bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of immunoactive and immunotolerant CD4+ T cells in breast cancer by measuring activity of signaling pathways that determine immune cell function
Authors: Wesseling-Rozendaal Yvonne , van Doorn Arie , Willard-Gallo Karen , van de Stolpe Anja
Published: October 2020

Cancer immunotolerance can be reversed by checkpoint blockade immunotherapy in some patients, but response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses against cancer. Conversion to an immune suppressive state impairs the anti-cancer immune response and is mainly effected by CD4+ Treg cells. A number of signal transduction pathways activate and control functions of CD4+ T cell subsets. As previously described, assays have been developed which enable quantitative measurement of the activity of signal transduction pathways (e.g. TGFβ, NFκB, PI3K-FOXO, JAK-STAT1/2, JAK-STAT3, Notch) in a cell or tissue sample. Using these assays, pathway activity profiles for various CD4+ T cell subsets were defined and cellular mechanisms underlying breast cancer-induced immunotolerance investigatedin vitro. Results were used to measure the immune response state in a clinical breast cancer study.

Methods

Signal transduction pathway activity scores were measured on Affymetrix expression microarray data of resting and immune-activated CD4+ T cells, immune-activated CD4+ T cells incubated with breast cancer tissue supernatants, CD4+ Th1, Th2, and Treg cells, and of clinical study samples in which CD4+ T cells were derived from blood, lymph node and cancer tissue from primary breast cancer patients (n=10).

Results

In vitroCD4+ T cell activation induced PI3K, NFκB, JAK-STAT1/2, and JAK-STAT3 pathway activity. Simultaneous incubation with primary cancer supernatant reduced PI3K and NFκB, and partly reduced JAK-STAT3, pathway activity, while simultaneously increasing TGFβ pathway activity; characteristic of an immune tolerant state. CD4+ Th1, Th2, and Treg cells all had a specific pathway activity profile, with activated immune suppressive Treg cells characterized by high NFκB, JAK-STAT3, TGFβ, and Notch pathway activity scores. An immune tolerant pathway profile was identified in CD4+ T cells from tumor infiltrate of a subset of primary breast cancer patients which could be contributed to activated Treg cells. A Treg pathway profile was also identified in blood samples.

Conclusion

Signaling pathway assays can be used to quantitatively measure the functional immune response state of lymphocyte subsetsin vitroandin vivo. Clinical results suggest that in primary breast cancer the adaptive immune response of CD4+ T cells has frequently been replaced by immunosuppressive Treg cells, potentially causing resistance to checkpoint inhibition.In vitrostudy results suggest that this effect is mediated by soluble factors from cancer tissue (e.g. TGFβ). Signaling pathway activity analysis on TIL and/or blood samples is expected to improve predicting and monitoring response to checkpoint inhibitor immunotherapy.
Discriminative SKP2 interactions with CDK-cyclin complexes support a cyclin A-specific role in p27KIP1 degradation
Authors: Salamina Marco , Montefiore Bailey C. , Liu Mengxi , Wood Daniel J. , Heath Richard , Ault James R. , Wang Lan-Zhen , Korolchuk Svitlana , Baslé Arnaud , Pastok Martyna W. , Reeks Judith , Tatum Natalie J. , Sobott Frank , Arold Stefan T. , Pagano Michele , Noble Martin E.M. , Endicott Jane A.
Published: October 2020

The SCFSKP2ubiquitin ligase relieves G1 checkpoint control of CDK-cyclin complexes by promoting p27KIP1 degradation. We describe reconstitution of stable complexes containing SKP1-SKP2 and CDK1-cyclin B or CDK2-cyclin A/E, mediated by the CDK regulatory subunit CKS1. We further show that a direct interaction between a SKP2 N-terminal motif and cyclin A can stabilize SKP1-SKP2-CDK2-cyclin A complexes in the absence of CKS1. We identify the SKP2 binding site on cyclin A and demonstrate the site is not present in cyclin B or cyclin E. This site is distinct from but overlapping with features that mediate binding of p27KIP1 and other G1 cyclin regulators to cyclin A. We propose that the capacity of SKP2 to engage with CDK2-cyclin A by more than one structural mechanism provides a way to fine tune the degradation of p27KIP1 and distinguishes cyclin A from other G1 cyclins to ensure orderly cell cycle progression.
Simulation-guided engineering of antibiotics for improved bacterial uptake
Authors: Ferreira Ricardo J. , Aguilar Valeria , Villamil Giraldo Ana M. , Kasson Peter M.
Published: October 2020

