bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the Urotensin II/UT G Protein-Coupled Receptor to Counteract Angiogenesis and Mesenchymal Hypoxia/Necrosis in Glioblastoma
Authors: Le Joncour Vadim , Guichet Pierre-Olivier , Dembélé Kleouforo-Paul , Mutel Alexandre , Campisi Daniele , Perzo Nicolas , Desrues Laurence , Modzelewski Romain , Couraud Pierre-Olivier , Honnorat Jérôme , Ferracci François-Xavier , Marguet Florent , Laquerrière Annie , Vera Pierre , Bohn Pierre , Langlois Olivier , Morin Fabrice , Gandolfo Pierrick , Castel Hélène
Published: April 2021

Glioblastomas (GBMs) are the most common primary brain tumors characterized by strong invasiveness and angiogenesis. GBM cells and microenvironment secrete angiogenic factors and also express chemoattractant G protein-coupled receptors (GPCRs) to their advantage. We investigated the role of the vasoactive peptide urotensin II (UII) and its receptor UT on GBM angiogenesis and tested potential ligand/therapeutic options based on this system. On glioma patient samples, the expression of UII and UT increased with the grade with marked expression in the vascular and peri-necrotic mesenchymal hypoxic areas being correlated with vascular density. In vitro human UII stimulated human endothelial HUV-EC-C and hCMEC/D3 cell motility and tubulogenesis. In mouse-transplanted Matrigel sponges, mouse (mUII) and human UII markedly stimulated invasion by macrophages, endothelial, and smooth muscle cells. In U87 GBM xenografts expressing UII and UT in the glial and vascular compartments, UII accelerated tumor development, favored hypoxia and necrosis associated with increased proliferation (Ki67), and induced metalloproteinase (MMP)-2 and -9 expression in Nude mice. UII also promoted a “tortuous” vascular collagen-IV expressing network and integrin expression mainly in the vascular compartment. GBM angiogenesis and integrin αvβ3 were confirmed by in vivo99mTc-RGD tracer imaging and tumoral capture in the non-necrotic area of U87 xenografts in Nude mice. Peptide analogs of UII and UT antagonist were also tested as potential tumor repressor. Urotensin II-related peptide URP inhibited angiogenesis in vitro and failed to attract vascular and inflammatory components in Matrigel in vivo. Interestingly, the UT antagonist/biased ligand urantide and the non-peptide UT antagonist palosuran prevented UII-induced tubulogenesis in vitro and significantly delayed tumor growth in vivo. Urantide drastically prevented endogenous and UII-induced GBM angiogenesis, MMP, and integrin activations, associated with GBM tumoral growth. These findings show that UII induces GBM aggressiveness with necrosis and angiogenesis through integrin activation, a mesenchymal behavior that can be targeted by UT biased ligands/antagonists.
High-Yield Human Induced Pluripotent Stem Cell-Derived Monocytes and Macrophages Are Functionally Comparable With Primary Cells
Authors: Cui Di , Franz Alexandra , Fillon Sophie A. , Jannetti Linda , Isambert Timo , Fundel-Clemens Katrin , Huber Heinrich J. , Viollet Coralie , Ghanem Alexander , Niwa Akira , Weigle Bernd , Pflanz Stefan
Published: April 2021

Macrophages are pivotal effectors of host immunity and regulators of tissue homeostasis. Understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (hiPSC)-derived monocytes and macrophages, as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of macrophage biology and implication in human diseases. In this study, we present a fully optimized differentiation protocol of hiPSC-derived monocytes and granulocyte-macrophage colony-stimulating factor (GM-CSF) or macrophage colony-stimulating factor (M-CSF). We present characterization of iPSC-derived myeloid lineage cells at phenotypic, functional, and transcriptomic levels, in comparison with corresponding subsets of peripheral blood-derived cells. We also highlight the application of hiPSC-derived monocytes and macrophages as a gene-editing platform for functional validation in research and drug screening, and the study also provides a reference for cell therapies.
Electrochemical Formation Mechanism of Microdroplets on Pure Iron
Authors: Tang Xiao , Li Juanjuan , Wu Yuan , Hu Hao , Ma Chao Ran , Li Yan , Fan Haiming
Published: April 2021

The electrochemical formation mechanism of microdroplets formed around a primary droplet of 3.5% NaCl solution on an iron-plated film was investigated by quartz crystal microbalance (QCM) and concentric three-electrode array (CTEA) measurements. During the initial stage, the microdroplets mainly originate from evaporation owing to cathodic polarization and electric current of the localized corrosion cell under the primary droplet. The maximal electrochemical potential difference between the anode and cathode was measured to be 0.36 V and acted as the driving force for the formation of microdroplets. The maximums of anodic and cathodic electric current density of pure iron under the NaCl droplet are 764 and −152 μA/cm2, respectively. Propagation of microdroplets in the developing stage attributes to horizontal movement of the electrolyte, water evaporation, and recondensation from primary and capillary condensation from moist air. The results of the study suggest that the initiation and propagation of microdroplets could promote and accelerate marine atmospheric corrosion.
Green Synthesis of Luminescent Gold-Zinc Oxide Nanocomposites: Cell Imaging and Visible Light–Induced Dye Degradation
Authors: Bharti Kanika , Lone Shahbaz Ahmad , Singh Ankita , Nathani Sandip , Roy Partha , Sadhu Kalyan K.
Published: April 2021

