bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring Extreme Impacts of Rugulopteryx okamurae (Dictyotales, Ochrophyta) in El Estrecho Natural Park (Biosphere Reserve). Showing Radical Changes in the Underwater Seascape
Authors: García-Gómez José Carlos , Florido Marta , Olaya-Ponzone Liliana , Rey Díaz de Rada Jorge , Donázar-Aramendía Iñigo , Chacón Manuel , Quintero Juan José , Magariño Salvador , Megina César
Published: April 2021

The invasive macroalga Rugulopteryx okamurae represents an unprecedented case of bioinvasion by marine macroalgae facing the European coasts. Since the first apparition of the species in the Strait of Gibraltar in 2015, its fast dispersion along the introduced habitats constitutes a real challenge to develop monitoring strategies that ahead of its impacts. The present study uses three different approaches to address impacts on the benthic ecosystems, at the same time offers relevant data for future management actions in El Estrecho Natural Park (PNE). Information obtained by monitoring permanent sentinel stations revealed a significant loss in resident species coverage after the moment of maximum growth in 2017. Thus, despite coverage of R. okamurae did not strongly varied in the latter years, impacts generated remain high in the habitats studied. Estimations of the invasive species coverage by combining cartographic image analysis and in situ data predicted a major occupation (over 85% coverage) between 10 and 30 m, coinciding with the maximum rocky surface areas (m2) mapped on the PNE. Furthermore, a Citizen Science research collaboration evidenced impacts on the benthic seascape through an ad hoc exploration of images that allowed a “before” and “after” comparison of the invasion process in the same geographic locations. This has made it possible to graphically demonstrate severe changes in the underwater seascape and, therefore, the general impact of this new biological invasion. The spatial colonization estimations combined with the impacts reported by both scientific [Sessile Bioindicators in Permanent Quadrats (SBPQ) sentinel stations] and civilian (Citizen Science) monitoring methodologies claim the urgent development of further studies that allow the design of monitoring strategies against R. okamurae expansion across the Mediterranean and Atlantic waters.
Elevated microRNA-21 Is a Brake of Inflammation Involved in the Development of Nasal Polyps
Authors: Liu Ruowu , Du Jintao , Zhou Jiao , Zhong Bing , Ba Luo , Zhang Jie , Liu Yafeng , Liu Shixi
Published: April 2021

Background

CRSwNP is an inflammatory disease but the mechanism is not yet fully understood. MiR-21, a member of miRNAs, has been reported to play roles in mediating inflammation. However, the expression of miR-21 and its role in patients with CRSwNP remain elusive.

Methods

Turbinates from control subjects, uncinate processes from CRSsNP, polyp tissues from CRSwNP, and nasal epithelial cells brushed from nasal mucosa were collected. The expression of miR-21 and cytokines in nasal tissues and epithelial cells were detected by qPCR. The localization of miR-21 was detected by ISH, and its target was identified by bioinformation analysis, qPCR, IHC, WB, and luciferase reporter system. The protein and mRNA of PDCD4 and NF-κB P65 were determined by WB and qPCR after miR-21 transfection in HNEpC. The role of miR-21 on cytokines was analyzed in HNEpC and nasal polyp explants.

Results

MiR-21 was upregulated in CRSwNP relative to control subjects by qPCR, which was determined mainly in nasal epithelial cells of CRSwNP by ISH. Both pro-inflammation cytokines (IL-1β, IL-6, IL-8, IL-25, and TSLP) and a suppressive cytokine (IL-10) were overexpressed in the epithelial cells of CRSwNP. The expression of miR-21 was positively correlated with IL-10 and negatively correlated with IL-6, IL-8, IL-33, and TSLP in the epithelial cells of CRSwNP. As a potential target of miR-21, the expression of PDCD4 was negatively correlated with miR-21 in CRSwNP. In HNEpC, miR-21 could reduce the expression of PDCD4 at both mRNA and protein levels, and bioinformation analysis and luciferase reporter system confirmed PDCD4 as one target of miR-21. Furthermore, miR-21 could decrease the activation of NF-κB and increase IL-10 mRNA. Both SEB and LPS could elevate miR-21, with IL-25, IL-33, TSLP induced by SEB and IL-1β, IL-6, IL-8 induced by LPS, while the miR-21 could regulate the expression of IL-33, TSLP, IL-1β, IL- 6 and IL-8 in vitro and ex vivo. Clinically, miR-21 expression was inversely correlated with the Lund-Mackay CT scores and the Lund-Kennedy scores in CRSwNP.