The Gram-negative bacterial outer membrane poses a major obstacle to the development of much-needed antibiotics against drug-resistant infections. Its chemical composition and porin proteins differ from Gram-positive bacteria and mammalian cells, and heuristics developed for mammalian cell uptake apply poorly. Recently, machinelearning methods have predicted small-molecule uptake into Gram-negative bacteria, offering the possibility to rationally optimize this aspect of antibiotic lead development. Here, we report physics-based methods to prospectively predict Gram-negative bacterial uptake, select, and synthesize promising chemical derivatives targetingE. coliDNA gyrase B. Our methods do not require empirical parameterization and are readily adaptable to new chemical scaffolds. These physics-based predictions well capture experimentally measured uptake (r > 0.95) and are indeed predictive of antimicrobial activity (r > 0.92). These methods can be used prospectively in combination with target-binding simulations to optimize both bacterial uptake and target binding, overcoming important barriers to antibiotic lead generation before small-molecule synthesis.
CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entire SARS-CoV-2 proteome and show kinetics of early differentiation
Authors: Kared Hassen , Redd Andrew D , Bloch Evan M , Bonny Tania S. , Sumatoh Hermi , Kairi Faris , Carbajo Daniel , Abel Brian , Newell Evan W , Bettinotti Maria P. , Benner Sarah E. , Patel Eshan U. , Littlefield Kirsten , Laeyendecker Oliver , Shoham Shmuel , Sullivan David , Casadevall Arturo , Pekosz Andrew , Nardin Alessandra , Fehlings Michael , Tobian Aaron AR , Quinn Thomas C
Published: October 2020

Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understanding its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. 132 distinct SARS-CoV-2-specific CD8+ T cell epitope responses across six different HLAs were detected, corresponding to 52 unique reactivities. T cell responses were directed against several structural and non-structural virus proteins. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.
The impact of preprint servers in the formation of novel ideas
Authors: Satish Swarup , Yao Zonghai , Drozdov Andrew , Veytsman Boris
Published: October 2020

We study whether novel ideas in biomedical literature appear first in preprints or traditional journals. We develop a Bayesian method to estimate the time of appearance for a phrase in the literature, and apply it to a number of phrases, both automatically extracted and suggested by experts. We see that presently most phrases appear first in the traditional journals, but there is a number of phrases with the first appearance on preprint servers. A comparison of the general composition of texts from bioRxiv and traditional journals shows a growing trend of bioRxiv being predictive of traditional journals. We discuss the application of the method for related problems.
Synergistic effect of deoxynucleosides and AAV gene therapy for thymidine kinase 2 deficiency
Authors: Lopez-Gomez Carlos , Sanchez-Quintero Maria J. , Lee Eung Jeon , Kleiner Gulio , Xie Jun , Akman Hasan Orhan , Gao Guangping , Hirano Michio
Published: October 2020

Autosomal recessive thymidine kinase 2 (TK2) mutations causes TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with deoxycytidine and thymidine ameliorates mitochondrial defects and extends lifespan ofTk2knock-in mouse (TK2−/−); however, efficacy is limited by age- and tissue-dependent expression of the cytosolic enzymes Tk1 and Dck. Thus, therapies aimed at systemic restoration of TK2 activity are needed. Here, we demonstrate that delivery of human TK2 cDNA to Tk2−/−mice using AAV9 efficiently rescued Tk2 activity in all the tissues tested except kidney, delayed disease onset, and increased lifespan. Sequential treatment of Tk2−/−mice with AAV9 first followed by AAV2 at different ages allowed us to reduce the viral dose while further prolonging the lifespan. Furthermore, addition of deoxycytidine and deoxythymidine supplementation to AAV9 + AAV2 treated Tk2−/−mice dramatically improved mtDNA copy numbers in liver and kidney, animal growth, and lifespan. These data indicate that combined pharmacological and gene therapies may be highly efficacious for human TK2 deficiency.
Joint automatic metabolite identification and quantification of a set of1H NMR spectra
Authors: Lefort Gaëlle , Liaubet Laurence , Marty-Gasset Nathalie , Canlet Cécile , Vialaneix Nathalie , Servien Rémi
Published: October 2020

Metabolomics is a promising approach to characterize phenotypes or to identify biomarkers. It is also easily accessible through NMR, which can provide a comprehensive understanding of the metabolome of any living organisms. However, the analysis of1H NMR spectrum remains difficult, mainly due to the different problems encountered to perform automatic identification and quantification of metabolites in a reproducible way. In addition, methods that perform automatic identification and quantification of metabolites often do it for one given complex mixture spectrum. Hence, when a set of complex mixture spectra coming from the same experiment has to be processed, the approach is simply repeated independently for every spectrum, despite their resemblance. Here, we present a new method that is the first to identify and quantify metabolites by integrating information coming from several complex spectra of the same experiment. The performances of this new method are then evaluated on both simulated and real datasets. The results show an improvement in the metabolite identification and in the accuracy of metabolite quantifications, especially when the concentration is low. This joint procedure is available in version 2.0 ofASICSpackage.
Angiotensin-converting enzyme 2 (ACE2) is upregulated in Alzheimer’s disease brain
Authors: Ding Qiyue , Shults Nataliia V. , Harris Brent T. , Suzuki Yuichiro J.
Published: October 2020

