bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain
Authors: Rahman-Enyart Afrida , Yang Wenbin , Yaggie Ryan E. , White Bryan , Welge Michael , Auvil Loretta , Berry Matthew , Bushell Colleen , Rosen John M. , Rudick Charles N. , Schaeffer Anthony J. , Klumpp David J. 
Published: January 2021

ABSTRACTDysbiosis of gut microbiota is associated with many pathologies, yet host factors modulating microbiota remain unclear. Interstitial cystitis/bladder pain syndrome (IC/BPS or “IC”) is a debilitating condition of chronic pelvic pain often with co-morbid urinary dysfunction and anxiety/depression, and recent studies find fecal dysbiosis in IC/BPS patients. We previously identified the locus encoding acyloxyacyl hydrolase,Aoah, as a modulator of pelvic pain severity in a murine IC/BPS model. AOAH-deficient mice spontaneously develop rodent correlates of pelvic pain, increased responses to induced pelvic pain models, voiding dysfunction, and anxious/depressive behaviors. Here, we report that AOAH-deficient mice exhibit dysbiosis of GI microbiota. AOAH-deficient mice exhibit an enlarged cecum, a phenotype long associated with germ-free rodents, and reduced trans-epithelial electrical resistance consistent with a “leaky gut” phenotype. AOAH-deficient ceca showed altered gene expression consistent with inflammation, Wnt signaling, and urologic disease. 16S rRNA sequencing of stool revealed altered microbiota in AOAH-deficient mice, and GC-MS identified altered metabolomes. Co-housing AOAH-deficient mice with wild type mice resulted in converged microbiota and altered predicted metagenomes. Co-housing also abrogated the pelvic pain phenotype of AOAH-deficient mice, which was corroborated by oral gavage of AOAH-deficient mice with stool slurry of wild type mice. Converged microbiota also alleviated comorbid anxiety-like behavior in AOAH-deficient mice. Oral gavage of AOAH-deficient mice with anaerobes cultured from IC/BPS stool resulted in exacerbation of pelvic allodynia. Together, these data indicate that AOAH is a host determinant of normal gut microbiota, and the dysbiosis associated with AOAH deficiency contributes to pelvic pain. These findings suggest that the gut microbiome is a potential therapeutic target for IC/BPS.
A coupled mechano-biochemical framework for root meristem morphogenesis
Authors: Marconi Marco , Gallemi Marçal , Benková Eva , Wabnik Krzysztof 
Published: January 2021

AbstractPlants grow roots to adjust their bodies to dynamic changes in the surrounding environment. How do plant roots emerge from the stem cell reservoir during embryogenesis is however poorly understood. Here, we present a bottom-up strategy to address this challenge by combining empirical observations with advanced computer modeling techniques. We demonstrate that the anisotropy of root growth results from differential growth rates of adjacent tissues, whereas the root meristem development incorporates a multi-level feedback loop between complex transport network of phytohormone auxin, auxin-dependent cell growth and cytoskeleton rearrangements.In silicomodel predictions are in close agreement within vivopatterns of anisotropic growth, auxin distribution, and cell polarity, as well as several root phenotypes caused by chemical, mechanical, or genetic perturbations. Our findings reveal a minimal set of design principles connecting tissue mechanics, cell anisotropy, and directional transport that are sufficient for self-organization of the root meristem shape. A mobile auxin signal transported through immobile cells orchestrates polarity and growth mechanics to instruct the morphogenesis of an independent organ.
An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay
Authors: Fritz Sarah E. , Ranganathan Soumya , Wang Clara D. , Hogg J. Robert 
Published: January 2021

