bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Sensitized Genetic Screen to Identify Novel Regulators and Components of the Drosophila Janus Kinase/Signal Transducer and Activator of Transcription Pathway
Authors: Bach Erika A , Vincent Stephane , Zeidler Martin P , Perrimon Norbert 
Published: April 2021

Abstract
The JAK/STAT pathway exerts pleiotropic effects on a wide range of developmental processes in Drosophila. Four key components have been identified: Unpaired, a secreted ligand; Domeless, a cytokine-like receptor; Hopscotch, a JAK kinase; and Stat92E, a STAT transcription factor. The identification of additional components and regulators of this pathway remains an important issue. To this end, we have generated a transgenic line where we misexpress the upd ligand in the developing Drosophila eye. GMR-upd transgenic animals have dramatically enlarged eye-imaginal discs and compound eyes that are normally patterned. We demonstrate that the enlarged-eye phenotype is a result of an increase in cell number, and not cell volume, and arises from additional mitoses in larval eye discs. Thus, the GMR-upd line represents a system in which the proliferation and differentiation of eye precursor cells are separable. Removal of one copy of stat92E substantially reduces the enlarged-eye phenotype. We performed an F1 deficiency screen to identify dominant modifiers of the GMR-upd phenotype. We have identified 9 regions that enhance this eye phenotype and two specific enhancers: C-terminal binding protein and Daughters against dpp. We also identified 20 regions that suppress GMR-upd and 13 specific suppressors: zeste-white 13, pineapple eye, Dichaete, histone 2A variant, headcase, plexus, kohtalo, crumbs, hedgehog, decapentaplegic, thickveins, saxophone, and Mothers against dpp.
A Temperature-Sensitive Allele of Drosophila sesB Reveals Acute Functions for the Mitochondrial Adenine Nucleotide Translocase in Synaptic Transmission and Dynamin Regulation
Authors: Rikhy Richa , Ramaswami Mani , Krishnan K S 
Published: April 2021

Abstract
Rapidly reversible, temperature-sensitive (ts) paralytic mutants of Drosophila have been useful in delineating immediate in vivo functions of molecules involved in synaptic transmission. Here we report isolation and characterization of orangi (org), an enhancer of shibire (shi), a ts paralytic mutant in Drosophila dynamin. org is an allele of the stress sensitive B (sesB) locus that encodes a mitochondrial adenine nucleotide translocase (ANT) and results in a unique ts paralytic behavior that is accompanied by a complete loss of synaptic transmission in the visual system. sesBorg reduces the restrictive temperature for all shits alleles tested except for shits1. This characteristic allele-specific interaction of sesBorg with shi is shared by abnormal wing discs (awd), a gene encoding nucleoside diphosphate kinase (NDK). sesBorg shows independent synergistic interactions, an observation that is consistent with a shared pathway by which org and awd influence shi function. Genetic and electrophysiological analyses presented here, together with the observation that the sesBorg mutation reduces biochemically assayed ANT activity, suggest a model in which a continuous mitochondrial ANT-dependent supply of ATP is required to sustain NDK-dependent activation of presynaptic dynamin during a normal range of synaptic activity.
Drosophila Calmodulin Mutants With Specific Defects in the Musculature or in the Nervous System
Authors: Wang Bo , Sullivan Kathleen M C , Beckingham Kathy 
Published: April 2021

Abstract
We have studied lethal mutations in the single calmodulin gene (Cam) of Drosophila to gain insight into the in vivo functions of this important calcium sensor. As a result of maternal calmodulin (CaM) in the mature egg, lethality is delayed until the postembryonic stages. Prior to death in the first larval instar, Cam nulls show a striking behavioral abnormality (spontaneous backward movement) whereas a mutation, Cam7, that results in a single amino acid change (V91G) produces a very different phenotype: short indented pupal cases and pupal death with head eversion defects. We show here that the null behavioral phenotype originates in the nervous system and involves a CaM function that requires calcium binding to all four sites of the protein. Further, backward movement can be induced in hypomorphic mutants by exposure to high light levels. In contrast, the V91G mutation specifically affects the musculature and causes abnormal calcium release in response to depolarization of the muscles. Genetic interaction studies suggest that failed regulation of the muscle calcium release channel, the ryanodine receptor, is the major defect underlying the Cam7 phenotype.
Patterns of Nucleotide Polymorphism and Divergence in the Odorant-Binding Protein Genes OS-E and OS-F: Analysis in the Melanogaster Species Subgroup of Drosophila
Authors: Sánchez-Gracia Alejandro , Aguadé Montserrat , Rozas Julio 
Published: April 2021