Conclusion

MiR-21 could be a prominent negative feedback factor in the inflammation process to attenuate the expression of pro-inflammatory cytokines, thereby playing an anti-inflammation role in CRSwNP.
The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases
Authors: Qiu Wen Q. , Luo Shaopeiwen , Ma Stefanie A. , Saminathan Priyanka , Li Herman , Gunnersen Jenny M. , Gelbard Harris A. , Hammond Jennetta W.
Published: April 2021

The Sez6 family consists of Sez6, Sez6L, and Sez6L2. Its members are expressed throughout the brain and have been shown to influence synapse numbers and dendritic morphology. They are also linked to various neurological and psychiatric disorders. All Sez6 family members contain 2-3 CUB domains and 5 complement control protein (CCP) domains, suggesting that they may be involved in complement regulation. We show that Sez6 family members inhibit C3b/iC3b opsonization by the classical and alternative pathways with varying degrees of efficacy. For the classical pathway, Sez6 is a strong inhibitor, Sez6L2 is a moderate inhibitor, and Sez6L is a weak inhibitor. For the alternative pathway, the complement inhibitory activity of Sez6, Sez6L, and Sez6L2 all equaled or exceeded the activity of the known complement regulator MCP. Using Sez6L2 as the representative family member, we show that it specifically accelerates the dissociation of C3 convertases. Sez6L2 also functions as a cofactor for Factor I to facilitate the cleavage of C3b; however, Sez6L2 has no cofactor activity toward C4b. In summary, the Sez6 family are novel complement regulators that inhibit C3 convertases and promote C3b degradation.
Lipoxin A4 Restores Septic Renal Function via Blocking Crosstalk Between Inflammation and Premature Senescence
Authors: Chen Chaojin , Qiu Rongzong , Yang Jing , Zhang Qian , Sun Guoliang , Gao Xiaofeng , Hei Ziqing , Ji Haocong
Published: April 2021

Acute kidney injury (AKI) occurs in half of patients with septic shock, resulting in unacceptably high mortality. However, effective preventive treatments are still lacking. We hypothesized that pretreatment with lipoxin A4 (LXA4), known to promote inflammation resolution, may attenuate septic AKI via blocking crosstalk between inflammation and cellular senescence. In this study, rats developed AKI following cecal ligation and puncture (CLP), as evidenced by a dynamic increase in serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and pathological injury, accompanied by increased levels of inflammation (IL-6, TNF-α, and HMGB1) and tubular cell senescence. While, on the one hand, inhibition of senescence with rapamycin restored renal function and attenuated septic inflammatory response, on the other hand, LXA4 administration inhibited renal inflammation and tubular epithelial cell senescence after CLP. Ultimately, pretreatment with LXA4 significantly restored renal function and increased the survival rate of rats after CLP. Furthermore, LXA4 inhibited NF-κB-mediated inflammatory response and the p53/p21 senescence pathway in vivo and in vitro. However, the effect was reversed by PPAR-γ siRNA and antagonist. These results indicated that LXA4 exerted its renoprotective effects by blocking the crosstalk between inflammation and premature senescence in a PPAR-γ-dependent manner. Our findings also suggested that premature senescence plays a critical role in septic AKI and that inhibition of the crosstalk between inflammation and premature senescence may represent a new and major mechanism through which LXA4 attenuates septic AKI.
Immunological Consequences of In Utero Exposure to Foreign Antigens
Authors: Chen Jeng-Chang
Published: April 2021

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen’s observation of blood cell sharing in twin calves. Owen’s conceptual framework subsequently constituted the backbone of Medawar’s “actively acquired tolerance” as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as “self” so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically towardin uteromarrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar followingin uteroexposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of “actively acquired tolerance” might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens.
Decreased Serum 25-(OH)-D Level Associated With Muscle Enzyme and Myositis Specific Autoantibodies in Patients With Idiopathic Inflammatory Myopathy
Authors: Yu Zhen , Cheng Hao , Liang Yuying , Ding Tingting , Yan Chenglan , Gao Chong , Wen Hongyan
Published: April 2021

Objectives

To determine whether there is serum vitamin D deficiency and the low levels of serum vitamin D are correlated with serological and immunological indexes in patients with idiopathic inflammatory myopathy (IIM).

Methods

A total of 63 newly diagnosed patients with IIM, and 55 age- and sex- matched healthy controls were enrolled. Serum levels of 25-(OH)-D were measured by enzyme-linked immunosorbent assay. The correlations of 25-(OH)-D levels with disease indicators and T cell subsets were analyzed.

Result

The levels of serum 25-(OH)-D in IIM were significantly lower than those in healthy controls (9.36 ± 5.56 vs 26.56 ± 5.37 ng/ml, p<0.001). The levels of serum liver enzyme ALT and AST and muscle enzyme CK, CKMB, LDH and HBDH were elevated as deficiency of vitamin D. In addition, the serum 25-(OH)-D levels were negatively correlated to ALT (r = -0.408, p = 0.001) and AST (r = -0.338, p = 0.007). The 25-(OH)-D levels in IIM patients in presence of anti-Jo-1 were significantly lower than those in patients without anti-Jo-1 (5.24 ± 3.17 vs 9.32 ± 5.60 ng/ml; p = 0.037). Similar results were found in patients with or without anti-Mi-2 antibody. The serum 25-(OH)-D levels were positively associated with total T (r = 0.203, p = 0.012) and Treg cells (r = 0.331, p = 0.013). The patients with deficient levels of vitamin D were more likely to have heliotrope, gastrointestinal and liver involvement.

