bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental characterization and automatic identification of stridulatory sounds inside wood
Authors: Bedoya Carol L. , Nelson Ximena J. , Brockerhoff Eckehard G. , Pawson Stephen , Hayes Michael 
Published: September 2021

ABSTRACTThe propagation of animal vocalizations in water and in air is a well-studied phenomenon, but sound produced by bark and wood boring insects, which feed and reproduce inside trees, is poorly understood. Often being confined to the dark and chemically-saturated habitat of wood, many bark- and woodborers have developed stridulatory mechanisms to communicate acoustically. Despite their ecological and economic importance and the unusual medium used for acoustic communication, very little is known about sound production in these insects, or their acoustic interactions inside trees. Here, we use bark beetles (Scolytinae) as a model system to study the effects of wooden tissue on the propagation of insect stridulations and propose algorithms for their automatic identification. We characterize distance-dependence of the spectral parameters of stridulatory sounds, propose data-based models for the power decay of the stridulations in both outer and inner bark, provide optimal spectral ranges for stridulation detectability, and develop automatic methods for their detection and identification. We also discuss the acoustic discernibility of species cohabitating the same log. The species tested can be acoustically identified with 99% of accuracy at distances up to 20 cm and detected to the greatest extent in the 2-6 kHz frequency band. Phloem was a better medium for sound transmission than bark.
Effects of age and surface instability on the control of the center of mass
Authors: van den Bogaart Maud , Bruijn Sjoerd M. , Spildooren Joke , van Dieën Jaap H. , Meyns Pieter 
Published: September 2021

AbstractDuring standing, posture can be controlled by accelerating the Center of Mass (CoM) through shifting the center of pressure (CoP) within the base of support by applying ankle moments (“CoP mechanism”), or through the “counter-rotation mechanism”, i.e., changing the angular momentum of segments around the CoM to change the direction of the ground reaction force. Postural control develops over the lifespan; at both the beginning and the end of the lifespan adequate postural control appears more challenging. In this study, we aimed to assess mediolateral balance performance and the related use of the postural control mechanisms in children, older adults and young adults when standing on different (unstable) surfaces. Sixteen pre-pubertal children (6-9y), 17 young adults (18-24y) and eight older adults (65-80y) performed bipedal upright standing trials of 16 seconds on a rigid surface and on three balance boards that could freely move in the frontal plane, varying in height (15-19 cm) of the surface of the board above the point of contact with the floor. Full body kinematics (16 segments, 48 markers, using SIMI 3D-motion analysis system (GmbH) and DeepLabCut and Anipose) were retrieved. Performance related outcome measures, i.e., the number of trials with balance loss and the Root Mean Square (RMS) of the time series of the CoM acceleration, the contributions of the CoP mechanism and the counter-rotation mechanism to the CoM acceleration in the frontal plane and selected kinematic measures, i.e. the orientation of the board and the head and the Mean Power Frequency (MPF) of the balance board orientation and the CoM acceleration were determined. Balance loss only occurred when standing on the highest balance board, twice in one older adult once in one young adult. In children and older adults, the RMS of the CoM accelerations were larger, corresponding to poorer balance performance. Across age groups and conditions, the contribution of the CoP mechanism to the total CoM acceleration was much larger than that of the counter-rotation mechanisms, ranging from 94%-113% vs 23%-38% (with totals higher than 100% indicating opposite effects of both mechanisms). Deviations in head orientation were small compared to deviations in balance board orientation. We hypothesize that the CoP mechanism is dominant, since the counter-rotation mechanism would conflict with stabilizing the orientation of the head in space.
Disruption of fish gut microbiota composition and holobiont’s metabolome by cyanobacterial blooms
Authors: Gallet Alison , Halary Sébastien , Duval Charlotte , Huet Hélène , Duperron Sébastien , Marie Benjamin 
Published: September 2021

