bluuebunny/crossref_metadata_2025 huggingface dataset:
A interação entre professor e aluno na educação infantil: reflexo no desenvolvimento da aprendizagem e socialização da criança
Authors: Pereira Cássia Regina Dias , Lorencin Aurora Lopes
Published: April 2021

A pesquisa analisou a interação entre o docente e o discente na Educação Infantil, considerando-a um fenômeno legalizado, que objetiva a introdução da criança no contexto sócio educacional. É um estudo de caráter qualitativo e bibliográfico, que permite observar a variação do tema perante o contexto histórico social. As ações educativas efetivadas no âmbito da Educação Infantil favorecem a interação da criança com o meio e as demais pessoas. Essa relação inclui elementos socioculturais, históricos e econômicos que refletem no desenvolvimento do aluno. A pesquisa se fundamenta na história, considerando a interação social imprescindível à educação escolar. O convívio e o diálogo estabelecido entre professor e aluno, na Educação Infantil, podem resultar em implicações de variáveis positivas ou negativas no que diz respeito à iniciativa, participação, segurança e criatividade na resolução das tarefas escolares. Essa educação, como ato e processo de educar e transmitir saberes que assegurem a formação e desenvolvimento físico, cognitivo e sociocultural do aluno, firmou-se com a efetivação de políticas públicas como a Constituição Federal de 1988 e a Lei de Diretrizes e Bases nº9394/96 que asseguram à criança seu direito a Educação. Ao considerar a infância parte direta da criança no contexto educacional, o perfil do professor da Educação Infantil se diferencia dos demais docentes, uma vez que seu público alvo lhe exige uma competência polivalente, versátil e multifuncional. Na Educação Infantil o professor é visto pelo aluno como figura de estima, sendo o mediador entre os conhecimentos externos e a apreensão de saberes.
Raman Fingerprint of Extracellular Vesicles and Conditioned Media for the Reproducibility Assessment of Cell-Free Therapeutics
Authors: Carlomagno Cristiano , Giannasi Chiara , Niada Stefania , Bedoni Marzia , Gualerzi Alice , Brini Anna Teresa
Published: April 2021

Extracellular Vesicles (EVs) and Conditioned Medium (CM) are promising cell-free approaches to repair damaged and diseased tissues for regenerative rehabilitation purposes. They both entail several advantages, mostly in terms of safety and handling, compared to the cell-based treatment. Despite the growing interest in both EVs and CM preparations, in the light of a clinical translation, a number of aspects still need to be addressed mainly because of limits in the reproducibility and reliability of the proposed protocols. Raman spectroscopy (RS) is a non-destructive vibrational investigation method that provides detailed information about the biochemical composition of a sample, with reported ability in bulk characterization of clusters of EVs from different cell types. In the present brief report, we acquired and compared the Raman spectra of the two most promising cell-free therapeutics, i.e., EVs and CM, derived from two cytotypes with a history in the field of regenerative medicine, adipose-derived mesenchymal stem/stromal cells (ASCs) and dermal fibroblasts (DFs). Our results show how RS can verify the reproducibility not only of EV isolation, but also of the whole CM, thus accounting for both the soluble and the vesicular components of cell secretion. RS can provide hints for the identification of the soluble factors that synergistically cooperate with EVs in the regenerative effect of CM. Still, we believe that the application of RS in the pipeline of cell-free products preparation for therapeutic purposes could help in accelerating translation to clinics and regulatory approval.
Gold Nanoparticles in Cancer Theranostics
Authors: Gao Qinyue , Zhang Jingjing , Gao Jie , Zhang Zhengyang , Zhu Haitao , Wang Dongqing
Published: April 2021

Conventional cancer treatments, such as surgical resection, radiotherapy, and chemotherapy, have achieved significant progress in cancer therapy. Nevertheless, some limitations (such as toxic side effects) are still existing for conventional therapies, which motivate efforts toward developing novel theranostic avenues. Owning many merits such as easy surface modification, unique optical properties, and high biocompatibility, gold nanoparticles (AuNPs and GNPs) have been engineered to serve as targeted delivery vehicles, molecular probes, sensors, and so on. Their small size and surface characteristics enable them to extravasate and access the tumor microenvironment (TME), which is a promising solution to realize highly effective treatments. Moreover, stimuli-responsive properties (respond to hypoxia and acidic pH) of nanoparticles to TME enable GNPs’ unrivaled control for effective transport of therapeutic cargos. In this review article, we primarily introduce the basic properties of GNPs, further discuss the recent progress in gold nanoparticles for cancer theranostics, with an additional concern about TME stimuli-responsive studies.
TRP Channels in Brain Tumors
Authors: Chinigò Giorgia , Castel Hélène , Chever Oana , Gkika Dimitra
Published: April 2021

