bluuebunny/crossref_metadata_2025 huggingface dataset:
Microfluidic System to Analyze the Effects of Interleukin 6 on Lymphatic Breast Cancer Metastasis
Authors: Cho Hyeon-Yeol , Choi Jin-Ha , Kim Kyeong-Jun , Shin Minkyu , Choi Jeong-Woo
Published: February 2021

Metastasis is the primary cause of a large number of cancer-associated deaths. By portraying the precise environment of the metastasis process in vitro, the microfluidic system provides useful insights on the mechanisms underlying cancer cell migration, invasion, colonization, and the procurement of supplemental nutrients. However, current in vitro metastasis models are biased in studying blood vessel-based metastasis pathways and thus the understanding of lymphatic metastasis is limited which is also closely related to the inflammatory system. To understand the effects of inflammatory cytokines in lymphatic metastasis, we developed a three-channel microfluidic system by mimicking the lymph vessel-tissue-blood vessel (LTB) structure. Based on the LTB chip, we successfully confirmed the inflammatory cytokine, interleukin 6 (IL-6), -mediated intercellular communication in the tumor microenvironment during lymphatic metastasis. The IL-6 exposure to different subtypes of breast cancer cells was induced epithelial-mesenchymal transition (EMT) and improved tissue invasion property (8-fold). And the growth of human vein endothelial cells toward the lymph vessel channel was observed by VEGF secretion from human lymphatic endothelial cells with IL-6 treatment. The proposed LTB chip can be applied to analyze the intercellular communication during the lymphatic metastasis process and be a unique tool to understand the intercellular communication in the cancer microenvironment under various extracellular stimuli such as inflammatory cytokines, stromal reactions, hypoxia, and nutrient deficiency.
Scaffold-Dependent Mechanical and Architectural Cues Guide Osteochondral Defect Healing in silico
Authors: Tortorici Martina , Petersen Ansgar , Ehrhart Klara , Duda Georg N. , Checa Sara
Published: February 2021

Osteochondral defects in joints require surgical intervention to relieve pain and restore function. However, no current treatment enables a complete reconstitution of the articular surface. It is known that both mechanical and biological factors play a key role on osteochondral defect healing, however the underlying principles and how they can be used in the design of treatment strategies remain largely unknown. To unravel the underlying principles of mechanobiology in osteochondral defect healing, i.e., how mechanical stimuli can guide biological tissue formation, we employed a computational approach investigating the scaffold-associated mechanical and architectural properties that would enable a guided defect healing. A previous computer model of the knee joint was further developed to simulate healing of an empty osteochondral defect. Then, scaffolds were implanted in the defect and their architectures and material properties were systematically varied to identify their relevance in osteochondral defect healing. Scaffold mechanical and architectural properties were capable of influencing osteochondral defect healing. Specifically, scaffold material elastic modulus values in the range of cancellous bone (low GPa range) and a scaffold architecture that provided stability, i.e., resistance against displacement, in both the main loading direction and perpendicular to it supported the repair process. The here presented model, despite its simplifications, is regarded as a powerful tool to screen for promising properties of novel scaffold candidates fostering osteochondral defect regeneration prior to their implementation in vivo.
Genetic Mechanisms Underlying Cortical Evolution in Mammals
Authors: Franchini Lucía Florencia
Published: February 2021

The remarkable sensory, motor, and cognitive abilities of mammals mainly depend on the neocortex. Thus, the emergence of the six-layered neocortex in reptilian ancestors of mammals constitutes a fundamental evolutionary landmark. The mammalian cortex is a columnar epithelium of densely packed cells organized in layers where neurons are generated mainly in the subventricular zone in successive waves throughout development. Newborn cells move away from their site of neurogenesis through radial or tangential migration to reach their specific destination closer to the pial surface of the same or different cortical area. Interestingly, the genetic programs underlying neocortical development diversified in different mammalian lineages. In this work, I will review several recent studies that characterized how distinct transcriptional programs relate to the development and functional organization of the neocortex across diverse mammalian lineages. In some primates such as the anthropoids, the neocortex became extremely large, especially in humans where it comprises around 80% of the brain. It has been hypothesized that the massive expansion of the cortical surface and elaboration of its connections in the human lineage, has enabled our unique cognitive capacities including abstract thinking, long-term planning, verbal language and elaborated tool making capabilities. I will also analyze the lineage-specific genetic changes that could have led to the modification of key neurodevelopmental events, including regulation of cell number, neuronal migration, and differentiation into specific phenotypes, in order to shed light on the evolutionary mechanisms underlying the diversity of mammalian brains including the human brain.
Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Perspectives
Authors: Abreu Soraia C. , Lopes-Pacheco Miquéias , Weiss Daniel J. , Rocco Patricia R. M.
Published: February 2021

