bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico design of Phl p 6 variants with altered folding stability significantly impacts antigen processing, immunogenicity and immune polarization
Authors: Winter Petra , Stubenvoll Stefan , Scheiblhofer Sandra , Joubert Isabella A , Strasser Lisa , Briganser Carolin , Tuck Soh Wai , Hofer Florian , Kamenik Anna Sophia , Dietrich Valentin , Michelini Sara , Laimer Josef , Lackner Peter , Horejs-Hoeck Jutta , Tollinger Martin , Liedl Klaus R. , Brandstetter Johann , Huber Christian G. , Richard Weiss 
Published: February 2020

AbstactIntroductionProtein fold stability has been proposed to represent an intrinsic feature contributing to immunogenicity and immune polarization by influencing the amount of peptide-MHC II complexes (pMHCII). Usingin silicoprediction, we introduced point mutations in proteins that either increase or decrease their fold-stability without altering immunodominant epitopes or changing the overall structure of the protein. Here, we investigated how modulation of the fold-stability of the grass pollen allergen Phl p 6 affects its ability to stimulate immune responses and T cell polarization.MethodsUsing the MAESTRO software tool, stabilizing or destabilizing mutations were selected and verified by molecular dynamics simulations. The mutants were expressed in E. coli, purified tag-free, and analyzed for thermal stability and resistance to endolysosomal proteases. The resulting peptides were analysed by degradome assay and mass spectrometry. The structure of the most stable mutant protein was obtained by X-ray crystallography. We evaluated the capacity of the mutants to stimulate T cell proliferationin vitro, as well as antibody responses and T cell polarizationin vivoin an adjuvant-free BALB/c mouse model.ResultsFour stabilizing and two destabilizing mutations were identified by MAESTRO. Experimentally determined changes in thermal stability compared to the wild type protein ranged from -5 to +14 °C. Destabilization led to faster proteolytic processingin vitro, whereas highly stabilized mutants were degraded very slowly. However, the overall pattern of identified peptides remained very similar. This was confirmed in bone marrow derived dendritic cells that processed and presented the immune dominant epitope from a destabilized mutant more efficiently.In vivo, stabilization resulted in a shift in immune polarization as indicated by higher levels of IgG2a and increased secretion of TH1/TH17 cytokines.ConclusionMAESTRO was very efficient in detecting single point mutations that increase or reduce fold-stability. Thermal stability correlated well with susceptibility to protease resistance and presentation of pMHCII on the surface of dendritic cellsin vitro. This change in processing kinetics significantly influenced the polarization of T cell responsesin vivo. Modulating the fold-stability of proteins thus has the potential to optimize and polarize immune responses, which opens the door to more efficient design of molecular vaccines.
Forelimb unloading impairs glenohumeral muscle development in growing rats
Authors: Tushak Sophia K. , Tamburro Margaret K. , Fawcett Emily B. , Merritt LE Lauren E. , Saul Katherine R. , Cole Jacqueline H. 
Published: February 2020

AbstractProper joint loading is essential for healthy musculoskeletal development. Many pediatric neuromuscular disorders cause irreversible muscle impairments resulting from both physiological changes and mechanical unloading of the joint. While previous studies have examined the effects of hindlimb unloading on musculoskeletal development in the lower limb, none have examined solely forelimb unloading. Thus, a large deficit in knowledge of the effect of upper limb unloading exists and must be addressed in order to better understand how the glenohumeral joint adapts during development. Two forelimb unloading models were developed to study the effects of varying degrees of unloading on the glenohumeral joint in growing rats: forelimb suspension (n=6, intervention 21 days post-natal) with complete unloading of both limbs via a novel suspension system and forearm amputation (n=8, intervention 3-6 days post-natal) with decreased loading and limb use in one limb after below-elbow amputation. After 8 weeks of unloading, changes in muscle architecture and composition were examined in ten muscles surrounding the shoulder. Results were compared to control rats from a previous study (n=8). Both methods of altered loading significantly affected muscle mass, sarcomere length, and optimal muscle length compared to control rats, with the biceps long head and triceps long head observing the most marked differences. Forearm amputation also significantly affected muscle mass, sarcomere length, and optimal muscle length in the affected limb relative to the contralateral limb. Muscle composition, assessed by collagen content, remained unchanged in all groups. This study demonstrated that forearm amputation, which was administered closer to birth, had greater effects on muscle than forelimb suspension, which was administered a few weeks later than amputation.
Motor cortical plasticity in response to skill acquisition in adult monkeys
Authors: Gupta Ankur , Nashef Abdulraheem , Israely Sharon , Segal Michal , Harel Ran , Prut Yifat 
Published: February 2020