Malignant glioma including glioblastoma (GBM) is the most common group of primary brain tumors. Despite standard optimized treatment consisting of extensive resection followed by radiotherapy/concomitant and adjuvant therapy, GBM remains one of the most aggressive human cancers. GBM is a typical example of intra-heterogeneity modeled by different micro-environmental situations, one of the main causes of resistance to conventional treatments. The resistance to treatment is associated with angiogenesis, hypoxic and necrotic tumor areas while heterogeneity would accumulate during glioma cell invasion, supporting recurrence. These complex mechanisms require a focus on potential new molecular actors to consider new treatment options for gliomas. Among emerging and underexplored targets, transient receptor potential (TRP) channels belonging to a superfamily of non-selective cation channels which play critical roles in the responses to a number of external stimuli from the external environment were found to be related to cancer development, including glioma. Here, we discuss the potential as biological markers of diagnosis and prognosis of TRPC6, TRPM8, TRPV4, or TRPV1/V2 being associated with glioma patient overall survival. TRPs-inducing common or distinct mechanisms associated with their Ca2+-channel permeability and/or kinase function were detailed as involving miRNA or secondary effector signaling cascades in turn controlling proliferation, cell cycle, apoptotic pathways, DNA repair, resistance to treatment as well as migration/invasion. These recent observations of the key role played by TRPs such as TRPC6 in GBM growth and invasiveness, TRPV2 in proliferation and glioma-stem cell differentiation and TRPM2 as channel carriers of cytotoxic chemotherapy within glioma cells, should offer new directions for innovation in treatment strategies of high-grade glioma as GBM to overcome high resistance and recurrence.
Immune Response: A Missed Opportunity Between Vitamin D and Radiotherapy
Authors: Yu Xinyue , Liu Baocai , Zhang Ning , Wang Qian , Cheng Guanghui
Published: April 2021

Radiotherapy (RT) is a mainstay treatment in several types of cancer and acts by mediating various forms of cancer cell death, although it is still a large challenge to enhance therapy efficacy. Radiation resistance represents the main cause of cancer progression, therefore, overcoming treatment resistance is now the greatest challenge for clinicians. Increasing evidence indicates that immune response plays a role in reprogramming the radiation-induced tumor microenvironment (TME). Intriguingly, radiation-induced immunosuppression possibly overwhelms the ability of immune system to ablate tumor cells. This induces an immune equilibrium, which, we hypothesize, is an opportunity for radiosensitizers to make actions. Vitamin D has been reported to act in synergistic with RT by potentiating antiproliferative effect induced by therapeutics. Additionally, vitamin D can also regulate the TME and may even lead to immunostimulation by blocking immunosuppression following radiation. Previous reviews have focused on vitamin D metabolism and epidemiological trials, however, the synergistic effect of vitamin D and existing therapies remains unknown. This review summarizes vitamin D mediated radiosensitization, radiation immunity, and vitamin D-regulated TME, which may contribute to more successful vitamin D-adjuvant radiotherapy.
Ecto-5′-Nucleotidase (CD73) Regulates the Survival of CD8+ T Cells
Authors: Rosemblatt Mariana V. , Parra-Tello Brian , Briceño Pedro , Rivas-Yáñez Elizabeth , Tucer Suat , Saavedra-Almarza Juan , Hörmann Pilar , Martínez Brandon A. , Lladser Álvaro , Rosemblatt Mario , Cekic Caglar , Bono María Rosa , Sauma Daniela
Published: April 2021

Ecto-5′-nucleotidase (CD73) is an enzyme present on the surface of tumor cells whose primary described function is the production of extracellular adenosine. Due to the immunosuppressive properties of adenosine, CD73 is being investigated as a target for new antitumor therapies. We and others have described that CD73 is present at the surface of different CD8+ T cell subsets. Nonetheless, there is limited information as to whether CD73 affects CD8+ T cell proliferation and survival. In this study, we assessed the impact of CD73 deficiency on CD8+ T cells by analyzing their proliferation and survival in antigenic and homeostatic conditions. Results obtained from adoptive transfer experiments demonstrate a paradoxical role of CD73. On one side, it favors the expression of interleukin-7 receptor α chain on CD8+ T cells and their homeostatic survival; on the other side, it reduces the survival of activated CD8+ T cells under antigenic stimulation. Also, upon in vitro antigenic stimulation, CD73 decreases the expression of interleukin-2 receptor α chain and the anti-apoptotic molecule Bcl-2, findings that may explain the reduced CD8+ T cell survival observed in this condition. These results indicate that CD73 has a dual effect on CD8+ T cells depending on whether they are subject to an antigenic or homeostatic stimulus, and thus, special attention should be given to these aspects when considering CD73 blockade in the design of novel antitumor therapies.
Stimulation of c-Jun/AP-1-Activity by the Cell Cycle Inhibitor p57Kip2
Authors: Kullmann Michael Keith , Pegka Fragka , Ploner Christian , Hengst Ludger
Published: April 2021