Alzheimer’s disease is a chronic neurodegenerative disorder and represents the main cause of dementia. Currently, the world is suffering from the pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses angiotensin-converting enzyme 2 (ACE2) as a receptor to enter the host cells. In COVID-19, neurological manifestations have been reported to occur. The present study demonstrates that the protein expression level of ACE2 is upregulated in the brain of Alzheimer’s disease patients. The increased ACE2 expression is not age-dependent, suggesting the direct relationship between Alzheimer’s disease and the ACE2 expression. Oxidative stress has been implicated in the pathogenesis of Alzheimer’s disease, and Alzheimer’s disease brains examined in this study also exhibited higher carbonylated proteins as well as increased thiol oxidation state of peroxiredoxin 6 (Prx6). The positive correlation was found between the increased ACE2 protein expression and oxidative stress in Alzheimer’s disease brain. Thus, the present study reveals the relationships between Alzheimer’s disease and ACE2, the receptor for SARS-CoV-2. These results warrant monitoring Alzheimer’s disease patients with COVID-19 carefully for the possible higher viral load in the brain and long-term adverse neurological consequences.
TheRpi-mcq1resistance gene family recognizesAvr2ofPhytophthora infestansbut is distinct fromR2
Authors: Aguilera-Galvez Carolina , Chu Zhaohui , Omy Sumaiya Haque , Wouters Doret , Gilroy Eleanor M. , Vossen Jack H. , Visser Richard G.F , Birch Paul , Jones Jonathan D.G , Vleeshouwers Vivianne G.A.A
Published: October 2020

Potato late blight, which is caused by the destructive oomycete pathogenPhytophthora infestans, is a major threat to global food security. Several nucleotide binding, leucine-rich repeat (NLR)ResistancetoP. infestans(Rpi) genes have been introgressed into potato cultivars from wildSolanumspecies that are native to Mexico, but these were quickly defeated. Positional cloning inSolanum mochiquense, combined with allele mining inSolanum huancabambense,were used to identify a new family ofRpigenes from PeruvianSolanumspecies.Rpi-mcq1,Rpi-hcb1.1andRpi-hcb1.2confer race-specific resistance to a panel ofP. infestansisolates. Effector assays showed that theRpi-mcq1family mediates a hypersensitive response upon recognition of the RXLR effector AVR2, which had previously been found to be exclusively recognized by the family of R2 resistance proteins. TheRpi-mcq1andR2genes are distinct and reside on chromosome IX and IV, respectively. This is the first report of two unrelated R protein families that recognize the same AVR protein. We anticipate that this likely is a consequence of a geographically separated dynamic co-evolution ofRgene families ofSolanumwith an important effector gene ofP. infestans.

Author summary

Potato is the largest non-grain staple crop and essential for food security world-wide. However, potato plants are continuously threatened by the notorious oomycete pathogenPhytophthora infestansthat causes late blight. This devastating disease has led to the Irish famine more then 150 years ago, and is still a major threat for potato. Resistance againstP. infestanscan be found in wild relatives of potato, which carry resistance genes that belong to the nucleotide binding site-leucine-rich repeat (NLR) class. Known NLR proteins typically recognize a matching effector fromPhytophthora, which leads to a hypersensitive resistance response (HR). For example, R2 from MexicanSolanumspecies recognizes AVR2 fromP. infestans. So far, theseRgenes exclusively match to oneAvrgene. Here, we identified a new class of NLR proteins that are different from R2, but also recognize the same effector AVR2. This new family of NLR occurs in South AmericanSolanumspecies, and we anticipate that it is likely a product of a geographically separated co-evolution with AVR2. This is the first report of two unrelated R protein families that recognize the same AVR protein.
The Bioprocess TEA Calculator: An online techno-economic analysis tool to evaluate the commercial competitiveness of potential bioprocesses
Authors: Lynch Michael D.
Published: October 2020

Techno-economic analysis connects R&D, engineering, and business. By linking process parameters to financial metrics, it allows researchers to understand the factors controlling the potential success of their technologies. In particular, metabolic and bioprocess engineering, as disciplines, are aimed at engineering cells to synthesize products with an ultimate goal of commercial deployment. As a result it is critical to be able to understand the potential impact of strain engineering strategies and lab scale results on commercial potential. To date, while numerous techno-economic models have been developed for a wide variety of bioprocesses, they have either required process engineering expertise to adapt and/or use or do not directly connect financial outcomes to potential strain engineering results. Despite the clear value of techno-economic analysis, these challenges have made it inaccessible to many researchers. I have developed this online calculator (https://bioprocesstea.comORhttp://bioprocess-tea-calculator.herokuapp.com/) to make the basic capabilities of early-stage techno-economic analysis of bioprocesses readily accessible. The tool, currently focused on aerobic fermentation processes, can be used to understand the impact of fermentation level metrics on the commercial potential of a bioprocess for the production of a wide variety of organic molecules. Using the calculator, I review the commercially relevant targets for an aerobic bioprocess for the production of diethyl malonate.

Highlights

A generalized techno-economic analysis tool for aerobic fermentation based bioprocesses.