Conclusions

Vitamin D deficiency existed in IIM patients, which was significantly correlated with muscle enzyme, presence of anti-Jo-1 and anti-Mi-2 antibody, and the absolute numbers of total T and Treg cells in IIM. It is suggested that vitamin D may play an important role in the immunological pathogenesis of IIM.
Immune Polarization Potential of the S. aureus Virulence Factors SplB and GlpQ and Modulation by Adjuvants
Authors: Mrochen Daniel M. , Trübe Patricia , Jorde Ilka , Domanska Grazyna , Brandt Cindy van den , Bröker Barbara M.
Published: April 2021

Protection against Staphylococcus aureus is determined by the polarization of the anti-bacterial immune effector mechanisms. Virulence factors of S. aureus can modulate these and induce differently polarized immune responses in a single individual. We proposed that this may be due to intrinsic properties of the bacterial proteins. To test this idea, we selected two virulence factors, the serine protease-like protein B (SplB) and the glycerophosphoryl diester phosphodiesterase (GlpQ). In humans naturally exposed to S. aureus, SplB induces a type 2-biased adaptive immune response, whereas GlpQ elicits type 1/type 3 immunity. We injected the recombinant bacterial antigens into the peritoneum of S. aureus-naïve C57BL/6N mice and analyzed the immune response. This was skewed by SplB toward a Th2 profile including specific IgE, whereas GlpQ was weakly immunogenic. To elucidate the influence of adjuvants on the proteins’ polarization potential, we studied Montanide ISA 71 VG and Imject™Alum, which promote a Th1 and Th2 response, respectively. Alum strongly increased antibody production to the Th2-polarizing protein SplB, but did not affect the response to GlpQ. Montanide enhanced the antibody production to both S. aureus virulence factors. Montanide also augmented the inflammation in general, whereas Alum had little effect on the cellular immune response. The adjuvants did not override the polarization potential of the S. aureus proteins on the adaptive immune response.
IFNγ, and to a Lesser Extent TNFα, Provokes a Sustained Endothelial Costimulatory Phenotype
Authors: Valenzuela Nicole M.
Published: April 2021

Background

Vascular endothelial cells (EC) are critical for regulation of local immune responses, through coordination of leukocyte recruitment from the blood and egress into the tissue. Growing evidence supports an additional role for endothelium in activation and costimulation of adaptive immune cells. However, this function remains somewhat controversial, and the full repertoire and durability of an enhanced endothelial costimulatory phenotype has not been wholly defined.

Methods

Human endothelium was stimulated with continuous TNFα or IFNγ for 1-48hr; or primed with TNFα or IFNγ for only 3hr, before withdrawal of stimulus for up to 45hr. Gene expression of cytokines, costimulatory molecules and antigen presentation molecules was measured by Nanostring, and publicly available datasets of EC stimulation with TNFα or IFNγ were leveraged to further corroborate the results. Cell surface protein expression was detected by flow cytometry, and secretion of cytokines was assessed by Luminex and ELISA. Key findings were confirmed in primary human endothelial cells from 4-6 different vascular beds.

Results

TNFα triggered mostly positive immune checkpoint molecule expression on endothelium, including CD40, 4-1BB, and ICOSLG but in the context of only HLA class I and immunoproteasome subunits. IFNγ promoted a more tolerogenic phenotype of high PD-L1 and PD-L2 expression with both HLA class I and class II molecules and antigen processing genes. Both cytokines elicited secretion of IL-15 and BAFF/BLyS, with TNFα stimulated EC additionally producing IL-6, TL1A and IL-1β. Moreover, endothelium primed for a short period (3hr) with TNFα mostly failed to alter the costimulatory phenotype 24-48hr later, with only somewhat augmented expression of HLA class I. In contrast, brief exposure to IFNγ was sufficient to cause late expression of antigen presentation, cytokines and costimulatory molecules. In particular HLA class I, PD-1 ligand and cytokine expression was markedly high on endothelium two days after IFNγ was last present.