SummaryCortical maps often undergo plastic changes during learning or in response to injury. In sensory areas, these changes are thought to be triggered by alterations in the pattern of converging inputs and a functional reassignment of the deprived cortical region. In the motor cortex, training on a task that engages distal effectors was shown to increase their cortical representation (as measured by response to intracortical microstimulation). However, this expansion could be a specific outcome of using a demanding dexterous task. We addressed this question by measuring the long-term changes in cortical maps of monkeys that were sequentially trained on two different tasks involving either proximal or distal joints. We found that motor cortical remodeling in adult monkeys was symmetric such that both distal and proximal movements can comparably alter motor maps in a fully reversible manner according to task demands. Further, we found that the change in mapping often included a switch between remote joints (e.g., a finger site switched to a shoulder site) and reflected a usage-consistent reorganization of the map rather than the local expansion of one representation into nearby sites. Finally, although cortical maps were considerably affected by the performed task, motor cortical neurons throughout the motor cortex were equally likely to fire in a task-related manner independent of the task and/or the recording site. These results may imply that in the motor system, enhanced motor efficiency is achieved through a dynamical allocation of larger cortical areas and not by specific recruitment of task-relevant cells.
Latent learning drives sleep-dependent plasticity in distinct CA1 subpopulations
Authors: Guo Wei , Zhang Jie J. , Newman Jonathan P. , Wilson Matthew A. 
Published: February 2020

AbstractLatent learning allows the brain the transform experiences into cognitive maps, a form of implicit memory, without reinforced training. Its mechanism is unclear. We tracked the internal states of the hippocampal neural ensembles and discovered that during latent learning of a spatial map, the state space evolved into a low-dimensional manifold that topologically resembled the physical environment. This process requires repeated experiences and sleep in-between. Further investigations revealed that a subset of hippocampal neurons, instead of rapidly forming place fields in a novel environment, remained weakly tuned but gradually developed correlated activity with other neurons. These ‘weakly spatial’ neurons bond activity of neurons with stronger spatial tuning, linking discrete place fields into a map that supports flexible navigation.
Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity
Authors: Quillien Aurélie , Boulet Manon , Ethuin Séverine , Vandel Laurence 
Published: February 2020

ABSTRACTDuring development, the vertebrate vasculature undergoes major growth and remodeling. While the transcriptional cascade underlying blood vessel formation starts to be better characterized, little is known concerning the role and mode of action of epigenetic enzymes during this process. Here, we explored the role of the Protein Arginine Methyl Transferase Prmt5 during blood vessel formation and hematopoiesis in zebrafish. Through the generation of aprmt5mutant, we highlighted a key role of Prmt5 in both hematopoiesis and blood vessel formation. Notably, we showed that Prmt5 promotes vascular morphogenesis through the transcriptional control of ETS transcription factors and adhesion proteins in endothelial cells. Interestingly, we found that Prmt5 methyltransferase activity is not required to regulate gene expression, and the comparison of chromatin architecture impact on reporter genes expression leads us to propose that Prmt5 rather regulates transcription by acting as a scaffold protein that facilitates chromatin looping in these cells.
Biosonar spatial resolution along the distance axis: revisiting the clutter interference zone
Authors: Wagenhäuser Peter A. , Wiegrebe Lutz , Baier A. Leonie 
Published: February 2020

AbstractUnlike all other remote senses like vision or hearing, echolocation allows estimating the distance of an object. Not only have echolocating bats and toothed whales been shown to measure distance by echolocation extremely precisely, distance information is even topographically represented by a neuro-computational map in bats’ auditory cortex. This topographic representation and the corresponding tuning of cortical cells to object distance suggests the bats may be able to perceptually resolve multiple, simultaneously present objects along the distance axis. Here we use a novel psychophysical paradigm with complex phantom targets to quantity spatial resolution along the distance axis in the echolocating batPhyllostomus discolor. We show that our bats can indeed perceptually resolve objects along the distance axis when they are separated by about 40 cm (around a reference distance of 108 cm) along the distance axis. These results are well comparable to earlier work on bats’ clutter interference zone (Simmons et al., 1988) and confirm those results with a more robust psychophysical paradigm.Summary statementEcholocating bats perceive absolute distance to objects by measuring the time delay between call and echo. In addition, they possess spatial resolution along the distance axis.
ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum
Authors: Wang Bo , Liang Song , Wang Yan-Yan , Wang Yu , Xia Chao-Ming 
Published: February 2020