Relates strain and process improvements to projected commercial financial outcomes

Commercial bioprocess targets to produce diethyl malonate are estimated to include fermentation titers >150 g/L, rates > 5g/L-hr and > 90% yield, with downstream purification yields > 90% and purification costs limited to less than 20% of total.
Linking big biomedical datasets to modular analysis with Portable Encapsulated Projects
Authors: Sheffield Nathan C. , Stolarczyk Michał , Reuter Vincent P. , Rendeiro André F.
Published: October 2020

Organizing and annotating biological sample data is critical in data-intensive bioinformatics. Unfortunately, metadata formats from a data provider are often incompatible with requirements of a processing tool. There is no broadly accepted standard to organize metadata across biological projects and bioinformatics tools, restricting the portability and reusability of both annotated datasets and analysis software. To address this, we present Portable Encapsulated Projects (PEP), a formal specification for biological sample metadata structure. The PEP specification accommodates typical features of data-intensive bioinformatics projects with many samples, whether from individual experiments, organisms, or single cells. In addition to standardization, the PEP specification provides descriptors and modifiers for different organizational layers of a project, which improve portability among computing environments and facilitate use of different processing tools. PEP includes a schema validator framework, allowing formal definition of required metadata attributes for any type of biomedical data analysis. We have implemented packages for reading PEPs in both Python and R to provide a language-agnostic interface for organizing project metadata. PEP therefore presents an important step toward unifying data annotation and processing tools in data-intensive biological research projects.
Metal Dependent Dynamic Equilibrium: A Regulatory Mechanism for M17 Aminopeptidases fromPlasmodium falciparumandPlasmodium vivax
Authors: Malcolm Tess R. , Belousoff Matthew J. , Venugopal Hariprasad , Borg Natalie A. , Drinkwater Nyssa , Atkinson Sarah C. , McGowan Sheena
Published: October 2020

M17 leucyl aminopeptidases are metal-dependent exopeptidases that rely on oligomerization to diversify their functional roles. The M17 aminopeptidases fromPlasmodium falciparum(PfA-M17) andPlasmodium vivax(Pv-M17) function as catalytically active hexamers to acquire free amino acids from human hemoglobin and are drug targets for the design of novel anti-malarial agents. In this study, we found that the active site metal ions essential for catalytic activity have a secondary structural role mediating the formation of active hexamers. We found thatPfA-M17 andPv-M17 exist in a metal-dependent dynamic equilibrium between active hexameric species and smaller inactive species, that can be controlled by manipulating the identity and concentration of metal ions available. Mutation of residues involved in metal ion binding impaired catalytic activity and the formation of active hexamers. Structural resolution of thePv-M17 hexameric species revealed thatPfA-M17 andPv-M17 bind metal ions and substrates in a conserved fashion, althoughPv-M17 forms the active hexamer more readily and processes substrates faster thanPfA-M17. On the basis of solution studies and structures determined by cryo-electron microscopy, we propose a dynamic equilibrium between monomer dimer tetramer hexamer, which becomes directional towards the large oligomeric states with the addition of metal ions. M17 aminopeptidases can exploit this sophisticated metal-dependent dynamic equilibrium to regulate formation of the catalytically active hexamer and therefore regulate catalysis.
Implantation and Gastrulation Abnormalities Characterize Early Embryonic Lethal Mouse Lines
Authors: Yoon Yeonsoo , Riley Joy , Gallant Judith , Xu Ping , Rivera-Pérez Jaime A.
Published: October 2020

The period of development between the zygote and embryonic day 9.5 in mice includes multiple developmental milestones essential for embryogenesis. The preeminence of this period of development has been illustrated in loss of function studies conducted by the International Mouse Phenotyping Consortium (IMPC) which have shown that close to one third of all mouse genes are essential for survival to weaning age and a significant number of mutations cause embryo lethality before E9.5. Here we report a systematic analysis of 21 pre-E9.5 lethal lines generated by the IMPC. Analysis of pre- and post-implantation embryos revealed that the majority of the lines exhibit mutant phenotypes that fall within a window of development between implantation and gastrulation with few pre-implantation and no post-gastrulation phenotypes. Our study provides multiple genetic inroads into the molecular mechanisms that control early mammalian development and the etiology of human disease, in particular, the genetic bases of infertility and pregnancy loss. We propose a strategy for an efficient assessment of early embryonic lethal mutations that can be used to assign phenotypes to developmental milestones and outline the time of lethality.
Repeatability of soma and neurite metrics in cortical and subcortical grey matter
Authors: Genc Sila , Chamberland Maxime , Koller Kristin , Tax Chantal M.W. , Zhang Hui , Palombo Marco , Jones Derek K.
Published: October 2020

