bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conserved signaling pathways antagonize and synergize with co-opteddoublesexto control development of novel mimetic butterfly wing patterns
Authors: VanKuren Nicholas W. , Doellman Meredith M. , Sheikh Sofia I. , Palmer Droguett Daniela H. , Massardo Darli , Kronforst Marcus R. 
Published: September 2022

ABSTRACTNovel phenotypes are increasingly recognized to have evolved by co-option of conserved genes into new developmental contexts, yet the impact of co-option on existing developmental programs remains obscure. Here we provide insight into this process by characterizing the consequences ofdoublesexco-option on wing color pattern development inPapilioswallowtail butterflies. doublesexis the master regulator of insect sex differentiation but has been co-opted to control the switch between discrete mimetic and non-mimetic, male-like color patterns inPapilio polytesand its close relatives. Here we show that development of the mimetic color pattern inP. polytesis caused by a pulse ofdsxexpression early in female wing development that results in a corresponding pulse of differential expression that both alters color pattern development and quickly becomes decoupled fromdsxexpression itself. Differentially expressed genes were enriched in canonical Wnt and Hedgehog signaling pathway genes, but case studies of key genes using RNAi and antibody stains suggested opposing, novel roles for the two pathways in mimetic color pattern development. The pulse of Dsx expression caused Engrailed, the key transcription factor effector of Hh signaling, to gain anterior expression in early pupal wing development. However, Dsx and En became decoupled by mid-pupal development when En pre-figured melanic and red patterns and Dsx pre-figured white patterns. In contrast, Wnt signaling antagonizes Dsx in restricted regions of the wing to refine the mimetic color pattern. Our results therefore provide strong experimental evidence thatdsxco-option significantly altered spatiotemporal activities of conserved wing patterning pathways to promote and refine the development of a novel adaptive color pattern. Altogether, our findings provide strong evidence for how co-opted genes can both cause and elicit changes to established gene regulatory networks during the evolution and development of novel phenotypes.
Critical role of growth medium for detecting drug interactions in Gram-negative bacteria that model in vivo responses
Authors: Davis Kathleen P. , Morales Yoelkys , McCabe Anne L. , Mecsas Joan , Aldridge Bree B. 
Published: September 2022

AbstractThe rise in infections caused by multidrug-resistant (MDR) bacteria has necessitated a variety of clinical approaches, including the use of antibiotic combinations. Antibiotic susceptibility is affected in part by the growth state of bacteria within various tissues. Here we tested the hypothesis that drug-drug interactions vary in different media, and hence, using a medium that reflects tissue environments will better predict in vivo outcomes. We systematically studied pair-wise antibiotic interactions in three different media (CAMHB, a urine mimetic, and a lung mimetic) using three Gram-negative ESKAPE pathogens, Acinetobacter baumannii (Ab), Klebsiella pneumoniae (Kp), and Pseudomonas aeruginosa (Pa). There were pronounced differences in responses to antibiotic combinations between the three bacterial species grown in the same medium. However, within species, Pa responded to drug combinations similarly when grown in all three different media, whereas Ab responded similarly when grown in CAMHB and a lung mimetic medium. By contrast, drug interactions in Kp were poorly correlated across three different media. To assess whether distinct media were predictive of antibiotic interactions in Kp in the lungs of mice, we developed a treatment strategy and tested three antibiotic combination pairs. Measurements obtained in vitro from lung mimetic medium, but not rich medium, predicted in vivo outcomes. This work demonstrates that antibiotic interactions are highly variable when comparing across three gram-negative pathogens and highlights the importance of growth medium by showing a superior correlation between in vitro interactions in a growth medium that resembles the tissue environment and in vivo outcomes.
Striatal dopamine integrates cost, benefit and motivation
Authors: Eshel Neir , Touponse Gavin C. , Wang Allan R. , Osterman Amber K. , Shank Amei N. , Groome Alexandra M. , Taniguchi Lara , Cardozo Pinto Daniel F. , Tucciarone Jason , Bentzley Brandon S. , Malenka Robert C. 
Published: September 2022

