bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlled Infection Experiment With Aphanomyces astaci Provides Additional Evidence for Latent Infections and Resistance in Freshwater Crayfish
Authors: Francesconi Caterina , Makkonen Jenny , Schrimpf Anne , Jussila Japo , Kokko Harri , Theissinger Kathrin
Published: September 2021

For 150 years the crayfish plague disease agentAphanomyces astacihas been the cause of mass mortalities among native European crayfish populations. However, recently several studies have highlighted the great variability ofA. astacivirulence and crayfish resistance toward the disease. The main aim of this study was to compare the response of two crayfish species, the European native noble crayfish (Astacus astacus) and the invasive alien marbled crayfish (Procambarus virginalis), to anA. astacichallenge with a highly virulent strain from haplogroup B and a lowly virulent strain from haplogroup A. In a controlled infection experiment we showed a high resistance of marbled crayfish against anA. astaciinfection, with zoospores from the highly virulent haplogroup B strain being able to infect the crayfish, but unable to cause signs of disease. Furthermore, we demonstrated a reduced virulence in theA. astacistrain belonging to haplogroup A, as shown by the light symptoms and the lack of mortality in the generally susceptible noble crayfish. Interestingly, in both marbled crayfish and noble crayfish challenged with this strain, we observed a significant decrease of the detected amount of pathogen’s DNA during the experiment, suggesting that thisA. astacihaplogroup A strain has a decreased ability of penetrating into the cuticle of the crayfish. Our results provide additional evidence of how drastically strains belonging toA. astacihaplogroup B and haplogroup A differ in their virulence. This study confirmed the adaptation of one specificA. astacihaplogroup A strain to their novel European hosts, supposedly due to reduced virulence. This feature might be the consequence ofA. astaci’s reduced ability to penetrate into the crayfish. Finally, we experimentally showed that marbled crayfish are remarkably resistant against the crayfish plague disease and could potentially be latently infected, acting as carriers of highly virulentA. astacistrains.
Long-Term Conservation Effects of Protected Areas in Stochastic Population Dynamics
Authors: Takashina Nao
Published: September 2021

Terrestrial and marine protected areas are essential tools in mitigating anthropogenic impacts and promoting population persistence and resource sustainability. Adequately implemented protected areas (PAs) aim to promote conservation by increasing population size and reducing its variability. To resolve how these effects depend on PA features, I develop and analyze new models of stochastic processes that encompass the fluctuations generated by demographic or environmental stochasticity in PAs management. The stochastic model is built upon individual processes. In the model, density-independent mortality, migration between PAs and non-PAs, organism preference for PAs, and size characterize the features of the PA. The effect of PAs size is also examined. The long-term conservation effects are quantified using the coefficient of variation (CV) of population size in PAs, where a lower CV indicates higher robustness in stochastic variations. The results from this study demonstrate that sufficiently reduced density-independent mortality in PAs and high site preference for PAs and immigration rate into PAs are likely to decrease the CV. However, different types of stochasticity induce rather different consequences: under demographic stochasticity, the CV is always reduced because PAs increase the population size therein, but an increased population size by PAs does not always decrease the CV under environmental stochasticity. The deterministic dynamics of the model are investigated, facilitating effective management decisions.
Adaptive Phenotypic Plasticity Stabilizes Evolution in Fluctuating Environments
Authors: Lalejini Alexander , Ferguson Austin J. , Grant Nkrumah A. , Ofria Charles
Published: September 2021

Fluctuating environmental conditions are ubiquitous in natural systems, and populations have evolved various strategies to cope with such fluctuations. The particular mechanisms that evolve profoundly influence subsequent evolutionary dynamics. One such mechanism is phenotypic plasticity, which is the ability of a single genotype to produce alternate phenotypes in an environmentally dependent context. Here, we use digital organisms (self-replicating computer programs) to investigate how adaptive phenotypic plasticity alters evolutionary dynamics and influences evolutionary outcomes in cyclically changing environments. Specifically, we examined the evolutionary histories of both plastic populations and non-plastic populations to ask: (1) Does adaptive plasticity promote or constrain evolutionary change? (2) Are plastic populations better able to evolve and then maintain novel traits? And (3), how does adaptive plasticity affect the potential for maladaptive alleles to accumulate in evolving genomes? We find that populations with adaptive phenotypic plasticity undergo less evolutionary change than non-plastic populations, which must rely on genetic variation from de novo mutations to continuously readapt to environmental fluctuations. Indeed, the non-plastic populations undergo more frequent selective sweeps and accumulate many more genetic changes. We find that the repeated selective sweeps in non-plastic populations drive the loss of beneficial traits and accumulation of maladaptive alleles, whereas phenotypic plasticity can stabilize populations against environmental fluctuations. This stabilization allows plastic populations to more easily retain novel adaptive traits than their non-plastic counterparts. In general, the evolution of adaptive phenotypic plasticity shifted evolutionary dynamics to be more similar to that of populations evolving in a static environment than to non-plastic populations evolving in an identical fluctuating environment. All natural environments subject populations to some form of change; our findings suggest that the stabilizing effect of phenotypic plasticity plays an important role in subsequent adaptive evolution.
Microbial Substrate Utilization and Vegetation Shifts in Boreal Forest Floors of Western Canada
Authors: Lloret Emily , Quideau Sylvie
Published: September 2021