Green synthesis of gold-zinc oxide (Au-ZnO) nanocomposite was successfully attempted under organic solvent–free conditions at room temperature. Prolonged stirring of the reaction mixture introduced crystallinity in the ZnO phase of Au-ZnO nanocomposites. Luminescence properties were observed in these crystalline Au-ZnO nanocomposites due to in situ embedding of gold nanoparticles (AuNP) of 5–6 nm diameter on the surface. This efficient strategy involved the reduction of Au(III) by Zn(0) powder in aqueous medium, where sodium citrate (NaCt) was the stabilizing agent. Reaction time and variation of reagent concentrations were investigated to control the Au:Zn ratio within the nanocomposites. The reaction with the least amount of NaCt for a long duration resulted in Au-ZnO/Zn(OH)2 nanocomposite. X-ray photoelectron spectroscopy (XPS) confirmed the formation of Zn(OH)2 and ZnO in the same nanocomposite. These nanocomposites were reconnoitered as bioimaging materials in human cells and applied for visible light–induced photodegradation of rhodamine-B dye.
In Vitro and In Situ Activity-Based Labeling of Fibroblast Activation Protein with UAMC1110-Derived Probes
Authors: Van Rymenant Yentl , Tanc Muhammet , Van Elzen Roos , Bracke An , De Wever Olivier , Augustyns Koen , Lambeir Anne-Marie , Kockx Mark , De Meester Ingrid , Van Der Veken Pieter
Published: April 2021

Fibroblast activation protein (FAP) is a proline-selective protease that belongs to the S9 family of serine proteases. It is typically highly expressed in the tumor microenvironment (TME) and especially in cancer-associated fibroblasts, the main cell components of the tumor stroma. The exact role of its enzymatic activity in the TME remains largely unknown. Hence, tools that enable selective, activity-based visualization of FAP within the TME can help to unravel FAP’s function. We describe the synthesis, biochemical characterization, and application of three different activity-based probes (biotin-, Cy3-, and Cy5-labeled) based on the FAP-inhibitor UAMC1110, an in-house developed molecule considered to be the most potent and selective FAP inhibitor available. We demonstrate that the three probes have subnanomolar FAP affinity and pronounced selectivity with respect to the related S9 family members. Furthermore, we report that the fluorescent Cy3- and Cy5-labeled probes are capable of selectively detecting FAP in a cellular context, making these chemical probes highly suitable for further biological studies. Moreover, proof of concept is provided for in situ FAP activity staining in patient-derived cryosections of urothelial tumors.
Improving the Thermostability and Activity of Transaminase From Aspergillus terreus by Charge-Charge Interaction
Authors: Cao Jia-Ren , Fan Fang-Fang , Lv Chang-Jiang , Wang Hong-Peng , Li Ye , Hu Sheng , Zhao Wei-Rui , Chen Hai-Bin , Huang Jun , Mei Le-He
Published: April 2021

Transaminases that promote the amination of ketones into amines are an emerging class of biocatalysts for preparing a series of drugs and their intermediates. One of the main limitations of (R)-selective amine transaminase from Aspergillus terreus (At-ATA) is its weak thermostability, with a half-life (t1/2) of only 6.9 min at 40°C. To improve its thermostability, four important residue sites (E133, D224, E253, and E262) located on the surface of At-ATA were identified using the enzyme thermal stability system (ETSS). Subsequently, 13 mutants (E133A, E133H, E133K, E133R, E133Q, D224A, D224H, D224K, D224R, E253A, E253H, E253K, and E262A) were constructed by site-directed mutagenesis according to the principle of turning the residues into opposite charged ones. Among them, three substitutions, E133Q, D224K, and E253A, displayed higher thermal stability than the wild-type enzyme. Molecular dynamics simulations indicated that these three mutations limited the random vibration amplitude in the two α-helix regions of 130–135 and 148–158, thereby increasing the rigidity of the protein. Compared to the wild-type, the best mutant, D224K, showed improved thermostability with a 4.23-fold increase in t1/2 at 40°C, and 6.08°C increase in T5010. Exploring the three-dimensional structure of D224K at the atomic level, three strong hydrogen bonds were added to form a special “claw structure” of the α-helix 8, and the residues located at 151–156 also stabilized the α-helix 9 by interacting with each other alternately.
Biogas Conversion to Syngas Using Advanced Ni-Promoted Pyrochlore Catalysts: Effect of the CH4/CO2 Ratio
Authors: le Saché Estelle , Alvarez Moreno Andrea , Reina Tomas Ramirez
Published: April 2021