Abstract
The Olfactory Specific-E and -F genes (OS-E and OS-F) belong to the odorant-binding protein gene family, which includes the general odorant-binding proteins and the pheromone-binding proteins. In Drosophila melanogaster, these genes are arranged in tandem in a genomic region near the centromere of chromosome arm 3R. We examined the pattern of DNA sequence variation in an ∼7-kb genomic region encompassing the two OS genes in four species of the melanogaster subgroup of Drosophila and in a population sample of D. melanogaster. We found that both the OS-E and the OS-F gene are present in all surveyed species. Nucleotide divergence estimates would support that the two genes are functional, although they diverge in their functional constraint. The pattern of nucleotide variation in D. melanogaster also differed between genes. Variation in the OS-E gene region exhibited an unusual and distinctive pattern: (i) a relatively high number of fixed amino acid replacements in the encoded protein and (ii) a peak of nucleotide polymorphism around the OS-E gene. These results are unlikely under the neutral model and suggest the action of natural selection in the evolution of the two odorant-binding protein genes.
Genetic Modifier Screens in Drosophila Demonstrate a Role for Rho1 Signaling in Ecdysone-Triggered Imaginal Disc Morphogenesis
Authors: Ward Robert E , Evans Janelle , Thummel Carl S 
Published: April 2021

Abstract
Drosophila adult leg development provides an ideal model system for characterizing the molecular mechanisms of hormone-triggered morphogenesis. A pulse of the steroid hormone ecdysone at the onset of metamorphosis triggers the rapid transformation of a flat leg imaginal disc into an immature adult leg, largely through coordinated changes in cell shape. In an effort to identify links between the ecdysone signal and the cytoskeletal changes required for leg morphogenesis, we performed two large-scale genetic screens for dominant enhancers of the malformed leg phenotype associated with a mutation in the ecdysoneinducible broad early gene (br1). From a screen of &gt;750 independent deficiency and candidate mutation stocks, we identified 17 loci on the autosomes that interact strongly with br1. In a complementary screen of ∼112,000 F1 progeny of EMS-treated br1 animals, we recovered 26 mutations that enhance the br1 leg phenotype [E(br) mutations]. Rho1, stubbloid, blistered (DSRF), and cytoplasmic Tropomyosin were identified from these screens as br1-interacting genes. Our findings suggest that ecdysone exerts its effects on leg morphogenesis through a Rho1 signaling cascade, a proposal that is supported by genetic interaction studies between the E(br) mutations and mutations in the Rho1 signaling pathway. In addition, several E(br) mutations produce unexpected defects in midembryonic morphogenetic movements. Coupled with recent evidence implicating ecdysone signaling in these embryonic morphogenetic events, our results suggest that a common ecdysone-dependent, Rho1-mediated regulatory pathway controls morphogenesis during the two major transitions in the life cycle, embryogenesis and metamorphosis.
Genetic Interactions Between the RhoA and Stubble-stubbloid Loci Suggest a Role for a Type II Transmembrane Serine Protease in Intracellular Signaling During Drosophila Imaginal Disc Morphogenesis
Authors: Bayer Cynthia A , Halsell Susan R , Fristrom James W , Kiehart Daniel P , von Kalm Laurence 
Published: April 2021