AbstractBackgroundCyanobacterial blooms are one of the most common stress encountered by metazoans living in freshwater lentic systems such as lakes and ponds. Blooms reportedly impair fish health, notably through oxygen depletion and production of bioactive compounds including cyanotoxins. However, in the times of the “microbiome revolution”, it is surprising that so little is still known regarding the influence of blooms on fish microbiota. In this study, an experimental approach is used to demonstrate that blooms affect fish microbiome composition and functions, as well as the metabolome of holobionts. To this end, the model teleost Oryzias latipes is exposed to simulated Microcystis aeruginosa blooms of various intensities in a microcosm setting, and the response of bacterial gut communities is evaluated in terms of composition, metagenome-encoded functions and metabolome profiling.ResultsThe gut bacterial community of O. latipes exhibits marked responses to the presence of M. aeruginosa blooms in a dose-dependent manner. Notably, abundant gut-associated Firmicutes almost disappear, while potential opportunists increase. The holobiont’s gut metabolome displays major changes, while functions encoded in the metagenome of bacterial partners are more marginally affected. Bacterial communities tend to return to original composition after the end of the bloom suggesting post-bloom resilience, and remain sensitive in case of a second bloom, reflecting a highly reactive gut community.ConclusionIn the context of increasingly frequent and intense blooms worldwide, results point to the relevance of accounting for short- and long-term microbiome-related effects in fish ecology, with potential outcomes relevant to conservation biology as well as aquaculture.
No substantial pre-existing B cell immunity against SARS-CoV-2 in healthy adults
Authors: Ercanoglu Meryem Seda , Gieselmann Lutz , Dähling Sabrina , Poopalasingam Nareshkumar , Detmer Susanne , Koch Manuel , Korenkov Michael , Halwe Sandro , Klüver Michael , Di Cristanziano Veronica , Janicki Hanna , Schlotz Maike , Worczinski Johanna , Gathof Birgit , Gruell Henning , Zehner Matthias , Becker Stephan , Vanshylla Kanika , Kreer Christoph , Klein Florian 
Published: September 2021

SummaryPre-existing immunity against SARS-CoV-2 may have critical implications for our understanding of COVID-19 susceptibility and severity. Various studies recently provided evidence of pre-existing T cell immunity against SARS-CoV-2 in unexposed individuals. In contrast, the presence and clinical relevance of a pre-existing B cell immunity remains to be fully elucidated. Here, we provide a detailed analysis of the B cell response to SARS-CoV-2 in unexposed individuals. To this end, we extensively investigated the memory B cell response to SARS-CoV-2 in 150 adults sampled pre-pandemically. Comprehensive screening of donor plasma and purified IgG samples for binding and neutralization in various functional assays revealed no substantial activity against SARS-CoV-2 but broad reactivity to endemic betacoronaviruses. Moreover, we analyzed antibody sequences of 8,174 putatively SARS-CoV-2-reactive B cells on a single cell level and generated and tested 158 monoclonal antibodies. None of the isolated antibodies displayed relevant binding or neutralizing activity against SARS-CoV-2. Taken together, our results show no evidence of relevant pre-existing antibody and B cell immunity against SARS-CoV-2 in unexposed adults.
High-Dimensional Gene Expression and Morphology Profiles of Cells across 28,000 Genetic and Chemical Perturbations
Authors: Haghighi Marzieh , Caicedo Juan , Cimini Beth A. , Carpenter Anne E. , Singh Shantanu 
Published: September 2021

AbstractCells can be perturbed by various chemical and genetic treatments and the impact on the cells’ gene expression (transcription, i.e. mRNA levels) and morphology (in an image-based assay) can be measured. The patterns observed in this high-dimensional profile data can power a dozen applications in drug discovery and basic biology research, but both types of profiles are rarely available for large-scale experiments. Here, we provide a collection of four datasets with both gene expression and morphological profile data useful for developing and testing multi-modal methodologies. Roughly a thousand features are measured for each of the two data types, across more than 28,000 thousand chemical and genetic perturbations. We define biological problems that use the shared and complementary information in these two data modalities, provide baseline analysis and evaluation metrics for multi-omic applications, and make the data resource publicly available (http://broad.io/rosetta).
Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques
Authors: Speranza Emily , Purushotham Jyothi N. , Port Julia R. , Schwarz Benjamin , Flagg Meaghan , Williamson Brandi N. , Feldmann Friederike , Singh Manmeet , Pérez-Pérez Lizzette , Sturdevant Gail L. , Roberts Lydia M. , Carmody Aaron , Schulz Jonathan E. , Doremalen Neeltje van , Okumura Atsushi , Lovaglio Jamie , Hanley Patrick W. , Shaia Carl , Germain Ronald N. , Best Sonja M. , Munster Vincent J. , Bosio Catharine M. , de Wit Emmie 
Published: September 2021

AbstractAdvanced age is a key predictor of severe COVID-19. To gain insight into this relationship, particularly with respect to immune responses, we utilized the rhesus macaque model of SARS-CoV-2 infection. Two cohorts of eight older (16-23 years) and eight younger (3-5 years) rhesus macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at pre-defined timepoints in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication dynamics were limited between age cohorts. Transcriptional signatures of inflammation-associated genes in cells isolated from bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both younger and older animals. These findings suggested that age did not substantially skew major facets of acute disease in this model. However, age-specific divergence of immune responses emerged during the post-acute phase of infection (7-21 dpi). Older animals exhibited sustained local inflammatory innate responses while local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, in contrast to persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling in SARS-CoV-2-infected rhesus macaques suggests that age may delay or impair the induction of anti-viral cellular immune responses and delay efficient return to immune homeostasis following acute infection.
Visceral mesoderm signaling regulates assembly position and function of the Drosophila testis niche
Authors: Anllo Lauren , DiNardo Stephen 
Published: September 2021