Extracellular vesicles (EVs) have emerged as a potential therapy for several diseases. These plasma membrane-derived fragments are released constitutively by virtually all cell types—including mesenchymal stromal cells (MSCs)—under stimulation or following cell-to-cell interaction, which leads to activation or inhibition of distinct signaling pathways. Based on their size, intracellular origin, and secretion pathway, EVs have been grouped into three main populations: exosomes, microvesicles (or microparticles), and apoptotic bodies. Several molecules can be found inside MSC-derived EVs, including proteins, lipids, mRNA, microRNAs, DNAs, as well as organelles that can be transferred to damaged recipient cells, thus contributing to the reparative process and promoting relevant anti-inflammatory/resolutive actions. Indeed, the paracrine/endocrine actions induced by MSC-derived EVs have demonstrated therapeutic potential to mitigate or even reverse tissue damage, thus raising interest in the regenerative medicine field, particularly for lung diseases. In this review, we summarize the main features of EVs and the current understanding of the mechanisms of action of MSC-derived EVs in several lung diseases, such as chronic obstructive pulmonary disease (COPD), pulmonary infections [including coronavirus disease 2019 (COVID-19)], asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis (CF), among others. Finally, we list a number of limitations associated with this therapeutic strategy that must be overcome in order to translate effective EV-based therapies into clinical practice.
The miR-203a Regulatory Network Affects the Proliferation of Chronic Myeloid Leukemia K562 Cells
Authors: He Jinhua , Han Zeping , An Ziyi , Li Yumin , Xie Xingyi , Zhou Jiabin , He Sihua , Lv Yubing , He Mengling , Qu Hong , Liu Gexiu , Li Yuguang
Published: February 2021

To study the molecular mechanism by which miR-203a affects the development of CML, bioinformatics software was used to predict the upstream transcription factors and downstream target genes of miR-203a. A 5’-rapid amplification of cDNA ends assay was performed to detect gene transcription initiation sites. A chromatin immunoprecipitation assay was used to verify the binding of transcription factors and promoter regions. A double luciferase reporter gene vector was constructed to demonstrate the regulatory effect of miR-203a on target genes. Real-time PCR and western blotting were used to detect the relative expression levels of genes and proteins, respectively. The results showed that there was a binding site for the transcription factor EGR1 in the upstream promoter region of miR-203a. WT1, BMI1, and XIAP were identified as target genes regulated by miR-203a. EGR1 and miR-203a were downregulated in human peripheral blood mononuclear cells and the CML K562 cell line, while WT1, BMI1, and XIAP were upregulated. The transcription initiation site of miR-203a was identified in the upstream promoter region (G nucleotide at −339 bp), and the transcription factor EGR1 could bind to the promoter region (at −268 bp) of miR-203a and increase its expression. Over expression of miR-203a inhibited the proliferation of K562 cells. A rescue assay showed that overexpression of WT1, BMI1, and XIAP offset the antitumor effect of miR-203a. Conclusion, EGR1 positively regulated the expression of miR-203a, thus relieving the inhibition of miR-203a on the translation of its target genes (WT1, BMI1, and XIAP) and affecting the proliferation of K562 cells.
Primary Cilia in the Skin: Functions in Immunity and Therapeutic Potential
Authors: Toriyama Manami , Ishii Ken J.
Published: February 2021

The skin is the biggest organ and provides a physical and immunological barrier against pathogen infection. The distribution of primary cilia in the skin of mice has been reported, but which cells in human skin have them has not, and we still know very little about how they change in response to immune reactions or disease. This review introduces several studies that describe mechanisms of cilia regulation by immune reaction and the physiological relevance of cilia regulating proliferation and differentiation of stroma cells, including skin-resident Langerhans cells. We discuss the possibility of primary cilia pathology in allergic atopic dermatitis and the potential for therapies targeting primary cilia signaling.
Polarization of Macrophages in Insects: Opening Gates for Immuno-Metabolic Research
Authors: Bajgar Adam , Krejčová Gabriela , Doležal Tomáš
Published: February 2021

Insulin resistance and cachexia represent severe metabolic syndromes accompanying a variety of human pathological states, from life-threatening cancer and sepsis to chronic inflammatory states, such as obesity and autoimmune disorders. Although the origin of these metabolic syndromes has not been fully comprehended yet, a growing body of evidence indicates their possible interconnection with the acute and chronic activation of an innate immune response. Current progress in insect immuno-metabolic research reveals that the induction of insulin resistance might represent an adaptive mechanism during the acute phase of bacterial infection. In Drosophila, insulin resistance is induced by signaling factors released by bactericidal macrophages as a reflection of their metabolic polarization toward aerobic glycolysis. Such metabolic adaptation enables them to combat the invading pathogens efficiently but also makes them highly nutritionally demanding. Therefore, systemic metabolism has to be adjusted upon macrophage activation to provide them with nutrients and thus support the immune function. That anticipates the involvement of macrophage-derived systemic factors mediating the inter-organ signaling between macrophages and central energy-storing organs. Although it is crucial to coordinate the macrophage cellular metabolism with systemic metabolic changes during the acute phase of bacterial infection, the action of macrophage-derived factors may become maladaptive if chronic or in case of infection by an intracellular pathogen. We hypothesize that insulin resistance evoked by macrophage-derived signaling factors represents an adaptive mechanism for the mobilization of sources and their preferential delivery toward the activated immune system. We consider here the validity of the presented model for mammals and human medicine. The adoption of aerobic glycolysis by bactericidal macrophages as well as the induction of insulin resistance by macrophage-derived factors are conserved between insects and mammals. Chronic insulin resistance is at the base of many human metabolically conditioned diseases such as non-alcoholic steatohepatitis, atherosclerosis, diabetes, and cachexia. Therefore, revealing the original biological relevance of cytokine-induced insulin resistance may help to develop a suitable strategy for treating these frequent diseases.
Plasma Metabolic Profiling of Pediatric Sepsis in a Chinese Cohort
Authors: Li Guo-Bang , Hu Hong-Rong , Pan Wen-Feng , Li Bo , Ou Zhi-Ying , Liang Hui-Ying , Li Cong
Published: February 2021