Biogas is defined as the mixture of CH4 and CO2 produced by the anaerobic digestion of biomass. This particular mixture can be transformed in high valuable intermediates such as syngas through a process known as dry reforming (DRM). The reaction involved is highly endothermic, and catalysts capable to endure carbon deposition and metal particle sintering are required. Ni-pyrochlore catalysts have shown outstanding results in the DRM. However, most reported data deals with CH4/CO2 stoichiometric ratios resulting is a very narrow picture of the overall biogas upgrading via DRM. Therefore, this study explores the performance of an optimized Ni-doped pyrochlore, and Ni-impregnated pyrochlore catalysts in the dry reforming of methane, under different CH4/CO2 ratios, in order to simulate various representatives waste biomass feedstocks. Long-term stability tests showed that the ratio CH4/CO2 in the feed gas stream has an important influence in the catalysts' deactivation. Ni doped pyrochlore catalyst, presents less deactivation than the Ni-impregnated pyrochlore. However, biogas mixtures with a CH4 content higher than 60%, lead to a stronger deactivation in both Ni-catalysts. These results were in agreement with the thermogravimetric analysis (TGA) of the post reacted samples that showed a very limited carbon formation when using biogas mixtures with CH4 content <60%, but CH4/CO2 ratios higher than 1.25 lead to an evident carbon deposition. TGA analysis of the post reacted Ni impregnated pyrochlore, showed the highest amount of carbon deposited, even with lower stoichiometric CH4/CO2 ratios. The later result indicates that stabilization of Ni in the pyrochlore structure is vital, in order to enhance the coke resistance of this type of catalysts.
Truthfully Misleading: Truth, Informativity, and Manipulation in Linguistic Communication
Authors: Reboul Anne
Published: April 2021

Linguistic communication is geared toward the exchange of information, i.e., changing the addressee's world views. In other words, persuasion is the goal of speakers and the force of the speaker's commitment as indicated in the utterance is an important factor in persuasion. Other things being equal, the stronger the speaker's commitment, the easier the persuasion. However, if deception is detected, the stronger the speaker's commitment, the harsher the punishment, i.e., the damage to his or her reputation. One way for cheaters to avoid detection and/or to mitigate punishment is to downplay their commitment to what they mean through the utterance by making its content less informative, i.e., by producing underinformative utterances. Underinformativity is also a powerful way of triggering context-dependent and inference-based interpretation that goes beyond what is said. This allows speakers to indirectly communicate false content while producing an utterance that is literally true. This phenomenon oftruthfully misleadingis the topic of the present paper. As will be seen, it allows speakers to leave part of the responsibility for the false content to their hearers, with the triple effect that they can claim to have been misunderstood (plausible denial), claim that what they said was literally true, and explain the underinformativity of the utterance through ignorance.
Operationalizing Behavior Change Theory as Part of Persuasive Technology: A Scoping Review on Social Comparison
Authors: Lemke Mailin , de Vries Roelof A. J.
Published: April 2021

Theories from psychology or the social sciences are commonly used as a starting point when designing persuasive technologies that aim to evoke a specific behavior change. Ideally, using these theories would (1) help guide the design of the persuasive technology and (2) help evaluate and inform the theory. In this paper, we focused on the first aspect and looked at how papers report on how a theory guided the design of persuasive technology. We performed a scoping review focused on the operationalization of social comparison theory as part of persuasive design. We chose social comparison due to its ubiquitous use in persuasive design as well as its potential positive or negative influence on the user. The former requires careful consideration in a persuasive design prototype. We focused on the proceedings of the Persuasive Technology conference from 2006 to 2020 to gain an understanding of the use of social comparison theory as part of persuasive design. Twelve studies met our inclusion criteria. Explanations of how the theory guides design decisions leading to the final operationalization were sparse. We suggest that conducting manipulation checks and using a systematic approach to reporting design decisions including the potential grounding of design elements in theory could highlight and clarify theoretical insights, and could increase our understanding of how social comparison—and behavior change theory in general—could be efficiently operationalized in persuasive technologies.
Studying the Endothelial Glycocalyx in vitro: What Is Missing?
Authors: Haymet Andrew B. , Bartnikowski Nicole , Wood Emily S. , Vallely Michael P. , McBride Angela , Yacoub Sophie , Biering Scott B. , Harris Eva , Suen Jacky Y. , Fraser John F.
Published: April 2021

All human cells are coated by a surface layer of proteoglycans, glycosaminoglycans (GAGs) and plasma proteins, called the glycocalyx. The glycocalyx transmits shear stress to the cytoskeleton of endothelial cells, maintains a selective permeability barrier, and modulates adhesion of blood leukocytes and platelets. Major components of the glycocalyx, including syndecans, heparan sulfate, and hyaluronan, are shed from the endothelial surface layer during conditions including ischaemia and hypoxia, sepsis, atherosclerosis, diabetes, renal disease, and some viral infections. Studying mechanisms of glycocalyx damage in vivo can be challenging due to the complexity of immuno-inflammatory responses which are inextricably involved. Previously, both static as well as perfused in vitro models have studied the glycocalyx, and have reported either imaging data, assessment of barrier function, or interactions of blood components with the endothelial monolayer. To date, no model has simultaneously incorporated all these features at once, however such a model would arguably enhance the study of vasculopathic processes. This review compiles a series of current in vitro models described in the literature that have targeted the glycocalyx layer, their limitations, and potential opportunities for further developments in this field.
Analysis of the Migration Characteristics of Stormwater Runoff Pollutants on Different Underlying Surfaces in Guangzhou, China
Authors: Pan Yongjun , Li Zhiqi , Gao Yaoyao , Xiong Yongmei , Qiao Yu , Tao Yuzhu , Wu Qiaohua , Lin Wen , Qi Yueqiang , Long Jiayi , Ruan Lin , Dai Seping , Zang Chuanfu
Published: April 2021

