bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shavenbaby protein isoforms orchestrate the self-renewalversusdifferentiation ofDrosophilaintestinal stem cells
Authors: Al Hayek Sandy , Alsawadi Ahmad , Kambris Zakaria , Boquete Jean-Philippe , Bohère Jérôme , Ronsin Brice , Plaza Serge , Lemaitre Bruno , Payre François , Osman Dani 
Published: May 2019

SUMMARYSignaling pathways are key regulators of adult stem cell homeostasis and underlying mechanisms are often deregulated in cancers. Recent studies of epithelial tumors have involved OvoL/Svb transcription factors, which produce isoforms with antagonistic activities. Here we show that Svb, the unique OvoL factor inDrosophila, directly integrates multiple signaling inputs to coordinate the behavior of adult intestinal stem cell lineage. Under steady state, Svb mediates Wnt and EGFR signaling to ensure stem cell renewal and progenitor survival. This requires the post-translational processing of Svb into a transcriptional activator by Polished rice (Pri) regulatory peptides, under the regulation of ecdysone signaling. In response to PDM1, Svb expression is specifically maintained in enterocytes where it acts as a transcriptional repressor sufficient to override mitogenic signals and impose differentiation. Altogether, these results demonstrate that the OvoL/Svb transcriptional switch controls the balance between stem cell survival, self-renewal and differentiation.
The neutrophil enzyme myeloperoxidase directly modulates neuronal response after subarachnoid hemorrhage, a sterile injury model
Authors: Coulibaly Aminata P. , Pezuk Pinar , Varghese Paul , Gartman William , Triebwasser Danielle , Kulas Joshua A. , Liu Lei , Syed Mariam , Tvrdik Petr , Ferris Heather , Provencio J. Javier 
Published: May 2019

AbstractNeutrophil infiltration into the central nervous system (CNS) after injury is associated with cognitive deficits. Using a murine model of aneurysmal subarachnoid hemorrhage (SAH), we elucidate the location and mode of action of neutrophils in the CNS. Following SAH, neutrophils infiltrate the meninges, and not the brain parenchyma. Mice lacking functional myeloperoxidase (MPO KO), a neutrophil enzyme, lack both the meningeal neutrophil infiltration and the cognitive deficits associated with delayed cerebral injury from SAH. The re-introduction of biologically active MPO, and its substrate hydrogen peroxide, to the cerebrospinal fluid of MPO KO mice at the time of hemorrhage restores the spatial memory deficit observed after SAH. This implicates MPO as a mediator of neuronal dysfunction in SAH. Using primary neuronal and astrocyte cultures, we demonstrate that MPO directly affects the function of both cell types. Neurons exposed to MPO and its substrate show decreased calcium activity at baseline and after stimulation with potassium chloride. In addition, MPO and its substrate lead to significant astrocyte loss in culture, a result observed in the brain after SAH as well. These results show that, in SAH, the activity of innate immune cells in the meninges modulates the activity and function of the underlying brain tissue.
Role of aggregate size, multistability and communication in determining cell fate and patterning inM. xanthus
Authors: Del Angel Juan A. Arias , Rivera-Yoshida Natsuko , Escalante Ana E. , Martínez-Castilla León Patricio , Benítez Mariana 
Published: May 2019

1.AbstractThe emergence of multicellular organisms that exhibit cell differentiation and stereotypic spatial arrangements has been recognized as one of the major transitions in evolution. Myxobacteria have emerged as a useful study model to investigate multicellular evolution and development. Here, we propose a multiscale model that considers cellular adhesion and movement, molecular regulatory networks (MRNs), and cell-to-cell communication to study the emergence of cell fate determination and spatial patterning ofMyxococcus xanthusfruiting bodies. The model provides a dynamic accounting of the roles of MRN multistability, intercellular communication and conglomerate size in determining cell fate and patterning duringM. xanthusdevelopment. It also suggests that for cell fate determination and patterning to occur, the cell aggregate must surpass a minimum size. The model also allows us to contrast alternative scenarios for the C-signal mechanism and provides stronger support for an indirect effect (as a diffusible molecule) than a direct one (as a membrane protein).
Honey bee queens are vulnerable to heat-induced loss of fertility
Authors: McAfee Alison , Chapman Abigail , Higo Heather , Underwood Robyn , Milone Joseph , Foster Leonard J , Guarna M Marta , Tarpy David R , Pettis Jeffery S 
Published: May 2019