Sepsis represents one of the most pressing problems in pediatrics, characterized by pathogenic bacteria invading the blood, growing and multiplying in the blood circulation, and ultimately causing severe infections. Most children with sepsis have a rapid disease onset and frequently exhibit sudden high fever or first chills. Here we performed comprehensive metabolomic profiling of plasma samples collected from pediatric sepsis patients to identify specific metabolic alterations associated with these patients (n = 84, designated as case subjects) as compared to healthy cohorts (n = 59, designated as control subjects). Diagnostic models were constructed using MetaboAnalyst, R packages, and multiple statistical methods, such as orthogonal partial least squares-discriminant analysis, principal component analysis, volcano plotting, and one-way ANOVA. Our study revealed a panel of metabolites responsible for the discrimination between case and control subjects with a high predictive value of prognosis. Moreover, significantly altered metabolites in sepsis survivors versus deceased patients (non-survivors) were identified as those involved in amino acids, fatty acids, and carbohydrates metabolism. Nine metabolites including organic acids and fatty acids were also identified with significantly higher abundance in sepsis patients with related microbes, implicating greater potentials to distinguish bacterial species using metabolomic analysis than blood culture. Pathway enrichment analysis further revealed that fatty acid metabolism might play an important role in the pathogenesis of sepsis.
Considering the Prospect of Utilizing Anaerobic Membrane Biofouling Layers Advantageously for the Removal of Emerging Contaminants
Authors: BouNehme Sawaya Christelle , Harb Moustapha
Published: February 2021

Membrane biofilm formation has traditionally been perceived as a wholly negative occurrence in membrane filtration-based wastewater treatment systems due to its resultant effect on transmembrane pressure and energy expenditure. This is the case for both membrane bioreactor (MBR) systems, generally, and anaerobic membrane bioreactors (AnMBRs), specifically. Insight gained through recent research, however, has revealed a potentially positive aspect to biofouling in AnMBR systems—namely, the improved removal of certain emerging contaminants (both microbial and chemical) from wastewater that would not otherwise be retained by the microfiltration/ultrafiltration membranes that are commonly used. Although the exact reasons behind this are not yet understood, the biofilm-specific anaerobic microbial communities that develop on membrane surfaces may play a key role in the phenomenon. Mechanisms of biofouling development in AnMBRs have recently been proven distinctly different from those that govern fouling in aerobic MBR systems. Based on these differences, it may be possible to devise operational strategies that promote the development of anaerobic biofilms on membranes while also minimizing transmembrane pressure increases. If achievable, this would serve as a sustainable basis for reducing the release of emerging contaminants such as organic micropollutants (OMPs) and antibiotic resistance genes (ARGs) with treated wastewater effluents.
Reading Fictional Narratives to Improve Social and Moral Cognition: The Influence of Narrative Perspective, Transportation, and Identification
Authors: Wimmer Lena , Friend Stacie , Currie Gregory , Ferguson Heather J.
Published: February 2021

There is a long tradition in philosophy and literary criticism of belief in the social and moral benefits of exposure to fiction, and recent empirical work has examined some of these claims. However, little of this research has addressed the textual features responsible for the hypothesized cognitive effects. We present two experiments examining whether readers’ social and moral cognition are influenced by theperspectivefrom which a narrative is told (voice and focalization), and whether potential effects of perspective are mediated by transportation into the story or by identification with the protagonist. Both experiments employed a between-subjects design in which participants read a short story, either in the first-person voice using internal focalization, third-person voice using internal focalization, or third-person voice using external focalization. Social and moral cognition was assessed using a battery of tasks. Experiment 1 (N= 258) failed to detect any effects of perspective or any mediating roles of transportation or identification. Implementing a more rigorous adaptation of the third-person story using external focalization, Experiment 2 (N= 262) largely replicated this pattern. Taken together, the evidence reported here suggests that perspective does not have a significant impact on the extent to which narratives modulate social and moral cognition, either directly or indirectly via transportation and identification.
Update on Transcatheter Tricuspid Valve Replacement Therapies
Authors: Goldberg Ythan H. , Ho Edwin , Chau Mei , Latib Azeem
Published: February 2021