Stormwater runoff is identified as urban nonpoint source pollution that increasingly introduces contaminants to urban water bodies and impedes sustainable development. The pollution load of runoff varies due to the interception of different land cover types during the urban hydrological process. During the rainy season (June–August) in 2018, five different underlying surfaces (green roof, parking lot, urban road, parkway, and grassland) were selected in Guangzhou to analyze the migration characteristics of stormwater runoff pollutants. The concentrations of heavy metals, such as chromium (Cr), cadmium (Cd), lead (Pb), and mercury (Hg), as well as total nitrogen (TN), total phosphorus (TP), and polycyclic aromatic hydrocarbons (PAHs) were collected and analyzed on different underlying surfaces with the rainfall data at the beginning of a stormwater runoff event. The results showed that PAHs, heavy metals, and TP existed mainly in the form of particles; nitrogen was mainly present as ammonia and nitrate; and the TN, TP, PAHs, and heavy metal were significantly different in the stormwater runoff on each underlying surface. The pollutant concentration in urban road runoff was the highest, accounting for 40–70% of the total pollutant concentration in the stormwater runoff, and the pollutant concentration in green roof runoff was the lowest, accounting for 10–40% of the total pollutant concentration in the runoff. An obvious effect of initial rainfall erosion was observed during stormwater runoff from urban roads and parking lots, and the scouring effect on grasslands and green roofs was mainly due to the many factors affecting the underlying surface during the middle and late stages. The rates of reduction of heavy metals were the most significant. The effect of water purification was positively correlated with stormwater runoff duration. The rates of reduction of TN, heavy metals (Cr, Cd, and Hg), and PAHs in the grassland areas were 35.20 ± 26.28, 0.24 ± 10.13, 71.77 ± 10.97,32.62 ± 110.48, and 41.30 ± 8.78%, respectively. This study could provide a theoretical basis for preventing and managing pollutants in urban stormwater runoff.
Fostering Trauma-Informed and Eudaimonic Pedagogy in Music Education
Authors: Walzer Daniel
Published: April 2021

The arts and entertainment sectors remain fragile because of the global pandemic. Unemployment, physical and emotional stress, social isolation, a loss of purpose, and a problematic future are just a sample of the ongoing traumas that music educators and practitioners experience under duress. As an inherently social activity, music-making becomes especially difficult when the threat of infection persists, further exacerbating somatic trauma and decreased health and wellness. The sudden loss of daily contact with others, coupled with multiple kinds of crises, complicates matters for educators. How does one flourish when their livelihood, personal connections, and sense of meaning-making disappear? Likewise, how ought the music educator navigate such uncertainty when teaching others? To address these issues, psychologists have often turned to Trauma-Informed Care (TIC), a collaborative model between the practitioner and client that recognizes and validates the impact of painful memories and experiences. This article advocates for a compassionate eudaimonic pedagogy model that prioritizes healing and self-care for teachers and students and cultivating an ethos of critical digital pedagogy—itself a form of eudaimonia. Drawing on Noddings’ (1992, 1995, 2002) Philosophy of Care, the article concludes with suggestions on future connections between eudaimonia and music education.
Epistemic Emotions and Epistemic Cognition Predict Critical Thinking About Socio-Scientific Issues
Authors: Muis Krista R. , Chevrier Marianne , Denton Courtney A. , Losenno Kelsey M.
Published: April 2021

When thinking critically about socio-scientific issues, individuals’ expectations about the nature of knowledge and knowing, as well as their emotions when these expectations are met or not, may play an important role in critical thinking. In this study, we examined the role of epistemic emotions in mediating the effects of epistemic cognition on critical thinking when contending with conflicting information about genetically modified foods. Two hundred four university students completed a prior knowledge test on genetically modified foods, and then reported their epistemic beliefs about genetically modified foods. Participants then read a text that presented advantages and disadvantages of genetically modified foods, and reported the epistemic emotions they experienced during reading of that text. Participants then composed an argumentative essay about genetically modified foods, which were coded for critical thinking. Results from path analysis revealed that a belief in complex knowledge predicted less surprise and confusion, but more enjoyment. For the source of knowledge, a belief in the active construction of knowledge predicted less surprise and enjoyment. For justification for knowing, a belief that knowledge should be critically evaluated positively predicted curiosity, and negatively predicted confusion and boredom. Moreover, beliefs that knowledge about genetically modified foods is complex and uncertain positively predicted critical thinking. Confusion and anxiety also positively predicted critical thinking, whereas frustration negatively predicted critical thinking. Lastly, confusion mediated relations between epistemic beliefs and critical thinking. Results suggest complex relations between epistemic cognition, epistemic emotions, and critical thinking that have implications for educational practice as well as for future research on epistemic cognition and epistemic emotions.
Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications
Authors: Vitale Giovanni , Cozzolino Alessia , Malandrino Pasqualino , Minotta Roberto , Puliani Giulia , Saronni Davide , Faggiano Antongiulio , Colao Annamaria
Published: April 2021