ABSTRACTDopamine (DA) release in the ventral and dorsal striatum has been linked to reward processing and motivation, but there are longstanding controversies about whether DA release in these key target structures primarily reflects costs or benefits, and how these signals vary with motivation. Here we apply behavioral economic principles to generate demand curves for rewards while directly measuring DA release in the nucleus accumbens (NAc) and dorsolateral striatum (DLS) via a genetically-encoded sensor. By independently varying costs and benefits, we reveal that DA release in both structures incorporates reward magnitude and sunk cost. Surprisingly, motivation was inversely correlated with reward-evoked DA release; the higher the motivation for rewards the lower the reward-evoked DA release. These relationships between DA release, cost and motivation remained identical when we used optogenetic activation of striatal DA inputs as a reward. Our results reconcile previous disparate findings by demonstrating that during operant tasks, striatal DA release simultaneously encodes cost, benefit and motivation but in distinct manners over different time scales.
MR1 dependent MAIT cell activation is regulated by autophagy associated proteins
Authors: Phalora Prabhjeet , Ussher James , Hester Svenja , Marchi Emanuele , Mak Jeffrey Y. W. , Fairlie David P. , Klenerman Paul 
Published: September 2022

AbstractThe antigen presenting molecule, MR1, presents microbial metabolites to MAIT cells, a population of innate-like, anti-microbial T cells. It also presents an unidentified ligand to MR-1 restricted T cells in the setting of cancer. The cellular co-factors that mediate MR1 antigen presentation have yet to be fully defined. We performed a mass spectrometry-based proteomics screen to identify MR1 interacting proteins and identified the selective autophagy receptor SQSTM1/p62. CRISPR-Cas9-mediated knock out of SQSTM1/p62 increased MAIT cell activation in the presence of E.coli but not the synthetic ligand 5-OP-RU whereas depletion of Atg5 and Atg7, key autophagy proteins, increased MAIT activation irrespective of the ligand used. This regulation appears to occur at an early step in the trafficking pathway. This data implicates distinct roles for autophagy associated proteins in the regulation of MR1 activity and highlights the autophagy pathway as a key regulator of cellular antigen presentation.
Functionally conserved Pkd2, mutated in autosomal dominant polycystic kidney disease, localizes to the endoplasmic reticulum and regulates cytoplasmic calcium homeostasis in fission yeast
Authors: Koyano Takayuki , Kume Kazunori , Onishi Kaori , Matsuyama Makoto , Fukushima Masaki , Toda Takashi 
Published: September 2022

AbstractMutations in PKD1 or PKD2 genes lead to autosomal dominant polycystic kidney disease (ADPKD) that is the most frequent family inherited renal disorder. These genes encode polycystin-1/PC-1 and polycycstin-2/PC-2, respectively. Although the genetic basis of ADPKD is well established, the crucial functions of polycystins underlying onset and development of cyst formation remain elusive. Fission yeast Schizosaccharomyces pombe has a single polycystin homolog, Pkd2, which is essential for cell growth. In this study, the truncation analyses of Pkd2 reveal that Pkd2 localizes to not only the plasma membrane but also the endoplasmic reticulum (ER) and regulates cytoplasmic calcium signaling in fission yeast. Internal transmembrane domains within Pkd2 are sufficient for these processes. Surprisingly, more than half of Pkd2 is not required for cell viability. Cytoplasmic calcium levels are mainly regulated through C-terminus of Pkd2. Importantly, human Pkd2 also localizes to the ER and furthermore, fully complements the loss of fission yeast Pkd2. As the functions of polycystin-2 are conserved, fission yeast provides a suitable model to study the mechanism of ADPKD as well as polycystins.
Gut inflammation associated with age and Alzheimer’s disease pathology
Authors: Heston Margo B. , Hanslik Kendra L. , Zarbock Katie R. , Harding Sandra J. , Davenport-Sis Nancy J. , Kerby Robert L. , Chin Nathaniel , Sun Yi , Hoeft Ana , Deming Yuetiva , Vogt Nicholas M. , Betthauser Tobey J. , Johnson Sterling C. , Asthana Sanjay , Kollmorgen Gwendlyn , Suridjan Ivonne , Wild Norbert , Zetterberg Henrik , Blennow Kaj , Rey Federico E. , Bendlin Barbara B. , Ulland Tyler K. 
Published: September 2022

