bluuebunny/crossref_metadata_2025_split huggingface dataset:
Demography, class-structure and kin selection in continuous-time models
Authors: Rodrigues António M. M. 
Published: October 2018

AbstractThe Wright-Fisher infinite island model and the neighbour-modulated approach to kin selection have enabled major advances in the understanding of social evolution in a demographic context. Due to structural assumptions, however, some important evolutionary problems are difficult to solve within the Wright-Fisher discrete-time framework. Although these major constraints are relaxed in the Moran continuous-time framework, a formal treatment of the mathematics of kin selection in continuous-time class-structured populations is still lacking. Here, I employ the neighbour-modulated approach to formalise key features of the kin selection theory in continuous-time infinite-island models. Next, I derive a general form of Hamilton’s rule to enable an inclusive fitness interpretation of social behaviours. I consider class-structure at the group and individual level, and I focus on conditional and unconditional phenotypes. I illustrate how the general theory can be applied to solve a wide range of biological problems. Finally, I show how a simple extension of the framework allows for the study of problems pertaining to the transmission of parental quality. I show that while inheritance of parental quality may either promote or inhibit selection on conditional helping behaviours, unconditional behaviours are invariant with respect to the fidelity of inheritance.
Reducing RF-induced Heating near Implanted Leads through High-Dielectric Capacitive Bleeding of Current (CBLOC)
Authors: Golestanirad Laleh , Angelone Leonardo M , Kirsch John , Downs Sean , Keil Boris , Bonmassar Giorgio , Wald Lawrence L 
Published: October 2018

AbstractPatients with implanted medical devices such as deep brain stimulation or spinal cord stimulation are often unable to receive magnetic resonance imaging (MRI). This is because once the device is within the radiofrequency (RF) field of the MRI scanner, electrically conductive leads act as antenna, amplifying the RF energy deposition in the tissue and causing possible excessive tissue heating. Here we propose a novel concept in lead design in which 40cm lead wires are coated with a ~1.2mm layer of high dielectric constant material (155 < εr < 250) embedded in a weakly conductive insulation (σ = 20 S/m). The technique called High-Dielectric Capacitive Bleeding of Current, or CBLOC, works by forming a distributed capacitance along the lengths of the lead, efficiently dissipating RF energy before it reaches the exposed tip. Measurements during RF exposure at 64 MHz and 123 MHz demonstrated that CBLOC leads generated 20-fold less heating at 1.5 T, and 40-fold less heating at 3 T compared to control leads. Numerical simulations of RF exposure at 297 MHz (7T) predicted a 15-fold reduction in specific absorption rate (SAR) of RF energy around the tip of CBLOC leads compared to control leads.
Multiparameter cell characterization using nanofluidic technology facilitates real-time phenotypic and genotypic elucidation of intratumor heterogeneity
Authors: Beaumont Kristin G. , Hamou Wissam , Bozinovic Nenad , Silvers Thomas R. , Shah Hardik , Dave Arpit , Allette Kimaada , Strahl Maya , Wang Ying-chih , Arib Hanane , Antoine Alesia , Ellis Ethan , Smith Melissa , Bruhn Brandon , Dottino Peter , Martignetti John A. , Schadt Eric , White Mark , Sebra Robert 
Published: October 2018

ABSTRACTGenetic and functional complexity of bulk tumor has become evident through rapid advances in sequencing technologies. As a unique integrated approach to characterizing tumor heterogeneity, we demonstrate the multifaceted capabilities of a novel nanofluidic platform to enable single-cell phenotypic and genetic profiling of ovarian cancer patient-derived tumor cells. This approach has enabled increased resolution of tumor cell phenotypic and genetic heterogeneity, providing a better understanding of underlying biological drivers of the disease. A range of CA-125 expression levels is observed within cells from individuals, demonstrating clonal diversity consistent with other phenotypic data. Further, TP53 mutation analysis demonstrates a sub-population of cells exhibiting high mutation frequency that likely drives downstream growth kinetics and protein expression. Finally, genomic data is orthogonally used to address clonal heterogeneity across ovarian tumors when compared to bulk sequencing, illustrating the potential for single-cell sequencing data integrated with cellular functional and growth data toward future therapeutic intervention.
The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote resistance to endoplasmic reticulum stress
Authors: Schmidt Rolf M. , Schuck Sebastian 
Published: October 2018

ABSTRACTMisfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.
Reconstructing and characterizing focal amplifications in cancer using AmpliconArchitect
Authors: Deshpande Viraj , Luebeck Jens , Bakhtiari Mehrdad , Nguyen Nam-Phuong D , Turner Kristen M , Schwab Richard , Carter Hannah , Mischel Paul S , Bafna Vineet 
Published: October 2018

AbstractFocal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We developed a tool, AmpliconArchitect (AA), which can robustly reconstruct the fine structure of focally amplified regions using whole genome sequencing. AA-reconstructed amplicons in pan-cancer data and in virus-driven cervical cancer samples revealed many novel insights about focal amplifications. Specifically, the findings lend support to extrachromosomally mediated mechanisms for copy number expansion, and oncoviral pathogenesis.
The molecular pH-response mechanism of the plant light-stress sensor PsbS
Authors: Krishnan-Schmieden Maithili , Konold Patrick E. , Kennis John T.M. , Pandit Anjali 
Published: October 2018

AbstractPlants need to protect themselves from excess light, which causes photo-oxidative damage and lowers the efficiency of photosynthesis. Photosystem II subunit S (PsbS) is a pH sensor protein that plays a crucial role in plant photoprotection by detecting thylakoid lumen acidification in excess light conditions via two lumen-faced glutamates. However, how PsbS is activated under low-pH conditions is unknown. To reveal the molecular response of PsbS to low pH, we performed an NMR and infrared spectroscopic analysis ofPhyscomitrella patensPsbS and of the E176Q mutant in which an active glutamate has been replaced. The PsbS response mechanism at low pH involves the concerted action of repositioning of a short amphipathic helix containing E176 facing the lumen and folding of the luminal loop fragment adjacent to E71 to a 310-helix, providing clear evidence of a conformational pH switch. We propose that this concerted mechanism is a shared motif of proteins of the light-harvesting family that may control thylakoid inter-protein interactions driving photoregulatory responses.
Physiological genomics of dietary adaptation in a marine herbivorous fish
Authors: Heras Joseph , Chakraborty Mahul , Emerson J.J. , German Donovan P. 
Published: October 2018

AbstractAdopting a new diet is a significant evolutionary change and can profoundly affect an animal’s physiology, biochemistry, ecology, and its genome. To study this evolutionary transition, we investigated the physiology and genomics of digestion of a derived herbivorous fish, the monkeyface prickleback (Cebidichthys violaceus). We sequenced and assembled its genome and digestive transcriptome and revealed the molecular changes related to important dietary enzymes, finding abundant evidence for adaptation at the molecular level. In this species, two gene families experienced expansion in copy number and adaptive amino acid substitutions. These families, amylase, and bile salt activated lipase, are involved digestion of carbohydrates and lipids, respectively. Both show elevated levels of gene expression and increased enzyme activity. Because carbohydrates are abundant in the prickleback’s diet and lipids are rare, these findings suggest that such dietary specialization involves both exploiting abundant resources and scavenging rare ones, especially essential nutrients, like essential fatty acids.
Reduced variation in Wolbachia density of larval stages in comparison with adults of Onchocerca volvulus: implications for clinical outcome of infection?
Authors: Armoo Samuel , Doyle Stephen R , Hedtke Shannon M , Adjami Gilles A , Boakye Daniel A , Kuesel Annette C , Osei-Atweneboana Mike Y , Grant Warwick N 
Published: October 2018

AbstractBackgroundWolbachia are important endosymbionts of filarial parasites. The Wolbachia of Onchocerca volvulus, the filarial pathogen responsible for the human disease onchocerciasis, is implicated in the immunopathology of the disease and may be associated with disease severity dependent on the density of Wolbachia. However, little is known in regards to the density and heterogeneity of Wolbachia in microfilariae, the life stage that is thought to be responsible for the pathology.ResultsWe used a real-time qPCR relative copy number assay to estimate the number of Wolbachia genome(s) per nuclear genome of skin microfilariae (Mf), vector L1 and iL3, and nodulectomy adult male and female O. volvulus worms sampled in Ghana and the Democratic Republic of the Congo. Relatively low median Wolbachia copy numbers and variation was observed in the Mf and vector stages, in contrast to significantly higher median and more variable Wolbachia copy number from the iL3 stage to the adult worm stages.ConclusionsThis study provides the first insight into variation in Wolbachia density between the major life stages of the parasite. The relatively invariant ratios observed for Mf and vector stages is in strong contrast to the high degree of variability of Wolbachia to nuclear ratios in adults and may indicate that the mutualistic relationship between the nematode and Wolbachia in these earlier stages is regulated differently, and certainly more stringently, than the relationship in adults.
Dynamics of transposable element invasions with piRNA clusters
Authors: Kofler Robert 
Published: October 2018

