bluuebunny/crossref_metadata_2025_split huggingface dataset:
Passage of transmissible cancers in the Tasmanian devil is due to a dominant, shared peptide motif and a limited repertoire of MHC-I allotypes
Authors: Gastaldello A , Ramarathinam SH , Bailey A , Owen R , Turner S , Kontouli A , Elliott T , Skipp P , Purcell AW , Siddle HV 
Published: July 2020

AbstractTransmissible cancers are spread via the passage of malignant cells. The survival of the Tasmanian devil, the largest marsupial carnivore, is threatened by two independent transmissible cancers, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a peptide vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to Major Histocompatibility Complex class I molecules from the Tasmanian devil and its transmissible tumours. Comparison of the peptidomes from DFT1+IFNγ, DFT2 and host fibroblast cells demonstrates a shared motif, despite differences in MHC-I allotypes between the cell lines. Importantly, DFT1+IFNγ and DFT2 share the presentation of peptides derived from neural proteins, reflecting a common cellular origin that should be exploited for vaccine design. These results suggest that some polymorphisms between tumours and host are ‘hidden’ by a common peptide motif, providing the potential for permissive passage of infectious cells.
Mechanics and Differential Healing Outcomes of Small and Large Defect Injuries of the Tendon-Bone Attachment in the Rat Rotator Cuff
Authors: Sullivan Anna Lia , Locke Ryan C. , Klink Rachel K. , Leek Connor C. , Killian Megan L. 
Published: July 2020

ABSTRACTThe size of rotator cuff tears affects clinical outcomes following rotator cuff repair and is correlated with risk of re-injury. This study aimed to understand how defect size influences the structural and mechanical outcomes of the injured rotator cuff attachmentin vivo. We used our previously established model of full-thickness injury of the rotator cuff tendon-bone attachment in Long Evans rats to compare differences in healing outcomes between small and large defects. Biomechanical properties, gross morphology, bone remodeling, and cell and tissue morphology were assessed at 3- or 8-weeks of healing. At the time of injury (no healing), large defects had decreased mechanical properties compared to small defects, and both defect sizes had decreased mechanical properties compared to intact attachments. The mechanical properties of the defect groups were comparable after 8-weeks of healing and significantly improved compared to no healing but failed to return to intact levels. Local bone volume at the defect site was higher in large compared to small defects on average and increased from 3- to 8-weeks. Contrastingly, bone quality, measured as bone volume percentage and trabecular morphometry, of the total epiphysis and greater tubercle decreased from 3- to 8-weeks of healing and these changes were not dependent on defect size. Qualitatively, we observed that large defects had increased disorganized collagen and neovascularization compared to small defects. In this study, we demonstrated that not only small but also large defects do not regenerate the mechanical and structural integrity of the intact rat rotator cuff attachment following healingin vivo.Statement of Clinical SignificanceOur rat model of full-thickness rotator cuff tears may be beneficial to understand and prevent tear enlargementin vivo.
Natural combinatorial genetics and prolific polyamine production enable siderophore diversification in Serratia plymuthica
Authors: Cleto Sara , Haslinger Kristina , Prather Kristala L.J. , Lu Timothy K. 
Published: July 2020