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells dispersed in different organs. Receptor tyrosine kinases are a subclass of tyrosine kinases with a relevant role in several cellular processes including proliferation, differentiation, motility and metabolism. Dysregulation of these receptors is involved in neoplastic development and progression for several tumors, including NENs. In this review, we provide an overview concerning the role of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) system in the development and progression of NENs, the occurrence of fibrotic complications and the onset of drug-resistance. Although no specific FGFR kinase inhibitors have been evaluated in NENs, several clinical trials on multitarget tyrosine kinase inhibitors, acting also on FGF system, showed promising anti-tumor activity with an acceptable and manageable safety profile in patients with advanced NENs. Future studies will need to confirm these issues, particularly with the development of new tyrosine kinase inhibitors highly selective for FGFR.
Ocean Outreach in Australia: How a National Research Facility is Engaging with Community to Improve Scientific Literacy
Authors: Arthur Benjamin , Roberts Donna , Rae Ben , Marrison Matthew , McCleary Hannah , Abbott April , Musso Barbara
Published: April 2021

Marine systems across the globe are experiencing myriad pressures with consequences for their health, management and the industries and communities that depend on them. Critical to improved management of our oceans and coasts is effective education and communication that ultimately leads to improved societal value of the world’s oceans. In Australia, the national scientific research agency, CSIRO, operates critical national research infrastructure such as the Marine National Facility (MNF), which also plays an important role in marine education, training and communication. The MNF Outreach Program seeks to strategically engage the community in marine science, identifying audience segments and developing programs, activities and content to meet their specific information needs. The program is structured around three specific audience segments: Purpose Seekers, Nurturers and Lifelong Learners. With both at-sea and shore-based activities and programs including the Indigenous Time at Sea Scholarship, CAPSTAN sea-training, Educator on Board, Floating Classroom, live ship-to-shore crosses and media and social media programming, the MNF Outreach program delivers meaningful engagement through experiential learning opportunities, rather than simply addressing knowledge deficits. As marine issues are varied and complex, marine communication and education approaches must be equally multifaceted, and a successful outreach program will have a spectrum of activities of varying resource intensity (such as cost, time and appropriately skilled personnel) which are matched to clear target audience segments. With increasing recognition of the importance of science communication in informing science literacy and policy, publicly funded national research facilities have an essential role to play by shifting from traditional research-only roles to also provide for targeted education and outreach.
Projection of the Precipitation Extremes in Thailand Under Climate Change Scenario RCP8.5
Authors: Amnuaylojaroen Teerachai
Published: April 2021

This study explores the predicted extreme precipitation during 2020–2029 in Thailand, using the output of the nested regional climate model (NRCM) with the Representative Concentration Pathway (RCP) 8.5 emission scenario. The research used five different extreme precipitation indices, i.e., annual precipitation total (PRCPTOT), the annual number of rainy days (RD), simple daily intensity index (SDII), consecutive dry days (CDDs), and consecutive wet days (CWD). The PRCTOT was generally located in eastern Thailand, with significant declining trends, while the increasing trend was found in northern Thailand. The quantity of the PRCPTOT varies marginally from 100 to 200 mm per decade. The annual RD was influenced mostly by the negative trends in Thailand. A remarkable trend is a rising of annual SDII, with major statistical increases ranging from 5 to 20%. A widespread decline in CWD was found in most regions. The statistically significant pattern of CWD has been geographically concentrated in the northern, southern, and eastern regions of Thailand. Southern Thailand continues to decline by −10 to −30%. A drastic decline has been observed in the south of Thailand. Projected interannual precipitation variability shows that December–January–February (DJF) variability will be greater than either annual or June–July–August (JJA) variability in most years, with the exception of 2022, 2025, and 2026, in which the JJA variability will be greater than both the annual variability and the DJF variability.
Flexibility and Control of Circadian Activity, Migratory Restlessness and Fueling in Two Songbird Migrants
Authors: Åkesson Susanne , Ilieva Mihaela , Bianco Giuseppe
Published: April 2021

