bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibody:CD47 ratio regulates macrophage phagocytosis through competitive receptor phosphorylation
Authors: Suter Emily C. , Schmid Eva M. , Voets Erik , Francica Brian , Fletcher Daniel A. 
Published: August 2020

ABSTRACTCancer immunotherapies often modulate macrophage effector function by introducing either targeting antibodies that activate Fc gamma receptors or blocking antibodies that disrupt inhibitory SIRPα-CD47 engagement. Yet how these competing signals are integrated is poorly understood mechanistically, raising questions about how to effectively titrate immune responses. Here we find that macrophage phagocytic decisions are regulated by the ratio of activating ligand to inhibitory ligand on targets over a broad range of absolute molecular densities. Using endogenous as well as chimeric receptors, we show that activating:inhibitory ligand ratios of at least 10:1 are required to promote phagocytosis of model antibody-opsonized CD47-inhibited targets and that lowering this ratio reduces FcγR phosphorylation due to inhibitory phosphatases recruited to CD47-bound SIRPα. We demonstrate that ratiometric signaling is critical for phagocytosis of tumor cells and can be modified by blocking SIRPαin vitro, indicating that balancing targeting and blocking antibodies may be important for controlling macrophage phagocytosis in cancer immunotherapy.
Predator: A novel method for targeted protein degradation
Authors: Liu Chuanyang , Kuang Jingyu , Qiu Xinyuan , Min Lu , Li Wenying , Ma Jiaxin , Zhu Lingyun 
Published: August 2020

AbstractProtein expression and degradation are fundamental to cell function and physiological status of organisms. Interfering with protein expression not only provides powerful strategies to analyze the function of proteins but also inspires effective treatment methods for diseases caused by protein dysfunction. Recently, harnessing the power of the ubiquitin-proteasome system for targeted protein degradation (TPD) has become the focus of researches. Over the past two decades, TPD technologies, such as E3 ligase modification, PROTACs, and the Trim-Away method, have successfully re-oriented the ubiquitin-proteasome pathway and thus degraded many pathogenic proteins and even "undruggable" targets. However, A low-cost, convenient, and modularized TPD method is currently not available. Herein, we proposed a synthetic biology TPD method, termed Predator, by integrating the classic function of E3 ligase Trim21 and the expression of a bifunctional fusion protein that links Trim21 and the target protein, which leads to the formation of a ternary complex inside mammalian cells and therefore induce the ubiquitination and subsequent proteasome-dependent degradation of the target protein. We first proved this concept by using nanobody and scFv as the targeting module for the Predator system to degrade free GFP and membrane protein ErbB3, respectively. Then, we give an example of how the engineered Predator system can be developed towards biomedical solutions in the context of diabetes mellitus. Ligands-receptor interaction and adenovirus-mediated gene delivery were introduced to the Predator system, and we found this bifunctional fusion protein, in which glucagon was selected to function as the targeting module, downregulated the endogenous glucagon receptor (GCGR) and attenuated glucagon-stimulated glucose production in primary hepatocytes. Although preliminarily, our results showed that this Predator system is a highly modularized and convenient TPD method with good potential for both fundamental researches and clinical usage.Graphic abstract
Myocardial matrix material supports a proliferative microenvironment for cardiomyocytes
Authors: Wang Raymond M. , Cattaneo Paola , Camboa Nuno , Braden Rebecca , Luo Colin , Evans Sylvia , Christman Karen L. 
Published: August 2020

AbstractNovel therapeutics have sought to stimulate the endogenous repair mechanisms in the mammalian myocardium as the native regenerative potential of the adult cardiac tissue is limited. In particular, a myocardial matrix derived injectable hydrogel has shown efficacy and safety in various animal myocardial infarction (MI) including evidence of increased myocardium. In this study, investigation on the properties of this myocardial matrix material demonstrated its native capability as an effective reactive oxygen species (ROS) scavenger that can protect against oxidative stress and maintain cardiomyocyte proliferationin vitro. In vivoassessment of of myocardial matrix hydrogel treatment post-MI demonstrated increased thymidine analog uptake in cardiomyocytes compared to saline controls along with co-staining with cell cycle progression marker, phospho-histone H3. Overall, this study provides further evidence that properties of the myocardial matrix hydrogel promote an environment supportive of cardiomyocytes undergoing cell cycle progression.
Evidence for the plant recruitment of beneficial microbes to suppress soil-borne pathogen
Authors: Liu Hongwei , Li Jiayu , Cavalhais Lilia C. , Percy Cassandra , Verma Jay Prakash , Schenk Peer M. , Singh Brajesh 
Published: August 2020