Severe tricuspid regurgitation is relatively common, especially in the elderly, and portends poor survival. Neither medical therapy nor conventional surgery is efficacious for most patients. In contrast, transcatheter tricuspid valve interventions are showing promise to improve quality of life and mortality. Although there is more clinical experience with transcatheter tricuspid valve repair, there are many patients for which repair is either not possible or cannot optimally reduce the severity of tricuspid regurgitation. Transcatheter tricuspid valve replacement is rapidly emerging and may ultimately become the preferred treatment option. In this review, we discuss transcatheter tricuspid valve replacement, analyze the devices in development and in clinical trials, and highlight the advantages and drawbacks of transcatheter tricuspid valve replacement vs. repair.
Development and Application of Endothelial Cells Derived From Pluripotent Stem Cells in Microphysiological Systems Models
Authors: Kennedy Crystal C. , Brown Erin E. , Abutaleb Nadia O. , Truskey George A.
Published: February 2021

The vascular endothelium is present in all organs and blood vessels, facilitates the exchange of nutrients and waste throughout different organ systems in the body, and sets the tone for healthy vessel function. Mechanosensitive in nature, the endothelium responds to the magnitude and temporal waveform of shear stress in the vessels. Endothelial dysfunction can lead to atherosclerosis and other diseases. Modeling endothelial function and dysfunction in organ systemsin vitro, such as the blood–brain barrier and tissue-engineered blood vessels, requires sourcing endothelial cells (ECs) for these biomedical engineering applications. It can be difficult to source primary, easily renewable ECs that possess the function or dysfunction in question. In contrast, human pluripotent stem cells (hPSCs) can be sourced from donors of interest and renewed almost indefinitely. In this review, we highlight how knowledge of vascular EC developmentin vivois used to differentiate induced pluripotent stem cells (iPSC) into ECs. We then describe how iPSC-derived ECs are being used currently inin vitromodels of organ function and disease andin vivoapplications.
Embracing the Allelopathic Potential of Invasive Aquatic Plants to Manipulate Freshwater Ecosystems
Authors: Reynolds Sam A. , Aldridge David C.
Published: February 2021

Freshwater ecosystems provide essential resources and vital ecosystem services. These ecosystems exist in a delicate state of balance and are under increasing anthropogenic and climatic pressures. One of the major anthropogenic threats to freshwater ecosystems is eutrophication that often leads to algal blooms, some of which may be extremely harmful. Current chemical and physical interventions to prevent algal blooms can be expensive, ephemeral and disruptive to other aspects of the ecosystem. Therefore, there is interest in utilising biological methods of control. This study aimed to assess the viability of allelopathic repression of nuisance algae species by invasive aquatic plants. The allelopathic effect of Hydrocotyle ranunculoides (Floating Pennywort) and Crassula helmsii (Swamp Stonecrop) were tested in both whole plant and crushed plant states for their ability to affect the average population growth of monocultures and co-cultures of the green algae Chlorella vulgaris and the cyanobacterium Synechocystis sp. PCC6803. Methanol extracts from these species have been identified in the literature to have high allelopathic potential. The key findings of this study are that, for Chlorella: whole H. ranunculoides and crushed C. helmsii had a negative effect on the average population growth; whole H. ranunculoides had a greater negative effect than crushed H. ranunculoides; and crushed C. helmsii had a more negative effect than crushed H. ranunculoides. For Synechocystis: crushed C. helmsii had a greater negative effect on the average population growth than crushed H. ranunculoides; and the presence of Chlorella in co-culture experiments had a universally positive effect on its average population growth. The species-specific nature of these allelopathic interactions suggests that the use of allelopathy for algal bloom control may have to be assessed on a case-by-case basis and the use of combination treatments should be assessed. Moreover, the effects exerted by allelochemicals in open water systems is likely to be direct, indirect and context specific. Although this study explores the possibility of embracing the allelopathic potential of invasive aquatic plants, we do not encourage novel introductions of invasive species into open freshwater systems. However, potential allelopathic effects could be leveraged in already invaded systems, or in closed systems within an invaded range.
Comprehensive Analysis of Evolutionary Characterization and Expression for Monosaccharide Transporter Family Genes in Nelumbo nucifera
Authors: Wu Peng , Zhang Yongyan , Zhao Shuping , Li Liangjun
Published: February 2021