p57 is a member of the Cip/Kip family of cell cycle inhibitors which restrict the eukaryotic cell cycle by binding to and inhibiting cyclin/CDK complexes. They are considered as tumor suppressors and inactivating genomic mutations of p57 are associated with human overgrowth disorders. Increasing evidence suggests that p57 controls additional cellular processes beyond cell cycle control such as apoptosis, cell migration or transcription. Here we report that p57 can stimulate AP-1 promotor activity. While transactivation by c-Jun is strongly activated by p57, it did not enhance c-Fos induced transcription. This indicates that c-Jun is the target of p57 in the canonical AP-1 heterodimeric transcription factor. We could detect endogenous p57/c-Jun containing complexes in cells by co-immunoprecipitation. The strong stimulation of c-Jun activity is not the consequence of activating phosphorylation in the transactivation domain (TAD) of c-Jun, but rather due to negative interference with c-Jun repressors and positive interference with c-Jun activators. In contrast to full-length p57, the amino- and carboxy-terminal domains of p57 are insufficient for a significant activation of c-Jun induced transcription. When expressed in presence of full length p57, the p57C-terminus abrogated and theN-terminus enhanced c-Jun activation. This indicates that theC-terminus may bind and sequester a putative activator of c-Jun, whereas theN-terminus may sequester a c-Jun repressor. Interestingly, the p57 aminoterminus is sufficient for binding to the two c-Jun repressors HDAC1 and HDAC3. These data are consistent with a model of c-Jun activation where p57 is a part of large nuclear remodeling/transcription complexes. p57 might stimulate transcription by inhibiting transcription repressor proteins like HDACs via itsN-terminus and/or attracting transcription activators through itsC-terminus. These data suggest that in addition to its role as a CDK inhibitor and tumor suppressor, p57 may also exert tumor promoting functions by activation of the proto-oncoprotein c-Jun.
BMI1 Drives Steroidogenesis Through Epigenetically Repressing the p38 MAPK Pathway
Authors: Yu Jun , Wu Yibo , Li Hong , Zhou Hui , Shen Cong , Gao Tingting , Lin Meng , Dai Xiuliang , Ou Jian , Liu Meiling , Huang Xiaoyan , Zheng Bo , Sun Fei
Published: April 2021

Testosterone biosynthesis progressively decreases in aging males primarily as a result of functional changes to Leydig cells. Despite this, the mechanisms underlying steroidogenesis remain largely unclear. Using gene knock-out approaches, we and others have recently identified Bmi1 as an anti-aging gene. Herein, we investigate the role of BMI1 in steroidogenesis using mouse MLTC-1 and primary Leydig cells. We show that BMI1 can positively regulate testosterone production. Mechanistically, in addition to its known role in antioxidant activity, we also report that p38 mitogen-activated protein kinase (MAPK) signaling is activated, and testosterone levels reduced, in BMI1-deficient cells; however, the silencing of the p38 MAPK pathway restores testosterone production. Furthermore, we reveal that BMI1 directly binds to the promoter region of Map3k3, an upstream activator of p38, thereby modulating its chromatin status and repressing its expression. Consequently, this results in the inhibition of the p38 MAPK pathway and the promotion of steroidogenesis. Our study uncovered a novel epigenetic mechanism in steroidogenesis involving BMI1-mediated gene silencing and provides potential therapeutic targets for the treatment of hypogonadism.
Phospho-Regulation of Meiotic Prophase
Authors: Kar Funda M. , Hochwagen Andreas
Published: April 2021

Germ cells undergoing meiosis rely on an intricate network of surveillance mechanisms that govern the production of euploid gametes for successful sexual reproduction. These surveillance mechanisms are particularly crucial during meiotic prophase, when cells execute a highly orchestrated program of chromosome morphogenesis and recombination, which must be integrated with the meiotic cell division machinery to ensure the safe execution of meiosis. Dynamic protein phosphorylation, controlled by kinases and phosphatases, has emerged as one of the main signaling routes for providing readout and regulation of chromosomal and cellular behavior throughout meiotic prophase. In this review, we discuss common principles and provide detailed examples of how these phosphorylation events are employed to ensure faithful passage of chromosomes from one generation to the next.
Pescoids and Chimeras to Probe Early Evo-Devo in the Fish Astyanax mexicanus
Authors: Torres-Paz Jorge , Rétaux Sylvie
Published: April 2021

The fish speciesAstyanax mexicanuswith its sighted and blind eco-morphotypes has become an original model to challenge vertebrate developmental evolution. Recently, we demonstrated that phenotypic evolution can be impacted by early developmental events starting from the production of oocytes in the fish ovaries.A. mexicanusoffers an amenable model to test the influence of maternal determinants on cell fate decisions during early development, yet the mechanisms by which the information contained in the eggs is translated into specific developmental programs remain obscure due to the lack of specific tools in this emergent model. Here we describe methods for the generation of pescoids from yolkless-blastoderm explants to test the influence of embryonic and extraembryonic tissues on cell fate decisions, as well as the production of chimeric embryos obtained by intermorph cell transplantations to probe cell autonomous or non-autonomous processes. We show thatAstyanaxpescoids have the potential to recapitulate the main ontogenetic events observed in intact embryos, including the internalization of mesodermal progenitors and eye development, as followed withzic:GFPreporter lines. In addition, intermorph cell grafts resulted in proper integration of exogenous cells into the embryonic tissues, with lineages becoming more restricted from mid-blastula to gastrula. The implementation of these approaches inA. mexicanuswill bring new light on the cascades of events, from the maternal pre-patterning of the early embryo to the evolution of brain regionalization.
Rapid Detection of Aspergillus fumigatus Using Multiple Cross Displacement Amplification Combined With Nanoparticles-Based Lateral Flow
Authors: Jiang Luxi , Li Xiaomeng , Gu Rumeng , Mu Deguang
Published: April 2021

