T cell repertoire, decreased STAT5 phosphorylation and impaired immune synapse functioning in T cells. Although the patient presented with incomplete phenotype (absence of markedly increase IgE and eosinophil count), sclerosing cholangitis was incidentally detected, thus indicating that hypomorphic function and somatic reversion of DOCK8 may delay disease progression but do not necessarily prevent from severe complications.
IDO1 Expression in Ovarian Cancer Induces PD-1 in T Cells via Aryl Hydrocarbon Receptor Activation
Authors: Amobi-McCloud Adaobi , Muthuswamy Ravikumar , Battaglia Sebastiano , Yu Han , Liu Tao , Wang Jianmin , Putluri Vasanta , Singh Prashant K. , Qian Feng , Huang Ruea-Yea , Putluri Nagireddy , Tsuji Takemasa , Lugade Amit A. , Liu Song , Odunsi Kunle
Published: April 2021

The immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO1) and the PD-1/PD-L1 axis are potent mechanisms that impede effective anti-tumor immunity in ovarian cancer. However, whether the IDO pathway regulates PD-1 expression in T cells is currently unknown. Here we show that tumoral IDO1 expression led to profound changes in tryptophan, nicotinate/nicotinamide, and purine metabolic pathways in the ovarian tumor microenvironment, and to an increased frequency of PD-1+CD8+ tumor infiltrating T cells. We determined that activation of the aryl hydrocarbon receptor (AHR) by kynurenine induced PD-1 expression, and this effect was significantly abrogated by the AHR antagonist CH223191. Mechanistically, kynurenine alters chromatin accessibility in regulatory regions of T cell inhibitory receptors, allowing AHR to bind to consensus XRE motifs in the promoter region of PD-1. These results enable the design of strategies to target the IDO1 and AHR pathways for enhancing anti-tumor immunity in ovarian cancer.
Sexual Mismatch Between Vessel-Associated Foraging and Discard Consumption in a Marine Top Predator
Authors: Giménez Joan , Arneill Gavin E. , Bennison Ashley , Pirotta Enrico , Gerritsen Hans D. , Bodey Thomas W. , Bearhop Stuart , Hamer Keith C. , Votier Stephen , Jessopp Mark
Published: April 2021

Sex differences in diet and foraging behaviour are common in sexually dimorphic species, often driven by differences in the cost of locomotion or ability to exploit different ecological niches. However, sex-specific foraging strategies also occur in monomorphic or slightly dimorphic species where the drivers are poorly understood. Here, we study sex differences in foraging of northern gannets (Morus bassanus), where females are only slightly heavier than males. Using concurrently tracked gannets (298 full foraging trips from 81 individuals) and fishing vessels across 5 years, we quantify individual-based vessel-associated putative foraging, and relate this to discard consumption. We found a significant positive relationship between time spent in vessel-associated foraging and discard consumption for both sexes. However, while females showed greater proportions of vessel-associated foraging than males, discarded fish contributed less to the diet of females in all years. These results contrast with previous suggestions that female gannets interact with vessels less often than males, and are consistent with competitive exclusion of females from trawler-associated discards. Our findings give insight into sexual differences in foraging behaviour in the absence of dimorphism that are necessary to predict their response to environmental and anthropogenic changes.
Analysis of Long-Period Hazardous Waves in the Taiwan Marine Environment Monitoring Service
Authors: Doong Dong-Jiing , Fan Yang-Ming , Chen Jin Yih , Kao Chia Chuen
Published: April 2021

A service platform (referred to as Taiwan Marine Environment Monitoring Service) was designed to integrate marine environmental parameters, including wind, wave, tide, current and temperature components, from in-situ and remote sensing observations, ship reports and numerical models to support the safety of various marine-related activities in Taiwanese waters. Independent modules were developed and plugged into the platform to facilitate advanced analyses via the safe sea, particle tracking module, extreme waves, oil spill simulation, tsunami warning (TW), sea level rise, dangerous swell warning (DSW), and SST drop modules. This paper introduces the service platform and DSW and TW module analysis methods. A real-time analysis method for tsunami height is developed and validated; a criterial analysis of hazardous swells is also performed. This service platform is now in operation and has served more than 10 governmental institutions and numerous members of the public in Taiwan.
Additively Manufactured Absorbable Porous Metal Implants – Processing, Alloying and Corrosion Behavior
Authors: Jahr Holger , Li Yageng , Zhou Jie , Zadpoor Amir A. , Schröder Kai-Uwe
Published: April 2021