Sugar transporters, an important class of transporters for sugar function, regulate many processes associated with growth, maturation, and senescence processes in plants. In this study, a total of 35 NuMSTs were identified in the Nelumbo nucifera genome and grouped by conserved domains and phylogenetic analysis. Additionally, we identified 316 MST genes in 10 other representative plants and performed a comparative analysis with Nelumbo nucifera genes, including evolutionary trajectory, gene duplication, and expression pattern. A large number of analyses across plants and algae indicated that the MST family could have originated from STP and Glct, expanding to form STP and SFP by dispersed duplication. Finally, a quantitative real-time polymerase chain reaction and cis-element analysis showed that some of them may be regulated by plant hormones (e.g., abscisic acid), biotic stress factors, and abiotic factors (e.g., drought, excessive cold, and light). We found that under the four abiotic stress conditions, only NuSTP5 expression was upregulated, generating a stress response, and ARBE and LTR were present in NuSTP5. In summary, our findings are significant for understanding and exploring the molecular evolution and mechanisms of NuMSTs in plants.
Using eDNA Metabarcoding to Monitor Changes in Fish Community Composition After Barrier Removal
Authors: Muha Teja P. , Rodriguez-Barreto Deiene , O'Rorke Richard , Garcia de Leaniz Carlos , Consuegra Sofia
Published: February 2021

Artificial instream barriers are a major cause of habitat fragmentation that reduce population connectivity and gene flow by limiting fish movements. To mitigate their impacts, obsolete barriers are increasingly been removed worldwide, but few barrier removal projects are monitored. We employed a powerful Before-After-Downstream-Upstream (BADU) approach using environmental DNA (eDNA) metabarcoding to examine the effects on fish community composition of removing a weir in the river Lugg (England) that had been suggested to have a detrimental effect on salmonid migration. We found no change in fish community diversity or relative abundance after the removal above or below the weir, but detected an important effect of sampling season, likely related to the species' life cycles. eDNA detected nine fish species that were also identified by electrofishing sampling and one additional species (Anguilla anguilla) that was missed by traditional surveys. Our results suggest that monitoring of barrier removal projects should be carried out to ensure that any ecological benefits are properly documented and that eDNA metabarcoding is a sensitive technique to monitor the effects of barrier removal.
Epigenetics in Prader-Willi Syndrome
Authors: Mendiola Aron Judd P. , LaSalle Janine M.
Published: February 2021

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically characterized by two nutritional stages. Stage 1 is hypotonia characterized by poor muscle tone that leads to poor feeding behavior causing failure to thrive in early neonatal life. Stage 2 is followed by the development of extreme hyperphagia, also known as insatiable eating and fixation on food that often leads to obesity in early childhood. Other major features of PWS include obsessive-compulsive and hoarding behaviors, intellectual disability, and sleep abnormalities. PWS is genetic disorder mapping to imprinted 15q11.2-q13.3 locus, specifically at the paternally expressedSNORD116locus of small nucleolar RNAs and noncoding host gene transcripts.SNORD116is processed into several noncoding components and is hypothesized to orchestrate diurnal changes in metabolism through epigenetics, according to functional studies. Here, we review the current status of epigenetic mechanisms in PWS, with an emphasis on an emerging role forSNORD116in circadian and sleep phenotypes. We also summarize current ongoing therapeutic strategies, as well as potential implications for more common human metabolic and psychiatric disorders.
TRPM7 Kinase Is Essential for Neutrophil Recruitment and Function via Regulation of Akt/mTOR Signaling
Authors: Nadolni Wiebke , Immler Roland , Hoelting Kilian , Fraticelli Marco , Ripphahn Myriam , Rothmiller Simone , Matsushita Masayuki , Boekhoff Ingrid , Gudermann Thomas , Sperandio Markus , Zierler Susanna
Published: February 2021

During inflammation, neutrophils are one of the first responding cells of innate immunity, contributing to a fast clearance of infection and return to homeostasis. However, excessive neutrophil infiltration accelerates unsolicited disproportionate inflammation for instance in autoimmune diseases such as rheumatoid arthritis. Thetransient-receptor-potentialchannel-kinase TRPM7 is an essential regulator of immune system homeostasis. Naïve murine T cells with genetic inactivation of the TRPM7 enzyme, due to a point mutation at the active site, are unable to differentiate into pro-inflammatory T cells, whereas regulatory T cells develop normally. Moreover, TRPM7 is vital for lipopolysaccharides (LPS)-induced activation of murine macrophages. Within this study, we show that the channel-kinase TRPM7 is functionally expressed in neutrophils and has an important impact on neutrophil recruitment during inflammation. We find that human neutrophils cannot transmigrate along a CXCL8 chemokine gradient or produce reactive oxygen species in response to gram-negative bacterial lipopolysaccharide LPS, if TRPM7 channel or kinase activity are blocked. Using a recently identified TRPM7 kinase inhibitor, TG100-115, as well as murine neutrophils with genetic ablation of the kinase activity, we confirm the importance of both TRPM7 channel and kinase function in murine neutrophil transmigration and unravel that TRPM7 kinase affects Akt1/mTOR signaling thereby regulating neutrophil transmigration and effector function. Hence, TRPM7 represents an interesting potential target to treat unwanted excessive neutrophil invasion.
Vaccines in Congenital Toxoplasmosis: Advances and Perspectives
Authors: Barros Mariana , Teixeira Daniela , Vilanova Manuel , Correia Alexandra , Teixeira Natercia , Borges Margarida
Published: February 2021