Abstract
The Drosophila RhoA (Rho1) GTPase is essential for postembryonic morphogenesis of leg and wing imaginal discs. Mutations in RhoA enhance leg and wing defects associated with mutations in zipper, the gene encoding the heavy chain of nonmuscle myosin II. We demonstrate here that mutations affecting the RhoA signaling pathway also interact genetically with mutations in the Stubble-stubbloid (Sb-sbd) locus that encodes an unusual type II transmembrane serine protease required for normal leg and wing morphogenesis. In addition, a leg malformation phenotype associated with overexpression of Sb-sbd in prepupal leg discs is suppressed when RhoA gene dose is reduced, suggesting that RhoA and Sb-sbd act in a common pathway during leg morphogenesis. We also characterized six mutations identified as enhancers of zipper mutant leg defects. Three of these genes encode known members of the RhoA signaling pathway (RhoA, DRhoGEF2, and zipper). The remaining three enhancer of zipper mutations interact genetically with both RhoA and Sb-sbd mutations, suggesting that they encode additional components of the RhoA signaling pathway in imaginal discs. Our results provide evidence that the type II transmembrane serine proteases, a class of proteins linked to human developmental abnormalities and pathology, may be associated with intracellular signaling required for normal development.
Detection and Effects of a Homeologous Reciprocal Transposition in Brassica napus
Authors: Osborn Thomas C , Butrulle David V , Sharpe Andrew G , Pickering Kathryn J , Parkin Isobel A P , Parker John S , Lydiate Derek J 
Published: April 2021

Abstract
A reciprocal chromosomal transposition was identified in several annual oilseed Brassica napus genotypes used as parents in crosses to biennial genotypes for genetic mapping studies. The transposition involved an exchange of interstitial homeologous regions on linkage groups N7 and N16, and its detection was made possible by the use of segregating populations of doubled haploid lines and codominant RFLP markers. RFLP probes detected pairs of homeologous loci on N7 and N16 for which the annual and biennial parents had identical alleles in regions expected to be homeologous. The existence of an interstitial reciprocal transposition was confirmed by cytological analysis of synaptonemal complexes of annual × biennial F1 hybrids. Although it included approximately one-third of the physical length of the N7 and N16 chromosomes, few recombination events within the region were recovered in the progenies of the hybrids. Significantly higher seed yields were associated with the parental configurations of the rearrangement in segregating progenies. These progenies contained complete complements of homeologous chromosomes from the diploid progenitors of B. napus, and thus their higher seed yields provide evidence for the selective advantage of allopolyploidy through the fixation of intergenomic heterozygosity.
Comparison of adaptive multiple phenotype association tests using summary statistics in genome-wide association studies
Authors: Sitlani Colleen M , Baldassari Antoine R , Highland Heather M , Hodonsky Chani J , McKnight Barbara , Avery Christy L 
Published: April 2021

Abstract
Genome-wide association studies have been successful mapping loci for individual phenotypes, but few studies have comprehensively interrogated evidence of shared genetic effects across multiple phenotypes simultaneously. Statistical methods have been proposed for analyzing multiple phenotypes using summary statistics, which enables studies of shared genetic effects while avoiding challenges associated with individual-level data sharing. Adaptive tests have been developed to maintain power against multiple alternative hypotheses because the most powerful single-alternative test depends on the underlying structure of the associations between the multiple phenotypes and a single nucleotide polymorphism (SNP). Here we compare the performance of six such adaptive tests: two adaptive sum of powered scores (aSPU) tests, the unified score association test (metaUSAT), the adaptive test in a mixed-models framework (mixAda) and two principal-component-based adaptive tests (PCAQ and PCO). Our simulations highlight practical challenges that arise when multivariate distributions of phenotypes do not satisfy assumptions of multivariate normality. Previous reports in this context focus on low minor allele count (MAC) and omit the aSPU test, which relies less than other methods on asymptotic and distributional assumptions. When these assumptions are not satisfied, particularly when MAC is low and/or phenotype covariance matrices are singular or nearly singular, aSPU better preserves type I error, sometimes at the cost of decreased power. We illustrate this trade-off with multiple phenotype analyses of six quantitative electrocardiogram traits in the Population Architecture using Genomics and Epidemiology (PAGE) study.
Effective Host-Directed Therapy for Tuberculosis by Depletion of Myeloid-Derived Suppressor Cells and Related Cells Using a Diphtheria Toxin Fusion Protein
Authors: Parveen Sadiya , Lun Shichun , Urbanowski Michael E , Cardin Mitchell , Shen Jessica , Murphy John R , Bishai William R 
Published: April 2021