Juvenile songbirds rely on an endogenous program, encoding direction, distance, fueling, and timing of migration. Migratory distance is species-specific, expressed as a period of migratory restlessness, for which the length is correlated with distance, while fueling is modified to meet anticipated flight distances controlled by geomagnetic cues and amount of day-light available for foraging. How daylength affect onset and level of migratory activity and fueling decisions in wild birds have so far received limited attention. Here we study how photoperiod controls onset, level and extent of autumn migratory activity and fueling in juvenile diurnally migrating dunnocks, and nocturnally migrating European robins by experimentally increasing daylength. For both species, we kept a control group indoors at the location of capture in southern Sweden exposed to the natural photoperiod, and an experimental group with increased and advanced photoperiod by 2 h in the morning. Dunnocks initiated migratory activity at sunrise (or artificial sunrise) in both groups, demonstrating a highly responsive and flexible component for the onset of migration triggered by light. Experimental robins anticipated the end of nocturnal migratory activity predicting the earlier sunrise immediately after the time-shift and expressed this behavior already under darkness, supporting a fast-resetting mechanism to the new diel period. Timing of end of morning activity was not affected by the earlier sunrise in both species, suggesting a fixed endogenous control that persisted throughout the 13-day study period. Experimental dunnocks expressed higher overall activity and lower fuel loads than controls, while robins did not change their overall activity and fuel load in response to the shifted and increased photoperiod. These results reveal important adaptations for circadian timekeeping including both a flexible onset open to fast modifications and a more rigid end, with differential effects by the treatment on migratory activity and fueling in the two species.
Xp11.2 Duplication in Females: Unique Features of a Rare Copy Number Variation
Authors: Czakó Márta , Till Ágnes , Zima Judith , Zsigmond Anna , Szabó András , Maász Anita , Melegh Béla , Hadzsiev Kinga
Published: April 2021

Among the diseases with X-linked inheritance and intellectual disability, duplication of the Xp11.23p11.22 region is indeed a rare phenomenon, with less than 90 cases known in the literature. Most of them have been recognized with the routine application of array techniques, as these copy number variations (CNVs) are highly variable in size, occurring in recurrent and non-recurrent forms. Its pathogenic role is not debated anymore, but the information available about the pathomechanism, especially in affected females, is still very limited. It has been observed that the phenotype in females varies from normal to severe, which does not correlate with the size of the duplication or the genes involved, and which makes it very difficult to give an individual prognosis. Among the patients studied by the authors because of intellectual disability, epilepsy, and minor anomalies, overlapping duplications affecting the Xp11.23p11.22 region were detected in three females. Based on our detailed phenotype analysis, we concluded that Xp11.23p11.22 duplication is a neurodevelopmental disorder.
Targeting Innate Immunity to Combat Cutaneous Stress: The Vitiligo Perspective
Authors: Boniface Katia , Passeron Thierry , Seneschal Julien , Tulic Meri K.
Published: April 2021

Multiple factors are involved in the process leading to melanocyte loss in vitiligo including environmental triggers, genetic polymorphisms, metabolic alterations, and autoimmunity. This review aims to highlight current knowledge on how danger signals released by stressed epidermal cells in a predisposed patient can trigger the innate immune system and initiate a cascade of events leading to an autoreactive immune response, ultimately contributing to melanocyte disappearance in vitiligo. We will explore the genetic data available, the specific role of damage-associated-molecular patterns, and pattern-recognition receptors, as well as the cellular players involved in the innate immune response. Finally, the relevance of therapeutic strategies targeting this pathway to improve this inflammatory and autoimmune condition is also discussed.
Peripheral TIGIT+ T Follicular Helper Cells That Produce High Levels of Interleukin-21 via OX40 Represent Disease Activity in IgG4-Related Disease
Authors: Akiyama Mitsuhiro , Suzuki Katsuya , Yoshimoto Keiko , Yasuoka Hidekata , Kaneko Yuko , Takeuchi Tsutomu
Published: April 2021

Objectives

Multiple studies suggest that interleukin (IL)-21 plays a pivotal role in the differentiation of B cells and activation of cytotoxic T cells and is involved in the pathogenesis of IgG4-related disease (IgG4-RD). T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is a new marker of T follicular helper (Tfh) cells, yet its significance remains unknown. The objective of this study was to investigate whether TIGIT expression could detect high IL-21-producing peripheral Tfh populations and their association with disease activity in IgG4-RD.

Methods

TIGIT expression in peripheral CD4+T cell subsets was comprehensively analyzed by multi-color flow cytometry. Single cell mapping was performed by t-SNE method, and IL-21 production was compared in TIGIT+ and TIGIT-T cells. The effect of OX40 signal on cytokine expression was analyzed by RNA-sequencing. Clinical significance of TIGIT+ and TIGIT- peripheral T cells was analyzed in active patients with IgG4-RD, both at baseline and after 12 weeks of glucocorticoid treatment.

Results

Unbiased single cell mapping revealed two high IL-21-producing peripheral T cell populations; TIGIT+ Tfh and TIGIT-T helper cells. OX40 signal was associated with high IL-21 production in TIGIT+ Tfh and TIGIT-T helper cells. IL-21 production in Tfh cells correlated with the proportion of TIGIT+ cells in Tfh cells, serum IgG4 level, and scores of disease activity. Furthermore, the skewing toward peripheral TIGIT+ Tfh cells, particularly TIGIT+Tfh2 subset correlated with disease activity and was corrected by glucocorticoid treatment in IgG4-RD.