AbstractSiderophores are small molecules with unmatched capacity to scavenge iron from proteins and the extracellular milieu, where it mostly occurs as insoluble Fe3+. Siderophores chelate Fe3+for uptake into the cell, where it is reduced to soluble Fe2+. As iron is essential for bacterial survival, siderophores are key molecules in low soluble iron conditions. Bacteria have devised many strategies to synthesize proprietary siderophores to avoid siderophore piracy by competing organisms, e.g., by incorporating different polyamine backbones into siderophores, while maintaining the catechol moieties. We report thatSerratia plymuthicaV4 produces a variety of siderophores, which we term thesiderome, and which are assembled by the concerted action of enzymes encoded in two independent gene clusters. Besides assembling serratiochelin with diaminopropane,S. plymuthicautilizes putrescine and the same set of enzymes to assemble photobactin, a siderophore described forPhotorhabdus luminescens. The enzymes encoded by one of the gene clusters can independently assemble enterobactin. A third, independent operon is responsible for biosynthesis of the hydroxamate siderophore aerobactin, initially described inEnterobacter aerogenes. Mutant strains not synthesizing polyamine-siderophores significantly increased enterobactin production levels, though lack of enterobactin did not impact serratiochelin production. Knocking out SchF0, an enzyme involved in the assembly of enterobactin alone, significantly reduced bacterial fitness. This study illuminates the interplay between siderophore biosynthetic pathways and polyamine production superpathways, indicating routes of molecular diversification. Given its natural yields of diaminopropane (97.75 μmol/g DW) and putrescine (30.83 μmol/g DW),S. plymuthicacan be exploited for the industrial production of these compounds.Significance StatementSiderophores are molecules crucial for bacterial survival in low iron environments. Bacteria have evolved the capacity to pirate siderophores made by other bacterial strains and to diversify the structure of their own siderophores, to prevent piracy. We found thatSerratia plymuthicaV4 produces five different siderophores using three gene clusters and a polyamine production superpathway. The most well studied siderophore, enterobactin, rather than the strain’s proprietary and by far most abundant siderophore, serratiochelin, displayed a crucial role in the fitness ofS. plymuthica. Our results also indicate that this strain is a good candidate for engineering the large-scale production of diaminopropane (DAP), as without any optimization it produced the highest amounts of DAP reported for wild-type strains.
Prior hypotheses or regularization allow inference of diversification histories from extant timetrees
Authors: Morlon Hélène , Hartig Florian , Robin Stéphane 
Published: July 2020

AbstractPhylogenies of extant species are widely used to study past diversification dynamics1. The most common approach is to formulate a set of candidate models representing evolutionary hypotheses for how and why speciation and extinction rates in a clade changed over time, and compare those models through their probability to have generated the corresponding empirical tree. Recently, Louca & Pennell2reported the existence of an infinite number of ‘congruent’ models with potentially markedly different diversification dynamics, but equal likelihood, for any empirical tree (see also Lambert & Stadler3). Here we explore the implications of these results, and conclude that they neither undermine the hypothesis-driven model selection procedure widely used in the field nor show that speciation and extinction dynamics cannot be investigated from extant timetrees using a data-driven procedure.
Aminoglycoside antibiotics inhibit mycobacteriophage infection
Authors: Jiang Zheng , Wei Junwei , Peng Nan , Li Yingjun 
Published: July 2020

AbstractAntibiotic resistance is becoming the biggest current threat to global health. At the same time, phage therapy is witnessing a return of interest. The therapeutic use of bacteriophages, that infect and kill bacteria, is well suited to be a good strategy to combat antibiotic resistance. Furthermore, bacteriophages are increasingly used in combination with standard antibiotics against the drug-resistant pathogens. Interestingly, we found that the engineered mycobacteriophage phAE159 and natural phage D29 can not infect theMycobacterium tuberculosisin the presence of kanamycin, hygromycin or streptomycin, but there is no effect on the phage infection in the presence of spectinomycin. Based on a series of studies and structural analysis of the above four aminoglycoside antibiotics, we can speculate as to the mechanism by which amino sugar group of aminoglycoside was able to selectively inhibit mycobacteriophage DNA replication. This is a rare discovery that broad-spectrum antibiotics inhibit phage infection. We envisioned that this study will provide guidance for people to combine phage and antibiotics to treatM. tuberculosis.
Directed evolution reveals the mechanism of HitRS signal transduction inBacillus anthracis
Authors: Pi Hualiang , Chu Michelle L. , Ivan Samuel J. , Latario Casey J. , Toth Allen M. , Carlin Sophia M. , Hillebrand Gideon H. , Lin Hannah K. , Reppart Jared D. , Stauff Devin L. , Skaar Eric P. 
Published: July 2020