AbstractMyeloid-derived suppressor cells (MDSCs) are present in elevated numbers in tuberculosis patients and have been found to be permissive for Mycobacterium tuberculosis proliferation. To determine whether depletion of MDSCs may improve host control of tuberculosis, we used a novel diphtheria toxin-based fusion protein DABIL-4 that targets and depletes interleukin 4 (IL-4) receptor-positive cells. We show that DABIL-4 depletes both polymorphonuclear MDSCs and monocytic MDSCs, increases interferon-γ + T cells, and reduces the lung bacillary burden in a mouse tuberculosis model. These results indicate that MDSC-depleting therapies targeting the IL-4 receptor are beneficial in tuberculosis and offer an avenue towards host-directed tuberculosis therapy.
Mechanisms and regulation underlying membraneless organelle plasticity control
Authors: Ismail Hazrat , Liu Xu , Yang Fengrui , Li Junying , Zahid Ayesha , Dou Zhen , Liu Xing , Yao Xuebiao 
Published: April 2021

AbstractEvolution has enabled living cells to adopt their structural and functional complexity by organizing intricate cellular compartments, such as membrane-bound and membraneless organelles (MLOs), for spatiotemporal catalysis of physiochemical reactions essential for cell plasticity control. Emerging evidence and view support the notion that MLOs are built by multivalent interactions of biomolecules via phase separation and transition mechanisms. In healthy cells, dynamic chemical modifications regulate MLO plasticity, and reversible phase separation is essential for cell homeostasis. Emerging evidence revealed that aberrant phase separation results in numerous neurodegenerative disorders, cancer, and other diseases. In this review, we provide molecular underpinnings on (i) mechanistic understanding of phase separation, (ii) unifying structural and mechanistic principles that underlie this phenomenon, (iii) various mechanisms that are used by cells for the regulation of phase separation, and (iv) emerging therapeutic and other applications.
CoordinatingIfs
Authors: Khoo Justin 
Published: April 2021

AbstractAccounting for the behavior of conjoined and disjoined if-clauses is not easy for standard theories of conditionals that treat if as either an operator or restrictor. In this paper, I discuss four observations about coordinated if-clauses, and motivate a semantics for conditionals that reorients the compositional structure of the restrictor theory. On my proposal, if-clauses provide restrictions on modal domains, but they do so by way of a higher type intermediary—a set of propositions—that is collapsed by the modal. I argue that combining this view with an independently plausible type-shifting operation applied to or and and predicts the range of data we find for conditionals with coordinated if-clauses.
Synopsis of the 2020 U.S. VA/DoD Clinical Practice Guideline for the Management of Adult Overweight and Obesity
Authors: Mayer Stéphanie B , Graybill Sky , Raffa Susan D , Tracy Christopher , Gaar Earl , Wisbach Gordon , Goldstein Michael G , Sall James 
Published: April 2021

ABSTRACT

Introduction
In May of 2020, the U.S. Veterans Health Administration (VHA) and Department of Defense (DoD) approved a new joint clinical practice guideline for assessing and managing patients who have overweight and obesity. This guideline is intended to give healthcare teams a framework by which to screen, evaluate, treat, and manage the individual needs and preferences of VA and DoD patients who may have either of these conditions. It can be accessed at https://www.healthquality.va.gov/guidelines/CD/obesity/.

Materials and Methods
In January of 2019, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine’s tenets for trustworthy clinical practice guidelines.

Results
The guideline panel developed 12 key questions, systematically searched and evaluated the literature, created a 1-page algorithm, and advanced 18 recommendations using the Grading of Recommendations Assessment, Development, and Evaluation system.

Conclusions
This synopsis summarizes the key recommendations of the guideline regarding management of overweight and obesity, including referral to comprehensive lifestyle interventions that combine behavioral, dietary, and physical activity change, and additional tools of pharmacologic and procedural interventions. Additionally, recommendations based on evidence found in the literature for short-term weight loss are included. A clinical practice algorithm that is part of the guideline is also included. Additional materials, such as provider and patient summaries and a provider pocket card, are also available for public use, accessible at the U.S. Veterans Health Administration (VHA) Clinical Practice Guidelines (CPG) website listed above.
SpaceHub: A high-performance gravity integration toolkit for few-body problems in astrophysics
Authors: Wang Yi-Han , Leigh Nathan W C , Liu Bin , Perna Rosalba 
Published: April 2021