Treating large bone defects is still a clinical challenge without perfect solution, mainly due to the unavailability of suitable bone implants. Additively manufactured (AM) absorbable porous metals provide unparalleled opportunities to realize the challenging requirements for bone-mimetic implants. Firstly, multi-scale geometries of such implants can be customized to mimic the micro-architecture and mechanical properties of human bone. The interconnected porous structure additionally increases the surface area to facilitate adhesion and proliferation of bone cells. Finally, their absorption properties are tunable to maintain the structural integrity of the implant throughout the bone healing process, ensuring sufficient loadbearing when needed and full disintegration after their job is done. Such a combination of properties paves the way for complete bone regeneration and remodeling. It is important to thoroughly characterize the biodegradation behavior, mechanical properties, and bone regeneration ability when developing ideal porous absorbable metal implants. We review the state-of-the-art of absorbable porous metals manufactured by selective laser melting (SLM), with a focus on geometrical design, material type, processing, and post-treatment. The impact of the latter aspects on absorption behavior, resulting mechanical properties, and cytocompatibility will also be briefly discussed. In comparison to their solid inert counterparts, AM absorbable porous metals (APMs) have shown many unique properties and hold tremendous potential to further optimize their application-specific performance due to their flexible geometrical design. We further highlight challenges in adopting AM APMs for future Orthopedic solutions.
Graphene Oxide-Modified Microcapsule Self-Healing System for 4D Printing
Authors: Ma Bowen , Zhang Yuping , Wei Yongjie , Li Mingrui , Li Dongdong
Published: April 2021

Self-healing materials as a type of promising smart materials are gradually applied to electronics, biology, and engineering. In this study, we used in situ polymerization to make melamine-formaldehyde (MF) resin microcapsules to wrap the epoxy oxide as a repairing agent and Cu(MI)4Br2 as a latent-curing agent to protect epoxy oxide E-51 from broken melamine-formaldehyde resin microcapsules. In addition, graphene oxide was used as a reinforcing phase through its two-dimensional-layered structure to increase the tensile strength to 41.91 MPa, which is higher than the initial materials. The melamine-formaldehyde capsules and latent-curing agents were uniformly distributed in the materials according to the digital photos and scanning electron microscope (SEM) pictures. It is worth noting that the mechanical strength of the broken materials can be restored to 35.65 MPa after heating to 130°C for 2 h to repair the damage, and the self-healing efficiency reached up to 85.06%. Furthermore, we also fabricated the 4D printed material with a tensile strength of 50.93 MPa through a 3D printer. The obtained materials showed excellent repair effect, with a recovery rate of up to 87.22%. This study confirms that the designed self-healing system has potential applications in many areas due to its excellent self-healing performance, which provides valuable guidance for designing the 4D system.
Active Microbiome Structure and Functional Analyses of Freshwater Benthic Biofilm Samples Influenced by RNA Extraction Methods
Authors: Yao Yuan , Rao Subramanya , Habimana Olivier
Published: April 2021

Advances in high-throughput sequencing technologies have enabled extensive studies of freshwater biofilms and significant breakthroughs in biofilm meta-omics. To date, however, no standardized protocols have been developed for the effective isolation of RNA from freshwater benthic biofilms. In this study, we compared column-based kit RNA extraction with five RNAzol-based extractions, differentiated by various protocol modifications. The RNA products were then evaluated to determine their integrity, purity and yield and were subjected to meta-transcriptomic sequencing and analysis. Significant discrepancies in the relative abundance of active communities and structures of eukaryotic, bacterial, archaebacterial, and viral communities were observed as direct outcomes of the tested RNA extraction methods. The column isolation-based group was characterized by the highest relative abundance of Archaea and Eukaryota, while the organic isolation-based groups commonly had the highest relative abundances of Prokaryota (bacteria). Kit extraction methods provided the best outcomes in terms of high-quality RNA yield and integrity. However, these methods were deemed questionable for studies of active bacterial communities and may contribute a significant degree of bias to the interpretation of downstream meta-transcriptomic analyses.
TOR Inhibitors Synergistically Suppress the Growth and Development of Phytophthora infestans, a Highly Destructive Pathogenic Oomycete
Authors: Zhang Shumin , Khalid A. Rehman , Guo Dongmei , Zhang Jingping , Xiong Fangjie , Ren Maozhi
Published: April 2021