Congenital toxoplasmosis has a high impact on human disease worldwide, inducing serious consequences from fetus to adulthood. Despite this, there are currently no human vaccines available to prevent this infection. Most vaccination studies against Toxoplasma gondii infection used animal models in which the infection was established by exogenous inoculation. Here, we review recent research on potential T. gondii vaccines using animal models in which infection was congenitally established. Endeavors in this field have so far revealed that live or subunit vaccines previously found to confer protection against extrinsically established infections can also protect, at least partially, from vertically transmitted infection. Nevertheless, there is no consensus on the more adequate immune response to protect the host and the fetus in congenital infection. Most of the vaccination studies rely on the assessment of maternal systemic immune responses, quantification of parasitic loads in the fetuses, and survival indexes and/or brain parasitic burden in the neonates. More research must be carried out not only to explore new vaccines but also to further study the nature of the elicited immune protection at the maternal-fetal interface. Particularly, the cellular and molecular effector mechanisms at the maternal-fetal interface induced by immunization remain poorly characterized. Deeper knowledge on the immune response at this specific location will certainly help to refine the vaccine-induced immunity and, consequently, to provide the most effective and safest protection against T. gondii vertical infection.
Arthropods Under Pressure: Stress Responses and Immunity at the Pathogen-Vector Interface
Authors: Rosche Kristin L. , Sidak-Loftis Lindsay C. , Hurtado Joanna , Fisk Elizabeth A. , Shaw Dana K.
Published: February 2021

Understanding what influences the ability of some arthropods to harbor and transmit pathogens may be key for controlling the spread of vector-borne diseases. Arthropod immunity has a central role in dictating vector competence for pathogen acquisition and transmission. Microbial infection elicits immune responses and imparts stress on the host by causing physical damage and nutrient deprivation, which triggers evolutionarily conserved stress response pathways aimed at restoring cellular homeostasis. Recent studies increasingly recognize that eukaryotic stress responses and innate immunity are closely intertwined. Herein, we describe two well-characterized and evolutionarily conserved mechanisms, the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR), and examine evidence that these stress responses impact immune signaling. We then describe how multiple pathogens, including vector-borne microbes, interface with stress responses in mammals. Owing to the well-conserved nature of the UPR and ISR, we speculate that similar mechanisms may be occurring in arthropod vectors and ultimately impacting vector competence. We conclude this Perspective by positing that novel insights into vector competence will emerge when considering that stress-signaling pathways may be influencing the arthropod immune network.
The Immune System's Role in the Consequences of Mild Traumatic Brain Injury (Concussion)
Authors: Verboon Laura N. , Patel Hiren C. , Greenhalgh Andrew D.
Published: February 2021

Mild traumatic brain injury (mild TBI), often referred to as concussion, is the most common form of TBI and affects millions of people each year. A history of mild TBI increases the risk of developing emotional and neurocognitive disorders later in life that can impact on day to day living. These include anxiety and depression, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Actions of brain resident or peripherally recruited immune cells are proposed to be key regulators across these diseases and mood disorders. Here, we will assess the impact of mild TBI on brain and patient health, and evaluate the recent evidence for immune cell involvement in its pathogenesis.
Organ-Specific Surveillance and Long-Term Residency Strategies Adapted by Tissue-Resident Memory CD8+ T Cells
Authors: Stein Jens V. , Ruef Nora , Wissmann Stefanie
Published: February 2021

Tissue-resident CD8+ T cells (CD8+ TRM) populate lymphoid and non-lymphoid tissues after infections as first line of defense against re-emerging pathogens. To achieve host protection, CD8+ TRM have developed surveillance strategies that combine dynamic interrogation of pMHC complexes on local stromal and hematopoietic cells with long-term residency. Factors mediating CD8+ TRM residency include CD69, a surface receptor opposing the egress-promoting S1P1, CD49a, a collagen-binding integrin, and CD103, which binds E-cadherin on epithelial cells. Moreover, the topography of the tissues of residency may influence TRM retention and surveillance strategies. Here, we provide a brief summary of these factors to examine how CD8+ TRM reconcile constant migratory behavior with their long-term commitment to local microenvironments, with a focus on epithelial barrier organs and exocrine glands with mixed connective—epithelial tissue composition.
Butyrate Shapes Immune Cell Fate and Function in Allergic Asthma
Authors: Yip William , Hughes Michael R. , Li Yicong , Cait Alissa , Hirst Martin , Mohn William W. , McNagny Kelly M.
Published: February 2021

