bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allergen-induced airway matrix remodelling in mice can be prevented or reversed by targeting chitinase-like proteins
Authors: Parkinson James E , Adamson Antony , MacDonald Andrew S , Allen Judith E , Sutherland Tara E 
Published: August 2023

AbstractChitinase-like proteins (CLPs) are biomarkers of inflammation and airway remodelling in asthma, yet their direct contribution towards disease pathogenesis is unknown. Using a mouse model of allergen-induced type 2/type 17 airway inflammation we sought to directly investigate the role of the murine CLPs Ym1 and Ym2 during chronic lung pathology. Data demonstrated distinct chronic inflammatory roles for Ym2, IL-13, and IL-17a signalling pathways. Notably, only CLPs were key for initiating the pathogenic accumulation and re-organisation of the pulmonary extracellular matrix (ECM) environment. Furthermore, inhibition of CLPs after chronic pathology developed, reversed airway remodelling independently of chronic inflammation. These studies disentangle chronic IL-13 and IL-17a signalling from the development of allergic airway remodelling and instead highlight a central role for CLPs, which provides new avenues to therapeutically target aberrant ECM accumulation.
Digging deeper into pain – an ethological behavior assay correlating well-being in mice with human pain experience
Authors: Pattison Luke A. , Cloake Alexander , Chakrabarti Sampurna , Hilton Helen , Rickman Rebecca H. , Higham James P. , Meng Michelle Y. , Paine Luke W. , Dannawi Maya , Qiu Lanhui , Ritoux Anne , Bulmer David C. , Callejo Gerard , Smith Ewan St. John 
Published: August 2023

AbstractThe pressing need for safer, more efficacious analgesics is felt worldwide. Pre-clinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays which measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human chronic pain patients who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their on-going level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naïve mice of both sexes. By contrast, deficits in digging were seen following acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Lastly, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.
Cholinergic interneurons in the dorsal striatum play an important role in the acquisition of duration memory
Authors: Nishioka Masahiko , Hata Toshimichi 
Published: August 2023

AbstractAlthough the formation of duration memory is important to optimize the timing of behavior based on previous experiences, the neural mechanism of formation remains unclear. A previous study suggested that muscarinic acetylcholine 1 receptors (M1Rs) in the dorsal striatum of rats are involved in the consolidation of duration memory in interval timing. Therefore, cholinergic interneurons (ChIs) may also be involved in the formation of duration memory in interval timing because ChIs activate M1Rs in the dorsal striatum. In the Exp. 1A, rats underwent a peak interval (PI)-20 s training. During the training, two different trials were randomly presented. One was a food trial in which the initial lever press was reinforced 20 s after the start of the trial (i.e., fixed interval (FI), 20 s). The other was an empty trial in which the reinforcement did not occur for 80 s. After sufficient training, the rats responded at approximately 20 s in the empty trials. They were then subjected to a PI-40 s training (i.e., FI, 40 s) after ChI lesions were present in the dorsal striatum. In this training, the sham-lesioned group responded frequently at approximately 40 s, whereas the ChI-lesioned group responded at approximately 20 s. As the PI-40 s additional learning progressed in the Exp. 1B, the ChI-lesioned group frequently responded at approximately 40 s, similar to that of the sham-lesioned group. In the following PI-20 s re-shift training, the ChI-lesioned group responded similar to the sham-lesioned group. In Exp. 2 of another cohort, the results of a PI-20 s training after the occurrence of ChI lesions were similar to that before the presence of the lesion. Together, these results suggest that ChI lesions delayed only the acquisition of new duration memory, but had no effect on the adjustment of behavior associated with changing the reinforcement schedule of the PI-training and interval timing itself.
Efflux pump mutations inPseudomonas aeruginosacause low-level clinical resistance and high-level tolerance to antibiotics in patients
Authors: Laborda Pablo , Lolle Signe , Hernando-Amado Sara , Alcalde-Rico Manuel , Martínez José Luis , Molin Søren , Johansen Helle Krogh 
Published: August 2023