SummaryTissue homeostasis often requires a properly placed niche to support stem cells. Morphogenetic processes that position a niche are just being described. For the Drosophila testis we recently showed that pro niche cells, specified at disparate positions during early gonadogenesis, must assemble into one collective at the anterior of the gonad. We now find that Slit and FGF signals emanating from adjacent visceral mesoderm regulate assembly. In response to signaling, niche cells express islet, which we find is also required for niche assembly. Without signaling, niche cells specified furthest from the anterior are unable to migrate, remaining dispersed. Function of such niches is severely disrupted, with niche cells evading cell cycle quiescence, compromised in their ability to signal the incipient stem cell pool, and failing to orient stem cell divisions properly. Our work identifies both extrinsic signaling and intrinsic responses required for proper assembly and placement of the testis niche.
SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
Authors: Gamart Julie , Barozzi Iros , Laurent Frédéric , Reinhardt Robert , Martins Laurène Ramos , Oberholzer Thomas , Visel Axel , Zeller Rolf , Zuniga Aimée 
Published: September 2021

ABSTRACTSMAD4 regulates gene expression in response to BMP and TGFβ signal transduction and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we use an epitope-taggedSmad4allele for ChIP-seq analysis together with transcriptome analysis of wild-type and mouse forelimb buds lackingSmad4in the mesenchyme. This analysis identifies the SMAD4 target genes during establishment of the feedback signaling system and establishes that SMAD4 predominantly mediates BMP signal-transduction during early limb bud development. Unexpectedly, the initial analysis reveals that the expression of cholesterol biosynthesis enzymes is precociously down-regulated and intracellular cholesterol levels reduced inSmad4-deficient limb bud mesenchymal progenitors. The SMAD4 target GRNs includes genes, whose expression in the anterior limb bud is up-regulated by interactions of SMAD4 complexes with enhancers active in the anterior mesenchyme. This reveals a predominant function of SMAD4 in up-regulating target gene expression in the anterior limb bud mesenchyme. Analysis of differentially expressed genes that are shared betweenSmad4- andShh-deficient limb buds corroborates the positive role of SMAD4 in transcriptional regulation of anterior genes and reveals a repressive effect on posterior genes that are positively regulated by SHH signaling. This analysis uncovers the overall opposing effects of SMAD4-mediated BMP and SHH signalling on transcriptional regulation during early limb bud development. In summary, this analysis indicates that during early digit patterning and limb bud outgrowth, the anterior/proximal and proximo/distal expression dynamics of co-regulated genes are controlled by distinct and contrasting trans-regulatory inputs from SHH and SMAD4-mediated BMP signal transduction.
Classification of antimicrobial mechanism of action using bacterial time-lapse imaging
Authors: Ouyang Xudong , Hoeksma Jelmer , Siersma Tjalling K. , Hamoen Leendert W. , Hertog Jeroen den 
Published: September 2021

AbstractAntimicrobial resistance is a major threat to human health. Basic knowledge of antimicrobial mechanism of action (MoA) is imperative for patient care and for identification of novel antimicrobials. However, the process of antimicrobial MoA identification is relatively laborious. Here, we developed a simple, quantitative time-lapse fluorescence imaging method, Dynamic Bacterial Morphology Imaging (DBMI), to facilitate this process. It uses a membrane dye and a nucleoid dye to track the morphological changes of single Bacillus subtilis cells in response to antimicrobials for up to 60 min. DBMI of bacterial cells facilitated assignment of the MoAs of 14 distinct, known antimicrobial compounds to the five main classes. Using this method, we found that the poorly studied antimicrobial, harzianic acid, a secondary metabolite that we purified from the fungal culture of Oidiodendron flavum, targets the cell envelope. We conclude that DBMI is a simple method, which facilitates rapid classification of the MoA of antimicrobials in functionally distinct classes.
Targeted isolation of panels of diverse human protective broadly neutralizing antibodies against SARS-like viruses
Authors: He Wan-ting , Musharrafieh Rami , Song Ge , Dueker Katharina , Tse Longping V. , Martinez David R. , Schäfer Alexandra , Callaghan Sean , Yong Peter , Beutler Nathan , Torres Jonathan L. , Volk Reid M. , Zhou Panpan , Yuan Meng , Liu Hejuni , Anzanello Fabio , Capozzola Tazio , Parren Mara , Garcia Elijah , Rawlings Stephen A. , Smith Davey M. , Wilson Ian A. , Safonova Yana , Ward Andrew B. , Rogers Thomas F. , Baric Ralph S. , Gralinski Lisa E. , Burton Dennis R. , Andrabi Raiees 
Published: September 2021