SummaryEmerging experimental framework suggests that plants under biotic stress may actively seek help from soil microbes, but empirical evidence underlying such a ‘cry for help’ strategy is limited.We used integrated microbial community profiling, pathogen and plant transcriptive gene quantification and culture-based methods to systematically investigate a three-way interaction between the wheat plant, wheat-associated microbiomes andFusarium pseudograminearum(Fp).A clear enrichment of a dominant bacterium,Stenotrophomonas rhizophila(SR80), was observed in both the rhizosphere and root endosphere ofFp-infected wheat. SR80 reached 3.7×107cells g-1in the rhizosphere and accounted for up to 11.4% of the microbes in the root endosphere. Its abundance had a positive linear correlation with the pathogen load at base stems and expression of multiple defense genes in top leaves. Upon re-introduction in soils, SR80 enhanced plant growth, both the below- and above-ground, and induced strong disease resistance by priming plant defense in the aboveground plant parts, but only when the pathogen was presentTogether, the bacterium SR80 seems to have acted as an early warning system for plant defense. This work provides novel evidence for the potential protection of plants against pathogens by an enriched beneficial microbe via modulation of the plant immune system.
Bone marrow adipogenic lineage precursors (MALPs) promote osteoclastogenesis in bone remodeling and pathologic bone loss
Authors: Yu Wei , Zhong Leilei , Yao Lutian , Wei Yulong , Gui Tao , Li Ziqing , Kim Hyunsoo , Dyment Nathaniel , Liu Xiaowei S. , Yang Shuying , Choi Yongwon , Ahn Jaimo , Qin Ling 
Published: August 2020

AbstractBone is maintained by coupled activities of bone-forming osteoblasts/osteocytes and bone-resorbing osteoclasts and an alternation of this relationship can lead to pathologic bone loss such as in osteoporosis. It is well known that osteogenic cells support osteoclastogenesis via synthesizing RANKL. Interestingly, our recently identified bone marrow mesenchymal cell population—marrow adipogenic lineage precursors (MALPs) that form a multi-dimensional cell network in bone—was computationally demonstrated to be the most interactive with monocyte-macrophage lineage cells through highly and specifically expressing several osteoclast regulatory factors, including RANKL. Using an adipocyte-specificAdipoq-Creto label MALPs, we demonstrated that mice with RANKL deficiency in MALPs have a drastic increase of trabecular bone mass in long bones and vertebrae starting from 1 month of age but that their cortical bone is normal. This phenotype was accompanied by diminished osteoclast number and attenuated bone formation at the trabecular bone surface. Reduced RANKL signaling in calvarial MALPs also abolished osteolytic lesions after lipopolysaccharide (LPS) injections. Furthermore, in ovariectomized mice, elevated bone resorption was partially attenuated by RANKL deficiency in MALPs. In summary, our studies identified MALPs as a critical player in controlling bone remodeling during normal bone metabolism and pathological bone loss in a RANKL-dependent fashion.
Multifaceted functions of Rab23 on primary cilium and Hedgehog signaling-mediated granule cell proliferation
Authors: Hor CHH , Leong WY , Goh ELK 
Published: August 2020