AbstractThe nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. Previous studies indicate that the extension of a conserved regulatory loop in the UPF1LLhelicase core confers a decreased propensity to dissociate from RNA upon ATP hydrolysis relative to the major UPF1 isoform, designated UPF1SL. Using biochemical and transcriptome-wide approaches, we find that UPF1LLovercomes the protective RNA binding proteins PTBP1 and hnRNP L to preferentially bind and down-regulate long 3’UTRs normally shielded from NMD. Unexpectedly, UPF1LLsupports induction of NMD on new populations of substrate mRNAs in response to activation of the integrated stress response and impaired translation efficiency. Thus, while canonical NMD is abolished by moderate translational repression, UPF1LLactivity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.
Generation of a New Frizzled 2 Flox Mouse Model to Clarify Its Role in Development
Authors: Michalski Megan N. , Diegel Cassandra R. , Zhong Zhendong A. , Suino-Powell Kelly , Blazer Levi , Adams Jarrett ,   VAI Vivarium and Transgenics Core, Beddows Ian , Melcher Karsten , Sidhu Sachdev S. , Angers Stephane , Williams Bart O. 
Published: January 2021

AbstractIt is currently accepted that Wnt receptors, Frizzleds (Fzd), have high functional redundancy, making individual receptors challenging to target therapeutically. Specifically, Fzd2 is believed to be functionally redundant with Fzd1 and Fzd7, findings which were based largely on previously published global knockout mouse studies. Conversely, a Fzd2 global knockout mouse model developed by the International Mouse Phenotype Consortium (IMPC) is early embryonic lethal, suggesting Fzd2 is critical for early embryonic development. If global deletion of Fzd2 leads to early lethality, floxed models are necessary to identify tissue-specific phenotypes. We found that a previously published Fzd2 flox model does not fully delete Fzd2 function. To reconcile the contradictory findings in Fzd2 mouse models and allow for tissue-specific studies of Fzd2, we have generated a new flox model using a modified two-cell homologous recombination CRISPR approach. We demonstrated successful simultaneous insertion of twoloxPsites fully surrounding the Fzd2 gene and confirmed cre-mediated recombination deletes the sequence between theloxPsites leading to a Fzd2 null allele. Preliminary studies suggest global knockouts are early embryonic lethal and full characterization of the tissue-specific effects of Fzd2 deletion is currently underway. This work suggests Fzd2 uniquely regulates development and emphasizes the importance of thorough validation of newly generated mouse models.
Sweeps in time: leveraging the joint distribution of branch lengths
Authors: Bisschop Gertjan , Lohse Konrad , Setter Derek 
Published: January 2021

AbstractCurrent methods of identifying positively selected regions of the genome are limited by their underlying model in two key ways: the model cannot account for the timing of the adaptive event and the analytic predictions are limited to single nucleotide polymorphisms. Here we develop a tractable method of describing the effect of positive selection on the genealogical histories in the surrounding genome, explicitly modeling both the timing and context of the adaptive event. In addition, our framework allows us to go beyond simple polymorphism data. We are able to leverage information contained in patterns of linked variants, and even with very small sample sizes, our analytic framework has high power to identify historically adaptive regions of the genome and to correctly infer both the time and strength of selection. Finally, we derived the marginal distribution of genealogical branch lengths at a locus affected by selection acting at a linked site. This provides a much-needed link between current theoretical models to recent advances in simulation procedures that have allowed researchers both to examine the evolution of genealogical histories at the level of full chromosomes and build methods that attempt to reconstruct full ancestries from genome sequence data.
MS2AI: Automated repurposing of public peptide LC-MS data for machine learning applications
Authors: Rehfeldt Tobias Greisager , Krawczyk Konrad , Bøgebjerg Mathias , Schwämmle Veit , Röttger Richard 
Published: January 2021