AbstractAge-related disease may be mediated by low levels of chronic inflammation (“inflammaging”). Recent work suggests that gut microbes may contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer’s disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation and permeabilityper seremains unclear. To test whether greater gut inflammation is associated with older age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Here we found that calprotectin levels are higher with age, and that higher calprotectin was associated with greater amyloid burden among participants with an amyloid-confirmed AD dementia diagnosis. Calprotectin was also associated with cerebrospinal fluid markers of AD pathology and axonal degeneration, as well as with lower verbal memory function among cognitively unimpaired participants. Together, these findings suggest that intestinal inflammation may play a role in pathology development, and that it may exacerbate the progression toward AD.SummaryIntestinal inflammation is correlated with older age, Alzheimer’s disease (AD) dementia, and greater amyloid burden in participants with AD.
Comprehensive analysis of immune responses in CLL patients after heterologous COVID-19 vaccination
Authors: Lee Hye Kyung , Hoechstetter Manuela A. , Buchner Maike , Pham Trang Thu , Huh Jin Won , Müller Katharina , Zange Sabine , Buttlar Heiner von , Girl Philipp , Wölfel Roman , Brandmeier Lisa , Pfeuffer Lisa , Furth Priscilla A. , Wendtner Clemens-Martin , Hennighausen Lothar 
Published: September 2022

AbstractPatients with chronic lymphocytic leukemia (CLL) treated with B-cell pathway inhibitors and anti-CD20 antibodies exhibit low humoral response rate (RR) following SARS-CoV-2 vaccination. To investigate the relationship between the initial transcriptional response to vaccination with ensuing B and T cell immune responses, we performed a comprehensive immune transcriptome analysis flanked by antibody and T cell assays in peripheral blood prospectively collected from 15 CLL/SLL patients vaccinated with heterologous BNT162b2/ChAdOx1 with follow up at a single institution. The two-dose antibody RR was 40% increasing to 53% after booster. Patients on BTKi, venetoclax ± anti-CD20 antibody within 12 months of vaccination responded less well than those under BTKi alone. The two-dose T cell RR was 80% increasing to 93% after booster. Transcriptome studies revealed that seven patients showed interferon-mediated signaling activation within 2 days and one at 7 days after vaccination. Increasing counts of COVID-19 specific IGHV genes correlated with B-cell reconstitution and improved humoral RR. T cell responses in CLL patients appeared after vaccination regardless of treatment status. A higher humoral RR was associated with BTKi treatment and B-cell reconstitution. Boosting was particularly effective when intrinsic immune status was improved by CLL-treatment.
An expanded genetic toolbox to accelerate the creation ofAcholeplasma laidlawiidriven by synthetic genomes
Authors: Nucifora Daniel P. , Mehta Nidhi D. , Giguere Daniel J. , Karas Bogumil J. 
Published: September 2022

ABSTRACTAssembling synthetic bacterial genomes in yeast and genome transplantation has enabled an unmatched level of bacterial strain engineering, giving rise to cells with minimal and chemically synthetic genomes. However, this technology is currently limited to members of the Spiroplasma phylogenetic group, mostlyMycoplasmas, within theMollicuteclass. Here, we propose new genetic tools for developing these technologies forAcholeplasma laidlawii, which is phylogenetically distant fromMycoplasmasand, unlike mostMollicutes, uses a standard genetic code. We first investigated a donor-recipient relationship between twoA. laidlawiistrains through whole-genome sequencing. We then created multi-host shuttle plasmids and used them to optimize an electroporation protocol. We also demonstrated the use of evolution to create superior strains for DNA uptake via electroporation. For genome transplantation, we selectedA. laidlawii8195 as the recipient strain and created a PG-8A donor strain by inserting a Tn5 transposon carrying a tetracycline resistance gene. The tools presented here will improveAcholeplasmaresearch and accelerate the effort toward creatingA. laidlawiistrains driven by synthetic genomes.Graphical Abstract
Metamorphic proteins at the basis of human autophagy initiation and lipid transfer
Authors: Nguyen Anh , Lugarini Francesca , David Céline , Hosnani Pouya , Knotkova Barbora , Patel Anoshi , Parfentev Iwan , Friedrich Annabelle , Urlaub Henning , Meinecke Michael , Stork Björn , Faesen Alex C. 
Published: September 2022