Boreal forest soils are highly susceptible to global warming, and in the next few decades, are expected to face large increases in temperature and transformative vegetation shifts. The entire boreal biome will migrate northward, and within the main boreal forest of Western Canada, deciduous trees will replace conifers. The main objective of our research was to assess how these vegetation shifts will affect functioning of soil microbial communities and ultimately the overall persistence of boreal soil carbon. In this study, aspen and spruce forest floors from the boreal mixedwood forest of Alberta were incubated in the laboratory for 67 days without (control) and with the addition of three distinct 13C labeled substrates (glucose, aspen leaves, and aspen roots). Our first objective was to compare aspen and spruce substrate utilization efficiency (SUE) in the case of a labile C source (13C-glucose). For our second objective, addition of aspen litter to spruce forest floor mimicked future vegetation shifts, and we tested how this would alter substrate use efficiency in the spruce forest floor compared to the aspen. Tracking of carbon utilization by microbial communities was accomplished using 13C-PLFA analysis, and 13C-CO2 measurements allowed quantification of the relative contribution of each added substrate to microbial respiration. Following glucose addition, the aspen community showed a greater 13C-PLFA enrichment than the spruce throughout the 67-day incubation. The spruce community respired a greater amount of 13C glucose, and it also had a much lower glucose utilization efficiency compared to the aspen. Following addition of aspen litter, in particular aspen leaves, the aspen community originally showed greater total 13C-PLFA enrichment, although gram positive phospholipid fatty acids (PLFAs) were significantly more enriched in the spruce community. While the spruce community respired a greater amount of the added 13C-leaves, both forest floor types showed comparable substrate utilization efficiencies by Day 67. These results indicate that a shift from spruce to aspen may lead to a greater loss of the aspen litter through microbial respiration, but that incorporation into microbial biomass and eventually into the more persistent soil carbon pool may not be affected.
PacBio Single-Molecule Long-Read Sequencing Provides New Light on the Complexity of Full-Length Transcripts in Cattle
Authors: Chang Tianpeng , An Bingxing , Liang Mang , Duan Xinghai , Du Lili , Cai Wentao , Zhu Bo , Gao Xue , Chen Yan , Xu Lingyang , Zhang Lupei , Gao Huijiang , Li Junya
Published: September 2021

Cattle (Bos taurus) is one of the most widely distributed livestock species in the world, and provides us with high-quality milk and meat which have a huge impact on the quality of human life. Therefore, accurate and complete transcriptome and genome annotation are of great value to the research of cattle breeding. In this study, we used error-corrected PacBio single-molecule real-time (SMRT) data to perform whole-transcriptome profiling in cattle. Then, 22.5 Gb of subreads was generated, including 381,423 circular consensus sequences (CCSs), among which 276,295 full-length non-chimeric (FLNC) sequences were identified. After correction by Illumina short reads, we obtained 22,353 error-corrected isoforms. A total of 305 alternative splicing (AS) events and 3,795 alternative polyadenylation (APA) sites were detected by transcriptome structural analysis. Furthermore, we identified 457 novel genes, 120 putative transcription factors (TFs), and 569 novel long non-coding RNAs (lncRNAs). Taken together, this research improves our understanding and provides new insights into the complexity of full-length transcripts in cattle.
Geographic Variation of Phyllodiaptomus tunguidus Mitogenomes: Genetic Differentiation and Phylogeny
Authors: Zhang Xiao-Li , Liu Ping , Xu Shao-Lin , Rizo Eric Zeus , Zhang Qun , Dumont Henri J. , Han Bo-Ping
Published: September 2021

Phyllodiaptomus tunguidus (Copepoda: Calanoida) is largely endemic to and widespread in freshwater in southern China, where it inhabits a complex landscape from lowland to highland across an elevation gradient of 2000m. A deep genetic differentiation can be expected between its most distant geographic populations. Here, we sequenced nine mitogenomes from diverse populations. All mitogenomes contained 37 genes, including 13 protein-coding genes (PCG), two rRNA genes, 22 tRNA genes and one control region. Their base composition, genetic distance and tRNA structure indeed revealed a wide differentiation between mitogenomes. Two P. tunguidus from Guangxi near Vietnam differed from the other seven by up to 10.1%. Their tRNA-Arg had a complete clover-leaf structure, whereas that of the others did not contain an entire dihydrouridine arm. The nine mitogenomes also differed in the length of rRNA. NJ, ML, and Bayesian analyses all split them into two clades, viz. the two P. tunguidus from Guangxi (Clade 1), and the other seven (Clade 2). Both the structure and phylogeny of the mitogenomes suggest that P. tunguidus has complex geographic origin, and its populations in Clade 1 have long lived in isolation from those in Clade 2. They currently reach the level of subspecies or cryptic species. An extensive phylogenetic analysis of Copepoda further verified that Diaptomidae is the most recently diverging family in Calanoida and that P. tunguidus is at the evolutionary apex of the family.
Transcriptome Signature of Vγ9Vδ2 T Cells Treated With Phosphoantigens and Notch Inhibitor Reveals Interplay Between TCR and Notch Signaling Pathways
Authors: Madhok Ayush , Bhat Sajad Ahmad , Philip Chinna Susan , Sureshbabu Shalini Kashipathi , Chiplunkar Shubhada , Galande Sanjeev
Published: September 2021