Phytophthora infestans, one of most famous pathogenic oomycetes, triggered the Great Irish Famine from 1845 to 1852. The target of rapamycin (TOR) is well known as a key gene in eukaryotes that controls cell growth, survival and development. However, it is unclear about its function in controlling the mycelial growth, sporulation capacity, spore germination and virulence of Phytophthora infestans. In this study, key components of the TOR signaling pathway are analyzed in detail. TOR inhibitors, including rapamycin (RAP), AZD8055 (AZD), KU-0063794 (KU), and Torin1, inhibit the mycelial growth, sporulation capacity, spore germination, and virulence of Phytophthora infestans with AZD showing the best inhibitory effects on Phytophthora infestans. Importantly, compared with a combination of RAP + KU or RAP + Torin1, the co-application of RAP and AZD show the best synergistic inhibitory effects on P. infestans, resulting in the reduced dosage and increased efficacy of drugs. Transcriptome analysis supports the synergistic effects of the combination of RAP and AZD on gene expression, functions and pathways related to the TOR signaling pathway. Thus, TOR is an important target for controlling Phytophthora infestans, and synergism based on the application of TOR inhibitors exhibit the potential for controlling the growth of Phytophthora infestans.
Do Aerial Nitrogen Depositions Affect Fungal and Bacterial Communities of Oak Leaves?
Authors: Borruso Luigimaria , Bani Alessia , Pioli Silvia , Ventura Maurizio , Panzacchi Pietro , Antonielli Livio , Giammarchi Francesco , Polo Andrea , Tonon Giustino , Brusetti Lorenzo
Published: April 2021

The amount of nitrogen (N) deposition onto forests has globally increased and is expected to double by 2050, mostly because of fertilizer production and fossil fuel burning. Several studies have already investigated the effects of N depositions in forest soils, highlighting negative consequences on plant biodiversity and the associated biota. Nevertheless, the impact of N aerial inputs deposited directly on the tree canopy is still unexplored. This study aimed to investigate the influence of increased N deposition on the leaf-associated fungal and bacterial communities in a temperate forest dominated by Sessile oak [Quercus petraea (Matt.) Liebl.]. The study area was located in the Monticolo forest (South Tyrol, Italy), where an ecosystem experiment simulating an increased N deposition has been established. The results highlighted that N deposition affected the fungal beta-diversity and bacterial alpha-diversity without affecting leaf total N and C contents. We found several indicator genera of both fertilized and natural conditions within bacteria and fungi, suggesting a highly specific response to altered N inputs. Moreover, we found an increase of symbiotrophic fungi in N-treated, samples which are commonly represented by lichen-forming mycobionts. Overall, our results indicated that N-deposition, by increasing the level of bioavailable nutrients in leaves, could directly influence the bacterial and fungal community diversity.
Patterns of Microbiome Variation Among Infrapopulations of Permanent Bloodsucking Parasites
Authors: Doña Jorge , Virrueta Herrera Stephany , Nyman Tommi , Kunnasranta Mervi , Johnson Kevin P.
Published: April 2021