Conclusions

Endothelia from multiple vascular beds possess a wide range of other immune checkpoint molecules and cytokines that can shape the adaptive immune response. Our results further demonstrate that IFNγ elicits prolonged signaling that persists days after initiation and is sufficient to trigger substantial gene expression changes and immune phenotype in vascular endothelium.
Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity
Authors: Halder Namrita , Lal Girdhari
Published: April 2021

Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.
Chlamydia trachomatis Infection Impairs MHC-I Intracellular Trafficking and Antigen Cross-Presentation by Dendritic Cells
Authors: Del Balzo Diego , Capmany Anahí , Cebrian Ignacio , Damiani María Teresa
Published: April 2021

During cross-presentation, exogenous antigens (i.e. intracellular pathogens or tumor cells) are internalized and processed within the endocytic system and also by the proteasome in the cytosol. Then, antigenic peptides are associated with Major Histocompatibility Complex (MHC) class I molecules and these complexes transit to the plasma membrane in order to trigger cytotoxic immune responses through the activation of CD8+ T lymphocytes. Dendritic cells (DCs) are particularly adapted to achieve efficient antigen cross-presentation and their endocytic network displays important roles during this process, including a sophisticated MHC-I transport dependent on recycling compartments. In this study, we show that C. trachomatis, an obligate intracellular pathogen that exhibits multiple strategies to evade the immune system, is able to induce productive infections in the murine DC line JAWS-II. Our results show that when C. trachomatis infects these cells, the bacteria-containing vacuole strongly recruits host cell recycling vesicles, but no other endosomal compartments. Furthermore, we found that chlamydial infection causes significant alterations of MHC-I trafficking in JAWS-II DCs: reduced levels of MHC-I expression at the cell surface, disruption of the perinuclear MHC-I intracellular pool, and impairment of MHC-I endocytic recycling to the plasma membrane. We observed that all these modifications lead to a hampered cross-presentation ability of soluble and particulate antigens by JAWS-II DCs and primary bone marrow-derived DCs. In summary, our findings provide substantial evidence that C. trachomatis hijacks the DC endocytic recycling system, causing detrimental changes on MHC-I intracellular transport, which are relevant for competent antigen cross-presentation.
Photophore Distribution and Enzymatic Diversity Within the Photogenic Integument of the Cookie-Cutter Shark Isistius brasiliensis (Chondrichthyes: Dalatiidae)
Authors: Delroisse Jérôme , Duchatelet Laurent , Flammang Patrick , Mallefet Jérôme
Published: April 2021

The cookie-cutter shark Isistius brasiliensis (Squaliformes: Dalatiidae) is a deep-sea species that emits a blue luminescence ventrally, except at the level of a black band located beneath the jaw. This study aims to (i) investigate the distribution and histology of the photophores (i.e., light-emitting organs) along the shark body, (ii) describe the tissue-specific transcriptomes of the black band integument region (i.e., non-photogenic) and the ventral integument region (i.e., photogenic), (iii) describe the repertoire of enzyme-coding transcripts expressed the two integument regions, and (iv) analyze the potential expression of transcripts coding for luciferase-like enzymes (i.e., close homologs of known luciferases involved in the bioluminescence of other organisms). Our analyses confirm the black band’s non-photogenic status and photophore absence within this region. The sub-rostral area is the region where the photophore density is the highest. In parallel, paired-end Illumina sequencing has been used to generate two pilot transcriptomes, from the black band and the ventral integument tissues of one individual. In total, 68,943 predicted unigenes have been obtained (i.e., 64,606 for the black band transcriptome, 43,996 for the ventral integument transcriptome) with 43,473 unigenes showing significant similarities to known sequences from public databases. BLAST search analyses of known luciferases, coupled with comparative predicted gene expression (i.e., photogenic versus non-photogenic), support the hypothesis that the species uses an unknown luciferase system. An enzymatic repertoire was predicted based on the PRIAM database, and Enzyme Commission numbers were assigned for all detected enzyme-coding unigenes. These pilot transcriptomes based on a single specimen, and the predicted enzyme repertoire, constitute a valuable resource for future investigations on the biology of this enigmatic luminous shark.
Coastal Research Seen Through an Early Career Lens—A Perspective on Barriers to Interdisciplinarity in Norway
Authors: Deininger Anne , Martin Angela H. , Pardo Juan C. F. , Berg Paul R. , Bhardwaj Jyotirmoy , Catarino Diana , Fernández-Chacón Albert , Martinez-Swatson Karen , Ono Kotaro , Oomen Rebekah A. , Sodeland Marte , Sørdalen Tonje Knutsen , Synnes Ann-Elin Wårøy , Thorbjørnsen Susanna Huneide , Thormar Jonas
Published: April 2021