Aspergillus fumigatus is an opportunistic, ubiquitous, saprophytic mold which can cause infection in the lungs, nose, eyes, brain, and bones in humans, especially in immunocompromised patients. However, it is difficult to diagnose A. fumigatus infection quickly. Here, we introduce a new detection method, namely multiple cross displacement amplification (MCDA) combined with nanoparticle-based lateral flow biosensor (LFB) (MCDA-LFB), which was proved to be fast, reliable, and simple for detecting A. fumigatus. We designed a set of 10 primers targeting the gene annexin ANXC4 of A. fumigatus. The best MCDA condition is 66 °C for 35 min. The minimum concentration that can be detected by this method was 10 fg. In the case of 100 sputum samples, 20 (20%) and 15 (15%) samples were positive by MCDA-LFB and PCR method, respectively. MCDA-LFB and traditional culture method showed the same results. Compared with the culture method, the diagnostic accuracy of MCDA-LFB can reach 100%. It showed that the MCDA-LFB method has better detection ability than the PCR method. We found that the whole process could be controlled within 60 min including the preparation of DNA (20 min), MCDA reaction (35 min) and results reporting (2 min). These results show that this assay is suitable for the rapid, sensitive and specific detection of A. fumigatus in clinical samples.
Prevalence and Impact of Apolipoprotein E7 on LDL Cholesterol Among Patients With Familial Hypercholesterolemia
Authors: Tada Hayato , Yamagami Kan , Kojima Nobuko , Shibayama Junichi , Nishikawa Tetsuo , Okada Hirofumi , Nomura Akihiro , Usui Soichiro , Sakata Kenji , Takamura Masayuki , Kawashiri Masa-aki
Published: April 2021

Background:It has been suggested that a rare mutant apolipoprotein E7, APOE7 (p.Glu262Lys, p.Glu263Lys), has been identified to be associated with hyperlipoproteinemia in the general population. Moreover, its prevalence has been shown to be 0.005–0.06%. However, there are no prior data regarding its prevalence and impact on serum lipids in patients with familial hypercholesterolemia (FH).

Methods:We recruited 1,138 patients with clinically diagnosed FH [mean age = 48, men = 512, median low-density lipoprotein (LDL) cholesterol = 231 mg/dl]. The coding regions of three FH genes (LDLR, APOB, andPCSK9) and apolipoprotein E (APOE) gene were sequenced. We investigated the prevalence and impact of APOE7 mutant on serum lipid levels in patients with FH.

Results:We identified 29 patients (2.5 %) with a mutant APOE7 (heterozygote), which is apparently much higher than that of the general population. Moreover, when we focus on those without FH mutation (n= 540), we identified 21 patients (3.9 %) with a mutant APOE7. Patients with a mutant APOE7 exhibited significantly higher median LDL cholesterol and triglyceride levels compared with those without this rare mutant (249 vs. 218 mg/dl,p< 0.05, 216 vs. 164 mg/dl,p< 0.05, respectively). Moreover, LDL cholesterol levels in the APOE7-oligogenic FH individuals, with a pathogenic mutation in FH genes and APOE7 mutant, were significantly higher than that in monogenic FH patients (265 vs. 245 mg/dl,p< 0.05).

Conclusion:We identified more patients with a mutant APOE7 than expected among those diagnosed with FH clinically, especially among those without FH-causing mutation. This implies a mutant APOE7 may be one of the causes FH, especially among those without FH mutations.
The Evolving Story in the Genetic Analysis for Heart Failure
Authors: Miyazawa Kazuo , Ito Kaoru
Published: April 2021

Genomic studies of cardiovascular diseases have achieved great success, not only in Mendelian genetic diseases such as hereditary arrhythmias and cardiomyopathies, but also in common diseases such as ischemic heart disease and atrial fibrillation. However, only limited success has been achieved in heart failure due to the complexity of its disease background. In this paper, we will review the genetic research for heart failure to date and discuss how we can discover new aspects of heart failure from the viewpoint of genomic perspective.
Sensitivity of the Seismic Moment Released During Fluid Injection to Fault Hydromechanical Properties and Background Stress
Authors: Wynants-Morel Nicolas , De Barros Louis , Cappa Frédéric
Published: April 2021

Fluid pressure perturbations in subsurface rocks affect the fault stability and can induce both seismicity and aseismic slip. Nonetheless, observations show that the partitioning between aseismic and seismic fault slip during fluid injection may strongly vary among reservoirs. The processes and the main fault properties controlling this partitioning are poorly constrained. Here we examine, through 3D hydromechanical modeling, the influence of fault physical properties on the seismic and aseismic response of a permeable fault governed by a slip-weakening friction law. We perform a series of high-rate, short-duration injection simulations to evaluate the influence of five fault parameters, namely the initial permeability, the dilation angle, the friction drop, the critical slip distance, and the initial proximity of stress to failure. For sake of comparison between tests, all the simulations are stopped for a fixed rupture distance relative to the injection point. We find that while the fault hydraulic behavior is mainly affected by the change in initial permeability and the dilation angle, the mechanical and seismic response of the fault strongly depends on the friction drop and the initial proximity of stress to failure. Additionally, both parameters, and to a lesser extent the initial fault permeability and the critical slip distance, impact the spatiotemporal evolution of seismic events and the partitioning between seismic and aseismic moment. Moreover, this study shows that a modification of such parameters does not lead to a usual seismic moment-injected fluid volume relationship, and provides insights into why the fault hydromechanical properties and background stress should be carefully taken into account to better anticipate the seismic moment from the injected fluid volume.
Application of Automated Throw Backstripping Method to Characterize Recent Faulting Activity Migration in the Al Hoceima Bay (Northeast Morocco): Geodynamic Implications
Authors: Tendero-Salmerón Víctor , Lafosse Manfred , d’Acremont Elia , Rabaute Alain , Azzouz Omar , Ercilla Gemma , Makkaoui Mohamed , Galindo-Zaldivar Jesus
Published: April 2021