AbstractAutophagy is a conserved intracellular degradation pathway that uses de novo doublemembrane vesicle (autophagosome) formation to target a wide range of cytoplasmic material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length sevensubunit human autophagy initiation supercomplex and found at its core ATG13-101 and transmembrane protein ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to adopt topologically distinct folds. The slow spontaneous conversion between folds creates a rate-limiting step to regulate selfassembly of the super-complex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.
Sequential Activation and Local Unfolding Control Poly(A)-Binding Protein Condensation
Authors: Chen Ruofan , Kahan Darren , Shangguan Julia , Sachleben Joseph R. , Riback Joshua A. , Drummond D. Allan , Sosnick Tobin R. 
Published: September 2022

AbstractEukaryotic cells form biomolecular condensates to sense and adapt to their environment1,2. Poly(A)-binding protein (Pab1), a canonical stress granule marker3,4, condenses upon heat shock or starvation, promoting adaptation5. The molecular basis of condensation has remained elusive due to a dearth of techniques to probe structure directly in condensates. Here we apply hydrogen-deuterium exchange/mass spectrometry (HDX-MS) to investigate the molecular mechanism of Pab1’s condensation. We find that Pab1’s four RNA recognition motifs (RRMs) undergo different levels of partial unfolding upon condensation, and the changes are similar for thermal and pH stresses. Although structural heterogeneity is observed, the ability of MS to describe individual subpopulations allows us to identify which regions become partially unfolded and contribute to the condensate’s interaction network. Our data yield a clear molecular picture of Pab1’s stress-triggered condensation, which we term sequential activation, wherein each RRM becomes activated at a temperature where it partially unfolds and associates with other likewise activated RRMs to form the condensate. This model thus implies that sequential activation is dictated by the underlying free energy surface, an effect we refer to as thermodynamic specificity. Our study represents a methodological advance for elucidating the interactions that drive biomolecular condensation that we anticipate will be widely applicable. Furthermore, our findings demonstrate how condensation can use thermodynamic specificity to perform an acute response to multiple, stresses, a potentially general mechanism for stress-responsive proteins.
LEAP2 is a more conserved ligand than ghrelin for fish GHSRs
Authors: Li Hao-Zheng , Shao Xiao-Xia , Wang Ya-Fen , Liu Ya-Li , Xu Zeng-Guang , Guo Zhan-Yun 
Published: September 2022

ABSTRACTRecently, liver-expressed antimicrobial peptide 2 (LEAP2) was identified as an endogenous competitive antagonist and an inverse agonist of the ghrelin receptor GHSR. However, its functions in lower vertebrates are not well understood. Our recent study demonstrated that both LEAP2 and ghrelin are functional towards a fish GHSR from Latimeria chalumnae, an extant coelacanth believed to be one of the closest ancestors of tetrapods. However, amino acid sequence alignment identified that the 6.58 position (Ballesteros-Weinstein numbering system) of most fish GHSRs are not occupied by an aromatic Phe residue, which is absolutely conserved in all known GHSRs from amphibians to mammals, and is responsible for human GHSR binding to its agonist, ghrelin. To test whether these unusual fish receptors are functional, we studied the ligand binding properties of three representative fish GHSRs, two from Danio rerio (zebrafish) and one from Larimichthys crocea (large yellow croaker). After overexpression in human embryonic kidney 293T cells, the three fish GHSRs retained normal binding to all tested LEAP2s, except for a second LEAP2 from L. crocea. However, they displayed almost no binding to all chemically synthesized n-octanoylated ghrelins, despite these ghrelins all retaining normal function towards human and coelacanth GHSRs. Thus, it seems that LEAP2 is a more conserved ligand than ghrelin towards fish GHSRs. Our results not only provided new insights into the interaction mechanism of GHSRs with LEAP2s and ghrelins, but also shed new light on the functions of LEAP2 and ghrelin in different fish species.
Online environmentally adaptive trajectory planning for rotorcraft unmanned aerial vehicles
Authors: Tong Chunming , Liu Zhenbao , Dang Qingqing , Wang Jingyan , Cheng Yao 
Published: September 2022