The value of interdisciplinarity for solving complex coastal problems is widely recognized. Many early career researchers (ECRs) therefore actively seek this type of collaboration through choice or necessity, for professional development or project funding. However, establishing and conducting interdisciplinary research collaborations as an ECR has many challenges. Here, we identify these challenges through the lens of ECRs working in different disciplines on a common ecosystem, the Norwegian Skagerrak coast. The most densely populated coastline in Norway, the Skagerrak coast, is experiencing a multitude of anthropogenic stressors including fishing, aquaculture, eutrophication, climate change, land runoff, development, and invasive species. The Skagerrak coastline has also been the focus of environmental science research for decades, much of which aims to inform management of these stressors. The region provides a fantastic opportunity for interdisciplinary collaboration, both within and beyond the environmental sciences. This perspective article identifies the barriers ECRs in Norway face in establishing interdisciplinary and collaborative research to inform management of coastal ecosystems, along with their root causes. We believe our discussion will be of broad interest to all research institutions who employ or educate ECRs (in Norway and worldwide), and to those who develop funding mechanisms for ECRs and interdisciplinary research.
The Effect of Coronary Angiography Timing on Cardiac Surgery Associated Acute Kidney Injury Incidence and Prognosis
Authors: Liu Kang , Li Meiyuan , Li Li , Wu Buyun , Xu Xueqiang , Ge Yifei , Mao Huijuan , Xing Changying
Published: April 2021

Introduction: Acute kidney injury has been identified as a common complication of cardiac surgery. To date, the effect of the time interval from coronary angiography to cardiac surgery on postoperative acute kidney injury is still controversial. The aim of this study was to investigate the relationship between the timing of coronary angiography and cardiac surgery associated acute kidney injury.

Methods: Eight hundred thirteen patients who underwent coronary angiography and cardiac surgery successively from January 2017 to December 2018 were included in this retrospective cohort study. We applied multivariate logistic regression, propensity score analysis, and subgroup analysis to evaluate the association between the time interval and postoperative acute kidney injury incidence and prognosis. Meta-analysis was conducted to verify the results.

Results: The overall incidence of the cardiac surgery associated acute kidney injury was 28.8%. Age (OR = 1.046, 95%CI: 1.017–1.075), cardiopulmonary bypass (OR = 3.439, 95%CI: 1.316–8.986) and diabetes (OR = 2.522, 95%CI: 1.439–4.417) were found to be independent risk factors of postoperative acute kidney injury in multivariate logistic regression and propensity score analysis. Undergoing cardiac surgery within 7 days after coronary angiography was not associated with increased incidence of postoperative acute kidney injury or worse prognosis. Meta-analysis obtained consistent results.

Conclusions: The time interval shorter than 7 days had no influence on cardiac surgery associated acute kidney injury incidence and prognosis. The decision of delaying the surgery should be made after comprehensive evaluation of the patient.
The Potent Trypanocidal Effect of LQB303, a Novel Redox-Active Phenyl-Tert-Butyl-Nitrone Derivate That Causes Mitochondrial Collapse in Trypanosoma cruzi
Authors: Macedo Carolina Machado , Saraiva Francis Monique de Souza , Paula Jéssica Isis Oliveira , Nascimento Suelen de Brito , Costa Débora de Souza dos Santos , Costa Paulo Roberto Ribeiro , Dias Ayres Guimarães , Paes Marcia Cristina , Nogueira Natália Pereira
Published: April 2021

Chagas disease, which is caused by Trypanosoma cruzi, establishes lifelong infections in humans and other mammals that lead to severe cardiac and gastrointestinal complications despite the competent immune response of the hosts. Furthermore, it is a neglected disease that affects 8 million people worldwide. The scenario is even more frustrating since the main chemotherapy is based on benznidazole, a drug that presents severe side effects and low efficacy in the chronic phase of the disease. Thus, the search for new therapeutic alternatives is urgent. In the present study, we investigated the activity of a novel phenyl-tert-butyl-nitrone (PBN) derivate, LQB303, against T. cruzi. LQB303 presented trypanocidal effect against intracellular [IC50/48 h = 2.6 μM] and extracellular amastigotes [IC50/24 h = 3.3 μM] in vitro, leading to parasite lysis; however, it does not present any toxicity to host cells. Despite emerging evidence that mitochondrial metabolism is essential for amastigotes to grow inside mammalian cells, the mechanism of redox-active molecules that target T. cruzi mitochondrion is still poorly explored. Therefore, we investigated if LQB303 trypanocidal activity was related to the impairment of the mitochondrial function of amastigotes. The investigation showed there was a significant decrease compared to the baseline oxygen consumption rate (OCR) of LQB303-treated extracellular amastigotes of T. cruzi, as well as reduction of “proton leak” (the depletion of proton motive force by the inhibition of F1Fo ATP synthase) and “ETS” (maximal oxygen consumption after uncoupling) oxygen consumption rates. Interestingly, the residual respiration (“ROX”) enhanced about three times in LQB303-treated amastigotes. The spare respiratory capacity ratio (SRC: cell ability to meet new energy demands) and the ATP-linked OCR were also impaired by LQB303 treatment, correlating the trypanocidal activity of LQB303 with the impairment of mitochondrial redox metabolism of amastigotes. Flow cytometric analysis demonstrated a significant reduction of the ΔΨm of treated amastigotes. LQB303 had no significant influence on the OCR of treated mammalian cells, evidencing its specificity against T. cruzi mitochondrial metabolism. Our results suggest a promising trypanocidal activity of LQB303, associated with parasite bioenergetic inefficiency, with no influence on the host energy metabolism, a fact that may point to an attractive alternative therapy for Chagas disease.
Positive Effects of Crop Diversity on Productivity Driven by Changes in Soil Microbial Composition
Authors: Stefan Laura , Hartmann Martin , Engbersen Nadine , Six Johan , Schöb Christian
Published: April 2021