Automation of the throw backstripping method has proven to be an effective tool for the determination of the evolution of tectonic activity in wide fault zones. This method has been applied to the Al Hoceima Bay (southwesternmost Mediterranean, Alboran Sea) for a time period covering the last 280 kyr on 672 faults imaged on 265 high-resolution seismic reflection profiles. This area was affected by major earthquakes and corresponds to a transtensional basin deformed by growth faults. The automated application of throw backstripping allowed for a faster deciphering of the migration of tectonic activity. Results show a westward migration of the deformation with quickly increasing deformation rates in the most recent time frames near Al Hoceima, one of the most populated cities. This migration is in agreement with the current seismicity, the GPS data, and recent brittle deformation data. Vertical throw rates of up to 0.47 mm/year have been calculated, for the most recent time periods, in segments of the Bokkoya fault zone. The westward migration of the deformation fits with the reconstruction suggested by the westernmost Mediterranean geodynamic models during the Pleistocene epoch, and it might be the consequence of the interaction between the northwest (NW) movement of the South Alboran indenter and the back Rif south-westward displacement. The highly accurate constraints of the evolution of the tectonic activity offered by this automation will substantially improve the seismic hazard assessment.
Tooth Microwear Texture in the Eastern Atlantic Harbour Seals (Phoca vitulina vitulina) of the German Wadden Sea and Its Implications for Long Term Dietary and Ecosystem Changes
Authors: Bethune Elehna , Schulz-Kornas Ellen , Lehnert Kristina , Siebert Ursula , Kaiser Thomas M.
Published: April 2021

Marine mammals are increasingly threatened in their habitat by various anthropogenic impacts. This is particularly evident in prey abundance. Understanding the dietary strategies of marine mammal populations can help predict implications for their future health status and is essential for their conservation. In this study we provide a striking example of a new dietary proxy in pinnipeds to document marine mammal diets using a dental record. In this novel approach, we used a combination of 49 parameters to establish a dental microwear texture (DMTA) as a dietary proxy of feeding behaviour in harbour seals. This method is an established approach to assess diets in terrestrial mammals, but has not yet been applied to pinnipeds. Our aim was to establish a protocol, opening DMTA to pinnipeds by investigating inter- and intra-individual variations. We analysed the 244 upper teeth of 78 Atlantic harbour seals (Phoca vitulina vitulina). The specimens were collected in 1988 along the North Sea coast (Wadden Sea, Germany) and are curated by the Zoological Institute of Kiel University, Germany. An increasing surface texture roughness from frontal to distal teeth was found and related to different prey processing biomechanics. Ten and five year old individuals were similar in their texture roughness, whereas males and females were similar to each other with the exception of their frontal dentition. Fall and summer specimens also featured no difference in texture roughness. We established the second to fourth postcanine teeth as reference tooth positions, as those were unaffected by age, sex, season, or intra-individual variation. In summary, applying indirect dietary proxies, such as DMTA, will allow reconstructing dietary traits of pinnipeds using existing skeletal collection material. Combining DMTA with time series analyses is a very promising approach to track health status in pinniped populations over the last decades. This approach opens new research avenues and could help detect dietary shifts in marine environments in the past and the future.
Deep Learning Enables Fast and Accurate Imputation of Gene Expression
Authors: Viñas Ramon , Azevedo Tiago , Gamazon Eric R. , Liò Pietro
Published: April 2021

A question of fundamental biological significance is to what extent the expression of a subset of genes can be used to recover the full transcriptome, with important implications for biological discovery and clinical application. To address this challenge, we propose two novel deep learning methods, PMI and GAIN-GTEx, for gene expression imputation. In order to increase the applicability of our approach, we leverage data from GTEx v8, a reference resource that has generated a comprehensive collection of transcriptomes from a diverse set of human tissues. We show that our approaches compare favorably to several standard and state-of-the-art imputation methods in terms of predictive performance and runtime in two case studies and two imputation scenarios. In comparison conducted on the protein-coding genes, PMI attains the highest performance in inductive imputation whereas GAIN-GTEx outperforms the other methods in in-place imputation. Furthermore, our results indicate strong generalization on RNA-Seq data from 3 cancer types across varying levels of missingness. Our work can facilitate a cost-effective integration of large-scale RNA biorepositories into genomic studies of disease, with high applicability across diverse tissue types.
Comprehensive Analysis of CDR3 Sequences in Gluten-Specific T-Cell Receptors Reveals a Dominant R-Motif and Several New Minor Motifs
Authors: Dahal-Koirala Shiva , Risnes Louise Fremgaard , Neumann Ralf Stefan , Christophersen Asbjørn , Lundin Knut E. A. , Sandve Geir Kjetil , Qiao Shuo-Wang , Sollid Ludvig M.
Published: April 2021