While interspecific variation in microbiome composition can often be readily explained by factors such as host species identity, there is still limited knowledge of how microbiomes vary at scales lower than the species level (e.g., between individuals or populations). Here, we evaluated variation in microbiome composition of individual parasites among infrapopulations (i.e., populations of parasites of the same species living on a single host individual). To address this question, we used genome-resolved and shotgun metagenomic data of 17 infrapopulations (balanced design) of the permanent, bloodsucking seal louse Echinophthirius horridus sampled from individual Saimaa ringed seals Pusa hispida saimensis. Both genome-resolved and read-based metagenomic classification approaches consistently show that parasite infrapopulation identity is a significant factor that explains both qualitative and quantitative patterns of microbiome variation at the intraspecific level. This study contributes to the general understanding of the factors driving patterns of intraspecific variation in microbiome composition, especially of bloodsucking parasites, and has implications for understanding how well-known processes occurring at higher taxonomic levels, such as phylosymbiosis, might arise in these systems.
Emerging Concern for Silver Nanoparticle Resistance in Acinetobacter baumannii and Other Bacteria
Authors: McNeilly Oliver , Mann Riti , Hamidian Mohammad , Gunawan Cindy
Published: April 2021

The misuse of antibiotics combined with a lack of newly developed ones is the main contributors to the current antibiotic resistance crisis. There is a dire need for new and alternative antibacterial options and nanotechnology could be a solution. Metal-based nanoparticles, particularly silver nanoparticles (NAg), have garnered widespread popularity due to their unique physicochemical properties and broad-spectrum antibacterial activity. Consequently, NAg has seen extensive incorporation in many types of products across the healthcare and consumer market. Despite clear evidence of the strong antibacterial efficacy of NAg, studies have raised concerns over the development of silver-resistant bacteria. Resistance to cationic silver (Ag+) has been recognised for many years, but it has recently been found that bacterial resistance to NAg is also possible. It is also understood that exposure of bacteria to toxic heavy metals like silver can induce the emergence of antibiotic resistance through the process of co-selection. Acinetobacter baumannii is a Gram-negative coccobacillus and opportunistic nosocomial bacterial pathogen. It was recently listed as the “number one” critical level priority pathogen because of the significant rise of antibiotic resistance in this species. NAg has proven bactericidal activity towards A. baumannii, even against strains that display multi-drug resistance. However, despite ample evidence of heavy metal (including silver; Ag+) resistance in this bacterium, combined with reports of heavy metal-driven co-selection of antibiotic resistance, little research has been dedicated to assessing the potential for NAg resistance development in A. baumannii. This is worrisome, as the increasingly indiscriminate use of NAg could promote the development of silver resistance in this species, like what has occurred with antibiotics.
Captivity Is Associated With Gut Mycobiome Composition in Tibetan Macaques (Macaca thibetana)
Authors: Sun Binghua , Xia Yingna , Garber Paul A. , Amato Katherine R. , Gomez Andres , Xu Xiaojuan , Li Wenbo , Huang Mingjing , Xia Dongpo , Wang Xi , Li Jinhua
Published: April 2021

Although recent studies have revealed that gut fungi may play an important functional role in animal biology and health, little is known concerning the effects of anthropogenic pressures on the gut mycobiome. Here, we examined differences of the gut mycobiome in wild and captive populations of Tibetan macaques (Macaca thibetana) targeting the fungal internal transcribed spacer (ITS) and using next generation sequencing. Our findings demonstrate that the diversity, composition, and functional guild of the Tibetan macaque gut mycobiome differ across populations living in different habitats. We found that Tibetan macaques translocated from the wild into a captive setting for a period of 1 year, were characterized by a reduction in fungal diversity and an increase in the abundance of potential gut fungal pathogens compared to wild individuals. Furthermore, we found that the relative abundance of two main fungal guilds of plant pathogens and ectomycorrhizal fungi was significantly lower in captive individuals compared to those living in the wild. Our results highlight that, in addition to bacteria, gut fungi vary significantly among individuals living in captive and wild settings. However, given limited data on the functional role that fungi play in the host’s gut, as well as the degree to which a host’s mycobiome is seeded from fungi in the soil or ingested during the consumption of plant and animal foods, controlled studies are needed to better understand the role of the local environment in seeding the mycobiome.
The Road of Solid Tumor Survival: From Drug-Induced Endoplasmic Reticulum Stress to Drug Resistance
Authors: Cao Shulong , Tang Jingyi , Huang Yichun , Li Gaofeng , Li Zhuoya , Cai Wenqi , Yuan Yuning , Liu Junlong , Huang Xuqun , Zhang Haiyuan
Published: April 2021