Intensive agriculture has major negative impacts on ecosystem diversity and functioning, including that of soils. The associated reduction of soil biodiversity and essential soil functions, such as nutrient cycling, can restrict plant growth and crop yield. By increasing plant diversity in agricultural systems, intercropping could be a promising way to foster soil microbial diversity and functioning. However, plant–microbe interactions and the extent to which they influence crop yield under field conditions are still poorly understood. In this study, we performed an extensive intercropping experiment using eight crop species and 40 different crop mixtures to investigate how crop diversity affects soil microbial diversity and activity, and whether these changes subsequently affect crop yield. Experiments were carried out in mesocosms under natural conditions in Switzerland and in Spain, two countries with drastically different soils and climate, and our crop communities included either one, two or four species. We sampled and sequenced soil microbial DNA to assess soil microbial diversity, and measured soil basal respiration as a proxy for soil activity. Results indicate that in Switzerland, increasing crop diversity led to shifts in soil microbial community composition, and in particular to an increase of several plant-growth promoting microbes, such as members of the bacterial phylumActinobacteria. These shifts in community composition subsequently led to a 15 and 35% increase in crop yield in 2 and 4-species mixtures, respectively. This suggests that the positive effects of crop diversity on crop productivity can partially be explained by changes in soil microbial composition. However, the effects of crop diversity on soil microbes were relatively small compared to the effects of abiotic factors such as fertilization (three times larger) or soil moisture (three times larger). Furthermore, these processes were context-dependent: in Spain, where resources were limited, soil microbial communities did not respond to crop diversity, and their effect on crop yield was less strong. This research highlights the potential beneficial role of soil microbial communities in intercropping systems, while also reflecting on the relative importance of crop diversity compared to abiotic drivers of microbiomes and emphasizing the context-dependence of crop–microbe relationships.
Developmental Landscape of Potential Vaccine Candidates Based on Viral Vector for Prophylaxis of COVID-19
Authors: Bezbaruah Rajashri , Borah Pobitra , Kakoti Bibhuti Bhushan , Al-Shar’I Nizar A. , Chandrasekaran Balakumar , Jaradat Da’san M. M. , Al-Zeer Munir A. , Abu-Romman Saeid
Published: April 2021

Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, arose at the end of 2019 as a zoonotic virus, which is the causative agent of the novel coronavirus outbreak COVID-19. Without any clear indications of abatement, the disease has become a major healthcare threat across the globe, owing to prolonged incubation period, high prevalence, and absence of existing drugs or vaccines. Development of COVID-19 vaccine is being considered as the most efficient strategy to curtail the ongoing pandemic. Following publication of genetic sequence of SARS-CoV-2, globally extensive research and development work has been in progress to develop a vaccine against the disease. The use of genetic engineering, recombinant technologies, and other computational tools has led to the expansion of several promising vaccine candidates. The range of technology platforms being evaluated, including virus-like particles, peptides, nucleic acid (DNA and RNA), recombinant proteins, inactivated virus, live attenuated viruses, and viral vectors (replicating and non-replicating) approaches, are striking features of the vaccine development strategies. Viral vectors, the next-generation vaccine platforms, provide a convenient method for delivering vaccine antigens into the host cell to induce antigenic proteins which can be tailored to arouse an assortment of immune responses, as evident from the success of smallpox vaccine and Ervebo vaccine against Ebola virus. As per the World Health Organization, till January 22, 2021, 14 viral vector vaccine candidates are under clinical development including 10 nonreplicating and four replicating types. Moreover, another 39 candidates based on viral vector platform are under preclinical evaluation. This review will outline the current developmental landscape and discuss issues that remain critical to the success or failure of viral vector vaccine candidates against COVID-19.
TRIM21, a New Component of the TRAIL-Induced Endogenous Necrosome Complex
Authors: Simoes Eugénio Mélanie , Faurez Florence , Kara-Ali Ghania H. , Lagarrigue Mélanie , Uhart Perrine , Bonnet Marion C. , Gallais Isabelle , Com Emmanuelle , Pineau Charles , Samson Michel , Le Seyec Jacques , Dimanche-Boitrel Marie-Thérèse
Published: April 2021