Gluten-specific CD4+ T cells are drivers of celiac disease (CeD). Previous studies of gluten-specific T-cell receptor (TCR) repertoires have found public TCRs shared across multiple individuals, biased usage of particular V-genes and conserved CDR3 motifs. The CDR3 motifs within the gluten-specific TCR repertoire, however, have not been systematically investigated. In the current study, we analyzed the largest TCR database of gluten-specific CD4+ T cells studied so far consisting of TCRs of 3122 clonotypes from 63 CeD patients. We established a TCR database from CD4+ T cells isolated with a mix of HLA-DQ2.5:gluten tetramers representing four immunodominant gluten epitopes. In an unbiased fashion we searched by hierarchical clustering for common CDR3 motifs among 2764 clonotypes. We identified multiple CDR3α, CDR3β, and paired CDR3α:CDR3β motif candidates. Among these, a previously known conserved CDR3β R-motif used by TRAV26-1/TRBV7-2 TCRs specific for the DQ2.5-glia-α2 epitope was the most prominent motif. Furthermore, we identified the epitope specificity of altogether 16 new CDR3α:CDR3β motifs by comparing with TCR sequences of 231 T-cell clones with known specificity and TCR sequences of cells sorted with single HLA-DQ2.5:gluten tetramers. We identified 325 public TCRα and TCRβ sequences of which 145, 102 and 78 belonged to TCRα, TCRβ and paired TCRαβ sequences, respectively. While the number of public sequences was depended on the number of clonotypes in each patient, we found that the proportion of public clonotypes from the gluten-specific TCR repertoire of given CeD patients appeared to be stable (median 37%). Taken together, we here demonstrate that the TCR repertoire of CD4+ T cells specific to immunodominant gluten epitopes in CeD is diverse, yet there is clearly biased V-gene usage, presence of public TCRs and existence of conserved motifs of which R-motif is the most prominent.
Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications
Authors: Li Yijia , Wu Yangzhe , Hu Yi
Published: April 2021

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.
T Cell-Mediated Immune Responses to AAV and AAV Vectors
Authors: Ertl Hildegund C. J.
Published: April 2021

Adeno-associated virus (AAV)-mediated gene transfer has benefited patients with inherited diseases, such as hemophilia B, by achieving long-term expression of the therapeutic transgene. Nevertheless, challenges remain due to rejection of AAV-transduced cells, which in some, but not all, patients can be prevented by immunosuppression. It is assumed that CD8+ T cells induced by natural infections with AAVs are recalled by the AAV vector’s capsid and upon activation eliminate cells expressing the degraded capsid antigens. Alternatively, it is feasible that AAV vectors, especially if given at high doses, induce de novo capsid- or transgene product-specific T cell responses. This chapter discusses CD8+ T cell responses to AAV infections and AAV gene transfer and avenues to prevent their activation or block their effector functions.
Effects of Climate Change in Marine Ecosystems Based on the Spatiotemporal Age Structure of Top Predators: A Case Study of Bigeye Tuna in the Pacific Ocean
Authors: Lan Kuo-Wei , Wu Yan-Lun , Chen Lu-Chi , Naimullah Muhamad , Lin Tzu-Hsiang
Published: April 2021

How top predators behave and are distributed depend on the conditions in their marine ecosystem through bottom−up forcing; this is because where and when these predators can feed and spawn are limited and change often. This study investigated how the catch rates of immature and mature cohorts of bigeye tuna (BET) varied across space and time; this was achieved by analyzing data on the Taiwanese longline fishery in the western and central Pacific Ocean (WCPO). We also conducted a case study on the time series patterns of BET cohorts to explore the processes that underlie the bottom-up control of the pelagic ecosystem that are influenced by decadal climate events. Wavelet analysis results revealed crucial synchronous shifts in the connection between the pelagic ecosystems at low trophic levels in relation to the immature BET cohort. Many variables exhibited decreasing trends after 2004–2005, and we followed the Pacific Decadal Oscillation (PDO) as a bottom-up control regulator. The results indicated that low recruitment into the mature cohort occurs 3 years after a decrease in the immature cohort’s food stocks, as indicated by a 3-year lag in our results. This finding demonstrated that, by exploring the connection between low-trophic-level species and top predators at various life stages, we can better understand how climate change affects the distribution and abundance of predator fish.
Diel and Seasonal Variability in Kelp Forest Soundscapes Off the Southern California Coast
Authors: Butler Jack , Pagniello Camille M. L. S. , Jaffe Jules S. , Parnell P. Ed , Širović Ana
Published: April 2021