Gamma delta (γδ) T cells, especially the Vγ9Vδ2 subtype, have been implicated in cancer therapy and thus have earned the spotlight in the past decade. Although one of the most important properties of γδ T cells is their activation by phosphoantigens, which are intermediates of the Mevalonate and Rohmer pathway of isoprenoid biosynthesis, such as IPP and HDMAPP, respectively, the global effects of such treatments on Vγ9Vδ2 T cells remain elusive. Here, we used the high-throughput transcriptomics approach to elucidate the transcriptional changes in human Vγ9Vδ2 T cells upon HDMAPP, IPP, and anti-CD3 treatments in combination with interleukin 2 (IL2) cytokine stimulation. These activation treatments exhibited a dramatic surge in transcription with distinctly enriched pathways. We further assessed the transcriptional dynamics upon inhibition of Notch signaling coupled with activation treatments. We observed that the metabolic processes are most affected upon Notch inhibitionviaGSI-X. The key effector genes involved in gamma–delta cytotoxic function were downregulated upon Notch blockade even in combination with activation treatment, suggesting a transcriptional crosstalk between T-cell receptor (TCR) signaling and Notch signaling in Vγ9Vδ2 T cells. Collectively, we demonstrate the effect of the activation of TCR signaling by phosphoantigens or anti-CD3 on the transcriptional status of Vγ9Vδ2 T cells along with IL2 stimulation. We further show that the blockade of Notch signaling antagonistically affects this activation.
Predator-Prey in Tumor-Immune Interactions: A Wrong Model or Just an Incomplete One?
Authors: Kareva Irina , Luddy Kimberly A. , O’Farrelly Cliona , Gatenby Robert A. , Brown Joel S.
Published: September 2021

Tumor-immune interactions are often framed as predator-prey. This imperfect analogy describes how immune cells (the predators) hunt and kill immunogenic tumor cells (the prey). It allows for evaluation of tumor cell populations that change over time during immunoediting and it also considers how the immune system changes in response to these alterations. However, two aspects of predator-prey type models are not typically observed in immuno-oncology. The first concerns the conversion of prey killed into predator biomass. In standard predator-prey models, the predator relies on the prey for nutrients, while in the tumor microenvironment the predator and prey compete for resources (e.g. glucose). The second concerns oscillatory dynamics. Standard predator-prey models can show a perpetual cycling in both prey and predator population sizes, while in oncology we see increases in tumor volume and decreases in infiltrating immune cell populations. Here we discuss the applicability of predator-prey models in the context of cancer immunology and evaluate possible causes for discrepancies. Key processes include “safety in numbers”, resource availability, time delays, interference competition, and immunoediting. Finally, we propose a way forward to reconcile differences between model predictions and empirical observations. The immune system is not just predator-prey. Like natural food webs, the immune-tumor community of cell types forms an immune-web of different and identifiable interactions.
Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy
Authors: Yang Dongyong , Dai Fangfang , Yuan Mengqin , Zheng Yajing , Liu Shiyi , Deng Zhimin , Tan Wei , Chen Liping , Zhang Qianjie , Zhao Xiaomiao , Cheng Yanxiang
Published: September 2021

Transforming growth factor-β (TGF-β) is composed of three isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-β1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-β1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-β1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-β1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.
Low Abundance Fusobacterium Nucleatum Supports Early Pregnancy Development – An In Vitro Study
Authors: Heusler Martha , Einenkel Rebekka , Ehrhardt Jens , Muzzio Damián Oscar , Zygmunt Marek
Published: September 2021

Pregnancy success depends greatly on a balanced immune homeostasis. The detection of bacterial components in the upper reproductive tract in non-pregnant and pregnant women raised questions on its possible beneficial role in reproductive health. The local conditions that allow the presence of bacteria to harmonize with the establishment of pregnancy are still unknown. Among the described bacterial species in endometrial and placental samples,Fusobacterium nucleatumwas found. It has been observed thatF. nucleatumcan induce tumorigenesis in colon carcinoma, a process that shares several features with embryo implantation. We propose that low concentrations ofF. nucleatummay improve trophoblast function without exerting destructive responses. InactivatedF. nucleatumandE. coliwere incubated with the trophoblastic cell lines HTR8/SVneo, BeWo, and JEG-3. Viability, proliferation, migratory capacity, invasiveness and the secretion of chemokines, other cytokines and matrix metalloproteinases were assessed. The presence ofF. nucleatumsignificantly induced HTR8/SVneo invasion, accompanied by the secretion of soluble mediators (CXCL1, IL-6 and IL-8) and metalloproteinases (MMP-2 and MMP-9). However, as concentrations ofF. nucleatumincreased, these did not improve invasiveness, hindered migration, reduced cell viability and induced alterations in the cell cycle. Part of theF. nucleatumeffects on cytokine release were reverted with the addition of a TLR4 blocking antibody. Other effects correlated with the level of expression of E-cadherin on the different cell lines tested. Low amounts ofF. nucleatumpromote invasion of HTR8/SVneo cells and induce the secretion of important mediators for pregnancy establishment. Some effects were independent of LPS and correlated with the expression of E-cadherin on trophoblasts.
Host Genetics and Antiviral Immune Responses in Adult Patients With Multisystem Inflammatory Syndrome
Authors: Ronit Andreas , Jørgensen Sofie E. , Roed Casper , Eriksson Robert , Iepsen Ulrik W. , Plovsing Ronni R. , Storgaard Merete , Gustafsson Finn , Hansen Ann-Brit E. , Mogensen Trine H.
Published: September 2021