AbstractIn mammals and in invertebrates the proliferation of a newly invading transposable element (TE) is thought to be stopped by a random insertion of one member of the invading TE family into a piRNA cluster. This view is known as the trap model. Here we explore the dynamics of TE invasions under the trap model using large-scale computer simulations. We found that piRNA clusters confer a substantial benefit, effectively preventing extinction of host populations from an uncontrollable proliferation of deleterious TEs. We show that TE invasions under the trap model consists of three distinct phases: first the TE rapidly amplifies within the population, next TE proliferation is stopped by segregating cluster insertions and finally the TE is permanently inactivated by fixation of a cluster insertion. Suppression by segregating cluster insertions is unstable and bursts of TE activity may yet occur. The transpositon rate and the population size mostly influence the length of the phases but not the amount of TEs accumulating during an invasion. Solely the size of piRNA clusters was identified as a major factor influencing TE abundance. Investigating the impact of different cluster architectures we found that a single non-recombining cluster (e.g. the somatic cluster flamenco in Drosophila) is more efficient in stopping invasions than clusters distributed over several chromosomes (e.g germline cluster in Drosophila). With the somatic architecture fewer TEs accumulate during an invasion and fewer cluster insertions are required to stop the TE. The inefficiency of the germline architecture stems from recombination among cluster sites which makes it necessary that each diploid carries, on the average, four cluster insertions, such that most individuals will end up with at least one cluster insertion. Surprisingly we found that negative selection in a model with piRNA clusters can lead to a novel equilibrium state, where TE copy numbers remain stable despite only some individuals in a population carrying a cluster insertion. Finally when applying our approach to real data fromDrosophila melanogasterwe found that the trap model reasonably well accounts for the abundance of germline TEs but not of somatic TEs. The abundance of somatic TEs, such as gypsy, is much lower than expected.
High-resolution models of actin-bound myosin from EPR of a bifunctional spin label
Authors: Binder Benjamin P. , Thompson Andrew R. , Thomas David D. 
Published: October 2018

AbstractWe have employed two complementary high-resolution electron paramagnetic resonance (EPR) techniques with a bifunctional spin label (BSL) to test and refine protein structural models based on crystal structures and cryo-EM. We demonstrate this approach by investigating the effects of nucleotide binding on the structure of myosin’s catalytic domain (CD), while myosin is in complex with actin. Unlike conventional spin labels attached to single Cys, BSL reacts with a pair of Cys; in this study, we thoroughly characterize BSL’s rigid, highly stereoselective attachment to protein α-helices, which permits accurate measurements of orientation and distance. Distance constraints were obtained from double electron-electron resonance (DEER) on myosin constructs labeled with BSL specifically at two sites. Constraints for orientation of individual helices were obtained previously from continuous-wave EPR (CW-EPR) of myosin labeled at specific sites with BSL in oriented muscle fibers. We have shown previously that CW-EPR of BSL quantifies helix orientation within actin-bound myosin; here we show that the addition of high-resolution distance constraints by DEER alleviates remaining spatial ambiguity, allowing for direct testing and refinement of atomic structural models. This approach is applicable to any orientable complex (e.g., membranes or filaments) in which site-specific di- Cys mutation is feasible.
Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures
Authors: Li Shuai , Dugué Pierre-Antoine , Baglietto Laura , Severi Gianluca , Wong Ee Ming , Nguyen Tuong L. , Stone Jennifer , English Dallas R. , Southey Melissa C. , Giles Graham G. , Hopper John L. , Milne Roger L. 
Published: November 2018