AbstractAll species need to reproduce to maintain viable populations, but heat stress kills sperm cells across the animal kingdom and rising frequencies of heatwaves are a threat to biodiversity. Honey bees (Apis mellifera) are globally distributed micro-livestock; therefore, they could serve as environmental biomonitors for fertility losses. Here, we found that queens have two potential routes of temperaturestress exposure: within colonies and during routine shipping. Our data suggest that temperatures of 15 to 38°C are safe for queens at a tolerance threshold of 11.5% loss of sperm viability, which is the viability difference associated with queen failure in the field. Heat shock activates expression of specific stressresponse proteins in the spermatheca, which could serve as molecular biomarkers (indicators) for heat stress. This protein fingerprint may eventually enable surveys for the prevalence of heat-induced loss of sperm viability in diverse landscapes as part of a biomonitoring program.
Long metabarcoding of the eukaryotic rDNA operon to phylogenetically and taxonomically resolve environmental diversity
Authors: Jamy Mahwash , Foster Rachel , Barbera Pierre , Czech Lucas , Kozlov Alexey , Stamatakis Alexandros , Bass David , Burki Fabien 
Published: May 2019

AbstractHigh-throughput environmental DNA metabarcoding has revolutionized the analysis of microbial diversity, but this approach is generally restricted to amplicon sizes below 500 base pairs. These short regions contain limited phylogenetic signal, which makes it impractical to use environmental DNA in full phylogenetic inferences. However, new long-read sequencing technologies such as the Pacific Biosciences platform may provide sufficiently large sequence lengths to overcome the poor phylogenetic resolution of short amplicons. To test this idea, we amplified soil DNA and used PacBio Circular Consensus Sequencing (CCS) to obtain a ~4500 bp region of the eukaryotic rDNA operon spanning most of the small (18S) and large subunit (28S) ribosomal RNA genes. The CCS reads were first treated with a novel curation workflow that generated 650 high-quality OTUs containing the physically linked 18S and 28S regions of the long amplicons. In order to assign taxonomy to these OTUs, we developed a phylogeny-aware approach based on the 18S region that showed greater accuracy and sensitivity than similarity-based and phylogenetic placement-based methods using shorter reads. The taxonomically-annotated OTUs were then combined with available 18S and 28S reference sequences to infer a well-resolved phylogeny spanning all major groups of eukaryotes, allowing to accurately derive the evolutionary origin of environmental diversity. A total of 1019 sequences were included, of which a majority (58%) corresponded to the new long environmental CCS reads. Comparisons to the 18S-only region of our amplicons revealed that the combined 18S-28S genes globally increased the phylogenetic resolution, recovering specific groupings otherwise missing. The long-reads also allowed to directly investigate the relationships among environmental sequences themselves, which represents a key advantage over the placement of short reads on a reference phylogeny. Altogether, our results show that long amplicons can be treated in a full phylogenetic framework to provide greater taxonomic resolution and a robust evolutionary perspective to environmental DNA.
Rotavirus Calcium Dysregulation Manifests as Dynamic Calcium Signaling in the Cytoplasm and Endoplasmic Reticulum
Authors: Chang-Graham Alexandra L. , Perry Jacob L. , Strtak Alicia C. , Ramachandran Nina K. , Criglar Jeanette M. , Philip Asha A. , Patton John T. , Estes Mary K. , Hyser Joseph M. 
Published: May 2019