COVID-19 associated multisystem inflammatory syndrome (MIS) is a rare condition mostly affecting children but also adults (MIS-A). Although severe systemic inflammation and multiorgan dysfunction are hallmarks of the syndrome, the underlying pathogenesis is unclear. We aimed to provide novel immunological and genetic descriptions of MIS-A patients. Cytokine responses (IL-6, IL-1β, TNFα, CXCL10, type I, II and III interferons) following SARS-CoV-2 infection of peripheral blood mononuclear cells in vitro were analyzed as well as antibodies against IFNα and IFNω (by ELISA) in patients and healthy controls. We also performed whole exome sequencing (WES) of patient DNA. A total of five patients (ages 19, 23, 33, 38, 50 years) were included. The patients shared characteristic features, although organ involvement and the time course of disease varied slightly. SARS-CoV-2 in vitro infection of patient PBMCs revealed impaired type I and III interferon responses and reduced CXCL10 expression, whereas production of proinflammatory cytokines were less affected, compared to healthy controls. Presence of interferon autoantibodies was not detected. Whole exome sequencing analysis of patient DNA revealed 12 rare potentially disease-causing variants in genes related to autophagy, classical Kawasaki disease, restriction factors and immune responses. In conclusion, we observed an impaired production of type I and III interferons in response to SARS-CoV-2 infection and detected several rare potentially disease-causing gene variants potentially contributing to MIS-A.
The Effect of JAK1/2 Inhibitors on HIV Reservoir Using Primary Lymphoid Cell Model of HIV Latency
Authors: de Armas Lesley R. , Gavegnano Christina , Pallikkuth Suresh , Rinaldi Stefano , Pan Li , Battivelli Emilie , Verdin Eric , Younis Ramzi T. , Pahwa Rajendra , Williams Siôn L. , Schinazi Raymond F. , Pahwa Savita
Published: September 2021

HIV eradication is hindered by the existence of latent HIV reservoirs in CD4+ T cells. Therapeutic strategies targeting latent cells are required to achieve a functional cure, however the study of latently infected cells from HIV infected persons is extremely challenging due to the lack of biomarkers that uniquely characterize them. In this study, the dual reporter virus HIVGKO was used to investigate latency establishment and maintenance in lymphoid-derived CD4+ T cells. Single cell technologies to evaluate protein expression, host gene expression, and HIV transcript expression were integrated to identify and analyze latently infected cells. FDA-approved, JAK1/2 inhibitors were tested in this system as a potential therapeutic strategy to target the latent reservoir. Latent and productively infected tonsillar CD4+ T cells displayed similar activation profiles as measured by expression of CD69, CD25, and HLADR, however latent cells showed higher CXCR5 expression 3 days post-infection. Single cell analysis revealed a small set of genes, including HIST1-related genes and the inflammatory cytokine, IL32, that were upregulated in latent compared to uninfected and productively infected cells suggesting a role for these molecular pathways in persistent HIV infection. In vitro treatment of HIV-infected CD4+ T cells with physiological concentrations of JAK1/2 inhibitors, ruxolitinib and baricitinib, used in clinical settings to target inflammation, reduced latent and productive infection events when added 24 hr after infection and blocked HIV reactivation from latent cells. Our methods using an established model of HIV latency and lymphoid-derived cells shed light on the biology of latency in a crucial anatomical site for HIV persistence and provides key insights about repurposing baricitinib or ruxolitinib to target the HIV reservoir.
Review: Insights on Current FDA-Approved Monoclonal Antibodies Against Ebola Virus Infection
Authors: Tshiani Mbaya Olivier , Mukumbayi Philippe , Mulangu Sabue
Published: September 2021

The unprecedented 2013-2016 West Africa Ebola outbreak accelerated several medical countermeasures (MCMs) against Ebola virus disease (EVD). Several investigational products (IPs) were used throughout the outbreak but were not conclusive for efficacy results. Only the Randomized Controlled Trial (RCT) on ZMapp was promising but inconclusive. More recently, during the second-largest Ebola outbreak in North Kivu and Ituri provinces, Democratic Republic of the Congo (DRC), four IPs, including one small molecule (Remdesivir), two monoclonal antibody (mAb) cocktails (ZMapp and REGN-EB3) and a single mAb (mAb114), were evaluated in an RCT, the Pamoja Tulinde Maisha (PALM) study. Two products (REGN-EB3 and mAb114) demonstrated efficacy as compared to the control arm, ZMapp. There were remarkably few side effects recorded in the trial. The FDA approved both medications in this scientifically sound study, marking a watershed moment in the field of EVD therapy. These products can be produced relatively inexpensively and can be stockpiled. The administration of mAbs in EVD patients appears to be safe and effective, while several critical knowledge gaps remain; the impact of early administration of Ebola-specific mAbs on developing a robust immune response for future Ebola virus exposure is unknown. The viral mutation escape, leading to resistance, presents a potential limitation for single mAb therapy; further improvements need to be explored. Understanding the contribution of Fc-mediated antibody functions such as antibody-dependent cellular cytotoxicity (ADCC) of those approved mAbs is still critical. The potential merit of combination therapy and post-exposure prophylaxis (PEP) need to be demonstrated. Furthermore, the PALM trial has accounted for 30% of mortality despite the administration of specific treatments. The putative role of EBOV soluble Glycoprotein (sGP) as a decoy to the immune system, the virus persistence, and relapses might be investigated for treatment failure. The development of pan-filovirus or pan-species mAbs remains essential for protection. The interaction between FDA-approved mAbs and vaccines remains unclear and needs to be investigated. In this review, we summarize the efficacy and safety results of the PALM study and review current research questions for the further development of mAbs in pre-exposure or emergency post-exposure use.
Mycobacterium tuberculosis Rv0927c Inhibits NF-κB Pathway by Downregulating the Phosphorylation Level of IκBα and Enhances Mycobacterial Survival
Authors: Xia Aihong , Li Xin , Quan Juanjuan , Chen Xiang , Xu Zhengzhong , Jiao Xinan
Published: September 2021