AbstractBacterial twocomponentsystems (TCSs) have been studied for decades; however, most work has focused on individual domains or proteins. Systematic characterization of an entire TCS could provide a mechanistic understanding of these important signal transduction systems. Here, genetic selections were employed to dissect the molecular basis of signal transduction by the HitRS system that has been implicated in detecting cell envelope stress in the pathogenBacillus anthracis. Numerous point mutations were isolated within HitRS, 17 of which were in a 50-residue HAMP domain. Mutational analysis revealed the importance of hydrophobic interactions within the HAMP domain and highlighted its essentiality in TCS signaling. In addition, these data defined residues critical for activities intrinsic to HitRS, uncovered specific interactions among individual domains and between the two signaling proteins, and revealed that phosphotransfer is the rate-limiting step for signal transduction. This study establishes the use of unbiased genetic selections to study TCS signaling, provides a comprehensive mechanistic understanding of an entire TCS, and lays the foundation for development of novel antimicrobial therapeutics against this important infectious threat.
Gradual Compaction of the Nascent Peptide During Cotranslational Folding on the Ribosome
Authors: Liutkute Marija , Maiti Manisankar , Samatova Ekaterina , Enderlein Jörg , Rodnina Marina V. 
Published: July 2020

ABSTRACTNascent polypeptides begin to fold in the constrained space of the ribosomal peptide exit tunnel. Here we use force profile analysis (FPA) and photo-induced energy-transfer fluorescence correlation spectroscopy (PET-FCS) to show how a small α-helical domain, the N-terminal domain of HemK, folds cotranslationally. Compaction starts vectorially as soon as the first α-helical segments are synthesized. As nascent chain grows, emerging helical segments dock onto each other and continue to rearrange at the vicinity of the ribosome. Inside or in the proximity of the ribosome, the nascent peptide undergoes structural fluctuations on the μs time scale. The fluctuations slow down as the domain moves away from the ribosome. Folding mutations have little effect on folding within the exit tunnel, but abolish the final domain stabilization. The results show the power of FPA and PET-FCS in solving the trajectory of cotranslational protein folding and in characterizing the dynamic properties of folding intermediates.
A self-regenerating synthetic cell model
Authors: Lavickova Barbora , Laohakunakorn Nadanai , Maerkl Sebastian J. 
Published: July 2020

AbstractSelf-regeneration is a fundamental function of all living systems. Here we demonstrate molecular self-regeneration in a synthetic cell model. By implementing a minimal transcription-translation system within microfluidic reactors, the system was able to regenerate essential protein components from DNA templates and sustained synthesis activity for over a day. By mapping genotype-phenotype landscapes combined with computational modeling we found that minimizing resource competition and optimizing resource allocation are both critically important for achieving robust system function. With this understanding, we achieved simultaneous regeneration of multiple proteins by determining the required DNA ratios necessary for sustained self-regeneration. This work introduces a conceptual and experimental framework for the development of a self-replicating synthetic cell.
Modelling the interplay between the CD4+/CD8+T-cell ratio and the expression of MHC-I in tumours
Authors: Hurry Christian John , Mozeika Alexander , Annibale Alessia 
Published: July 2020

AbstractDescribing the anti-tumour immune response as a series of cellular kinetic reactions from known immunological mechanisms, we create a mathematical model that shows the CD4+/CD8+T-cell ratio, T-cell infiltration and the expression of MHC-I to be interacting factors in tumour elimination. Methods from dynamical systems theory and non-equilibrium statistical mechanics are used to model the T-cell dependent anti-tumour immune response. Our model predicts a critical level of MHC-I expression which determines whether or not the tumour escapes the immune response. This critical level of MHC-I depends on the helper/cytotoxic T-cell ratio. However, our model also suggests that the immune system is robust against small changes in this ratio. We also find that T-cell infiltration and the specificity of the intra-tumour TCR repertoire will affect the critical MHC-I expression. Our work suggests that the functional form of the time evolution of MHC-I expression may explain the qualitative behaviour of tumour growth seen in patients.Mathematics Subject Classification (2010)MSC 37C25 · MSC 82C99 · MSC 37N25 · MSC 92B99
The role of population structure in computations through neural dynamics
Authors: Dubreuil Alexis , Valente Adrian , Beiran Manuel , Mastrogiuseppe Francesca , Ostojic Srdjan 
Published: July 2020