AbstractSonic Hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors could cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that brain-specific knockout of a Shh pathway repressorRab23in mice caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly,Rab23-depleted GCPs exhibited up-regulated basal level of Shh pathway activities despite reduced ciliation, and were desensitized against stimulations by Shh and Smoothened (Smo) agonist in primary GCP culture. These results illustrate dual functions of Rab23 in repressing the basal level of Shh signaling, while facilitating Shh signal transduction via Shh/Smo on primary cilium. Collectively, our findings unravel instrumental roles ofRab23in GCP proliferation and ciliogenesis.Rab23’spotentiation of Shh signaling pathway through the primary cilium and Smo, suggests a potential new therapeutic for Smo/primary cilium-driven medulloblastoma.Author SummaryC.H.H conceived, designed, lead, and performed allin vitroandin vivoexperiments, analyzed data and wrote the manuscript. W.Y performed QPCR experiments and primary GCP cultures and analyzed data. E.L.G conceived and directed the study.
Bridging the Gap: From Neuroanatomical Knowledge to Tractography of Brain Pathways
Authors: Gallardo Guillermo , Wassermann Demian , Anwander Alfred 
Published: August 2020

AbstractDespite recent advances in tractography, the gap remains wide between the descriptions of white-matter pathways in the literature and the methods to reconstruct and study them from dMRI images. Here, we tackle this challenge by proposing a language to define white matter tracts, namely WMQLT, and a tool to automatically reconstruct pathways from their WMQLTqueries. Our method is performant, flexible enough to allow defining tracts using multiple modalities, and allows to extend ROI-based reconstruction methods. Leveraging our language, we define 19 major brain tracts, alongside their subdivisions, and reconstruct them in a large population. We show that the shape of the reconstructed pathways, as well as their connectivity and lateralizations are in accordance with the current neuroanatomical literature. Finally, we showcase our technique in two scenarios: computing the functional subdivisions of a tract, and assessing the role of handedness and gender in the lateralization of language-related tracts.
Different dimensions of robustness - noise, topology and rates - are nearly independent in chemical switches
Authors: Moza Sahil , Bhalla Upinder S. 
Published: August 2020

Life prospers despite adverse conditions in many unpredictable dimensions. This requires that cellular processes work reliably, that is they are robust against many kinds of perturbations. For example, a cellular decision to differentiate should be stable despite changes in metabolic conditions and stochasticity due to thermal noise. For evolutionary stability, the same differentiation switch should function despite mutations or the evolution of further regulatory inputs. We asked how cellular decision making responds to these three forms of perturbation, expressed in chemical terms as rate parameters, stochasticity, and reaction topology. Remarkably, we found that there was no correlation between noise robustness and either of the others and only a weak correlation between robustness to parameters and topology. Thus, a given chemical switch could be robust to noise yet sensitive to parametric or topological changes. However, we found families of reaction topologies derived from a common core bistable with symmetric feedback loops, which retained bistability despite the removal of reactions or substantially changing parameters. We propose that evolution involving chemical switches must navigate a complex landscape involving multiple forms of robustness, and the only way for a given switch to have a systematic advantage in robustness is to come from a ‘good family’ of mirrorsymmetric topologies.Significance StatementLife endures despite metabolic fluctuations and environmental assaults. For the thousands of cellular decisions to continue to work, they must be robust to these perturbations. Many cellular decisions are made and stored by chemical switches, which like light switches retain their state – on or off – even after the trigger is gone. We computationally explored what makes chemical switches robust. It turns out that some are robust to thermal noise, others to mutations that disable part of the switch, or to changes in chemical conditions. Surprisingly, these different forms of robustness are mostly independent. However, chemical switches come in families built around core reactions, and these families tend to score high or low on several measures of robustness.
Adaptive laboratory evolution restores solvent tolerance in plasmid-curedPseudomonas putidaS12; a molecular analysis
Authors: Kusumawardhani Hadiastri , Furtwängler Benjamin , Blommestijn Matthijs , Kaltenytė Adelė , van der Poel Jaap , Kolk Jevan , Hosseini Rohola , de Winde Johannes H. 
Published: August 2020