Through long-term coevolution with its host, Mycobacterium tuberculosis (M. tuberculosis) uses multiple strategies to escape host defenses. The M. tuberculosis Rv0927c protein is predicted to be a short-chain dehydrogenase/reductase related to bacterial metabolism. However, the role of Rv0927c during M. tuberculosis infection remains unclear. Here, we observed that Rv0927c inhibited the expression of IL-6, TNF-α, and IL-1β, an effect dependent on NF-κB and p38 pathways. Western blot analysis of macrophages infected with recombinant Mycobacterium smegmatis strains showed that Rv0927c attenuated NF-κB activation by downregulating the phosphorylation of IκBα. Additionally, Rv0927c enhanced intracellular survival of M. smegmatis and pathological effects in mice. In conclusion, our findings demonstrate that Rv0927c functions as a regulator of inflammatory genes and enhances the survival of M. smegmatis.
The Role of C-Reactive Protein in Kidney, Bladder, and Prostate Cancers
Authors: O’Brian Daniel , Prunty Megan , Hill Alexander , Shoag Jonathan
Published: September 2021

C-Reactive Protein (CRP) is associated with diverse outcomes in patients with, or suspected to have, genitourinary malignancies. CRP levels have been shown to be associated with the probability of a prostate cancer diagnosis in patients with elevated PSA, the probability of biochemical recurrence following definitive treatment for localized prostate cancer, and decreased overall survival for patients with advanced disease. In patients with bladder and kidney cancers, CRP levels have been associated with disease progression, stage, and cancer-specific survival. Despite the abundance of correlative studies, the relationship between CRP levels and genitourinary cancer pathogenesis is not clearly understood. Here, we review the evidence for CRP as a biomarker in genitourinary (GU) cancers, with specific focus on potential clinical applications.
Recognition of Multiple Hybrid Insulin Peptides by a Single Highly Diabetogenic T-Cell Receptor
Authors: Parras Daniel , Solé Patricia , Delong Thomas , Santamaría Pere , Serra Pau
Published: September 2021

The mechanisms underlying the major histocompatibility complex class II (MHCII) type 1 diabetes (T1D) association remain incompletely understood. We have previously shown that thymocytes expressing the highly diabetogenic, I-Ag7-restricted 4.1-T-cell receptor (TCR) are MHCII-promiscuous, and that, in MHCII-heterozygous mice, they sequentially undergo positive and negative selection/Treg deviation by recognizing pro- and anti-diabetogenic MHCII molecules on cortical thymic epithelial cells and medullary hematopoietic antigen-presenting cells (APCs), respectively. Here, we use a novel autoantigen discovery approach to define the antigenic specificity of this TCR in the context of I-Ag7. This was done by screening the ability of random epitope–GS linker–I-Aβg7chain fusion pools to form agonistic peptide–MHCII complexes on the surface of I-Aαdchain-transgenic artificial APCs. Pool deconvolution, I-Ag7-binding register-fixing, TCR contact residue mapping, and alanine scanning mutagenesis resulted in the identification of a 4.1-TCR recognition motif XL(G/A)XEXE(D/E)X that was shared by seven agonistic hybrid insulin peptides (HIPs) resulting from the fusion of several different chromogranin A and/or insulin C fragments, including post-translationally modified variants. These data validate a novel, highly sensitive MHCII-restricted epitope discovery approach for orphan TCRs and suggest thymic selection of autoantigen-promiscuous TCRs as a mechanism for the murine T1D–I-Ag7-association.
Evidences of Z- and W-Linked Regions on the Genome of Fenneropenaeus chinensis
Authors: Wang Qiong , Lv Jianjian , Ren Xianyun , Wang Jiajia , Jia Shaoting , He Yuying , Li Jian
Published: September 2021