The microbiome plays a fundamental role in how the immune system develops and how inflammatory responses are shaped and regulated. The “gut-lung axis” is a relatively new term that highlights a crucial biological crosstalk between the intestinal microbiome and lung. A growing body of literature suggests that dysbiosis, perturbation of the gut microbiome, is a driving force behind the development, and severity of allergic asthma. Animal models have given researchers new insights into how gut microbe-derived components and metabolites, such as short-chain fatty acids (SCFAs), influence the development of asthma. While the full understanding of how SCFAs influence allergic airway disease remains obscure, a recurring theme of epigenetic regulation of gene expression in several immune cell compartments is emerging. This review will address our current understanding of how SCFAs, and specifically butyrate, orchestrates cell behavior, and epigenetic changes and will provide a detailed overview of the effects of these modifications on immune cells in the context of allergic airway disease.
MicroRNA-2187 Modulates the NF-κB and IRF3 Pathway in Teleost Fish by Targeting TRAF6
Authors: Gao Wenya , Chang Renjie , Sun Yuena , Xu Tianjun
Published: February 2021

The innate immune organs and cells detect the invasion of pathogenic microorganisms, which trigger the innate immune response. A proper immune response can protect the organisms from pathogen invasion. However, excessive immunity can destroy immune homeostasis, leading to uncontrolled inflammation or pathogen transmission. Evidence shows that the miRNA-mediated immune regulatory network in mammals has had a significant impact, but the antibacterial and antiviral responses involved in miRNAs need to be further studied in lower vertebrates. Here, we report that miR-2187 as a negative regulator playing a critical role in the antiviral and antibacterial response of miiuy croaker. We find that pathogens such asVibrio anguillarumandSiniperca chuatsirhabdovirus(SCRV) can up-regulate the expression of miR-2187. Elevated miR-2187 is capable of reducing the production of inflammatory factors and antiviral genes by targeting TRAF6, thereby avoiding excessive inflammatory response. Furthermore, we proved that miR-2187 modulates innate immunity through TRAF6-mediated NF-κB and IRF3 signaling pathways. The above results indicate that miR-2187 acts as an immune inhibitor involved in host antibacterial and antiviral responses, thus enriching the immune regulatory network of the interaction between host and pathogen in lower vertebrates.
Immunological Endotyping of Chronic Critical Illness After Severe Sepsis
Authors: Fenner Brittany P. , Darden D. B. , Kelly Lauren S. , Rincon Jaimar , Brakenridge Scott C. , Larson Shawn D. , Moore Frederick A. , Efron Philip A. , Moldawer Lyle L.
Published: February 2021

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early “cytokine or genomic storm,” but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed.
Effectiveness of Improved Use of Chewing Gum During Capsule Endoscopy in Decreasing Gastric Transit Time: A Prospective Randomized Controlled Study
Authors: Huang Liang , Hu Yue , Chen Fang , Liu Shan , Lu Bin
Published: February 2021

Background/Aim: Chewing gum throughout small bowel capsule endoscopy (SBCE) increases completion rates (CRs) but decreases small bowel transit time (SBTT) and diagnostic yield (DY). We determined the effects of chewing gum early during SBCE on gastric transit time (GTT), SBTT, CR, DY, and gastroscopy intervention.

Methods: We prospectively enrolled patients (ages 16–80 years) undergoing SBCE between January and June 2019. Patients were randomized to a chewing gum group (103 patients) and a control group (102 patients). Patients in the former group chewed one piece of gum for ~15 min every 30 min during the first hour of SBCE. Two gastroenterologists blinded to the study group examined the data.

Results: GTT was shorter in the chewing gum group (29.0 min, interquartile range: 17.0–52.0 min) than in the control group [42.5 min (23.25–60 min); P = 0.01]. SBTT was similar in the two groups [318.5 min (239.5–421.3 min) vs. 287.0 min (216.0–386.0 min); P = 0.08]. Gastroscopy rate was lower in the chewing gum group (15.53 vs. 32.35%, P = 0.005). CR (95.15 vs. 89.22%, P = 0.114) and DY (67.96 vs. 59.80%, P = 0.224) did not differ between the groups. The number of abnormal-lesion types detected per patient was higher in the chewing gum group [1.0 (0.0–2.0) vs. 2.0 (0.0–2.0); P = 0.049].

Conclusions: Chewing gum early during SBCE significantly reduced GTT and gastroscopy intervention, with no influence on SBTT (Trial number: NCT03815136).
Comparing Efficacy and Safety of Empirical vs. Guided Therapy for Non-cardiac Chest Pain: A Pragmatic Randomized Trial
Authors: Abdul Kadir Noor Purdah , Ma Zheng Feei , Abdul Hafidz Muhammad Ilham , Annamalai Chandramouli , Jayaraman Thevaraajan , Hamid Nurhazwani , Norhasliza Siti , Abd Aziz Azliani , Yusof Zurkurnai , Lee Hady , Lee Yeong Yeh
Published: February 2021

Background: Non-cardiac chest pain is common with two-thirds due to gastroesophageal reflux disease (GERD).

Objective: To evaluate the effectiveness and safety of guided vs. empirical therapy in non-cardiac chest pain.