AbstractMotivationLiquid-chromatography mass-spectrometry (LC-MS) is the established standard for analyzing the proteome in biological samples by identification and quantification of thousands of proteins. Machine learning (ML) promises to considerably improve the analysis of the resulting data, however, there is yet to be any tool that mediates the path from raw data to modern ML applications. More specifically, ML applications are currently hampered by three major limitations: (1) absence of balanced training data with large sample size; (2) unclear definition of sufficiently information-rich data representations for e.g. peptide identification; (3) lack of benchmarking of ML methods on specific LC-MS problems.ResultsWe created the MS2AI pipeline that automates the process of gathering vast quantities of mass spectrometry (MS) data for large scale ML applications. The software retrieves raw data from either in-house sources or from the proteomics identifications database, PRIDE. Subsequently, the raw data is stored in a standardized format amenable for ML encompassing MS1/MS2 spectra and peptide identifications. This tool bridges the gap between MS and AI, and to this effect we also present an ML application in the form of a convolutional neural network for the identification of oxidized peptides.AvailabilityAn open source implementation of the software can be found freely available for non-commercial use athttps://gitlab.com/roettgerlab/ms2ai.Contactveits@bmb.sdu.dkSupplementary informationSupplementary data are available atBioinformaticsonline.
Iron-loading is a prominent feature of activated microglia in Alzheimer’s disease patients
Authors: Kenkhuis Boyd , Somarakis Antonios , de Haan Lorraine , Dzyubachyk Oleh , IJsselsteijn Marieke E , de Miranda Noel FCC , Lelieveldt Boudewijn PF , Dijkstra Jouke , van Roon-Mom Willeke MC , Höllt Thomas , van der Weerd Louise 
Published: January 2021

AbstractBrain iron accumulation has been found to accelerate disease progression in Amyloid β-positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key-players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant Aβ-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Amyloid-β load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with Aβ.
Maximum likelihood estimation of the geometric niche preemption model
Authors: Graffelman Jan 
Published: January 2021

AbstractThe geometric series or niche preemption model is an elementary ecological model in biodiversity studies. The preemption parameter of this model is usually estimated by regression or iteratively by using May’s equation. This article proposes a maximum likelihood estimator for the niche preemption model, assuming a known number of species and multinomial sampling. A simulation study shows that the maximum likelihood estimator outperforms the classical estimators in this context in terms of bias and precision. We obtain the distribution of the maximum likelihood estimator and use it to obtain confidence intervals for the preemption parameter and to develop a preemptionttest that can address the hypothesis of equal geometric decay in two samples. We illustrate the use of the new estimator with some empirical data sets taken from the literature and provide software for its use.
Utilisation of semiconductor sequencing for detection of actionable fusions in solid tumours
Authors: Loddo Marco , Hardisty Keeda-Marie , Haddow Tiffany , Thatcher Robert , Williams Gareth H 
Published: January 2021

AbstractOncogenic fusions represent compelling druggable targets in solid tumours highlighted by the recent site agnostic FDA approval of larotrectinib for NTRK rearrangements. However screening for fusions in routinely processed tissue samples is constrained due to degradation of nucleic acid as a result of formalin fixation., To investigate the clinical utility of semiconductor sequencing optimised for detection of actionable fusion transcripts in formalin fixed samples, we have undertaken an analysis of test trending data generated by a clinically validated next generation sequencing platform designed to capture 867 of the most clinically relevant druggable driver-partner oncogenic fusions. Here we showacross a real-life cohort of 1112 patients with solid tumours that actionable fusions occur at high frequency (7.4%) with linkage to a wide range of targeted therapy protocols including seven fusion-drug matches with FDA/EMA approval and/or NCCN/ESMO recommendations and 80 clinical trials. The majority of actionable fusions identified were independent of tumour type in keeping with signalling via evolutionary conserved Wnt/β-catenin, RAS/RAF/MEK/ERK, PI3K/AKT/MTOR, PLCy/PKC and JAK/STAT pathways. Taken together our data indicates that semiconductor sequencing for detection of actionable fusions can be integrated into routine diagnostic pathology workflows enabling the identification of personalised treatment options that have potential to improve clinical cancer management across many tumour types.
SARS-CoV-2 emerging complexity
Authors: Bertacchini Francesca , Bilotta Eleonora , Pantano Pietro Salvatore 
Published: January 2021