Soundscape ecology is a relatively new field that can provide insights into the structure and health of marine habitats. Though this field is growing, the acoustics of many marine habitats, including the giant kelp forests off Southern California, remain poorly studied. Here, we examine the diel and seasonal periodicity of kelp forest soundscapes within a protected and unprotected site off San Diego, CA. Singular value decomposition was used to identify frequency bands of interest, enabling tracking of these bands through seasons to examine their variability. Four frequency bands were identified: (1) 60–130 Hz, which encompassed a putative fish chorus, (2) 300–500 Hz, which encompassed a different putative fish chorus, (3) a band that encompassed humming generated by Plainfin Midshipmen Poricthys notatus (fundamental frequency: 85–95 Hz, and two subharmonics 175–185 Hz and 265–275 Hz), and (4) a band that encompassed the snaps of snapping shrimps from 2.5 to 7.5 kHz. Overall, kelp forest soundscapes exhibited diel and seasonal variability. In particular, the two putative fish choruses dominated the dusk soundscapes during late spring and summer, and the Midshipmen hums persisted throughout nights in summer. Snapping shrimp sounds exhibited stereotypic crepuscular activity, with peaks in acoustic energy in the 2.5–7.5 kHz band occurring at dusk and dawn. In addition, vessel noise was identified and found to exhibit strong seasonal and spatial variation. Vessel noise was greatest during August and September at the protected site and was generally lower during the winter and spring months. These findings help establish reference acoustic indices for the kelp forests off Southern California, within and outside of a protected area, and can provide resource managers with information on how well a marine reserve protects a species of interest, as well as the putative human visitation of these protected areas.
Endophytes From Algae, a Potential Source for New Biologically Active Metabolites for Disease Management in Aquaculture
Authors: Deutsch Ynon , Gur Lior , Berman Frank Ilana , Ezra David
Published: April 2021

Endophytes are microorganisms that live inside the plant tissue without causing external symptoms. All plants in nature harbor endophytes. Some endophytes produce and secrete biologically active compounds, known as secondary metabolites, which can help the host plant cope with bacterial, fungal, and other pest pathogens. Endophytes are isolated from aquatic plants and algae. Diseases are detrimental in the aquaculture industry where chemical pesticides and antibiotics are widely used in an attempt to cope with fish pathogens. However, the ability to prevent disease outbreaks in aquaculture is currently extremely limited. Here, we isolated 173 bacterial and fungal endophytes from 16 Mediterranean seaweed and 4 algae from fresh or thermo-mineral water. We found 88 endophytes (51%) with biological activity against four common aquaculture pathogens. Fifty endophytes (29%) caused mortality of at least one of these four pathogens. We identified 23 bioactive endophytes, 18 of which are from the Bacilli class. Our findings suggest that macroalgae from different aquatic environments can serve as a good source of potential biocontrol agents against aquaculture diseases. To the best of our knowledge, there are no published studies demonstrating the use of algal endophytes to control aquaculture diseases. Our study may lead to finding new molecules for use as novel environmentally friendly products that will solve one of the most challenging problems for the growing aquaculture industry: pathogens and pests.
Fieldable Environmental DNA Sequencing to Assess Jellyfish Biodiversity in Nearshore Waters of the Florida Keys, United States
Authors: Ames Cheryl Lewis , Ohdera Aki H. , Colston Sophie M. , Collins Allen G. , Fitt William K. , Morandini André C. , Erickson Jeffrey S. , Vora Gary J.
Published: April 2021

Recent advances in molecular sequencing technology and the increased availability of fieldable laboratory equipment have provided researchers with the opportunity to conduct real-time or near real-time gene-based biodiversity assessments of aquatic ecosystems. In this study, we developed a workflow and portable kit for fieldable environmental DNA sequencing (FeDS) and tested its efficacy by characterizing the breadth of jellyfish (Medusozoa) taxa in the coastal waters of the Upper and Lower Florida Keys. Environmental DNA was isolated from seawater collection events at eight sites and samples were subjected to medusozoan 16S rRNA gene and metazoan mitochondrial cytochrome oxidase 1 gene profiling via metabarcoding onsite. In total, FeDS yielded 175,326 processed sequence reads providing evidence for 53 medusozoan taxa. Our most salient findings revealed eDNA from: (1) two venomous box jellyfish (Cubozoa) species, including taxa whose stings cause the notorious Irukandji envenomation syndrome; (2) two species of potentially introduced stalked jellyfish (Staurozoa); and (3) a likely cryptic species of upside-down jellyfish (Scyphozoa). Taken together, the results of this study highlight the merits of FeDS in conducting biodiversity surveys of endemic and introduced species, and as a potential tool for assessing envenomation and/or conservation-related threats.
Conservation Implications of Sabellaria spinulosa Reef Patches in a Dynamic Sandy-Bottom Environment
Authors: van der Reijden Karin J. , Koop Leo , Mestdagh Sebastiaan , Snellen Mirjam , Herman Peter M. J. , Olff Han , Govers Laura L.
Published: April 2021