Conclusions

OX40 is associated with high IL-21 production in peripheral TIGIT+ Tfh cells, and the increase in peripheral TIGIT+ Tfh cells reflects disease activity in IgG4-RD.
The Role of B Cells and B Cell Therapies in Immune-Mediated Liver Diseases
Authors: Cargill Tamsin , Culver Emma L.
Published: April 2021

B cells form a branch of the adaptive immune system, essential for the body’s immune defense against pathogens. B cell dysfunction has been implicated in the pathogenesis of immune mediated liver diseases including autoimmune hepatitis, IgG4-related hepatobiliary disease, primary biliary cholangitis and primary sclerosing cholangitis. B cells may initiate and maintain immune related liver diseases in several ways including the production of autoantibodies and the activation of T cells via antigen presentation or cytokine production. Here we comprehensively review current knowledge on B cell mechanisms in immune mediated liver diseases, exploring disease pathogenesis, B cell therapies, and novel treatment targets. We identify key areas where future research should focus to enable the development of targeted B cell therapies.
Maintenance of Barrier Tissue Integrity by Unconventional Lymphocytes
Authors: Cox Joshua R. , Cruickshank Sheena M. , Saunders Amy E.
Published: April 2021

Mucosal surfaces, as a first barrier with the environment are especially susceptible to damage from both pathogens and physical trauma. Thus, these sites require tightly regulated repair programs to maintain barrier function in the face of such insults. Barrier sites are also enriched for unconventional lymphocytes, which lack rearranged antigen receptors or express only a limited range of such receptors, such as ILCs (Innate Lymphoid Cells), γδ T Cells and MAIT (Mucosal-Associated Invariant T Cells). Recent studies have uncovered critical roles for unconventional lymphocytes in regulating mucosal barrier function, and, in particular, have highlighted their important involvement in barrier repair. The production of growth factors such as amphiregulin by ILC2, and fibroblast growth factors by γδ T cells have been shown to promote tissue repair at multiple barrier sites. Additionally, MAIT cells have been shown to exhibit pro-repair phenotypes and demonstrate microbiota-dependent promotion of murine skin healing. In this review we will discuss how immune responses at mucosal sites are controlled by unconventional lymphocytes and the ways in which these cells promote tissue repair to maintain barrier integrity in the skin, gut and lungs.
A Substrate-Independent Benthic Sampler (SIBS) for Hard and Mixed-Bottom Marine Habitats: A Proof-of-Concept Study
Authors: Keeley Nigel , Laroche Olivier , Birch Murray , Pochon Xavier
Published: April 2021

Sea cage fish farms are increasingly situated over hard and mixed substrate habitats for production and waste-dispersion reasons; yet in many cases, these installations are not being effectively managed with respect to benthic impacts due to the lack of a practical sampling method. This study presents the first set of results from a newly developed Substrate Independent Benthic Sampler (SIBS) device that captures the unconsolidated organic and inorganic matter that overlies almost all substrates. The contents of the samples were analyzed using extracted environmental DNA (eDNA) followed by metabarcoding of the bacterial 16S rRNA gene. SIBS microbial assemblages reliably changed with proximity to farm and concurred with visual assessments of impact. Moreover, the approach appeared to be very sensitive with respect to the enrichment gradient, being able to discern influences at distances of 500–1500 m from the impact source. Other spatial differences, due to region and farm, were small in comparison, and the effect of the underlying substrate type was minor. The samples contained sufficient previously described bacterial bioindicator taxa from enriched sediments, such that a meaningful biotic index could be calculated, thereby placing them on a well-established benthic enrichment spectrum with established environmental thresholds. SIBS-derived bacterial data provide a powerful new approach for mapping spatial boundaries of farm effects irrespective of substrate type and topography. More importantly, the tool should also permit quantitative assessment of benthic enrichment levels irrespective of substrate type from depths of at least 100 m. It therefore has the potential to solve the hard-bottom problem that has until now prohibited effective environmental monitoring at mixed and hard-bottom locations.
Production and Characterization of TES-EPDM Foams With Paraffin for Thermal Management Applications
Authors: Valentini Francesco , Fambri Luca , Dorigato Andrea , Pegoretti Alessandro
Published: April 2021