AbstractLike many viruses, rotavirus (RV) dysregulates calcium homeostasis by elevating cytosolic calcium ([Ca2+]cyt) and decreasing endoplasmic reticulum (ER) stores. While an overall, monophasic increase in [Ca2+]cyt during RV infection has been shown, the nature of the RV-induced aberrant calcium signals and how they manifest over time at the single-cell level have not been characterized. Thus, we generated cell lines and human intestinal enteroids (HIEs) stably expressing cytosolic and/or ER-targeted genetically-encoded calcium indicators to characterize calcium signaling throughout RV infection by time-lapse imaging. We found that RV induces highly dynamic [Ca2+]cyt signaling that manifest as hundreds of discrete [Ca2+]cyt spikes, which increase during peak infection. Knockdown of nonstructural protein 4 (NSP4) attenuates the [Ca2+]cyt spikes, consistent with its role in dysregulating calcium homeostasis. RV-induced [Ca2+]cyt spikes were primarily from ER calcium release and were attenuated by inhibiting the store-operated calcium entry (SOCE) channel Orai1. RV-infected HIEs also exhibited prominent [Ca2+]cyt spikes that were attenuated by inhibiting SOCE, underlining the relevance of these [Ca2+]cyt spikes to gastrointestinal physiology and role of SOCE in RV pathophysiology. Thus, our discovery that RV increases [Ca2+]cyt by dynamic Ca2+signaling, establishes a new, paradigm-shifting understanding of the spatial and temporal complexity of virus-induced Ca2+signaling.
Corticomuscular control of walking in older people and people with Parkinson’s disease
Authors: Roeder Luisa , Boonstra Tjeerd W , Kerr Graham K 
Published: May 2019

AbstractChanges in human gait that result from ageing or neurodegenerative diseases are multifactorial. Here we assess the effects of age and Parkinson’s disease (PD) on corticospinal control in electrophysiological activity recorded during treadmill and overground walking. Electroencephalography (EEG) from 10 electrodes and electromyography (EMG) from two leg muscles were acquired from 22 healthy young, 24 healthy older and 20 adults with PD. Event-related power, corticomuscular coherence (CMC) and inter-trial coherence were assessed for EEG from bilateral sensorimotor cortices and EMG from tibialis anterior muscles during the double support phase of the gait cycle. CMC and EMG power in the low beta band (13-21 Hz) was significantly decreased in older and PD participants compared to young people, but there was no difference between older and PD groups. Older and PD participants spent shorter time in the swing phase than young individuals. These findings indicate age-related changes in the temporal coordination of gait. The decrease in beta CMC suggests reduced cortical input to spinal motor neurons in older people during the double support phase. We also observed multiple changes in electrophysiological measures at high beta and low gamma frequencies during treadmill compared to overground walking, indicating task-dependent differences in corticospinal locomotor control.
Bridging the TB data gap: in silico extraction of rifampicin-resistant tuberculosis diagnostic test results from whole genome sequence data
Authors: Ng Kamela Charmaine S. , Ngabonziza Jean Claude S. , Lempens Pauline , de Jong Bouke Catherine , van Leth Frank , Meehan Conor Joseph 
Published: May 2019

AbstractBackgroundMycobacterium tuberculosis rapid diagnostic tests (RDTs) are widely employed in routine laboratories and national surveys for detection of rifampicin-resistant (RR)-TB. However, as next generation sequencing technologies have become more commonplace in research and surveillance programs, RDTs are being increasingly complemented by whole genome sequencing (WGS). While comparison between RDTs is difficult, all RDT results can be derived from WGS data. This can facilitate continuous analysis of RR-TB burden regardless of the data generation technology employed. By converting WGS to RDT results, we enable comparison of data with different formats and sources particularly for low and middle income high TB burden countries that employ different diagnostic algorithms for drug resistance surveys. This allows national TB control programs (NTPs) and epidemiologists to utilize all available data in the setting for improved RR-TB surveillance.MethodsWe developed the Python-based MTB Genome to Test (MTBGT) tool that transforms WGS-derived data into laboratory-validated results of the primary RDTs – Xpert MTB/RIF, XpertMTB/RIF Ultra, GenoType MDRTBplus v2.0, and GenoscholarNTM+MDRTB II. The tool was validated through RDT results of RR-TB strains with diverse resistance patterns and geographic origins and applied on routine-derived WGS data.ResultsThe MTBGT tool correctly transformed the SNP data into the RDT results and generated tabulated frequencies of the RDT probes as well as rifampicin susceptible cases. The tool supplemented the RDT probe reactions output with the RR-conferring mutation based on identified SNPs. The MTBGT tool facilitated continuous analysis of RR-TB and Xpert probe reactions from different platforms and collection periods in Rwanda.ConclusionOverall, the MTBGT tool allows low and middle income countries to make sense of the increasingly generated WGS in light of the readily available RDT results, and assess whether currently implemented RDTs adequately detect RR-TB in their setting. With its feature to transform WGS to RDT results and facilitate continuous RR-TB data analysis, the MTBGT tool may bridge the gap between and among data from periodic surveys, continuous surveillance, research, and routine tests, and may be integrated within the existing national connectivity platform for use by the NTP and epidemiologists to improve setting-specific RR-TB control. The MTBGT source code and accompanying documentation is available at https://github.com/KamelaNg/MTBGT.
Corticostriatal stimulation compensates for medial frontal inactivation during interval timing
Authors: Emmons Eric B. , Kennedy Morgan , Kim Youngcho , Narayanan Nandakumar S. 
Published: May 2019

AbstractPrefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions can compensate for impaired prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals in the DMS shifted response times and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
K. pneumoniaeST258 genomic variability and bacteriophage susceptibility
Authors: Venturini Carola , Zakour Nouri Ben , Bowring Bethany , Morales Sandra , Cole Robert , Kovach Zsuzsanna , Branston Steven , Kettle Emma , Thomson Nicholas , Iredell Jonathan 
Published: May 2019

AbstractMultidrug resistant carbapenemase-producingKlebsiella pneumoniaecapable of causing severe disease in humans is classified as an urgent threat by health agencies worldwide. Bacteriophages are being actively explored as potential therapeutics against these multidrug resistant pathogens. We are currently developing bacteriophage therapy against carbepenem-resistantK. pneumoniaebelonging to the genetically diverse, globally disseminated clonal group CG258. In an effort to define a robust experimental approach for effective selection of lytic viruses for therapy, we have fully characterized the bacterial genomes of 18 target strains, tested them against novel lytic bacteriophages, and generated phage-susceptibility profiles. The genomes ofK. pneumoniaeisolates carryingblaNDMandblaKPCwere sequenced and isolates belonging to CG258 were selected for susceptibility testing using a panel of lytic bacteriophages (n=65). The localK. pneumoniaeCG258 population was dominated by isolates belonging to sequence type ST258 clade 1 (86%). The primary differences between ST258 genomes were variations in the capsular locus (cps) and in prophage content. We showed that CG258-specific lytic phages primarily target the capsule, and that successful infection is blocked in many, post-adsorption, by immunity conferred by existing prophages. Five bacteriophages specifically active againstK. pneumoniaeST258 clade 1 (n=5) belonging to the Caudovirales order were selected for further characterization. Our findings show that effective control ofK. pneumoniaeCG258 with phage will require mixes of diverse lytic viruses targeting all relevantcpsvariants and allowing for variable prophage content. These insights will facilitate identification and selection of therapeutic phage candidates against this serious pathogen.ImportanceBacteriophages are natural agents that exclusively and selectively kill bacteria and have the potential to be useful in the treatment of multidrug resistant infections.K. pneumoniaeCG258 is a main agent of life-threatening sepsis that is often resistant to last-line antibiotics. Our work highlights some key requirements for developing bacteriophage preparations targeting this pathogen. By defining the genomic profile of our clinicalK. pneumoniaeCG258 population and matching it with bacteriophage susceptibility patterns, we found that bacteriophage ability to lyse each strain correlates well withK. pneumoniaeCG258 structural subtypes (capsule variants). This indicates that preparation of bacteriophage therapeutics targeting this pathogen should aim at including phages against each bacterial capsular subtype. This necessitates a detailed understanding of the diversity of circulating isolates in different geographical areas in order to make rational therapeutic choices.
Performance analysis of novel toxin-antidote CRISPR gene drive systems
Authors: Champer Jackson , Kim Isabel , Champer Samuel E. , Clark Andrew G. , Messer Philipp W. 
Published: May 2019