Diffusion magnetic resonance imaging is a technique which has long been used to study white matter microstructurein vivo. Recent advancements in hardware and modelling techniques have opened up interest in disentangling tissue compartments in the grey matter. In this study, we evaluate the repeatability of soma and neurite density imaging in a sample of six healthy adults scanned five times on an ultra-strong gradient magnetic resonance scanner (300 mT/m). Repeatability was expressed as an intraclass correlation coefficient (ICC). Our findings reveal that measures of soma density (mean ICC=.976), neurite density (mean ICC=.959) and apparent soma size (mean ICC=.923) are highly reliable across multiple cortical and subcortical networks. Overall, we demonstrate the promise of moving advanced grey matter microstructural imaging towards applications of development, ageing, and disease.
Electrostatic Plasma Membrane Targeting Contributes to Dlg Function in Cell Polarity and Tumorigenesis
Authors: Lu Juan , Dong Wei , Tao Yan , Hong Yang
Published: October 2020

Discs large (Dlg) is an essential polarity protein and a tumor suppressor originally characterized inDrosophilabut is also well conserved in vertebrates. Like the majority of polarity proteins, plasma membrane (PM)/cortical localization of Dlg is required for its function in polarity and tumorigenesis, but the exact mechanisms targeting Dlg to PM remain to be fully elucidated. Here we show that, similar to the recently discovered polybasic polarity proteins such as Lgl and aPKC, Dlg also contains a positively charged polybasic domain that electrostatically binds the PM phosphoinositides PI4P and PI(4,5)P2. Electrostatic targeting by the polybasic domain contributes significantly to the PM localization of Dlg in follicular and early embryonic epithelial cells, and is crucial for Dlg to regulate both polarity and tumorigenesis. The electrostatic PM targeting of Dlg is controlled by a potential phosphorylation-dependent allosteric regulation of its polybasic domain, and is specifically enhanced by the interactions between Dlg and another basolateral polarity protein and tumor suppressor Scrib. Our studies highlight an increasingly significant role of electrostatic PM targeting of polarity proteins in regulating cell polarity.
Rapid Cortical Adaptation and the Role of Thalamic Synchrony During Wakefulness
Authors: Wright Nathaniel C. , Borden Peter Y. , Liew Yi Juin , Bolus Michael F. , Stoy William M. , Forest Craig R. , Stanley Garrett B.
Published: October 2020

Rapid sensory adaptation is observed across all sensory systems, and strongly shapes sensory percepts in complex sensory environments. Yet despite its ubiquity and likely necessity for survival, the mechanistic basis is poorly understood. A wide range of primarily in-vitro and anesthetized studies have demonstrated the emergence of adaptation at the level of primary sensory cortex, with only modest signatures in earlier stages of processing. The nature of rapid adaptation and how it shapes sensory representations during wakefulness, and thus the potential role in perceptual adaptation, is underexplored, as are the mechanisms that underlie this phenomenon. To address these knowledge gaps, we recorded spiking activity in primary somatosensory cortex (S1) and the upstream ventral posteromedial (VPm) thalamic nucleus in the vibrissa pathway of awake male and female mice, and quantified responses to whisker stimuli delivered in isolation and embedded in an adapting sensory background. We found that cortical sensory responses were indeed adapted by persistent sensory stimulation; putative excitatory neurons were profoundly adapted, and inhibitory neurons only modestly so. Further optogenetic manipulation experiments and network modeling suggest this largely reflects adaptive changes in synchronous thalamic firing combined with robust engagement of feedforward inhibition, with little contribution from synaptic depression. Taken together, these results suggest that cortical adaptation in the regime explored here results from changes in the timing of thalamic input, and the way in which this differentially impacts cortical excitation and feedforward inhibition, pointing to a prominent role of thalamic gating in rapid adaptation of primary sensory cortex.

Significance Statement

Rapid adaptation of sensory activity strongly shapes representations of sensory inputs across all sensory pathways over the timescale of seconds, and has profound effects on sensory perception. Despite its ubiquity and theoretical role in the efficient encoding of complex sensory environments, the mechanistic basis is poorly understood, particularly during wakefulness. In this study in the vibrissa pathway of awake mice, we show that cortical representations of sensory inputs are strongly shaped by rapid adaptation, and that this is mediated primarily by adaptive gating of the thalamic inputs to primary sensory cortex and the differential way in which these inputs engage cortical sub-populations of neurons.
Mechanistic model of nutrient uptake explains dichotomy between marine oligotrophic and copiotrophic bacteria
Authors: Norris Noele , Levine Naomi M. , Fernandez Vicente I. , Stocker Roman
Published: October 2020