Biogenic reefs form biodiversity hotspots and are key components of marine ecosystems, making them priority habitats for nature conservation. However, the conservation status of biogenic reefs generally depends on their size and stability. Dynamic, patchy reefs may therefore be excluded from protection. Here, we studied epibenthos and epifauna density, richness, and community composition of patchy, dynamic Sabellaria spinulosa (ross worm) reefs in the North Sea. This study was conducted by comparing boxcore (endobenthos) and video transect (epifauna) data from two research campaigns in 2017 and 2019 to the Brown Bank area on the Dutch Continental Shelf, where S. spinulosa reefs were first discovered in 2017. The Brown Bank area is characterized by dynamic, migratory bedforms at multiple scales which potentially affect biogenic reef stability. We showed that S. spinulosa habitats had a patchy distribution and alternated with habitats comprised of plain sand. Average S. spinulosa habitat patch size was 5.57 ± 0.99 m and 3.94 ± 0.22 m in 2017 and 2019, respectively (mean ± SE), which especially in 2019 closely resembled the small-scale megaripple bedforms. Contrary to the endobenthos communities that were unaffected by S. spinulosa, epifauna density and species richness were at least two times higher in S. spinulosa habitats compared to sandy habitats, resulting in different community compositions between the two habitat types. We showed that S. spinulosa persisted in the area for almost 2 years. Although the stability of individual patches remained unclear, we demonstrated that even patchy biogenic reefs may promote density and local biodiversity of mobile, epibenthic species, very likely as a result of increased habitat heterogeneity provided by reef habitat patches. This indicates that patchy biogenic reefs that occur in dynamic environments may also have high ecological value and their conservation status should be (re)considered to ensure their protection.
Genetic Diversity in Marine Planktonic Ciliates (Alveolata, Ciliophora) Suggests Distinct Geographical Patterns – Data From Chinese and European Coastal Waters
Authors: Ganser Maximilian H. , Forster Dominik , Liu Weiwei , Lin Xiaofeng , Stoeck Thorsten , Agatha Sabine
Published: April 2021

Unraveling geographic distribution patterns of planktonic protists is a central goal in marine microbial ecology. Using a novel combination of recently developed phylogenetic and network analyses on a V4 18S rDNA metabarcoding dataset, we here analyzed the genetic diversity of marine planktonic ciliate communities in Chinese and European coastal waters. Thereby, our approach provided an unprecedented perspective on geographic patterns inferred from ciliate genetic diversity and accomplished a very fine resolution down to single nucleotides within operational taxonomic units (OTUs). While most OTUs (87%) exclusively contained sequences of either Chinese or European origin, those OTUs detected in both regions comprised the vast majority of reads (84%). Phylogenetic analyses of OTUs belonging to the same taxon revealed genetically distinct clades that were geographically restricted to either Chinese or European coastal waters. The detection of signature nucleotides emphasized this genetic distinction of Chinese and European clades. Second-level clustering of OTUs and reference sequences in two selected taxa (the oligotrichid Spirotontonia and the tintinnid Tintinnidium) revealed the presence of several potentially new species or ones lacking genetic reference data. Geographic patterns were also discovered by network analyses within 700 widespread and abundant OTUs; in 77 of these OTUs, European and Chinese sequences formed significantly assortative groups. These assortative groupings indicated a higher genetic similarity among sequences from the same region than between sequences from different regions. Our results demonstrate that detailed analyses of metabarcoding data down to single nucleotide differences expand our perception of geographical distribution patterns and provide insights into historic and ongoing effective dispersal in protists. The congruent discovery of geographic patterns at different levels of resolution (between and within OTUs) suggests that cosmopolitan distribution in marine planktonic ciliates is less common than previously postulated.
Research Priorities for Coastal Geoscience and Engineering: A Collaborative Exercise in Priority Setting From Australia
Authors: Power Hannah E. , Pomeroy Andrew W. M. , Kinsela Michael A. , Murray Thomas P.
Published: April 2021

We present the result of a collaborative priority setting exercise to identify emerging issues and priorities in coastal geoscience and engineering (CGE). We use a ranking process to quantify the criticality of each priority from the perspective of Australian CGE researchers and practitioners. 74 activities were identified across seven categories: Data Collection and Collation, Coastal Dynamics and Processes, Modelling, Engineering Solutions, Coastal Hazards and Climate Change, Communication and Collaboration, and Infrastructure, Innovation, and Funding. We found consistent and unanimous support for the vast majority of priorities identified by the CGE community, with 91% of priorities being allocated a score of ≥ 3 out of 5 (i.e., above average levels of support) by ≥ 75% of respondents. Data Collection and Collation priorities received the highest average score, significantly higher than four of the other six categories, with Coastal Hazards and Climate Change the second ranked category and Engineering Solutions the lowest scoring category. Of the 74 priorities identified, 11 received unified and strong support across the CGE community and indicate a critical need for: additional coastal data collection including topographic and bathymetric, hydrodynamic, oceanographic, and remotely sensed data; improved data compilation and access; improved understanding of extreme events and the quantification of future impacts of climate change on nearshore dynamics and coastal development; enhanced quantification of shoreline change and coastal inundation processes; and, additional funding to support CGE research and applications to mitigate and manage coastal hazards. The outcomes of this priority setting exercise can be applied to guide policy development and decision-making in Australia and jurisdictions elsewhere. Further, the research and application needs identified here will contribute to addressing key practical challenges identified at a national level. CGE research plays a critical role in identifying and enabling social, environmental, and economic benefits through the proactive management of coastal hazard impacts and informed planning to mitigate the potential impacts of growing coastal risk, particularly in a changing climate. The prevalence and commonalities of the challenges faced by coastal communities globally due to increasing pressures from coastal hazards in a changing climate suggest that our findings will be applicable to other settings.