ABSTRACT
We present the open source few-body gravity integration toolkit SpaceHub. SpaceHub offers a variety of algorithmic methods, including the unique algorithms AR-Radau, AR-Sym6, AR-ABITS, and AR-chain+ which we show outperform other methods in the literature and allow for fast, precise, and accurate computations to deal with few-body problems ranging from interacting black holes to planetary dynamics. We show that AR-Sym6 and AR-chain+, with algorithmic regularization, chain algorithm, active round-off error compensation and a symplectic kernel implementation, are the fastest and most accurate algorithms to treat black hole dynamics with extreme mass ratios, extreme eccentricities, and very close encounters. AR-Radau, the first regularized Radau integrator with round off error control down to 64 bits floating point machine precision, has the ability to handle extremely eccentric orbits and close approaches in long-term integrations. AR-ABITS, a bit efficient arbitrary precision method, achieves any precision with the least CPU cost compared to other open source arbitrary precision few-body codes. With the implementation of deep numerical and code optimization, these new algorithms in SpaceHub prove superior to other popular high precision few-body codes in terms of performance, accuracy, and speed.
The nature of sub-millimetre galaxies I: a comparison of AGN and star-forming galaxy SED fits
Authors: Shanks T , Ansarinejad B , Bielby R M , Heywood I , Metcalfe N , Wang L 
Published: April 2021

ABSTRACT
High-redshift sub-millimetre galaxies (SMGs) are usually assumed to be powered by star formation. However, it has been clear for some time that &gt;20 per cent of such sourcesbrighter than ≈3 mJy host quasars. Here, we analyse a complete sample of 12 sub-mm LABOCA/ALMA 870-μm sources in the centre of the William Herschel Deep Field (WHDF) with multiwavelength data available from the X-ray to the radio bands. Previously, two sources were identified as X-ray-absorbed quasars at z = 1.32 and z = 2.12. By comparing their spectral energy distributions (SEDs) with unabsorbed quasars in the same field, we confirm that they are dust reddened although at a level significantly lower than implied by their X-ray absorption. Then, we compare the SEDs of all the sources to dust-reddened AGN and star-forming galaxy models. This optical/NIR comparison combined with Spitzer MIR colours and faint Chandra X-ray detections shows that 7/12 SMGs are best fitted with an obscured quasar model, a further 3/12 show no preference between AGN and star-forming templates, leaving only a z = 0.046 spiral galaxy and one unidentified source. So in our complete sample, the majority (10/12) of bright SMGs are at least as likely to fit an AGN as a star-forming galaxy template, although no claim is made to rule out the latter as SMG power sources. We then suggest modifications to a previous SMG number count model and conclude that obscured AGN in SMGs may still provide the dominant contribution to both the hard X-ray and sub-millimetre backgrounds.
ALMA imaging of the M-dwarf Fomalhaut C’s debris disc
Authors: Cronin-Coltsmann Patrick F , Kennedy Grant M , Kalas Paul , Milli Julien , Clarke Cathie J , Duchêne Gaspard , Greaves Jane , Lawler Samantha M , Lestrade Jean-François , Matthews Brenda C , Shannon Andrew , Wyatt Mark C 
Published: April 2021

ABSTRACT
Fomalhaut C (LP 876-10) is a low mass M4V star in the intriguing Fomalhaut triple system and, like Fomalhaut A, possesses a debris disc. It is one of very few nearby M-dwarfs known to host a debris disc and of these has by far the lowest stellar mass. We present new resolved observations of the debris disc around Fomalhaut C with the Atacama Large Millimetre Array that allow us to model its properties and investigate the system’s unique history. The ring has a radius of 26 au and a narrow full width at half-maximum of at most 4.2 au. We find a 3σ upper limit on the eccentricity of 0.14, neither confirming nor ruling out previous dynamic interactions with Fomalhaut A that could have affected Fomalhaut C’s disc. We detect no 12CO J = 3-2 emission in the system and do not detect the disc in scattered light with HST/STIS or VLT/SPHERE. We find the original Herschel detection to be consistent with our ALMA model’s radial size. We place the disc in the context of the wider debris disc population and find that its radius is as expected from previous disc radius-host luminosity trends. Higher signal-to-noise observations of the system would be required to further constrain the disc properties and provide further insight to the history of the Fomalhaut triple system as a whole.