AbstractBackgroundHumoral immune responses play an important role in mediating liver granulomatous inflammation and fibrosis in schistosomiasis. Follicular helper T (Tfh) cells have a central role in mediating humoral immune responses. Generation of Tfh cells depends on inducible T cell costimulator (ICOS) signaling, but the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis.Methodology/Principal FindingsWe used a strain of ICOS-transgenic (Tg) mice to test the degrees of liver granulomatous inflammation and fibrosis, the frequency of splenic Tfh cells and soluble egg antigen-specific cytokine responses longitudinally in mice followingSchistosoma japonicum(S. japonicum)infection. In comparison with that in wide-type (WT) mice, significantly severer liver granulomatous inflammation and fibrosis and higher mortality were observed in ICOS-Tg mice. Significantly higher frequency of splenic Tfh cells was accompanied by significantly higher levels of Bcl-6 and CXCR5 expression in the livers of ICOS-Tg mice. Furthermore, significantly higher levels of SEA-specific IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21 and TGF-β1 responses, but lower levels of IFN-γ responses were detected in ICOS-Tg mice, which were abrogated by treatment with ICOS blockers in vitro. In addition, significantly higher levels of serum anti-SEA IgG were detected in ICOS-Tg mice.Conclusions/SignificanceThe ICOS-related signaling may promote the pathogenesis of murine schistosomiasis by polarizing Tfh cells, which may be immune check points for the prevention and intervention of schistosomiasis.Author summaryGranulomatous inflammation and fibrosis in the liver are the major pathogenic characteristics of schistosomiasis. ICOS is crucial for the development of Tfh cells, which are the key modulators of B cell activation and humoral immunity. However, the underlying molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis. Here, our results showed that the ICOS over-expression would significantly induce severer liver inflammation and fibrosis, higher frequency of splenic Tfh, higher levels of anti-SEA IgG as well as imbalanced SEA-specific cytokine responses in ICOS-Tg mice. The findings suggested that ICOS signaling may promote the pathogenesis of murine schistosoma-related liver inflammation and fibrosis by polarizing Tfh cells. Potentially, ICOS signaling and Tfh cells may be immune check points for the prevention and intervention of schistosomiasis.
Representing Organic Matter Thermodynamics in Biogeochemical Reactions via Substrate-Explicit Modeling
Authors: Song Hyun-Seob , Stegen James C. , Graham Emily B. , Lee Joon-Yong , Garayburu-Caruso Vanessa A. , Nelson William C. , Chen Xingyuan , Moulton J. David , Scheibe Timothy D. 
Published: February 2020

AbstractPredictive biogeochemical modeling requires data-model integration that enables explicit representation of the sophisticated roles of microbial processes that transform substrates. Data from high-resolution organic matter (OM) characterization are increasingly available and can serve as a critical resource for this purpose, but their incorporation into biogeochemical models is often prohibited due to an over-simplified description of reaction networks. To fill this gap, we proposed a new concept of biogeochemical modeling—termedsubstrate-explicit modeling—that enables parameterizing OM-specific oxidative degradation pathways and reaction rates based on the thermodynamic properties of OM pools. The resulting kinetic models are characterized by only two parameters regardless of the complexity of OM profiles, which can greatly facilitate the integration with reactive transport models for ecosystem simulations by alleviating the difficulty in parameter identification. For every detected organic molecule in a given sample, our approach provides a systematic way to formulate reaction kinetics from chemical formula, which enables the evaluation of the impact of OM character on biogeochemical processes across conditions. In a case study of two sites with distinct OM thermodynamics, our method not only predicted oxidative degradation to be primarily driven by thermodynamic efficiency of OM consistent with experimental rate measurements, but also revealed previously unknown critically important aspects of biogeochemical reactions, including their condition-specific response to carbon and/or oxygen limitations. Lastly, we showed that the proposed substrate-explicit modeling approach can be synergistically combined with enzyme-explicit approach to provide improved predictions. This result led us to presentintegrative biogeochemical modelingas a unifying framework that can ideally describe the dynamic interplay among microbes, enzymes, and substrates to address advanced questions and hypotheses in future studies. Altogether, the new modeling concept we propose in this work provides a foundational platform for unprecedented predictions of biogeochemical and ecosystem dynamics through enhanced integration with diverse experimental data and extant modeling approaches.
SAFE Acoustics: an open-source, real-time eco-acoustic monitoring network in the tropical rainforests of Borneo
Authors: Sethi Sarab S. , Ewers Robert M. , Jones Nick S. , Signorelli Aaron , Picinali Lorenzo , Orme C. David L. 
Published: February 2020