Fenneropenaeus chinensis is a commercially cultured shrimp in China. F. chinensis adults show significant sexual dimorphism, with larger females than males. However, sex determination (SD) of F. chinensis has not yet been elucidated. Clarification of the sex-determining system of F. chinensis could enrich our knowledge of the sex differentiation mechanism in crustaceans and facilitate the study of sex-controlling technologies. Here, we studied the sex-determining system of F. chinensis using the fixation index (FST) between the sexes to detect the genetic differentiation in resequencing data of multiple males and females. We located the candidate sex chromosome in the genome of F. chinensis and concluded the female heterogametic (ZW) SD system. We also assembled female-specific sequences, which could be used as molecular markers to identify the sex of F. chinensis. However, the differentiation of the F. chinensis Z and W chromosome is limited. RNA-seq data detected many genes with male-biased expression in the Z-specific region, which possibly could further intensify the divergency between the Z and W chromosomes.
The Effect of Microplastics on the Bioenergetics of the Mussel Mytilus coruscus Assessed by Cellular Energy Allocation Approach
Authors: Shang Yueyong , Wang Xinghuo , Chang Xueqing , Sokolova Inna M. , Wei Shuaishuai , Liu Wei , Fang James K. H. , Hu Menghong , Huang Wei , Wang Youji
Published: September 2021

Marine microplastics pollution is a major environmental concern in marine ecosystems worldwide, yet the biological impacts of microplastics on the coastal biota are not yet fully understood. We investigated the impact of suspended microplastics on the energy budget of the mussels Mytilus coruscus using the Cellular Energy Allocation (CEA) approach. The mussels were exposed to control conditions (no microplastics) or to one of the three concentrations of 2 μm polystyrene microspheres (10, 104, and 106 particles/L) for 14 days, followed by 7 days of recovery. Exposure to high concentrations of microplastics (104 or 106 particles/L) increased cellular energy demand (measured as the activity of the mitochondrial electron transport system, ETS) and depleted cellular energy stores (carbohydrates, lipids, and proteins) in the mussels whereas exposure to 10 particles/L had no effect. Carbohydrate levels decreased already after 7 days of microplastics exposure and were restored after 7 days of recovery. In contrast, the tissue levels of lipids and proteins declined more slowly (after 14 days of exposure) and did not fully recover after 7 days following the removal of microplastics. Therefore, the total energy content and the CEA declined after 7–14 days of exposure to high microplastics concentrations, and remained suppressed during 7 days of subsequent recovery. These findings demonstrate a negative impact of microplastics on energy metabolism at the cellular level that cannot be restored during a short time recovery. Given a close link of CEA with the organismal energy balance, suppression of CEA by microplastics exposure suggests that bioenergetics disturbances might lead to decreases in growth and productivity of mussels’ populations in environments with heavy microplastics loads.
Effects of Scattering of Luminescent Down-Shifting Particles Inside Ethylene-Vinyl Acetate Films on Reflection of Light
Authors: Razzaq Shehroz , Asghar Ali , Lou Chaogang
Published: September 2021

Silicon solar cells are suffering from a poor spectral response in short wavelength ranges due to the loss of higher energy photons. The luminescent down-shifting (LDS) materials have the ability to convert shorter wavelength photons into longer wavelength photons and improve the performance of the solar cells. However, besides the down-shifting effects, the introduction of LDS particles into ethylene-vinyl acetate (EVA) films on the solar cells also increases surface reflection, which will negatively influence the performance of the solar cells. In this study, the influence of the size of LDS particles inside EVA films on reflection is investigated theoretically. The results showed that the reflection results from the scattering by LDS particles, which depends on the particle’s size. The total reflection caused by LDS particles can be calculated according to the size distribution of LDS particles. This study is helpful in selecting LDS particles that can be applied to solar cells.
Microstructure and Mechanical Properties of Additively Manufactured Ni-Al Bronze Parts Using Cold Metal Transfer Process
Authors: Wang Rongcheng , Zhao Yang , Chang Qing , Yin Fengshi , Wang Xiaoming , Wang Wenyu , Ren Zhiqiang , Han Guofeng
Published: September 2021

In this paper, the microstructure and mechanical properties of the SG-CuAl8Ni6 Ni-Al bronze straight wall were studied, which was fabricated by the cold metal transfer (CMT) arc additive manufacturing technology. This Ni-Al bronze cladding layer of SG-CuAl8Ni6 is composed mainly of α-Cu, residual β phase, rich Pb phase and κ phase. The microstructure of this multilayer single-channel Ni-Al bronze straight wall circulating presents the overall periodic law, which changes from fine cellular crystals, columnar crystals to dendritic crystals with the increase of the distance from the substrate. The Vickers hardness value of the Ni-Al bronze straight wall decreases with the distance of substrate are between 155 and 185 HV0.5. The microhardness and elastic modulus of the Ni-Al bronze specimen are 1.57 times and 1.99 times higher than these of the brass matrix, respectively. The ultimate tensile strength (UTS) of the straight wall in the welding direction and 45° downward-sloping is greater than that of about 550 MPa in the stacking direction, and the elongation value in the welding direction is the highest. With the increase in interlayer temperature, the grain size increased gradually, and the tensile strength decreases slightly.
Comparison of Energy Expenditure Assessed Using Wrist- and Hip-Worn ActiGraph GT3X in Free-Living Conditions in Young and Older Adults
Authors: Guediri Amine , Robin Louise , Lacroix Justine , Aubourg Timothee , Vuillerme Nicolas , Mandigout Stephane
Published: September 2021