AbstractNeural computations are currently investigated using two separate approaches: sorting neurons into functional populations, or examining the low-dimensional dynamics of collective activity. Whether and how these two aspects interact to shape computations is currently unclear. Using a novel approach to extract computational mechanisms from networks trained on neuroscience tasks, here we show that the dimensionality of the dynamics and cell-class structure play fundamentally complementary roles. While various tasks can be implemented by increasing the dimensionality in networks with fully random population structure, flexible input-output mappings instead required a non-random population structure that can be described in terms of multiple sub-populations. Our analyses revealed that such a population structure enabled flexible computations through a mechanism based on gain-controlled modulations that flexibly shape the dynamical landscape of collective dynamics. Our results lead to task-specific predictions for the structure of neural selectivity, inactivation experiments, and for the implication of different neurons in multi-tasking.
Plasmodium bergheikinesin-5 associates with the spindle apparatus during cell division and is important for efficient production of infectious sporozoites
Authors: Zeeshan Mohammad , Brady Declan , Stanway Rebecca R. , Moores Carolyn A. , Holder Anthony A. , Tewari Rita 
Published: July 2020

AbstractKinesin-5 motors play essential roles in spindle apparatus assembly during cell division, by generating forces to establish and maintain the spindle bipolarity essential for proper chromosome segregation. Kinesin-5 is largely conserved structurally and functionally in model eukaryotes, but its role is unknown in thePlasmodiumparasite, an evolutionarily divergent organism with several atypical features of both mitotic and meiotic cell division. We have investigated the function and subcellular location of kinesin-5 during cell division throughout thePlasmodium bergheilife cycle. Deletion ofkinesin-5had little visible effect at any proliferative stage except sporozoite production in oocysts, resulting in a significant decrease in the number of motile sporozoites in mosquito salivary glands, which were able to infect a new vertebrate host. Live-cell imaging showed kinesin-5-GFP located on the spindle and at spindle poles during both atypical mitosis and meiosis. Fixed-cell immunofluorescence assays revealed kinesin-5 co-localized with α-tubulin and centrin-2 and a partial overlap with kinetochore marker NDC80 during early blood stage schizogony. Dual-colour live-cell imaging showed that kinesin-5 is closely associated with NDC80 during male gametogony, but not with kinesin-8B, a marker of the basal body and axonemes of the forming flagella. Treatment of gametocytes with microtubule-specific inhibitors confirmed kinesin-5 association with nuclear spindles and not cytoplasmic axonemal microtubules. Altogether, our results demonstrate that kinesin-5 is associated with the spindle apparatus, expressed in proliferating parasite stages, and important for efficient production of infectious sporozoites.
A stutter in the coiled coil domain ofE.colico-chaperone GrpE connects structure with function
Authors: Upadhyay Tulsi , Karekar Vaibhav V , Saraogi Ishu 
Published: July 2020

AbstractIn bacteria, the co-chaperone GrpE acts as a nucleotide exchange factor and plays an important role in controlling the chaperone cycle of DnaK. The functional form of GrpE is an asymmetric dimer, consisting of a long non-ideal coiled-coil. During heat stress, this region partially unfolds and prevents DnaK nucleotide exchange, ultimately ceasing the chaperone cycle. In this study, we elucidate the role of thermal unfolding of the coiled-coil domain ofE. coliGrpE in regulating its co-chaperonic activity. The presence of a stutter disrupts the regular heptad arrangement typically found in an ideal coiled coil resulting in structural distortion. Introduction of hydrophobic residues at the stutter altered the structural stability of the coiled-coil. Using an in vitro FRET assay, we show for the first time that the enhanced stability of GrpE resulted in an increased affinity for DnaK. However, the mutants were defective inin vitrofunctional assays, and were unable to support bacterial growth at heat shock temperature in agrpE-deletedE. colistrain. This work provides valuable insights into the functional role of a stutter in the GrpE coiled-coil, and its role in regulating the DnaK-chaperone cycle for bacterial survival during heat stress. More generally, our findings illustrate how a sequence specific stutter in a coiled-coil domain regulates the structure function trade-off in proteins.
Alcohol Dependence Differentially Alters Action and Outcome Related Orbitofrontal Cortex Activity
Authors: Cazares Christian , Schreiner Drew C. , Gremel Christina M. 
Published: July 2020