SUMMARYThe emergence of current SARS-CoV-2 variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy 1–7. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed 8, 9. Notably, several recent studies have revealed that vaccination of recovered COVID-19 donors results in enhanced nAb responses compared to SARS-CoV-2 infection or vaccination alone 10–13. Here, we utilized a targeted donor selection strategy to isolate a large panel of broadly neutralizing antibodies (bnAbs) to sarbecoviruses from two such donors. Many of the bnAbs are remarkably effective in neutralization against sarbecoviruses that use ACE2 for viral entry and a substantial fraction also show notable binding to non-ACE2-using sarbecoviruses. The bnAbs are equally effective against most SARS-CoV-2 VOCs and many neutralize the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor binding domain (RBD) as opposed to strain-specific nAbs to the receptor binding site that are commonly elicited in SARS-CoV-2 infection and vaccination 14–18. Consistent with targeting of conserved sites, select RBD bnAbs exhibited in vivo protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model. The generation of a large panel of potent bnAbs provides new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and, importantly, provides a molecular basis for effective design of pan-sarbecovirus vaccines.
CRISPR-Cas12a induced DNA double-strand breaks are repaired by locus-dependent and error-prone pathways in a fungal pathogen
Authors: Huang Jun , Rowe David , Zhang Wei , Suelter Tyler , Valent Barbara , Cook David E. 
Published: September 2021

AbstractCRISPR-Cas mediated genome engineering has revolutionized functional genomics. However, basic questions remain regarding the mechanisms of DNA repair following Cas-mediated DNA cleavage. We developed CRISPR-Cas12a ribonucleoprotein genome editing in the fungal plant pathogen, Magnaporthe oryzae, and found frequent donor DNA integration despite the absence of long sequence homology. Interestingly, genotyping from hundreds of transformants showed that frequent non-canonical DNA repair outcomes predominated the recovered genome edited strains. Detailed analysis using sanger and nanopore long-read sequencing revealed five classes of DNA repair mutations, including single donor DNA insertions, concatemer donor DNA insertions, large DNA deletions, deletions plus donor DNA insertions, and infrequently we observed INDELs. Our results show that different error-prone DNA repair pathways resolved the Cas12a-mediated double-strand breaks (DSBs) based on the DNA sequence of edited strains. Furthermore, we found that the frequency of the different DNA repair outcomes varied across the genome, with some tested loci resulting in more frequent large-scale mutations. These results suggest that DNA repair pathways provide preferential repair across the genome that could create biased genome variation, which has significant implications for genome engineering and the genome evolution in natural populations.
Combined free energy calculation and machine learning methods for understanding ligand unbinding kinetics
Authors: Badaoui Magd , Buigues Pedro J , Berta Dénes , Mandana Gaurav M. , Gu Hankang , Földes Tamás , Dickson Callum J , Hornak Viktor , Kato Mitsunori , Molteni Carla , Parsons Simon , Rosta Edina 
Published: September 2021

ABSTRACTThe determination of drug residence times, which define the time an inhibitor is in complex with its target, is a fundamental part of the drug discovery process. Synthesis and experimental measurements of kinetic rate constants are, however, expensive, and time-consuming. In this work, we aimed to obtain drug residence times computationally. Furthermore, we propose a novel algorithm to identify molecular design objectives based on ligand unbinding kinetics. We designed an enhanced sampling technique to accurately predict the free energy profiles of the ligand unbinding process, focusing on the free energy barrier for unbinding. Our method first identifies unbinding paths determining a corresponding set of internal coordinates (IC) that form contacts between the protein and the ligand, it then iteratively updates these interactions during a series of biased molecular-dynamics (MD) simulations to reveal the ICs that are important for the whole of the unbinding process. Subsequently, we performed finite temperature string simulations to obtain the free energy barrier for unbinding using the set of ICs as a complex reaction coordinate. Importantly, we also aimed to enable further design of drugs focusing on improved residence times. To this end, we developed a supervised machine learning (ML) approach with inputs from unbiased “downhill” trajectories initiated near the transition state (TS) ensemble of the string unbinding path. We demonstrate that our ML method can identify key ligand-protein interactions driving the system through the TS. Some of the most important drugs for cancer treatment are kinase inhibitors. One of these kinase targets is Cyclin Dependent Kinase 2 (CDK2), an appealing target for anticancer drug development. Here, we tested our method using two different CDK2 inhibitors for potential further development of these compounds. We compared the free energy barriers obtained from our calculations with those observed in available experimental data. We highlighted important interactions at the distal ends of the ligands that can be targeted for improved residence times. Our method provides a new tool to determine unbinding rates, and to identify key structural features of the inhibitors that can be used as starting points for novel design strategies in drug discovery.