AbstractThe novel SARS_CoV-2 virus, prone to variation when interacting with spatially extended ecosystems and within hosts1can be considered a complex dynamic system2. Therefore, it behaves creating several space-time manifestations of its dynamics. However, these physical manifestations in nature have not yet been fully disclosed or understood. Here we show 4-3 and 2-D space-time patterns of rate of infected individuals on a global scale, giving quantitative measures of transitions between different dynamical behaviour. By slicing the spatio-temporal patterns, we found manifestations of the virus behaviour such as cluster formation and bifurcations. Furthermore, by analysing the morphogenesis processes by entropy, we have been able to detect the virus phase transitions, typical of adaptive biological systems3. Our results for the first time describe the virus patterning behaviour processes all over the world, giving for them quantitative measures. We know that the outcomes of this work are still partial and more advanced analyses of the virus behaviour in nature are necessary. However, we think that the set of methods implemented can provide significant advantages to better analyse the viral behaviour in the approach of system biology4, thus expanding knowledge and improving pandemic problem solving.
Neural Basis for Regulation of Vasopressin Secretion by Anticipated Disturbances in Osmolality
Authors: Kim Angela , Madara Joseph C. , Wu Chen , Andermann Mark L. , Lowell Bradford B. 
Published: January 2021

AbstractWater balance, tracked by extracellular osmolality, is regulated by feedback and feedforward mechanisms. Feedback regulation is reactive, occurring as deviations in osmolality aredetected. Feedforward or presystemic regulation is proactive, occurring when disturbances in osmolality areanticipated. Vasopressin (AVP) is a key hormone regulating water balance and is released during hyperosmolality to limit renal water excretion. AVP neurons are under feedback and feedforward regulation. Not only do they respond to disturbances in blood osmolality, but they are also rapidly suppressed and stimulated, respectively, by drinking and eating, which will ultimately decrease and increase osmolality. Here, we demonstrate that AVP neuron activity is regulated by multiple anatomically-and functionally-distinct neural circuits. Notably, presystemic regulation during drinking and eating are mediated by non-overlapping circuits that involve the lamina terminalis and hypothalamic arcuate nucleus, respectively. These findings reveal neural mechanisms that support differential regulation of AVP release by diverse behavioral and physiological stimuli.
Historical trade routes for diversification of domesticated chickpea inferred from landrace genomics
Authors: Igolkina Anna A. , Noujdina Nina V. , Samsonova Maria G. , von Wettberg Eric , Longcore Travis , Nuzhdin Sergey 
Published: January 2021

AbstractAccording to archaeological records, chickpea (Cicer arietinum) was first domesticated in the Fertile Crescent 10 thousand years ago. Its subsequent diversification in South Asia, Ethiopia, and the Western Mediterranean, however, remains obscure and cannot be resolved using only archeological and historical evidence. In particular, chickpea has two market types: ‘desi’, which has a similar flower and seed coat color to chickpea’s wild relatives; and ‘kabuli’, which has light-colored seed, and is linguistically tied to Central Asia but has an unknown geographic origin.Based on the genetic data from 421 chickpea landraces from six geographic regions, we tested complex historical hypotheses of chickpea migration and admixture on two levels: within and between major regions of cultivation. For the former, we developed popdisp, a Bayesian model of population dispersal from a regional center towards sample locations, and confirmed that chickpea spread within each region along trade routes rather than by simple diffusion.For the latter, migration between regions, we developed another model, migadmi, that evaluates multiple and nested admixture events. Applying this model to desi populations, we found both Indian and Middle Eastern traces in Ethiopian chickpea, suggesting presence of a seaway from South Asia to Ethiopia — and the cultural legacy of the Queen of Sheba. As for the origin of kabuli chickpeas, we found significant evidence for an origin from Turkey rather than Central Asia.
Behavioral fingerprints predict insecticide and anthelmintic mode of action
Authors: McDermott-Rouse Adam , Minga Eleni , Barlow Ida , Feriani Luigi , Harlow Philippa H , Flemming Anthony J , Brown André EX 
Published: January 2021