AbstractPseudomonas putidaS12 is intrinsically solvent-tolerant and constitutes a promising platform for biobased production of aromatic compounds and biopolymers. The genome ofP. putidaS12 consists of a 5.8 Mbp chromosome, and a 580 kbp megaplasmid pTTS12 that carries several gene clusters involved in solvent tolerance. Removal of pTTS12 caused a significant reduction in solvent tolerance. In this study, we succeeded in restoring solvent tolerance in plasmid-curedP. putidaS12 using adaptive laboratory evolution (ALE), underscoring the innate solvent-tolerance of this strain.Whole genome sequencing revealed several single nucleotide polymorphisms (SNPs) and a mobile element insertion, enabling ALE-derived strains to survive and sustain growth in the presence of a high toluene concentration (10% v/v). Mutations were identified in an RND efflux pump regulatorarpR, resulting in constitutive upregulation of the multifunctional efflux pump ArpABC. SNPs were also found in the intergenic region and subunits of ATP synthase, RNA polymerase subunit β’, global two-component regulatory system (GacA/GacS) and a putative AraC-family transcriptional regulator Afr. RNA-seq analysis further revealed a constitutive down-regulation of energy consuming activities in ALE-derived strains, including flagellar assembly, F0F1 ATP synthase, and membrane transport proteins. Out results indicate that constitutive expression of an alternative solvent extrusion pump in combination with high metabolic flexibility ensures restoration of solvent-tolerance inP. putidaS12 lacking its megaplasmid.
Between predators and parasitoids: Complex interactions among shelter traits, predation and parasitism in a shelter‐building caterpillar community
Authors: Baer Christina S. , Marquis Robert J. 
Published: August 2020

Abstract

Shelter‐building is widespread in the animal world and such shelters often influence the success of their builders. Shelters built by caterpillars influence the likelihood of attacks by natural enemies, but how particular shelter traits influence caterpillar survival is not known. Furthermore, the differential effects of certain shelter traits on some natural enemies, such as predators, may lead to ‘enemy‐free space’ for other natural enemies (parasitoids). The parasitoid enemy‐free space hypothesis has not been directly tested for shelter‐building caterpillars.

To understand how shelter traits influence caterpillar survival, shelter traits, predation and parasitism were measured simultaneously for 24 caterpillar morphospecies (1,465 caterpillars) in a tropical dry forest and analysed in a phylogenetic context.

Shelter type, shelter openness and whether shelters accumulated frass had different amounts of phylogenetic signal, with frass accumulation displaying the most and shelter openness the least.

All three traits affected the frequency with which caterpillar species experienced predation. Predation was elevated in two shelter types (leaf folds and leaf rolls) compared to cut‐and‐fold shelters. Combinations of shelter openness and frass accumulation also affected predation, with closed frass‐free shelters having the lowest predation and closed frass‐filled shelters having the highest.

Parasitism was not affected by shelter traits but was strongly correlated with evolutionary history and negatively correlated with predation.

These results confirm a trade‐off between predation and parasitism and demonstrate that predation can be more frequent than parasitism. Different shelter types result in different amounts of predation. These defensive shelter traits and their effectiveness also vary phylogenetically. Together, our results suggest that predation and parasitism determine the success of shelter‐building caterpillars, and that success is a function of the specific shelter they construct. More generally, our results demonstrate the importance of considering the effects of defensive traits on both predators and parasitoids when investigating interactions between herbivores and natural enemies.

A free Plain Language Summary can be found within the Supporting Information of this article.
An empirical attack tolerance test alters the structure and species richness of plant–pollinator networks
Authors: Biella Paolo , Akter Asma , Ollerton Jeff , Nielsen Anders , Klecka Jan 
Published: August 2020

Abstract

Ecological network theory hypothesizes that the structuring of species interactions can convey stability to the system. Investigating how these structures react to species loss is fundamental for understanding network disassembly or their robustness. However, this topic has mainly been studied in‐silico so far.

Here, in an experimental manipulation, we sequentially removed four generalist plants from real plant–pollinator networks. We explored the effects on, and drivers of, species and interaction disappearance, network structure and interaction rewiring. First, we compared both the local extinctions of species and interactions and the observed network indices with those expected from three co‐extinction models. Second, we investigated the trends in network indices and rewiring rate after plant removal and the pollinator tendency at establishing novel links in relation to their proportional visitation to the removed plants. Furthermore, we explored the underlying drivers of network assembly with probability matrices based on ecological traits.