The World Health Organization has presented their recommendations for energy expenditure to improve public health. Activity trackers do represent a modern solution for measuring physical activity, particularly in terms of steps/day and energy expended in physical activity (active energy expenditure). According to the manufacturer's instructions, these activity trackers can be placed on different body locations, mostly at the wrist and the hip, in an undifferentiated manner. The objective of this study was to compare the absolute error rate of active energy expenditure measured by a wrist-worn and hip-worn ActiGraph GT3X+ over a 24-h period in free-living conditions in young and older adults. Over the period of a 24-h period, 22 young adults and 22 older adults were asked to wear two ActiGraph GT3X+ at two different body locations recommended by the manufacturer, namely one around the wrist and one above the hip. Freedson algorithm was applied for data analysis. For both groups, the absolute error rate tended to decrease from 1,252 to 43% for older adults and from 408 to 46% for young participants with higher energy expenditure. Interestingly, for both young and older adults, the wrist-worn ActiGraph provided a significantly higher values of active energy expenditure (943 ± 264 cal/min) than the hip-worn (288 ± 181 cal/min). Taken together, these results suggest that caution is needed when using active energy expenditure as an activity tracker-based metric to quantify physical activity.
Epidemiology, Mortality and Healthcare Resource Utilization Associated With Systemic Sclerosis-Associated Interstitial Lung Disease in France
Authors: Cottin Vincent , Larrieu Sophie , Boussel Loic , Si-Mohamed Salim , Bazin Fabienne , Marque Sébastien , Massol Jacques , Thivolet-Bejui Françoise , Chalabreysse Lara , Maucort-Boulch Delphine , Jouneau Stéphane , Hachulla Eric , Chollet Julien , Nasser Mouhamad
Published: September 2021

Objectives: To investigate the clinical characteristics, epidemiology, survival estimates and healthcare resource utilization and associated costs in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in France.

Methods: The French national administrative healthcare database, the Système National des Données de Santé (SNDS), includes data on 98.8% of the French population, including data relating to ambulatory care, hospitalizations and death. In our study, claims data from the SNDS were used to identify adult patients with SSc-ILD between 2010 and 2017. We collected data on clinical features, incidence, prevalence, survival estimates, healthcare resource use and costs.

Results: In total, 3,333 patients with SSc-ILD were identified, 76% of whom were female. Patients had a mean age [standard deviation (SD)] of 60.6 (14.4) years and a mean (SD) individual study duration of 3.9 (2.7) years. In 2016, the estimated overall incidence and prevalence were 0.69/100,000 individuals and 5.70/100,000 individuals, respectively. The overall survival estimates of patients using Kaplan–Meier estimation were 93, 82, and 55% at 1, 3, and 8 years, respectively. During the study, 98.7% of patients had ≥1 hospitalization and 22.3% of patients were hospitalized in an intensive care unit. The total annual mean healthcare cost per patient with SSc-ILD was €25,753, of which €21,539 was related to hospitalizations.

Conclusions: This large, real-world longitudinal study provides important insights into the epidemiology of SSc-ILD in France and shows that the disease is associated with high mortality, healthcare resource utilization and costs. SSc-ILD represents a high burden on both patients and healthcare services.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03858842.
Comparison Between Nylon and Polyglactin Sutures in Pediatric Cataract Surgery: A Randomized Controlled Clinical Trial
Authors: Melega Mathias V. , dos Reis Roberto , Lira Rodrigo Pessoa Cavalcanti , de Oliveira Denise Fornazari , Arieta Carlos Eduardo Leite , Alves Monica
Published: September 2021

Purpose: To compare the performance of nylon sutures to that of polyglactin sutures in pediatric patients undergoing cataract surgery.

Setting: University of Campinas (UNICAMP), Campinas, São Paulo, Brazil

Design: A prospective, randomized, partially masked, single-site clinical trial. (https://clinicaltrials.gov/ct2/show/NCT03812640).

Methods: A total of 80 eyes from 80 patients who underwent pediatric cataract surgery were randomized into two groups in block sizes of four. Group A consisted of 41 patients whose surgical incisions were sutured with polyglactin 10-0 material. Group B consisted of 39 patients whose surgical incisions were sutured with nylon 10-0 material. The primary outcome was frequency of suture-related complications in each group. Secondary outcomes were the frequency with which suture removal was necessary.

Results: The incidence of suture-related complications within 6 months of follow up was 0 out of 41 eyes (0.00%) in the polyglactin group and 17 out of 39 eyes (43.59%) in the nylon control group (p < 0.001). In all of the eyes with suture-related complications, the sutures were promptly removed. The most frequent complications were vascularization near the suture (17.95%) and loose sutures (17.95%). No ocular or systemic study-related adverse events were observed.

Conclusions: Polyglactin sutures were found to be safe and effective for pediatric patients undergoing cataract surgery. Their lower rate of complications and reduced likelihood of removal (and the subsequent need for general anesthesia) make their use preferrable to that of nylon sutures. This study represents the first controlled randomized clinical trial to compare nylon sutures to polyglactin sutures in pediatric patients undergoing cataract surgery.