Marine heterotrophic bacteria use a spectrum of nutrient uptake strategies, from that of copiotrophs—which dominate in nutrient-rich environments—to that of oligotrophs—which dominate in nutrient-poor environments. While copiotrophs possess numerous phosphotransferase systems (PTS), oligotrophs lack PTS and rely on ATP-binding cassette (ABC) transporters, which use binding proteins. Here we present a molecular-level model that explains the dichotomy between oligotrophs and copiotrophs as the consequence of trade-offs between PTS and ABC transport. When we approximate ABC transport in Michaelis–Menten form, we find, contrary to the canonical formulation, that its half-saturation concentrationKMis not a constant but instead a function of binding protein abundance. Thus, oligotrophs can attain nanomolarKMvalues using binding proteins with micromolar dissociation constants and while closely matching transport and metabolic capacities. However, this requires large periplasms and high abundances of binding proteins, whose slow diffusion limits uptake rate. We conclude that the use of binding proteins is critical for oligotrophic survival yet severely constrains maximal growth rates, thus fundamentally shaping the divergent evolution of oligotrophs and copiotrophs.
Structural basis for the initiation of COPII vesicle biogenesis
Authors: Joiner Aaron M.N. , Fromme J. Christopher
Published: October 2020

The first stage of the eukaryotic secretory pathway is the packaging of cargo proteins into COPII vesicles exiting the endoplasmic reticulum (ER). The cytoplasmic COPII vesicle coat machinery is recruited to the ER membrane by the activated, GTP-bound, form of the conserved Sar1 GTPase. Activation of Sar1 on the surface of the ER by Sec12, a membrane-anchored GEF (guanine nucleotide exchange factor), is therefore the initiating step of the secretory pathway. Here we report the structure of the complex between Sar1 and the cytoplasmic GEF domain of Sec12, both fromSaccharomyces cerevisiae. This structure, representing the key nucleotide-free activation intermediate, reveals how the potassium ion-binding K-loop disrupts the nucleotide binding site of Sar1. We describe an unexpected orientation of the GEF domain relative to the membrane surface and propose a mechanism for how Sec12 facilitates membrane insertion of the amphipathic helix exposed by Sar1 upon GTP-binding.
An exploratory analysis of the current chemical regulations and guidelines from the perspective of endocrine disrupting chemicals using public resources
Authors: Shanmugam Karthikeyan Bagavathy , Ravichandran Janani , Aparna S. R. , Samal Areejit
Published: October 2020

The regulatory assessment of endocrine disrupting chemicals (EDCs) is complex due to the lack of a standardized definition of EDCs and validated testing criteria. In spite of these challenges, there is growing scientific interest in EDCs which has resulted in the rapid expansion of published literature on endocrine disruption upon chemical exposure. Here, we explore how academic research leading to curated knowledgebases can inform current chemical regulations on EDCs. To this end, we present an updated knowledgebase, DEDuCT 2.0, containing 792 potential EDCs with supporting evidence from 2218 research articles. Thereafter, we study the distribution of potential EDCs across several chemical lists that reflect guidelines for use or regulations. Further, to understand the scale of possible exposure to the potential EDCs present in chemical lists, we compare them with high production volume chemicals. Notably, we find many potential EDCs are in use across various product categories such as ‘Food additives and Food contact materials’ and ‘Cosmetics and household products’. Several of these EDCs are also produced or manufactured in high volume across the world. Lastly, we illustrate using an example how diverse information in curated knowledgebases such as DEDuCT 2.0 can be helpful in the risk assessment of EDCs. In sum, we highlight the need to bridge the gap between academic and regulatory aspects of chemical safety, as a step towards the better management of environment and health hazards such as EDCs.
ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype
Authors: Corbet Marlene , Pineda Miguel A , Yang Kun , Tarafdar Anuradha , McGrath Sarah , Nakagawa Rinako , Lumb Felicity E , Harnett William , Harnett Margaret M
Published: October 2020

The parasitic worm product, ES-62 protects against collagen-induced arthritis, a mouse model of rheumatoid arthritis (RA) by suppressing the synovial fibroblast (SF) responses perpetuating inflammation and driving joint destruction. Such SF responses are shaped during disease progression by the inflammatory microenvironment of the joint that promotes remodelling of their epigenetic landscape, inducing an “aggressive” pathogenic SF phenotype. Critically, exposure to ES-62 in vivo induces a stably imprinted “safe” phenotype that exhibits responses more typical of healthy SFs. Surprisingly however, DNA methylome analysis reveals that rather than simply preventing the pathogenic rewiring of SFs, ES-62 induces further epigenetic remodelling, including targeting genes associated with ciliogenesis and differentiation, to program a distinct “protective” phenotype. Such unique behaviour signposts potential DNA methylation signatures predictive of pathogenesis and its resolution and hence, candidate mechanisms by which novel therapeutic interventions could prevent SFs from perpetuating joint inflammation and destruction in RA.
Time-dependent synergy for multi-agent anticancer therapy
Authors: Fujarewicz Krzysztof , Łakomiec Krzysztof
Published: October 2020

A synergy between two therapeutic agents occurs when the effect of using both is greater than the sum of the effects of using each of them separately. There are several methods of detecting synergies in the literature, but they do not take into account the relationship between the times in which the factors act. In the article, we propose and justify the use of second-order sensitivity analysis as a potential tool for the detection and visualization of this type of synergy. We test and illustrate the proposed approach using four exemplary models of combined radio-chemotherapy of cancer.
Protein-bound molybdenum cofactor is bioavailable and rescues molybdenum cofactor-deficientC. elegans
Authors: Warnhoff Kurt , Hercher Thomas W. , Mendel Ralf R. , Ruvkun Gary
Published: October 2020

