bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding
Authors: Wilson Genevieve C. K. , Buvoli Ada , Buvoli Massimo , Woulfe Kathleen C. , Walker Lori A. , Leinwand Leslie A. 
Published: September 2019

AbstractIntroductionMore than 400 mutations in β-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.MethodsBecause mice have very few slow skeletal muscles compared to humans, we generated mice expressing the β-myosin R1500P mutation or WT β-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation.ResultsThe mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules. Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate.ConclusionsWhile each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.
Enhancing natural killer cell function with gp41-targeting bispecific antibodies to combat HIV infection
Authors: Ramadoss Nitya S. , Zhao Nancy Q. , Richardson Barbra A. , Grant Philip M. , Kim Peter S. , Blish Catherine A. 
Published: September 2019

AbstractObjective(s)To develop and evaluate the activity of bispecific antibodies (bsAbs) to enhance NK cell antibody-dependent cellular cytotoxicity (ADCC) against HIV-infected cells.DesignThese bsAbs are based on patient-derived antibodies targeting the conserved gp41 stump of HIV Env, and also incorporate a high affinity scFv targeting the activating receptor CD16 on NK cells. Overall, we expect the bsAbs to provide increased affinity and avidity over their corresponding monoclonal antibodies, allowing for improved ADCC activity against Env-expressing target cells.MethodsbsAbs and their corresponding mAbs were expressed in 293T cells and purified. The binding of bsAbs and mAbs to their intended targets was determined using Bio-Layer Interferometry, as well as flow cytometry-based binding assays onin vitroinfected cells. The ability of these bsAbs to improve NK cell activity against HIV-infected cells was tested usingin vitroco-culture assays, using flow cytometry and calcein release to analyze NK cell degranulation and target cell killing, respectively.ResultsThe bsAbs bound gp41 with similar affinity to their corresponding mAbs, and had increased affinity for CD16. The bsAbs also bound to primary CD4 T cells infectedin vitrowith two different strains of HIV. In addition, the bsAbs induce increased NK cell degranulation and killing of autologous HIV-infected CD4 T cells.ConclusionsThese bsAbs may provide a promising strategy to improve NK-mediated immune targeting of infected cells during HIV infection.
Widespread Receptor Driven Modulation in Peripheral Olfactory Coding
Authors: Xu Lu , Li Wenze , Voleti Venkatakaushik , Hillman Elizabeth M. C. , Firestein Stuart 
Published: September 2019

AbstractWe utilized swept confocally aligned planar excitation (SCAPE) microscopy to measure odor-driven activity simultaneously in many (>10,000) olfactory sensory neurons distributed over large areas of intact mouse olfactory epithelium. This approach allowed us to investigate the responses to mixtures or blends of odors and their components, a more realistic stimulus than monomolecular odors. In up to 38% of responding cells, responses to a mixture of odors were different - absent, smaller or larger - than what would be expected from the sum of the individual components. Further investigation revealed instances of both antagonism and allosteric enhancement in the primary olfactory sensory neurons. All 10 of the odor compounds tested were found to act as both agonists and antagonists at different receptors. We present a hypothetical scheme for how modulation at the peripheral receptors increases the capability of the olfactory system to recognize patterns of complex odor mixtures. The widespread modulation of primary sensory receptors argues against a simple combinatorial code and should motivate a search for alternative coding strategies.
Live-cell imaging of early events following pollen perception in self-incompatibleArabidopsis thaliana
Authors: Rozier Frédérique , Riglet Lucie , Kodera Chie , Bayle Vincent , Durand Eléonore , Schnabel Jonathan , Gaude Thierry , Fobis-Loisy Isabelle 
Published: September 2019

AbstractEarly events occurring at the surface of the female organ are critical for plant reproduction, especially in species with a dry stigma. Following landing on the stigmatic papilla cells, the pollen hydrates and germinates a tube, which penetrates the cell wall and grows towards the ovules to convey the male gametes to the embryo sac. In self-incompatible (SI) species within the Brassicaceae, these processes are blocked when the stigma encounters an incompatible pollen. Here, based on the generation of SI-Arabidopsis lines and by setting up a live imaging system, we showed that control of pollen hydration has a central role in pollen selectivity. The faster pollen pumps water from the papilla during an initial period of 10 minutes, the faster it germinates. Furthermore, we found that the SI barriers act to block the proper hydration of incompatible pollen and when hydration is promoted by high humidity, an additional control prevents pollen tube penetration into the stigmatic wall. In papilla cells, actin bundles focalize at the contact site with the compatible pollen but not with the incompatible one, raising the possibility that stigmatic cells react to the mechanical pressure applied by the invading growing tube.HighlightA live imaging system coupled with self-incompatible Arabidopsis lines highlight the role of stigmatic cells in controlling pollen hydration and in reacting to pollen tube intrusion by remodeling actin cytoskeleton.
Temperature–Energy-space Sampling Molecular Dynamics: Deterministic, Iteration-free, and Single-replica Method utilizing Continuous Temperature System
Authors: Fukuda Ikuo , Moritsugu Kei 
Published: September 2019