Purpose
This paper aims to propose an environmentally adaptive trajectory planning system considering the dynamic characteristics of unmanned aerial vehicles (UAVs) and the distance between obstacles and the UAV. The system generates a smooth and safe flight trajectory online.

Design/methodology/approach
First, the hybrid A* search method considering the dynamic characteristics of the quadrotor is used to find the collision-free initial trajectory. Then, environmentally adaptive velocity cost is designed for environment-adaptive trajectory optimization using environmental gradient data. The proposed method adaptively adjusts the autonomous flight speed of the UAV. Finally, the initial trajectory is applied to the multi-layered optimization framework to make it smooth and dynamically viable.

Findings
The feasibility of the designed system is validated by online flight experiments, which are in unknown, complex situations.

Practical implications
The proposed trajectory planning system is integrated into a vision-based quadrotor platform. It is easily implementable onboard and computationally efficient.

Originality/value
A hybrid A* path searching method is proposed to generate feasible motion primitives by dispersing the input space uniformly. The proposed method considers the control input of the UAV and the search time as the heuristic cost. Therefore, the proposed method can provide an initial path with the minimum flying time and energy loss that benefits trajectory optimization. The environmentally adaptive velocity cost is proposed to adaptively adjust the flight speed of the UAV using the distance between obstacles and the UAV. Furthermore, a multi-layered environmentally adaptive trajectory optimization framework is proposed to generate a smooth and safe trajectory.
A strategy of the longitudinal control for the tandem wing configuration design
Authors: Figat Marcin 
Published: September 2022

Purpose
This paper presents first sight on the longitudinal control strategy for an aircraft in the tandem wing configuration. It is an aerodynamic strongly coupled configuration that needs a lot of detailed aerodynamic analysis which describes the mutual impact of the main parts of the aircraft. The purpose of this paper is to build the numerical model that allows to make an analysis of necessary flaps (front and rear) deflection and prepare the control strategy for this kind of aircraft.

Design/methodology/approach
Aircrafts’ aerodynamic characteristics were obtained using the MGAERO software which is a commercial computing fluid dynamics tool created by Analytical Methods, Inc. This software uses the Euler flow model. Results from this software were used in the static stability evaluation and trim condition analysis. The trim conditions are the outcome of the optimisation process whose goal was to find the best front and rear flap deflection to achieve the best lift to drag (L/D) ratio.

Findings
The main outcome of this investigation is the proposal of strategy for the front and rear flap deflection which ensured the maximum L/D ratio and satisfied the trim condition. Moreover, the analysis of the mutual impact of the front and rear wings and the analysis of the control surface impact on the aerodynamic characteristic of the aircraft are presented.

Research limitations/implications
In terms of aerodynamic computation, MGAERO software uses an inviscid flow model. However, this research is for the conceptual stage of the design and the MGAERO software grantee satisfied accurate respect to relatively low time of computations.

Practical implications
The ultimate goal is to build an aircraft in a tandem wing configuration and to conduct flying tests or wind tunnel tests. The presented result is one of the milestones to achieve this goal.

Originality/value
The aircraft in the tandem wing configuration is an aerodynamic-coupled configuration that needs detailed analysis to find the mutual interaction between the front and rear wings. Moreover, the mutual impact of the front and rear flaps is necessary too. Obtaining these results allowed this study to build the numerical model of the aircraft in the tandem wing configuration. It allows to find the best strategy of flap deflection, which allows to obtain the maximum L/D ratio and satisfy the trim condition.