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a well-known apoptosis inducer and a potential anticancer agent. When caspases and inhibitors of apoptosis proteins (IAPs) are inhibited, TRAIL induces necroptosis. Molecular mechanisms of necroptosis rely on kinase activation, and on the formation of a necrosome complex, bringing together the receptor-interacting protein kinases 1 and 3 (RIPK1, RIPK3), and the mixed lineage kinase domain-like protein (MLKL). In this study, mass spectrometry approach allowed to identify the tripartite motif containing 21 (TRIM21), an E3 ubiquitin-protein ligase as a new partner of the endogenous TRAIL-induced necrosome. Alteration of TRIM21 expression level, obtained by transient transfection of HT29 or HaCat cells with TRIM21-targeted siRNAs or cDNA plasmids coding for TRIM21 demonstrated that TRIM21 is a positive regulator of TRAIL-induced necroptosis. Furthermore, the invalidation of TRIM21 expression in HT29 cells by CRISPR-Cas9 technology also decreased cell sensitivity to TRAIL-induced necroptosis, a shortcoming associated with a reduction in MLKL phosphorylation, the necroptosis executioner. Thus, TRIM21 emerged as a new partner of the TRAIL-induced necrosome that positively regulates the necroptosis process.
Carbonic Anhydrase in Pacific Abalone Haliotis discus hannai: Characterization, Expression, and Role in Biomineralization
Authors: Sharker Md. Rajib , Kim Soo Cheol , Hossen Shaharior , Sumi Kanij Rukshana , Choi Sang Ki , Choi Kap Seong , Kho Kang Hee
Published: April 2021

Carbonic anhydrases (CAs) are universal zinc ion containing metalloenzymes that play a pivotal role in various physiological processes. In this study, a CA I (designated as Hdh CA I) was isolated and characterized from the mantle tissue of Pacific abalone, Haliotis discus hannai. The full-length cDNA sequence of Hdh CA I was 1,417-bp in length, encoding a protein of 337 amino acids with molecular weight of 37.58 kDa. Hdh CA I sequence possessed a putative signal peptide of 22 amino acids and a CA catalytic function domain. The predicted protein shared 94 and 78% sequence identities with Haliotis gigantea and Haliotis tuberculata CA I, respectively. Results of phylogenetic analysis indicated that Hdh CA I was evolutionarily close to CA I of H. gigantea and H. tuberculata with high bootstrap values. Significantly higher levels of Hdh CA I mRNA transcript were found in mantle than other examined tissues. In situ hybridization results showed strong hybridization signals in epithelial cells of the dorsal mantle pallial, an area known to synthesize and secrete proteins responsible for the nacreous layer formation of shell. This is the first study on Hdh CA I in H. discus hannai and the results may contribute to further study its physiological functions in shell biomineralization of abalone.
MicroRNA-653-5p Promotes Gastric Cancer Proliferation and Metastasis by Targeting the SOCS6-STAT3 Pathway
Authors: Li Zengliang , Fan Hao , Chen Wangwang , Xiao Jian , Ma Xiang , Ni Peidong , Xu Zekuan , Yang Li
Published: April 2021

MicroRNAs (miRNAs) are emerging as significant regulators of the tumorigenesis of gastric cancer (GC), and may be effective biomarkers for diagnosis, prognosis, and therapeutic targeting for GC. In this study, miR-653-5p was found to be significantly upregulated in GC tissues, serum, and cell lines and was strongly associated with poor prognosis in patients with GC. Furthermore, miR-653-5p promoted GC cell proliferation and metastasis in vivo and in vitro. Suppressor of cytokine signaling 6 (SOCS6) was directly targeted by miR-653-5p, and SOCS6 attenuated miR-653-5p-mediated GC cell growth, migration, and invasion. In addition, SOCS6-mediated inactivation of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway was also reversed by the administration of miR-653-5p. The findings from this study support a novel regulatory axis between miR-653-5p, SOCS6, and JAK2/STAT3 that may be a target for diagnosis and therapeutic intervention for GC.
Case Report: Repeated Low-Dose Rituximab Treatment Is Effective in Relapsing Neuro Behçet's Disease
Authors: Zhao Chao , Li Chuan , Duan Feng-ju , Yan Qi , Zhang Zhuo , Du Ying , Zhang Wei
Published: April 2021

Neuro Behçet's disease (NBD) is a rare but most aggressive manifestation of Behçet's disease (BD) with a poor prognosis, and some patients even present a relapsing and treatment-resistant progressive course. In some relapsing NBD cases, traditional corticosteroids and immunosuppressive drugs show limited efficacy, while benefits of biological agents, such as anti-B-lymphocyte CD20 biological agent rituximab (RTX), gradually represent potential therapeutic advantages with clinical rapid remission and long-time maintenance. However, up to now, the optimal dosage of RTX in NBD is still elucidated. Here, we report two patients with relapsing NBD, despite continuous high dose steroids and sufficient azathioprine treatment, still presenting severe and relapsing meningoencephalitis or brainstem involvement. Repeated low-dose RTX (100 mg × 3/1 week apart, 100 mg repeated every 6 months) is then attempted with rapid recovery and sustained remission. The approach in our cases may expand therapeutic options and provide helpful references for relapsing NBD treatment.
Presence of Atrial Fibrillation in Stroke Patients With Patent Foramen Ovale: Systematic Review and Meta-Analysis
Authors: Chen Jessie Ze-Jun , Thijs Vincent N.
Published: April 2021

Purpose: Patent foramen ovale (PFO) is associated with ischemic stroke, especially in patients with embolic stroke of undetermined source. This study aims to evaluate the presence of atrial fibrillation (AF) in ischemic stroke patients with PFO.