AbstractNovel invertebrate-killing compounds are required in agriculture and medicine to overcome resistance to existing treatments. Because insecticides and anthelmintics are discovered in phenotypic screens, a crucial step in the discovery process is determining the mode of action of hits. Visible whole-organism symptoms are combined with molecular and physiological data to determine mode of action. However, manual symptomology is laborious and requires symptoms that are strong enough to see by eye. Here we use high-throughput imaging and quantitative phenotyping to measureC. elegansbehavioral responses to compounds and train a classifier that predicts mode of action with an accuracy of 88% for a set of ten common modes of action. We also classify compounds within each mode of action to discover pharmacological relationships that are not captured in broad mode of action labels. High-throughput imaging and automated phenotyping could therefore accelerate mode of action discovery in invertebrate-targeting compound development and help to refine mode of action categories.
Fine mapping without phenotyping: Identification of selection targets in secondary Evolve and Resequence experiments
Authors: Langmüller Anna Maria , Dolezal Marlies , Schlötterer Christian 
Published: January 2021

AbstractEvolve and Resequence (E&R) studies investigate the genomic selection response of populations in an Experimental Evolution setup. Despite the popularity of E&R, empirical studies in sexually reproducing organisms typically suffer from an excess of candidate loci due to linkage disequilibrium, and single gene or SNP resolution is the exception rather than the rule. Recently, so-called “secondary E&R” has been suggested as promising experimental follow-up procedure to confirm putatively selected regions from a primary E&R study. Secondary E&R provides also the opportunity to increase mapping resolution by allowing for additional recombination events, which separate the selection target from neutral hitchhikers. Here, we use computer simulations to assess the effect of different crossing schemes, population size, experimental duration, and number of replicates on the power and resolution of secondary E&R. We find that the crossing scheme and population size are crucial factors determining power and resolution of secondary E&R: a simple crossing scheme with few founder lines consistently outcompetes crossing schemes where evolved populations from a primary E&R experiment are mixed with a complex ancestral founder population. Regardless of the experimental design tested, a population size of at least 4,800 individuals, which is roughly 5 times larger than population sizes in typical E&R studies, is required to achieve a power of at least 75%. Our study provides an important step towards improved experimental designs aiming to characterize causative SNPs in Experimental Evolution studies.SignificanceDespite the popularity of Evolve and Resequence (E&R) to investigate genomic selection responses, most studies that use sexually reproducing organisms have broad selection signatures and an excess of candidate loci due to linkage disequilibrium. In this study, we use computer simulations and statistical modelling to evaluate the effects of different experimental and population genetic parameters on the success of potential follow-up experiments (=secondary E&R) aiming to validate and fine-map selection signatures of primary studies. We found that a large population size in combination with a simple crossing scheme is key to the success of secondary E&R inDrosophila.
Gating the channel pore of ionotropic glutamate receptors with bacterial substrate binding proteins
Authors: Bernhard Max , Laube Bodo 
Published: January 2021

AbstractTetrameric ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission in the mammalian central nervous system and are involved in learning, memory formation, and pathological processes. Based on structural and sequence similarities of the ligand-binding and channel domains of iGluR subunits to bacterial binding proteins and potassium channels, iGluRs are thought to have originally arisen from their fusion. Here we report the functional coupling of the bacterial ectoine binding protein EhuB to the channel pore-forming transmembrane domains of the bacterial GluR0 receptor by stabilization of dimeric binding domains. Insertion of a disulfide bridge in the dimer interface abolished desensitization of the channel current analogous to mammalian iGluRs. These results demonstrate the functional compatibility of bacterial binding proteins to the gate of the channel pore of an iGluR. Moreover, our results highlight the modular structure and crucial role of binding domain dimerization in the functional evolution of iGluRs.