AbstractWe developed coupled Nosé–Hoover (NH) molecular dynamics equations of motion (EOM), wherein the heat-bath temperature for the physical system (PS) fluctuates according to an arbitrary predetermined weight. The coupled NH is defined by suitably jointing the NH EOM of the PS and the NH EOM of the temperature system (TS), where the inverse heat-bath temperature β is a dynamical variable. In this study, we define a method to determine the effective weight for enhanced sampling of the PS states. The method, based on ergodic theory, is reliable, and eliminates the need for time-consuming iterative procedures and resource-consuming replica systems. The resulting TS potential in a two dimensional (β, ϵ)-space forms a valley, and the potential minimum path forms a river flowing through the valley. β oscillates around the potential minima for each energy ϵ, and the motion of β derives a motion of ϵ and receives the ϵ’s feedback, which leads to a mutual boost effect. Thus, it also provides a specific dynamical mechanism to explain the features of enhanced sampling such that the temperature-space “random walk” enhances the energy-space “random walk.” Surprisingly, these mutual dynamics between β and ϵ naturally arise from the static probability theory formalism of double density dynamics that was previously developed, where the Liouville equation with an arbitrarily given probability density function is the fundamental polestar. Numerical examples using a model system and an explicitly solvated protein system verify the reliability, simplicity, and superiority of the method.
Measuring genome sizes using read-depth, k-mers, and flow cytometry: methodological comparisons in beetles (Coleoptera)
Authors: Pflug James M. , Holmes Valerie Renee , Burrus Crystal , Spencer Johnston J. , Maddison David R. 
Published: September 2019

ABSTRACTMeasuring genome size across different species can yield important insights into evolution of the genome and allow for more informed decisions when designing next-generation genomic sequencing projects. New techniques for estimating genome size using shallow genomic sequence data have emerged which have the potential to augment our knowledge of genome sizes, yet these methods have only been used in a limited number of empirical studies. In this project, we compare estimation methods using next-generation sequencing (k-mer methods and average read depth of single-copy genes) to measurements from flow cytometry, the gold standard for genome size measures, using ground beetles (Carabidae) and other members of the beetle suborder Adephaga as our test system. We also present a new protocol for using read-depth of single-copy genes to estimate genome size. Additionally, we report flow cytometry measurements for five previously unmeasured carabid species, as well as 21 new draft genomes and six new draft transcriptomes across eight species of adephagan beetles. No single sequence-based method performed well on all species, and all tended to underestimate the genome sizes, although only slightly in most samples. For one species,Bembidion haplogonum, most sequence-based methods yielded estimates half the size suggested by flow cytometry. This discrepancy for k-mer methods can be explained by a large number of repetitive sequences, but we have no explanation for why read-depth methods yielded results that were also strikingly low.
In vitro comparison of the internal ribosomal entry site activity from rodent hepacivirus and pegivirus
Authors: Sims Stuart , Michaelsen Kevin , Burkhard Sara , Fraefel Cornel 
Published: September 2019

AbstractThe 5’ untranslated region (5’ UTR) of rodent hepacivirus (RHV) and pegivirus (RPgV) contain sequence homology to the HCV type IV internal ribosome entry sites (IRES). Utilizing a monocistronic expression vector with an RNA polymerase I promoter to drive transcription we show cell-specific IRES translation and regions within the IRES required for full functionality. Focusing on RHV we further pseudotyped lentivirus with RHV and showed cell surface expression of the envelope proteins and transduction of murine hepatocytes.
A multi-view model for relative and absolute microbial abundances
Authors: Williamson Brian D. , Hughes James P. , Willis Amy D. 
Published: September 2019