Methods: We systematically searched EMBASE and MEDLINE databases on May 21, 2020 for studies that analyzed the presence of AF in patients with PFO. The primary outcome was the presence of AF in patients with PFO compared with those without. Outcomes were pooled using a random-effects model using the method of DerSimonian and Laird. We recorded demographic characteristics and the methods used for AF detection in the studies included (unspecified, history/medical records review, ECG, Holter monitor, or loop recorder).

Results: A total of 14 studies and 13,245 patients fulfilled the entry criteria. The average age was 61.2 years and 41.3% of the participants were female. There was a lower risk of AF in patients with PFO compared with those without (RR 0.52, 95% confidence interval, 0.41–0.63, p < 0.001). There was no evidence of heterogeneity. The lower risk of AF was found in cross-sectional and longitudinal studies and in studies stratified by average age (<60 or ≥60) and in cryptogenic stroke. Meta-regression by PFO detection technique suggested that studies using transoesophageal echocardiogram for PFO detection reported higher risk of AF (1.39, 95% confidence interval 1.14–1.70, p = 0.004).

Conclusion: The presence of a PFO in patients with ischemic stroke/TIA may be associated with a lower risk of AF. Few studies have estimated the risk of future AF in patients with PFO.
Hemodynamic Signal Changes During Motor Imagery Task Performance Are Associated With the Degree of Motor Task Learning
Authors: Iso Naoki , Moriuchi Takefumi , Fujiwara Kengo , Matsuo Moemi , Mitsunaga Wataru , Hasegawa Takashi , Iso Fumiko , Cho Kilchoon , Suzuki Makoto , Higashi Toshio
Published: April 2021

Purpose

This study aimed to investigate whether oxygenated hemoglobin (oxy-Hb) generated during a motor imagery (MI) task is associated with the motor learning level of the task.

Methods

We included 16 right-handed healthy participants who were trained to perform a ball rotation (BR) task. Hemodynamic brain activity was measured using near-infrared spectroscopy to monitor changes in oxy-Hb concentration during the BR MI task. The experimental protocol used a block design, and measurements were performed three times before and after the initial training of the BR task as well as after the final training. The BR count during training was also measured. Furthermore, subjective vividness of MI was evaluated three times after NIRS measurement using the Visual Analog Scale (VAS).

Results

The results showed that the number of BRs increased significantly with training (P < 0.001). VAS scores also improved with training (P < 0.001). Furthermore, oxy-Hb concentration and the region of interest (ROI) showed a main effect (P = 0.001). An interaction was confirmed (P < 0.001), and it was ascertained that the change in oxy-Hb concentrations due to training was different for each ROI. The most significant predictor of subjective MI vividness was supplementary motor area (SMA) oxy-Hb concentration (coefficient = 0.365).

Discussion

Hemodynamic brain activity during MI tasks may be correlated with task motor learning levels, since significant changes in oxy-Hb concentrations were observed following initial and final training in the SMA. In particular, hemodynamic brain activity in the SMA was suggested to reflect the MI vividness of participants.
Contextual Cueing Accelerated and Enhanced by Monetary Reward: Evidence From Event-Related Brain Potentials
Authors: Zhao Guang , Zhuang Qian , Ma Jie , Tu Shen , Li Shiyi
Published: April 2021

The vital role of reward in guiding visual attention has been supported by previous literatures. Here, we examined the motivational impact of monetary reward feedback stimuli on visual attention selection using an event-related potential (ERP) component called stimulus-preceding negativity (SPN) and a standard contextual cueing (CC) paradigm. It has been proposed that SPN reflects affective and motivational processing. We focused on whether incidentally learned context knowledge could be affected by reward. Both behavior and brain data demonstrated that contexts followed by reward feedback not only gave rise to faster implicit learning but also obtained a larger CC effect.
Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities
Authors: Namba Mark D. , Leyrer-Jackson Jonna M. , Nagy Erin K. , Olive M. Foster , Neisewander Janet L.
Published: April 2021

Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.
Myosin V Regulates Spatial Localization of Different Forms of Neurotransmitter Release in Central Synapses
Authors: Maschi Dario , Gramlich Michael W. , Klyachko Vitaly A.
Published: April 2021

Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.