The molybdenum cofactor (Moco) is a 520 dalton prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco-biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy, however the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematodeCaenorhabditis eleganscan take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up byC. elegansfrom its diet and is an effective dietary supplement, rescuing aC.elegansmodel of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.
ATF6 aggravates angiogenesis-osteogenesis coupling during ankylosing spondylitis by mediating FGF2 expression in chondrocytes
Authors: Ma Mengjun , Li Hongyu , Wang Peng , Yang Wen , Mi Rujia , Jiang Yuhang , Lu Yixuan , Shen Xin , Sui Pengfei , Wu Yanfeng , Shen Huiyong
Published: October 2020

Although angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in AS patients. Firstly, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and AS patient cartilage. The pro-angiogenic ability of human chondrocytes was enhanced through activated ATF6-FGF2 axis following long-term stimulation with inflammatory factors, e.g. TNF-α, IFN-γ or IL-17.

Mechanistically, ATF6 interacted with theFGF2promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesisin vitroand angiogenesis-osteogenesis couplingin vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.
An inverse modelling study on the local volume changes during early morphoelastic growth of the fetal human brain
Authors: Wang Z. , Martin B. , Weickenmeier J. , Garikipati K.
Published: October 2020

We take a data-driven approach to deducing the local volume changes accompanying early development of the fetal human brain. Our approach uses fetal brain atlas MRI data for the geometric changes in representative cases. Using a nonlinear continuum mechanics model of morphoelastic growth, we invert the deformation obtained from MRI registration to arrive at a field for the growth deformation gradient tensor. Our field inversion uses a combination of direct and adjoint methods for computing gradients of the objective function while constraining the optimization by the physics of morphoelastic growth. We thus infer a growth deformation gradient field that obeys the laws of morphoelastic growth. The errors between the MRI data and the forward displacement solution driven by the inverted growth deformation gradient field are found to be smaller than the reference displacement by well over an order of magnitude, and can be driven even lower. The results thus reproduce the three-dimensional growth during the early development of the fetal brain with controllable error. Our findings confirm that early growth is dominated by in plane cortical expansion rather than thickness increase.
Wide and Deep Learning for Automatic Cell Type Identification
Authors: Wilson Christopher M. , Fridley Brooke L. , Conejo-Garcia José , Wang Xuefeng , Yu Xiaoqing
Published: October 2020

Cell type classification is an important problem in cancer research, especially with the advent of single cell technologies. Correctly identifying cells within the tumor microenvironment can provide oncologists with a snapshot of how a patient’s immune system is reacting to the tumor. Wide deep learning (WDL) is an approach to construct a cell-classification prediction model that can learn patterns within high-dimensional data (deep) and ensure that biologically relevant features (wide) remain in the final model. In this paper, we demonstrate that the use of regularization can prevent overfitting and adding a wide component to a neural network can result in a model with better predictive performance. In particular, we observed that a combination of dropout andℓ2regularization can lead to a validation loss function that does not depend on the number of training iterations and does not experience a significant decrease in prediction accuracy compared to models withℓ1, dropout, or no regularization. Additionally, we show WDL can have superior classification accuracy when the training and testing of a model is completed data on that arise from the same cancer type, but from different platforms. More specifically, WDL compared to traditional deep learning models can substantially increase the overall cell type prediction accuracy (41 to 90%) and T-cell sub-types (CD4: 0 to 76%, and CD8: 61 to 96%) when the models were trained using melanoma data obtained from the 10X platform and tested on basal cell carcinoma data obtained using SMART-seq.
Speckle correlation as a monitor of X-ray free-electron laser induced crystal lattice deformation
Authors: Plumley Rajan , Sun Yanwen , Teitelbaum Samuel , Song Sanghoon , Sato Takahiro , Chollet Matthieu , Nelson Silke , Wang Nan , Sun Peihao , Robert Aymeric , Fuoss Paul , Sutton Mark , Zhu Diling
Published: October 2020

X-ray free-electron lasers (X-FELs) present new opportunities to study ultrafast lattice dynamics in complex materials. While the unprecedented source brilliance enables high fidelity measurement of structural dynamics, it also raises experimental challenges related to the understanding and control of beam-induced irreversible structural changes in samples that can ultimately impact the interpretation of experimental results. This is also important for designing reliable high performance X-ray optical components. In this work, X-FEL beam-induced lattice alterations are investigated by measuring the shot-to-shot evolution of near-Bragg coherent scattering from a single crystalline germanium sample. It is shown that X-ray photon correlation analysis of sequential speckle patterns measurements can be used to monitor the nature and extent of lattice rearrangements. Abrupt, irreversible changes are observed following intermittent high-fluence monochromatic X-ray pulses, thus revealing the existence of a threshold response to X-FEL pulse intensity.
A history of university income in the United Kingdom and Australia, 1922–2017
Authors: Pietsch Tamson
Published: October 2020

Purpose

The purpose of this paper is to create comparable time series data on university income in Australia and the UK that might be used as a resource for those seeking to understand the changing funding profile of universities in the two countries and for those seeking to investigate how such data were produced and utilised.