New materials capable of storing thermal energy in view of building applications have been developed from the foaming of ethylene-propylene diene monomer (EPDM) rubber with the addition of paraffin as a phase change material (PCM) at a melting temperature of about 21°C. Considering that the EPDM foams prepared by using traditional chemical blowing agents are generally characterized by a rather elevated environmental load, the salt leaching technique has been selected (and optimized) for the production of an EPDM foam with geometrical density of 0.41 g/cm3. It has been demonstrated that the produced foams were capable of retaining up to 62 wt% of paraffin after a 38-days leaking test. The role of the absorption of paraffin on the thermal and mechanical properties of the produced foams has been investigated. The effective thermal energy of the PCM content (PCMeff) measured by differential scanning calorimetry (DSC) was 52% both in the heating and cooling scans. Shore A test, compression set (CS) test, and quasi-static compression test above and below the thermal transition of the selected PCM have been performed, and a strong dependence of materials in respect to the testing temperature has been observed, with paraffin acting as a hardener above its melting point and as a softener below its melting point. Moreover, the evaluation of the thermal energy storage (TES) performance of the foams by monitoring their surface temperature during a heating/cooling process revealed that the time required from the samples to reach the set temperature due to the presence of paraffin was three times higher in comparison to the reference sample without paraffin. Moreover, in the plateau due to paraffin melting/crystallization, heating/cooling rates of around 0.4°C/min have been found, which are much lower with respect to that of a reference sample (>1.5°C/min). Thermal efficiency and thermal intervals for the application of EPDM/paraffin have been determined in a most accurate manner and therefore have been performed DSC at a heating/cooling rate of 1°C/min. These TES-EPDM foams exhibited a thermal capacity of 120–128 J/g with an operative interval in the range from −20°C to 40°C. The produced foams were capable of maintaining their geometry after being subjected to 240 heating/cooling cycles between 0 and 40°C, and their residual TES capacity was higher than 90% for all the samples (about 95% for the materials tested on aluminum substrate). The most interesting properties for TES applications were found for the produced foamsviasalt leaching with 60–80 microns NaCl.
Endogenous Opioid Levels Do Not Correlate With Itch Intensity and Therapeutic Interventions in Hepatic Pruritus
Authors: Düll Miriam M. , Wolf Katharina , Vetter Marcel , Dietrich Peter , Neurath Markus F. , Kremer Andreas E.
Published: April 2021

Background: Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy.

Methods: Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus (n = 29) and age-, gender- and disease-matched controls without pruritus (n = 27) as well as healthy controls (n = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0–10).

Results: PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate.

Conclusions: Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.
Electron Acceptor Availability Shapes Anaerobically Methane Oxidizing Archaea (ANME) Communities in South Georgia Sediments
Authors: Schnakenberg Annika , Aromokeye David A. , Kulkarni Ajinkya , Maier Lisa , Wunder Lea C. , Richter-Heitmann Tim , Pape Thomas , Ristova Petra Pop , Bühring Solveig I. , Dohrmann Ingrid , Bohrmann Gerhard , Kasten Sabine , Friedrich Michael W.
Published: April 2021

Anaerobic methane oxidizing archaea (ANME) mediate anaerobic oxidation of methane (AOM) in marine sediments and are therefore important for controlling atmospheric methane concentrations in the water column and ultimately the atmosphere. Numerous previous studies have revealed that AOM is coupled to the reduction of different electron acceptors such as sulfate, nitrate/nitrite or Fe(III)/Mn(IV). However, the influence of electron acceptor availability on the in situ ANME community composition in sediments remains largely unknown. Here, we investigated the electron acceptor availability and compared the microbial in situ communities of three methane-rich locations offshore the sub-Antarctic island South Georgia, by Illumina sequencing and qPCR of mcrA genes. The methanic zone (MZ) sediments of Royal Trough and Church Trough comprised high sulfide concentrations of up to 4 and 19 mM, respectively. In contrast, those of the Cumberland Bay fjord accounted for relatively high concentrations of dissolved iron (up to 186 μM). Whereas the ANME community in the sulfidic sites Church Trough and Royal Trough mainly comprised members of the ANME-1 clade, the order-level clade “ANME-1-related” (Lever and Teske, 2015) was most abundant in the iron-rich site in Cumberland Bay fjord, indicating that the availability of electron acceptors has a strong selective effect on the ANME community. This study shows that potential electron acceptors for methane oxidation may serve as environmental filters to select for the ANME community composition and adds to a better understanding of the global importance of AOM.
Drought Exposed Burkholderia seminalis JRBHU6 Exhibits Antimicrobial Potential Through Pyrazine-1,4-Dione Derivatives Targeting Multiple Bacterial and Fungal Proteins
Authors: Prasad Jay Kishor , Pandey Priyanka , Anand Richa , Raghuwanshi Richa
Published: April 2021

The present study aimed to explore the antimicrobial potentials of soil bacteria and identify the bioactive compounds and their likely targets through in silico studies. A total 53 bacterial isolates were screened for their antimicrobial potential of which the strain JRBHU6 showing highest antimicrobial activity was identified as Burkholderia seminalis (GenBank accession no. MK500868) based on 16S ribosomal RNA (rRNA) gene sequencing and phylogenetic analysis. B. seminalis JRBHU6 also produced hydrolytic enzymes chitinases and cellulase of significance in accrediting its antimicrobial nature. The bioactive metabolites produced by the isolate were extracted in different organic solvents among which methanolic extract showed best growth-suppressing activities toward multidrug resistant Staphylococcus aureus and fungal strains, viz Fusarium oxysporum, Aspergillus niger, Microsporum gypseum, Trichophyton mentagrophytes, and Trichoderma harzianum. The antimicrobial compounds were purified using silica gel thin layer chromatography and high-performance liquid chromatography (HPLC). On the basis of spectroscopic analysis, the bioactive metabolites were identified as pyrrolo(1,2-a)pyrazine-1,4-dione,hexahydro (PPDH) and pyrrolo(1,2-a)pyrazine-1,4-dione, hexahydro-3(2-methylpropyl) (PPDHMP). In silico molecular docking studies showed the bioactive compounds targeting fungal and bacterial proteins, among which PPDHMP was multitargeting in nature as reported for the first time through this study.