ABSTRACTGene drives can potentially fixate in a population by biasing inheritance in their favor, opening up a variety of potential applications in areas such as disease-vector control and conservation. CRISPR homing gene drives have shown much promise for providing an effective drive mechanism, but they typically suffer from the rapid formation of resistance alleles. Even if the problem of resistance can be overcome, the utility of such drives would still be limited by their tendency to spread into all areas of a population. To provide additional options for gene drive applications that are substantially less prone to the formation of resistance alleles and could potentially remain confined to a target area, we developed several designs for CRISPR-based gene drives utilizing toxin-antidote (TA) principles. These drives target and disrupt an essential gene with the drive providing rescue. Here, we assess the performance of several types of TA gene drive systems using modeling and individual-based simulations. We show that Toxin-Antidote Recessive Embryo (TARE) drive should allow for the design of robust, regionally confined, population modification strategies with high flexibility in choosing drive promoters and recessive lethal targets. Toxin-Antidote Dominant Embryo (TADE) drive requires a haplolethal target gene and a germline-restricted promoter but should enable the design of both faster regional population modification drives and even regionally-confined population suppression drives. Toxin-antidote dominant sperm (TADS) drive can be used for population modification or suppression. It spreads nearly as quickly as a homing drive and can flexibly use a variety of promoters, but unlike the other TA systems, it is not regionally confined and requires highly specific target genes. Overall, our results suggest that CRISPR-based TA gene drives provide promising candidates for further development in a variety of organisms and may allow for flexible ecological engineering strategies.
Density-Weighted Concentric Ring Trajectory using simultaneous multi-band acceleration: 3D Metabolite-cycled Magnetic Resonance Spectroscopy Imaging at 3 T
Authors: Xia Pingyu , Chiew Mark , Zhou Xiaopeng , Thomas Albert , Dydak Ulrike , Emir Uzay E 
Published: May 2019

AbstractSimultaneous multi-slice or multi-band parallel imaging is frequently used in fMRI to accelerate acquisition. In this study, we propose a new a non-water-suppressed multi-band MRSI using a density weighted concentric ring trajectory (DW-CRT) acquisition. The properties of multi-band acquisition scheme were compared against single-band acquisition in phantoms and in-vivo experiments. High-quality spectra were acquired for all simultaneously acquired three slices from a limited volume of interest with an in-plane resolution of 5 × 5 mm2 in 19.2 min. The achieved in vivo spectral quality of the multi-band method allowed the reliable metabolic mapping of four major metabolites with Cramér-Rao lower bounds below 50%, using a LCModel analysis. Metabolite maps and LCModel quality metrics were compared between multi-band and single-band acquisition schemes for both phantom and in-vivo measurements. Structural similarity (SSIM) index and conventional coefficient of variance analysis of both phantom and in-vivo measurements revealed a SSIM index higher than 0.83, corresponding to a coefficient of variance of less than 30%. These findings demonstrate that our multi-band DW-CRT MRSI demonstrate a multi-band acceleration, simultaneously acquired 3 slices, with no apparently loss in spectral quality, reducing scan time by a factor of 3 without any significant penalty.
A new role for Notch in the control of polarity and asymmetric cell division of developing T cells
Authors: Charnley Mirren , Ludford-Menting Mandy , Pham Kim , Russell Sarah M. 
Published: May 2019

AbstractA fundamental question in biology is how single cells can reliably produce progeny of different cell types. Notch signalling frequently facilitates fate determination. Asymmetric cell division (ACD) often controls segregation of Notch signalling by imposing unequal inheritance of regulators of Notch. Here, we assessed the functional relationship between Notch and ACD in mouse T cell development. To attain immunological specificity, developing T cells must pass through a pivotal stage termed β-selection, which involves Notch signalling and ACD. We assessed functional interactions between Notch and ACD during β-selection using direct presentation of Notch ligands, DL1 and DL4, and pharmacological inhibition of Notch signalling. Contrary to prevailing models, we find Notch controls distribution of Notch1 itself and cell fate determinants, α-Adaptin and Numb. Notch and CXCR4 signalling cooperated to drive polarity during division. Thus, Notch signalling directly orchestrates ACD, and Notch1 is differentially inherited by sibling cells.