ABSTRACTPseudomonas aeruginosais one of the microorganisms with high-risk regarding antimicrobial resistance, since it has an overwhelming capacity to acquire antibiotic resistance, mainly by mutations during persistent lung infections. Mutations inmexZ, encoding the local negative regulator of genes encoding the MexXY efflux pump, are very frequently acquired at early stages ofP. aeruginosainfections, while they are rarely selected forin vitro. Although traditionally related to resistance to the first-line drug tobramycin, caused by the overproduction of the aminoglycosides MexXY efflux pump, mutations inmexZare actually associated with low levels of aminoglycosides resistance when determined in the clinical microbiology laboratory. This very moderate but frequent phenotype suggests that these mutations may shape the infection process, beyond causing conventional resistance. Here we investigated the colonization strategy of amexZmutant, compared to a wild-type strain, in a human airway infection model. We observed that themexZmutant tends to accumulate inside the epithelial cell layer. This behaviour allows bacteria to colonise the epithelium while being more protected against diverse antibiotics. The altered colonization phenotype was caused by the overexpression oflecA, a Quorum Sensing regulated gene encoding a lectin involved inP. aeruginosatissue invasiveness.lecAupregulation was underlied by the competition for the shared porin, OprM, between the overproduced MexXY and the MexAB efflux pump, responsible for extruding Quorum Sensing molecules. These findings suggest that standardised antimicrobial susceptibility determined in the clinic may be misleading because antibiotic resistance often depends on the infection environment.
Coupling mountain pine beetle and forest population dynamics predicts transient outbreaks that are likely to increase in number with climate change
Authors: Brush Micah , Lewis Mark A. 
Published: August 2023

AbstractMountain pine beetle (MPB) in Canada have spread well beyond their historical range. Accurate modelling of the long-term dynamics of MPB is critical for assessing the risk of further expansion and informing management strategies, particularly in the context of climate change and variable forest resilience. Most previous models have focused on capturing a single outbreak without tree replacement. While these models are useful for understanding MPB biology and outbreak dynamics, they cannot accurately model long-term forest dynamics. Past models that incorporate forest growth tend to simplify beetle dynamics. We present a new model that couples forest growth to MPB population dynamics and accurately captures key aspects of MPB biology, including a threshold for the number of beetles needed to overcome tree defenses and beetle aggregation that facilitates mass attacks. These mechanisms lead to a demographic Allee effect, which is known to be important in beetle population dynamics. We show that as forest resilience decreases, a fold bifurcation emerges and there is a stable fixed point with a non-zero MPB population. We derive conditions for the existence of this equilibrium. We then simulate biologically relevant scenarios and show that the beetle population approaches this equilibrium with transient boom and bust cycles with period related to the time of forest recovery. As forest resilience decreases, the Allee threshold also decreases. Thus, if host resilience decreases under climate change, for example under increased stress from drought, then the lower Allee threshold makes transient outbreaks more likely to occur in the future.Statements and DeclarationsCompeting interestsThe authors declare no competing interests.Data availability statementData sharing is not applicable to this article as no datasets were generated or analysed during the current study. Code to produce the figures is available atgithub.com/micbru/MPBModel/.
Identifying predictors and determining mortality rates of septic cardiomyopathy and sepsis-related cardiogenic shock: A retrospective, observational study
Authors: Hendrickson Kathryn W. , Cirulis Meghan M. , Burk Rebecca E. , Lanspa Michael J , Peltan Ithan D. , Marshall Hunter , Groat Danielle , Jephson Al , Beesley Sarah J. , Brown Samuel M. 
Published: August 2023

AbstractIntroductionSeptic shock is a severe form of sepsis that has a high mortality rate, and a substantial proportion of these patients will develop cardiac dysfunction, often termed septic cardiomyopathy (SCM). Some SCM patients may develop frank cardiac failure, termed sepsis-related cardiogenic shock (SeRCS). Little is known of SeRCS. This study describes baseline characteristics of patients with SCM and SeRCS compared to patients with septic shock without cardiac dysfunction. We compare clinical outcomes among SCM, SeRCS, and septic shock, and identify risk factors for the development of SCM and SeRCS.MethodsSeptic patients admitted to the ICU with an echocardiogram obtained within 72 hours were included. Left ventricular ejection fraction of ≤55% was used to define SCM, and cardiac index ≤2.1 L/min/m2 among patients with SCM defined SeRCS. Machine learning was used to identify risk factors for development of SCM and SeRCS. Logistic regression was used to compare mortality among groups.ResultsAmong 1229 patients, 977 patients had septic shock without cardiac dysfunction, 207 had SCM, and 45 had SeRCS. In patients with septic shock, the strongest predictor for developing SCM and SeRCs was a prior history of cardiac dysfunction. Mortality did not significantly differ among the three groups.ConclusionsSCM and SeRCS affect a minority of patients with septic shock, disproportionately affecting individuals with a history of cardiac disease. We did not identify a mortality difference associated with SCM or SeRCS. Additional work is needed to define further subtypes and treatment options for this patient population.
Common drugs alter microbial protein expression, but not composition in fecal cultures from Crohn’s disease patients
Authors: Becker Heike E.F. , Mohren Ronny , Le N. Giang , Derijks Luc J.J. , Jonkers Daisy M.A.E. , Penders John 
Published: August 2023