Endoplasmic reticulum stress (ERS), which refers to a series of adaptive responses to the disruption of endoplasmic reticulum (ER) homeostasis, occurs when cells are treated by drugs or undergo microenvironmental changes that cause the accumulation of unfolded/misfolded proteins. ERS is one of the key responses during the drug treatment of solid tumors. Drugs induce ERS by reactive oxygen species (ROS) accumulation and Ca2+ overload. The unfolded protein response (UPR) is one of ERS. Studies have indicated that the mechanism of ERS-mediated drug resistance is primarily associated with UPR, which has three main sensors (PERK, IRE1α, and ATF6). ERS-mediated drug resistance in solid tumor cells is both intrinsic and extrinsic. Intrinsic ERS in the solid tumor cells, the signal pathway of UPR-mediated drug resistance, includes apoptosis inhibition signal pathway, protective autophagy signal pathway, ABC transporter signal pathway, Wnt/β-Catenin signal pathway, and noncoding RNA. Among them, apoptosis inhibition is one of the major causes of drug resistance. Drugs activate ERS and its downstream antiapoptotic proteins, which leads to drug resistance. Protective autophagy promotes the survival of solid tumor cells by devouring the damaged organelles and other materials and providing new energy for the cells. ERS induces protective autophagy by promoting the expression of autophagy-related genes, such as Beclin-1 and ATG5–ATG12. ABC transporters pump drugs out of the cell, which reduces the drug-induced apoptosis effect and leads to drug resistance. In addition, the Wnt/β-catenin signal pathway is also involved in the drug resistance of solid tumor cells. Furthermore, noncoding RNA regulates the ERS-mediated survival and death of solid tumor cells. Extrinsic ERS in the solid tumor cells, such as ERS in immune cells of the tumor microenvironment (TME), also plays a crucial role in drug resistance by triggering immunosuppression. In immune system cells, ERS in dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) influences the antitumor function of normal T cells, which results in immunosuppression. Meanwhile, ERS in T cells can also cause impaired functioning and apoptosis, leading to immunosuppression. In this review, we highlight the core molecular mechanism of drug-induced ERS involved in drug resistance, thereby providing a new strategy for solid tumor treatment.
The Prognostic Value of PERK in Cancer and Its Relationship With Immune Cell Infiltration
Authors: Wang Peng , Han Liying , Yu Moxin , Cao Zhengyu , Li Xiaoning , Shao Yunxia , Zhu Guoping
Published: April 2021

Background: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Recent research studies suggest that PERK, as an important receptor protein of unfolded protein response, is involved in the pathogenesis of many cancers. This study aimed to investigate PERK expression and its relationship with prognosis in pan-cancer and attempted to explore the relevant mechanism of PERK involved in the regulation of cancer pathogenesis.

Methods: The Oncomine and TIMER databases were used to analyze the expression of PERK between pan-cancer samples and normal samples. Survival analysis was performed using the PrognoScan, Kaplan–Meier (K-M) plotter, and UALCAN databases. Gene set enrichment analysis (GSEA) was used to perform the functional enrichment analysis of the PERK gene in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA). The TIMER database was used to investigate the correlation between PERK expression and tumor-infiltrating immune cells and analyze the relationship of PERK with marker genes of immune cells which were downloaded from the CellMarker database in BRCA, HNSC, and THCA.

Results: PERK was differentially expressed in various cancers, such as breast cancer, liver cancer, lung cancer, gastric carcinoma, lymphoma, thyroid cancer, leukemia, and head and neck squamous cell carcinomas. The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC. The results of GSEA indicated that PERK was mainly enriched in immune-related signaling pathways in BRCA, HNSC, and THCA. Moreover, PERK expression was significant positively correlated with infiltrating levels of macrophages and dendritic cells and was strongly associated with a variety of immune markers, especially macrophage mannose receptor 1 (MRC1, also called CD206) and T-helper cells (Th).

Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.