Methods: Adults with normal angiogram or stress test were randomized into either a guided or empirical group. In the guided group, after the ambulatory pH-impedance test, if GERD then dexlansoprazole 30 mg/day for 8 weeks, but if functional or hypersensitive chest pain, then theophylline SR 250 mg/day for 4 weeks. In the empirical group, dexlansoprazole 60 mg/day was given for 2 weeks. The primary outcome was global chest pain visual analog score (VAS) and secondary outcomes were Quality of Life in Reflux and Dyspepsia (QOLRAD), GERD questionnaire (GERDQ), and pH parameters, all determined at baseline, 2nd and 8th weeks.

Results: Of 200 screened patients, 132 were excluded, and of 68 randomized per-protocol, 33 were in the guided group and 35 in the empirical group. For between-group analysis, mean global pain scores were better with guided vs. empirical group at 8th week (P = 0.005) but not GERDQ or QOLRAD or any of pH measures (all P > 0.05). For within-group analysis, mean QOLRAD improved earliest at 8th week vs. baseline (P = 0.006) in the guided group and 2nd week vs. baseline (P = 0.011) in the empirical group but no differences were seen in other secondary outcomes (P > 0.05). No serious adverse events were reported.

Conclusions: Guided approach may be preferred over short-term empirical therapy in symptom response, however QOLRAD, acid-related symptoms, or pH measures are not significantly different (trial registration ID no. NCT03319121).
CYP11A1 Upregulation Leads to Trophoblast Oxidative Stress and Fetal Neurodevelopmental Toxicity That can be Rescued by Vitamin D
Authors: Wang Xiang , Li Mengxue , Zhang Xueguang , Li Yaqian , He Guolin , Dinnyés Andras , Sun Qun , Xu Wenming
Published: February 2021

During normal pregnancy, the placental trophoblast secretes a variety of steroid hormones and participates in the regulation of maternal physiological functions and fetal development. The CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme P450scc, which catalyzes the production of pregnenolone from cholesterol, which is the first step in the synthesis of all steroid hormones. Under the influence of genetic susceptibility and certain environmental factors, such as drugs and toxins, the expression of CYP11A1 can be upregulated, thereby affecting steroid metabolism and physiological functions in trophoblast cells, as well as fetal development. Here, we demonstrate that upregulation of CYP11A1 in the BeWo cell line triggers excessive mitochondrial oxidative stress, leads to mitochondrial damage and interleukin-6 release, and contributes to the inhibition of proliferation and DNA damage in neuronal stem cells (NSCs). Furthermore, oxidative stress and inflammation can be ameliorated by vitamin D3 in a dose-dependent manner, thereby facilitating the rescue of NSC impairment. Our findings reveal the underlying mechanism in which upregulation of CYP11A1 is detrimental to the physiological function of trophoblasts and demonstrate the beneficial effects of vitamin D supplementation in preventing placental and neurodevelopmental damage associated with CYP11A1 upregulation during pregnancy.
Neurobiological After-Effects of Low Intensity Transcranial Electric Stimulation of the Human Nervous System: From Basic Mechanisms to Metaplasticity
Authors: Korai Sohaib Ali , Ranieri Federico , Di Lazzaro Vincenzo , Papa Michele , Cirillo Giovanni
Published: February 2021

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.
Diffusion Tensor Imaging of Skeletal Muscle Contraction Using Oscillating Gradient Spin Echo
Authors: Mazzoli Valentina , Moulin Kevin , Kogan Feliks , Hargreaves Brian A. , Gold Garry E.
Published: February 2021

Diffusion tensor imaging (DTI) measures water diffusion in skeletal muscle tissue and allows for muscle assessment in a broad range of neuromuscular diseases. However, current DTI measurements, typically performed using pulsed gradient spin echo (PGSE) diffusion encoding, are limited to the assessment of non-contracted musculature, therefore providing limited insight into muscle contraction mechanisms and contraction abnormalities. In this study, we propose the use of an oscillating gradient spin echo (OGSE) diffusion encoding strategy for DTI measurements to mitigate the effect of signal voids in contracted muscle and to obtain reliable diffusivity values. Two OGSE sequences with encoding frequencies of 25 and 50 Hz were tested in the lower leg of five healthy volunteers with relaxed musculature and during active dorsiflexion and plantarflexion, and compared with a conventional PGSE approach. A significant reduction of areas of signal voids using OGSE compared with PGSE was observed in the tibialis anterior for the scans obtained in active dorsiflexion and in the soleus during active plantarflexion. The use of PGSE sequences led to unrealistically elevated axial diffusivity values in the tibialis anterior during dorsiflexion and in the soleus during plantarflexion, while the corresponding values obtained using the OGSE sequences were significantly reduced. Similar findings were seen for radial diffusivity, with significantly higher diffusivity measured in plantarflexion in the soleus muscle using the PGSE sequence. Our preliminary results indicate that DTI with OGSE diffusion encoding is feasible in human musculature and allows to quantitatively assess diffusion properties in actively contracting skeletal muscle. OGSE holds great potential to assess microstructural changes occurring in the skeletal muscle during contraction, and for non-invasive assessment of contraction abnormalities in patients with muscle diseases.