AbstractAge- and body mass index (BMI)-adjusted mammographie density is one the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie interindividual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, non-dense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant(P<10−7)association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all P>0.05/299 = 1.7 × 10−4). In summary, our study did not detect associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
Stochastic bacterial population dynamics prevent the emergence of antibiotic resistance from single cells
Authors: Alexander Helen K. , MacLean R. Craig 
Published: October 2018

AbstractA better understanding of how antibiotic exposure impacts the evolution of resistance is crucial for designing more sustainable treatment strategies. The conventional approach to relating antibiotic dose to resistance evolution within a bacterial population is to measure the range of concentrations over which resistant strain(s) are selectively favoured over a sensitive strain – the “mutant selection window”. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer. Using twoPseudomonas aeruginosastrains carrying distinct resistance plasmids, we show that single resistant cells have <5% probability of outgrowth at antibiotic concentrations as low as 1/8thof the resistant strain’s minimum inhibitory concentration. This low probability of establishment is due to detrimental effects of antibiotics on resistant cells, coupled with the inherently stochastic nature of cell division and death on the single-cell level, which leads to loss of many nascent resistant lineages. Our findings suggest that moderate doses of antibiotics, within the traditional mutant selection window, may be more effective at preventingde novoemergence of resistance than predicted by deterministic approaches.Significance statementThe emergence of antibiotic resistance poses a critical threat to the efficacy of antibiotic treatments. A resistant bacterial population must originally arise from a single cell that mutates or acquires a resistance gene. This single cell may, by chance, fail to successfully reproduce before it dies, leading to loss of the nascent resistant lineage. Here we show that antibiotic concentrations that selectively favour resistance are nonetheless sufficient to reduce the chance of outgrowth from a single cell to a very low probability. Our findings suggest that lower antibiotic concentrations than previously thought may be sufficient to prevent, with high probability, emergence of resistance from single cells.
A risk-reward tradeoff of high ribosome production in proliferating cells
Authors: Tye Blake W. , Commins Nicoletta , Springer Michael , Pincus David , Churchman L. Stirling 
Published: October 2018

AbstractTo achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs), which are required to produce thousands of new ribosomes every minute. Although ribosomes are essential in all cells, disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we modeled these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result immediately in acute loss of proteostasis (protein folding homeostasis). Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes. In response, proteostasis genes are activated by an Hsf1-dependent stress response pathway that is required for recovery from r-protein assembly stress. Importantly, we show that exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. Our results highlight ribosome assembly as a linchpin of cellular homeostasis, representing a key proteostasis vulnerability for rapidly proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic conditions that generate orphan r-proteins.
Laboratory contamination over time during low-biomass sample analysis
Authors: Weyrich Laura S. , Farrer Andrew G. , Eisenhofer Raphael , Arriola Luis A. , Young Jennifer , Selway Caitlin A. , Handsley-Davis Matilda , Adler Christina , Breen James , Cooper Alan 
Published: November 2018

AbstractBacteria are not only ubiquitous on earth but can also be incredibly diverse within clean laboratories and reagents. The presence of both living and dead bacteria in laboratory environments and reagents is especially problematic when examining samples with low endogenous content (e.g.skin swabs, tissue biopsies, ice, water, degraded forensic samples, or ancient material), where contaminants can outnumber endogenous microorganisms within samples. The contribution of contaminants within high-throughput studies remains poorly understood because of the relatively low number of contaminant surveys. Here, we examined 144 negative control samples (extraction blank and no-template amplification controls) collected in both typical molecular laboratories and an ultraclean ancient DNA laboratory over five years to characterize long-term contaminant diversity. We additionally compared the contaminant content within a homemade silica-based extraction method, commonly used to analyse low-endogenous samples, with a widely used commercial DNA extraction kit. The contaminant taxonomic profile of the ultraclean ancient DNA laboratory was unique compared to the modern molecular biology laboratories, and changed over time according to researchers, month, and season. The commercial kit contained higher microbial diversity and several human-associated taxa in comparison to the homemade silica extraction protocol. We recommend a minimum of two strategies to reduce the impacts of laboratory contaminants within low-biomass metagenomic studies: 1) extraction blank controls should be included and sequenced with every batch of extractions and 2) the contributions of laboratory contamination should be assessed and reported in each high-throughput metagenomic study.