AbstractThe absolute abundance of bacterial taxa in human host-associated environments play a critical role in reproductive and gastrointestinal health. However, obtaining the absolute abundance of many bacterial species is typically prohibitively expensive. In contrast, relative abundance data for many species is comparatively cheap and easy to collect (e.g., with universal primers for the 16S rRNA gene). In this paper, we propose a method to jointly model relative abundance data for many taxa and absolute abundance data for a subset of taxa. Our method provides point and interval estimates for the absolute abundance of all taxa. Crucially, our proposal accounts for differences in the efficiency of taxon detection in the relative and absolute abundance data. We show that modeling taxon-specific efficiencies substantially reduces the estimation error for absolute abundance, and controls the coverage of interval estimators. We demonstrate the performance of our proposed method via a simulation study, a sensitivity study where we jackknife the taxa with observed absolute abundances, and a study of women with bacterial vaginosis.
IRG1 controls host responses to restrict Mycobacterium tuberculosis infection
Authors: Machelart Arnaud , Belhaouane Imène , Deboosere Nathalie , Poncin Isabelle , Saint-André Jean-Paul , Pauwels Anne-Marie , Song Ok-Ryul , Jouny Samuel , Rouanet Carine , Poncet Anaïs , Marion Sabrina , Laine William , Kluza Jérôme , Muraille Eric , Beyaert Rudi , Majlessi Laleh , Canaan Stéphane , Brodin Priscille , Hoffmann Eik 
Published: September 2019

AbstractMycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains. Metabolic reprogramming of phagocytes can dramatically influence the intracellular colonization by Mtb and the key players involved in this process remain a matter of debate. Here, we demonstrate that aconitate decarboxylase 1 (Acod1; also known as immune-responsive gene 1, IRG1), which converts cis-aconitate into the metabolite itaconate, is a major player in controlling the acute phase of Mtb infection. Exposure of IRG1-deficient mice to a virulent Mtb strain (H37Rv) was lethal, while M. bovis BCG and the H37Ra attenuated Mtb strain induced neither lethality nor severe lung immunopathology. Lungs of IRG1-deficient mice infected by Mtb H37Rv displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Next, we show that IRG1, beyond its recruitment to Mtb-containing vacuoles, restricts Mtb replication and lipid droplets accumulation in phagocytes, hallmarks of a tight interplay between the bacillus and the host. Altogether, IRG1 confines the host response to create a favourable phagocytic environment for Mtb controlled intracellular replication.
Rapid and independent evolution of ancestral and novel defenses in a genus of toxic plants (Erysimum, Brassicaceae)
Authors: Züst Tobias , Strickler Susan R. , Powell Adrian F. , Mabry Makenzie E. , An Hong , Mirzaei Mahdieh , York Thomas , Holland Cynthia K. , Kumar Pavan , Erb Matthias , Petschenka Georg , Goméz José María , Perfectti Francisco , Müller Caroline , Pires J. Chris , Mueller Lukas A. , Jander Georg 
Published: September 2019

AbstractPhytochemical diversity is thought to result from coevolutionary cycles as specialization in herbivores imposes diversifying selection on plant chemical defenses. Plants in the speciose genusErysimum(Brassicaceae) produce both ancestral glucosinolates and evolutionarily novel cardenolides as defenses. Here we test macroevolutionary hypotheses on co-expression, co-regulation, and diversification of these potentially redundant defenses across this genus. We sequenced and assembled the genome ofE. cheiranthoidesand foliar transcriptomes of 47 additionalErysimumspecies to construct a highly resolved phylogeny, revealing that cardenolide diversity increased rapidly rather than gradually over evolutionary time. Concentrations, inducibility, and diversity of the two defenses varied independently among species, with no evidence for trade-offs. Closely related species shared similar cardenolide traits, but not glucosinolate traits, likely as a result of specific selective pressures acting on distinct molecular diversification mechanisms. Ancestral and novel chemical defenses inErysimumthus appear to provide complementary rather than redundant functions.
Regulatory non-coding small RNAs are diverse and abundant in an extremophilic microbial community
Authors: Gelsinger Diego R. , Uritskiy Gherman , Reddy Rahul , Munn Adam , Farney Katie , DiRuggiero Jocelyne 
Published: September 2019

ABSTRACTRegulatory small RNAs (sRNAs) represent a major class of regulatory molecules that play large-scale and essential roles in many cellular processes across all domains of life. Microbial sRNAs have been primarily investigated in a few model organisms and little is known about the dynamics of sRNA synthesis in natural environments, and the roles of these short transcripts at the community level. Analyzing the metatranscriptome of a model extremophilic community inhabiting halite nodules (salt rocks) from the Atacama Desert with SnapT – a new sRNA annotation pipeline – we discovered hundreds of intergenic (itsRNAs) and antisense (asRNAs) sRNAs. The halite sRNAs were taxonomically diverse with the majority expressed by members of the Halobacteria. We found asRNAs with expression levels negatively correlated with that of their putative overlapping target, suggesting a potential gene regulatory mechanism. A number of itsRNAs were conserved and significantly differentially expressed (FDR<5%) between 2 sampling time points allowing for stable secondary structure modeling and target prediction. This work demonstrates that metatranscriptomic field experiments link environmental variation with changes in RNA pools and have the potential to provide new insights into environmental sensing and responses in natural microbial communities through non-coding RNA mediated gene regulation.
Dopamine in the songbird auditory cortex shapes auditory preference
Authors: Barr Helena J. , Wall Erin M. , Woolley Sarah C. 
Published: September 2019