Clinical Trial Registration: URL: https://clinicaltrials.gov/ct2/show/, Identifier: NCT03812640.
Fluorinated PLGA-PEG-Mannose Nanoparticles for Tumor-Associated Macrophage Detection by Optical Imaging and MRI
Authors: Zambito Giorgia , Deng Siyuan , Haeck Joost , Gaspar Natasa , Himmelreich Uwe , Censi Roberta , Löwik Clemens , Di Martino Piera , Mezzanotte Laura
Published: September 2021

Tumor-associated macrophages (TAMs) promote cancer growth and metastasis, but their role in tumor development needs to be fully understood due to the dynamic changes of tumor microenvironment (TME). Here, we report an approach to visualize TAMs by optical imaging and by Fluorine-19 (19F) magnetic resonance imaging (MRI) that is largely applied to track immune cells in vivo. TAMs are targeted with PLGA-PEG-mannose nanoparticles (NPs) encapsulating perfluoro-15-crown-5-ether (PFCE) as MRI contrast agent. These particles are preferentially recognized and phagocytized by TAMs that overexpress the mannose receptor (MRC1/CD206). The PLGA-PEG-mannose NPs are not toxic and they were up-taken by macrophages as confirmed by in vitro confocal microscopy. At 48 h after intravenous injection of PLGA-PEG-mannose NPs, 4T1 xenograft mice were imaged and fluorine-19 nuclear magnetic resonance confirmed nanoparticle retention at the tumor site. Because of the lack of 19F background in the body, observed 19F signals are robust and exhibit an excellent degree of specificity. In vivo imaging of TAMs in the TME by 19F MRI opens the possibility for detection of cancer at earlier stage and for prompt therapeutic interventions in solid tumors.
Selenium-Enriched Lactobacillus acidophilus Ameliorates Dextran Sulfate Sodium-Induced Chronic Colitis in Mice by Regulating Inflammatory Cytokines and Intestinal Microbiota
Authors: Wu Zeyu , Pan Dan , Jiang Min , Sang Lixuan , Chang Bing
Published: September 2021

Aim: To evaluate the effect of Selenium-enriched Lactobacillus acidophilus (Se-enriched L. acidophilus) on dextran sulfate sodium (DSS)-induced colitis in mice.

Methods: Mice were randomly divided into four groups: a control group, a control + Se-enriched L. acidophilus group, a chronic colitis group, and a chronic colitis + Se-enriched L. acidophilus group (n = 10 each group). The mice were sacrificed on the 26th day. The disease activity index, survival rates, and histological injury score were determined. Cytokines produced by lamina propria lymphocytes (LPLs), the selenium (Se) concentrations in serum and colon tissue and the mouse intestinal microbiota were evaluated.

Results: Se-enriched L. acidophilus can improve histological injury and the disease activity index in mice with chronic colitis and reduce IL-1β, IL-6, IL-12p70, TNF-α, IL-23, IFN-γ, IL-17A, and IL-21 (P < 0.05) and increase IL-10 (P < 0.05) expression levels. Moreover, Se-enriched L. acidophilus can increase the β diversity of intestinal microbiota in mice with chronic colitis, significantly reduce the relative abundance of Lactobacillus and Romboutsia (P < 0.05), and significantly increase the relative abundance of Parasutterella (P < 0.05).

Conclusions: Se-enriched L. acidophilus can improve DSS-induced chronic colitis by regulating inflammatory cytokines and intestinal microbiota.
Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit–The EU Regulator's Perspective
Authors: Sheean Maria E. , Naumann-Winter Frauke , Capovilla Giuseppe , Kalland Maria Elisabeth , Malikova Eva , Mariz Segundo , Matusevicius Darius , Nistico Robert , Schwarzer-Daum Brigitte , Tsigkos Stelios , Tzogani Kyriaki , Larsson Kristina , Magrelli Armando , Stoyanova-Beninska Violeta
Published: September 2021

Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the “significant benefit.” In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them.
The Effects of Modest Alcohol Consumption on Non-alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Authors: Wongtrakul Wasit , Niltwat Sorachat , Charatcharoenwitthaya Phunchai
Published: September 2021

Background and Objective: There is no consensus regarding modest alcohol consumption in patients with non-alcoholic fatty liver disease (NAFLD) due to conflicting results. The aim of this meta-analysis was to examine the effects of modest alcohol consumption on histological severity, histological course, hepatocellular carcinoma, and long-term clinical outcomes in NAFLD patients.

Methods: We searched MEDLINE and EMBASE databases from inception to October 2020 for studies evaluating the effects of modest alcohol consumption among patients with NAFLD. A random-effects meta-analysis using pooled odds ratio (OR) and hazard ratio (HR) was calculated with 95% confidence interval (CI). Study quality was assessed with the Newcastle-Ottawa Scale.

Results: Fourteen cross-sectional or cohort studies with aggregate data on 14,435 patients were included in the analysis. Modest alcohol consumption resulted in lower risks for steatohepatitis (OR 0.59; 95% CI 0.45–0.78; I2 = 12%) and advanced fibrosis (OR 0.59, 95% CI 0.36–0.95; I2 = 75%). Histological follow-up data showed that modest alcohol use was associated significantly with less steatohepatitis resolution but not with fibrosis progression. The HR for developing hepatocellular carcinoma was 3.77 (95% CI 1.75–8.15; I2 = 0%). NAFLD patients with modest alcohol intake had a lower mortality risk than lifelong abstainers (HR 0.85; 95% CI 0.75–0.95; I2 = 64%).

Conclusion: This meta-analysis suggests that medical advice for modest alcohol drinking should be made cautiously in caring for an individual patient based on the clinical context. Practically, patients with steatohepatitis or advanced fibrosis should avoid alcohol use, whereas patients with low fibrosis risk may be allowed for modest and safe drinking.