AbstractAutomated monitoring approaches offer an avenue to deep, large-scale insight into how ecosystems respond to human pressures. Since sensor technology and data analyses are often treated independantly, there are no open-source examples of end-to-end, real-time ecological monitoring networks.Here, we present the complete implementation of an autonomous acoustic monitoring network deployed in the tropical rainforests of Borneo. Real-time audio is uploaded remotely from the field, indexed by a central database, and delivered via an API to a public-facing website.We provide the open-source code and design of our monitoring devices, the central web2py database and the ReactJS website. Furthermore, we demonstrate an extension of this infrastructure to deliver real-time analyses of the eco-acoustic data.By detailing a fully functional, open-source, and extensively tested design, our work will accelerate the rate at which fully autonomous monitoring networks mature from technological curiosities, and towards genuinely impactful tools in ecology.
No more fairytales: a quest for alternative narratives of sustainable business
Authors: O’Dochartaigh Aideen 
Published: February 2020

PurposeThe purpose of this paper is to explore storytelling in sustainability reporting. The author posits that large PLCs use their sustainability reports to support the construction of a fairytale of “sustainable business”, and asks if organisations with an alternative purpose (social enterprises, values-based SMEs) and/or ownership structure (co-operatives, partnerships) can offer a counter-narrative of the sustainability–business relationship.Design/methodology/approachThe paper uses the literature on storytelling and organisational mythmaking to gain insight into the construction of narratives and their impact on the reader. A narrative analysis is conducted of the sustainability reports of 40 organisations across a range of entity classes, including large PLCs, values-based SMEs, co-owned businesses and social enterprises.FindingsThe analysis indicates that the narratives presented in sustainability reporting are of much the same form across entity classes. The author argues on this basis that sustainability reports represent stories targeted at specific stakeholders rather than accounts of the organisation’s relationship with ecological and societal sustainability, and urges scholars to challenge organisations across entity classes to engage with sustainability at a planetary level.Originality/valueThe paper seeks to contribute to the literature in two ways. First, the author illustrates how the literature on storytelling can be used to analyse organisational narratives of sustainability, and how narrative forms and genres can be mobilised to support potential counter-narratives. Second, the author explores and ultimately challenges the proposition that organisations less often examined in the literature, such as social enterprises and co-operatives, can offer alternative narratives of the sustainability–business relationship.
The influence of firm performance and (level of) assurance on the believability of management's environmental report
Authors: Sheldon Mark D. , Jenkins J. Gregory 
Published: February 2020

PurposeThis study empirically examines perceptions of environmental report believability based on a firm's relative performance and level of assurance obtained on environmental activities under the recently clarified and recodified attestation standards in the United States.Design/methodology/approachThe paper uses a 2 × 3 between-subjects experiment to identify differences in 153 non-expert environmental report users' perceptions of report believability based on positive or negative firm performance and (level of) assurance provided by an accounting firm.FindingsResults show a main effect in that negative performance reports are perceived to be more believable than positive performance reports, as driven by negative performance reports being significantly more believable when no assurance is present. The firm performance effect is eliminated once limited or reasonable assurance is provided. Further, positive performance reports with limited, but not reasonable, assurance are perceived to be more believable than reports without assurance. No differences are identified within the negative performance condition.Practical implicationsLimited assurance might be used as an impression management tool to enhance the believability of positive performance environmental reports. Users, practitioners, and standard-setters should also be aware that users might believe environmental reports are assured, even when no such assurance has been provided.Originality/valueThis paper examines the impact of assured environmental reporting on users that review firms' environmental reports outside of a shareholder/investor role. The study also demonstrates conditions in which firm performance and assurance impact perceptions of report believability.
Analysis of the structure of different optimization strategies
Authors: Zemliak Alexander , Espinosa-Garcia Jorge 
Published: February 2020

PurposeIn this paper, on the basis of a previously developed approach to circuit optimization, the main element of which is the control vector that changes the form of the basic equations, the structure of the control vector is determined, which minimizes CPU time.Design/methodology/approachThe circuit optimization process is defined as a controlled dynamic system with a special control vector. This vector serves as the main tool for generalizing the problem of circuit optimization and produces a huge number of different optimization strategies. The task of finding the best optimization strategy that minimizes processor time can be formulated. There is a need to find the optimal structure of the control vector that minimizes processor time. A special function, which is a combination of the Lyapunov function of the optimization process and its time derivative, was proposed to predict the optimal structure of the control vector. The found optimal positions of the switching points of the control vector give a large gain in CPU time in comparison with the traditional approach.FindingsThe optimal positions of the switching points of the components of the control vector were calculated. They minimize processor time. Numerical results are obtained for various circuits.Originality/valueThe Lyapunov function, which is one of the main characteristics of any dynamic system, is used to determine the optimal structure of the control vector, which minimizes the time of the circuit optimization process.