ABSTRACTIn vocal communication, vocal signals can provide listeners with information and also elicit motivated responses. Auditory cortical and mesolimbic reward circuits are often considered to have distinct roles in these processes, with auditory cortical circuits responsible for detecting and discriminating sounds and mesolimbic circuits ascribing salience and modulating preference for those sounds. Here, we investigated whether dopamine within auditory cortical circuits themselves can shape the incentive salience of a vocal signal. Using female zebra finches, who show natural preferences for vocal signals produced by males (‘songs’), we found that pairing passive song playback with pharmacological manipulations of dopamine in the secondary auditory cortex drives changes to song preferences. Plasticity of song preferences by dopamine lasted for at least one week and was not influenced by norepinephrine manipulations. These data suggest that dopamine acting directly in sensory processing areas can shape the incentive salience of communication signals.
The consequences of mixed-species malaria parasite co-infections in mice and mosquitoes for disease severity, parasite fitness, and transmission success
Authors: Tang Jianxia , Templeton Thomas J. , Cao Jun , Culleton Richard 
Published: September 2019

AbstractThe distributions of human malaria parasite species overlap in most malarious regions of the world, and co-infections involving two or more malaria parasite species are common. Little is known about the consequences of interactions between species during co-infection for disease severity and parasite transmission success. Anti-malarial interventions can have disproportionate effects on malaria parasite species, and may locally differentially reduce the number of species in circulation. Thus, it is important to have a clearer understanding of how the interactions between species affect disease and transmission dynamics. Controlled competition experiments using human malaria parasites are impossible, and thus we assessed the consequences of mixed-species infections on parasite fitness, disease severity, and transmission success using the rodent malaria parasite species Plasmodium chabaudi, P. yoelii yoelii, and P. vinckei lentum. We compared the fitness of individual species within single species and co-infections in mice. We also assessed the disease severity of single versus mixed infections in mice by measuring mortality rates, anaemia, and weight loss. Finally, we compared the transmission success of parasites in single or mixed species infections by quantifying oocyst development in Anopheles stephensi mosquitoes. We found that co-infections of P. yoelii with either P. vinckei or P. chabaudi led to a dramatic increase in infection virulence, with 100% mortality observed in mixed species infections, compared to no mortality for P. yoelii and P. vinckei single infections, and 40% mortality for P. chabaudi single infections. The increased mortality in the mixed infections was associated with an inability to clear parasitaemia, with the non-P. yoelii parasite species persisting at higher parasite densities than in single infections. P. yoelii growth was suppressed in all mixed infections compared to single infections. Transmissibility of P. vinckei and P. chabaudi to mosquitoes was also reduced in the presence of P. yoelii in co-infections compared to single infections. The increased virulence of co-infections containing P. yoelii (reticulocyte restricted) and P. chabaudi or P. vinckei (predominantly normocyte restricted) may be due to parasite cell tropism and/or immune modulation of the host. We explain the reduction in transmission success of species in co-infections in terms of inter-species gamete incompatibility.
Autophagy-dependent filopodial kinetics restrict synaptic partner choice during Drosophila brain wiring
Authors: Kiral Ferdi Ridvan , Linneweber Gerit Arne , Georgiev Svilen Veselinov , Hassan Bassem A. , von Kleist Max , Hiesinger Peter Robin 
Published: September 2019

SummaryBrain wiring is remarkably precise, yet most neurons readily form synapses with incorrect partners when given the opportunity. Dynamic axon-dendritic positioning can restrict synaptogenic encounters, but the spatiotemporal interaction kinetics and their regulation remain essentially unknown inside developing brains. Here we show that the kinetics of axonal filopodia restrict synapse formation and partner choice for neurons that are not otherwise prevented from making incorrect synapses. Using 4D imaging in developing Drosophila brains, we show that filopodial kinetics are regulated by autophagy, a prevalent degradation mechanism whose role in brain development remains poorly understood. With surprising specificity, autophagosomes form in synaptogenic filopodia, followed by filopodial collapse. Altered autophagic degradation of synaptic building material quantitatively regulates synapse formation as shown by computational modeling and genetic experiments. Increased filopodial stability enables incorrect synaptic partnerships. Hence, filopodial autophagy restricts inappropriate partner choice through a process of kinetic exclusion that critically contributes to wiring specificity.