Design/methodology/approach

A statistical analysis of university income from all sources in the UK and Australia.

Findings

The article produces a new time series for Australia and a comparable time series for the UK. It suggests some of the ways these data related to broader patterns of economic change, sketches the possibility of strategic influence, and outlines some of their limitations.

Originality/value

This is the first study to systematically create a time series on Australian university income across the twentieth century and present it alongside a comparable dataset for the UK.
Investigating consumer behaviour for environmental, sustainable and social apparel
Authors: Byrd Kerri , Su Jin
Published: October 2020

Purpose

The purpose of this study is to investigate consumers' perceptions of and consumer behaviour towards apparel labels and environmental, sustainable and social apparel.

Design/methodology/approach

Quantitative research was conducted, and empirical data were collected from 399 US consumers.

Findings

Findings indicate that consumers expressed positive sentiments towards apparel sustainability, yet they lacked knowledge about socially and environmental practices within the apparel industry. Overall, it is apparent that the respondents have an interest in environmental and social labelling; but they are not aware of brands that sell these types of garments nor their validity. It was also found that consumers may not have much knowledge regarding environmental, sustainable and social apparel or their meanings.

Originality/value

By surveying the consumers about their perspectives on apparel labels and environmental, sustainable and social apparel, valuable market information was obtained. Sustainably and ethically produced garments are of demand as transparency in the apparel industry grows. Brands looking to become more transparent about their production methods will need to find new ways to reach their target market by accurately labelling products and educating their consumers about these label claims.
The development of inter-regional and intra-regional cooperation frameworks for multi-hazard early warning systems in South and South-East Asia
Authors: Borg Ruben Paul , Borg Axisa Glorianne , Ophiyandri Taufika , Hakam Abdul
Published: October 2020

Purpose

This paper aims to provide a framework for building resilience to coastal hazards with reference to Asian nations at the local, intra-regional and inter-regional levels. This framework provides a roadmap that will enable higher education institutions in the region to play a significant role in educating and training new leaders for disaster risk reduction (DRR) and in working directly with local communities to implement plans.

Design/methodology/approach

Events such as the 2004 tsunami highlighted the transboundary nature of coastal hazard and the importance of regional cooperation. A framework for inter- and intra-regional cooperation was developed through focus groups organised with community participants in five Asian nations exposed to coastal risks: Sri Lanka, Maldives, Myanmar, Indonesia and the Philippines.

Findings

Different stakeholders assessed inter- and intra-regional cooperation at different levels as a means to provide a baseline scenario to develop a capacity-building roadmap for such cooperation. The discussions organised through structured face-to-face encounters considered cooperation at different scales: international, regional, national and local. The framework key areas were developed and included knowledge databases, data and resource sharing and exchange education programmes.

Originality/value

Multi-hazard early warning for more resilient coastal communities is increasingly complex in view of the discourse related to the wider economic and social environments. The research proposes a framework for inter- and intra-regional cooperation at different scales; from local to regional and to the inter-continental dimensions and even through a bottom-up approach, together with the experts’ and managing authorities’ top-down positions.
Sentiment urgency emotion conversion over time for business intelligence
Authors: Soussan Tariq , Trovati Marcello
Published: October 2020

Purpose

Social media has become a vital part of any institute’s marketing plan. Social networks benefit businesses by allowing them to interact with their clients, grow brand exposure through offers and promotions and find new leads. It also offers vital information concerning the general emotions and sentiments directly connected to the welfare and security of the online community involved with the brand. Big organizations can make use of their social media data to generate planned and operational decisions. This paper aims to look into the conversion of sentiments and emotions over time.

Design/methodology/approach

In this work, a model called sentiment urgency emotion detection (SUED) from previous work will be applied on tweets from two different periods of time, one before the start of the COVID-19 pandemic and the other after it started to monitor the conversion of sentiments and emotions over time. The model has been trained to improve its accuracy and F1 score so that the precision and percentage of correctly predicted texts is high. This model will be tuned to improve results (Soussan and Trovati, 2020a; Soussan and Trovati, 2020b) and will be applied on a general business Twitter account of one of the largest chains of supermarkets in the UK to be able to see what sentiments and emotions can be detected and how urgent they are.

Findings

This will show the effect of COVID-19 pandemic on the conversions of the sentiments, emotions and urgencies of the tweets.

Originality/value

Sentiments will be compared between the two periods to evaluate how sentiments and emotions vary over time taking into consideration the COVID-19 as an affective factor. In addition, SUED will be tuned to enhance results and the knowledge that is mined when turning data into decisions is crucial because it will aid stakeholders handling the institute to evaluate the topics and issues that were mostly emphasized.