Our results indicate that the cumulative local extinctions of species and interactions increased faster with generalist plant loss than what was expected by co‐extinction models, which predicted the survival or disappearance of many species incorrectly, and the observed network indices were lowly correlated to those predicted by co‐extinction models. Furthermore, the real networks reacted in complex ways to plant removal. First, network nestedness decreased and modularity increased. Second, although species abundance was a main assembly rule, opportunistic random interactions and structural unpredictability emerged as plants were removed. Both these reactions could indicate network instability and fragility. Other results showed network reorganization, as rewiring rate was high and asymmetries between network levels emerged as plants increased their centrality. Moreover, the generalist pollinators that had frequently visited both the plants targeted of removal and the non‐target plants tended to establish novel links more than who either had only visited the removal plants or avoided to do so.

With the experimental manipulation of real networks, our study shows that despite their reorganizational ability, plant–pollinator networks changed towards a more fragile state when generalist plants are lost.

A free Plain Language Summary can be found within the Supporting Information of this article.
Variation in thermal traits describing sex determination and development in Western Australian sea turtle populations
Authors: Bentley Blair P. , Stubbs Jessica L. , Whiting Scott D. , Mitchell Nicola J. 
Published: August 2020

Abstract

Both the development rate and sex of sea turtle embryos depend on incubation temperature, as all species of sea turtle are ectotherms and show temperature‐dependent sex determination (TSD). Theory predicts that selection should act on populations to optimize developmental times and primary sex ratios.

In this study, we use a consistent methodology to measure development rates and model the reaction norm that defines TSD in three populations of flatback turtles Natator depressus and two populations of green turtles Chelonia mydas that nest in Western Australia.

We show that development rates vary between and within species, likely reflecting adaptation to local beach microclimates. Similarly, the parameters that define the TSD reaction norm vary between the two species, and among N. depressus populations, with pivotal temperatures (TPIV) varying by 1.5°C (29.6–31.1°C), and the transitional ranges of temperatures (TRT) varying by 1.4–3.3°C. In contrast, we found a similar TPIV for the two C. mydas populations, but a wider TRT at the northernmost tropical rookery.

Our findings support the view that thermal parameters in geographically separated populations of sea turtles are broadly similar, but the variation we describe will be highly relevant for predicting how populations will respond to climate change.

A free Plain Language Summary can be found within the Supporting Information of this article.
Scientific Advice at a Time of Emergency. SAGE and Covid‐19
Authors: Freedman Lawrence 
Published: August 2020

AbstractThe challenge for experts in government is often described as one of speaking unwelcome truths to a resistant power. Yet, just as problematic can be instances where the advice is welcome and so left unchallenged. Two such cases in which the UK government followed flawed expert advice are considered: intelligence assessments and military advice leading up to the 2003 Iraq War and the role of SAGE (the Scientific Advisory Group for Emergencies) during the first stages of the Covid‐19 pandemic in 2020. Governments need to interrogate advice and make sure that they understand its underlying assumptions and implications. It remains vital to protect the independence of the experts, but to get the best out of their advice early and active political engagement is required rather than an arms‐length relationship.
Researching Fact Checking: Present Limitations and Future Opportunities
Authors: Dias Nicholas , Sippitt Amy 
Published: August 2020

AbstractThe fact checking field has grown tremendously in the past decade, as has academic interest in the practice, with dozens of studies testing the effectiveness of corrections. However, research on fact checking is not yet optimised to help fact checkers address the global challenges of mis‐ and disinformation. In this paper, we review the literature on fact checking’s effects and identify two key gaps. First, we discuss the limited diversity and external validity of existing studies, which have overwhelmingly been conducted in Western countries and under artificial, experimental conditions. Second, we argue that research has narrowly focussed on the short‐term, corrective effects of individual fact checks, largely ignoring the multiple ways fact checkers conceive of their impact. Thus, research has overlooked the cultural and systemic changes that fact checkers pursue. We conclude by highlighting opportunities for further research and for improving communication between academics and fact checkers.