AbstractAlcohol dependence results in long-lasting deficits in decision-making and behavioral control. Neurobiological investigations have identified orbitofrontal cortex (OFC) as important for value contributions to decision-making as well as action control, and alcohol dependence induces long-lasting changes to OFC function that persist into protracted withdrawal. However, it is unclear which contributing OFC computations are disrupted in alcohol dependence. Here, we combined a well-validated mouse model of alcohol dependence with in vivo extracellular recordings during an instrumental task in which lever press duration serves as the contingency, and lever pressing is sensitive to outcome devaluation. We found prior alcohol dependence did not impair use of duration contingency control but did reduce sensitivity to outcome devaluation. Further, alcohol dependence increased OFC activity associated with lever-pressing but decreased OFC activity during outcome-related epochs. Hence, alcohol dependence induces a long-lasting disruption to OFC function such that activity associated with actions is enhanced, but OFC activity in relation to outcomes is diminished. This has important implications for hypotheses regarding compulsive and habitual phenotypes observed in addiction.
A Bayesian optimisation approach for rapidly mapping residual network function in stroke
Authors: Lorenz Romy , Johal Michelle , Dick Frederic , Hampshire Adam , Leech Robert , Geranmayeh Fatemeh 
Published: July 2020

AbstractPost-stroke cognitive and linguistic impairments are debilitating conditions, with current therapies only showing small improvements. Domain-general brain networks seem to play a critical role in stroke recovery and characterising their residual function with functional neuroimaging (fMRI) has the potential to yield biomarkers capable of guiding patient-specific rehabilitation. However, this is currently challenging in patients as such detailed characterisation requires too many different cognitive tasks. Here, we use neuroadaptive Bayesian optimisation to overcome this problem, an approach combining real-time fMRI with machine-learning. By intelligently searching across many tasks, this approach rapidly maps out patient-specific profiles of residual domain-general network function. Whereas controls have highly similar profiles, patients show idiosyncratic profiles of network abnormalities that are associated with behavioural performance. This approach can be extended to diverse brain networks and combined with brain stimulation or other therapeutics, thereby opening new avenues for precision medicine targeting diverse neurological and psychiatric conditions.
The Primary Tumor Immune Microenviornment Status Predicts the Response to Immunotherapy and Overall Survival in Breast Cancer
Authors: Moorthy Arjun , Quinn Aidan 
Published: July 2020

II.AbstractThe tumor immune microenvironment (TIME) of breast cancer is a known source of tumor heterogeneity and it has been increasingly recognized as having a role in the course of disease. In the present study, we used a computational approach to dissect the landscape of TIME states among TCGA breast cancer patients. Our central hypothesis is that the pre-existing TIME states represent a dimension which is informative about the prognosis and the response to immunotherapy. In order to test this hypothesis, we first classified breast cancer patients according to their primary TIME status. Next, we describe a TIME-based classification with prognostic value for overall survival among the TCGA patients. We further demonstrated that absolute quantification of mast cells, M0 macrophages, CD8 T cells and neutrophils were predictive of overall survival. In order to identify the TIME states which, predict response to immune checkpoint blockade, we performed a similar analysis of 11 different mouse models of primary invasive breast carcinoma that were subsequently treated with immune checkpoint inhibitor (ICI) therapy. These analyses revealed that the TIME content of M1 macrophages, monocytes and resting dendritic cells were predictive of sensitivity to ICI therapy. Taken together, these results indicate that (1) the landscape of human primary TIME states is diverse and can identify patients with more or less aggressive disease and (2) that pre-existing TIME states may be able to identify patients, of all molecular subtypes of breast cancer, who are good candidates for ICI therapy.