AbstractIntroductionA substantial number of Crohn’s disease (CD) patients experience side-effects and/or non-response to medical drugs. In part, this might be attributed to the interaction of the intestinal microbiome with xenobiotics. The aim of this study was to explore the effect of common CD drugs on the patient’s microbiomein vitro.MethodsThe fecal microbiome of each of 5 CD patients was exposed to 42 μg/ml budesonide, 55 μg/ml 6-mercaptopurine (6-MP), 5 or 15 μg/ml tofacitinib, or DMSO-control in defined culture medium in an anaerobic chamber at 37°C for 24 hours. Subsequently, DNA and proteins were isolated and subjected to 16 rRNA gene amplicon sequencing and LC-MS proteomic analysis, respectively.ResultsMetagenomic and metaproteomic analyses revealed larger differences between donors than between drug exposures. Exposure to 6-MP and tofacitinib resulted in a significant alteration in the metaproteome when compared to the control condition, whereas no effect could be observed for budesonide. Applying a stringent selection, 33 proteins were more abundant and 93 less abundant in all 6-MP cultures and could thereby discriminate clearly between 6-MP and control. In contrast to metaproteomic analyses, metagenomic analyses only detected a lower relative abundance ofColidextribacterin 15 μg/ml tofacitinib cultures, but not in overall richness, diversity or community structure.ConclusionTofacitinib and especially 6-MP clearly affect microbial function, but barely microbial compositionin vitro. These drug-induced functional changes may subsequently influence host physiology and potentially inflammation in CD. Our findings emphasize the relevance to include functional microbial studies when investigating drug-microbiota interactions. Further research needs to elucidate the impact of 6-MP-induced microbial alterations on intestinal physiology and inflammation in CD.
Polypyrimidine Tract-Binding Protein 1 and hnRNP A1 recognize unique features of the Sm site in U7 snRNA
Authors: Yang Xiao-cui , Dominski Zbigniew 
Published: August 2023

ABSTRACTU7 snRNA is a 60-nucleotide component of U7 snRNP, a multi-subunit endonuclease that cleaves precursors of metazoan replication-dependent histone mRNAs at the 3’ end, hence generating mature histone mRNAs. The Sm site in U7 snRNA differs from the Sm site in spliceosomal snRNAs and promotes the assembly of a unique Sm ring containing Lsm10 and Lsm11 instead of SmD1 and SmD2 found in the spliceosomal snRNPs. The assembly of the spliceosomal Sm ring depends on the SMN complex, with one of its nine subunits, Gemin5, recognizing the spliceosomal Sm site. While the assembly of the U7-specific Sm ring also requires the SMN complex, the unusual Sm site of U7 snRNA is not recognized by Gemin5, and the identity of its counterpart that performs this function in biogenesis of U7 snRNP, has not been determined. Here, we looked for proteins that bind U7 snRNA but not to its mutant altered within the Sm site. We identified Polypyrimidine Tract-Binding Protein 1 (PTBP1) as the main protein that meets this specificity. Binding of PTBP1 to U7 snRNA also depends on the upstream CUCUUU motif that base pairs with histone pre-mRNAs and defines substrate specificity of U7 snRNP. Thus, PTBP1 simultaneously recognizes two functionally essential and highly conserved sites within U7 snRNA. In addition to PTBP1, U7 snRNA interacts with hnRNP A1, which recognizes a different part of the U7-specific Sm site. Interestingly, the two proteins can form with U7 snRNA a larger complex, which also contains SMN protein, a subunit of the SMN complex. Altogether, these results raise the possibility that PTBP1 and hnRNP A1 act collectively to substitute for Gemin5 in the assembly of U7-specific Sm ring.
Mining alternative splicing patterns in scRNA-seq data using scASfind
Authors: Song Yuyao , Parada Guillermo , Lee Jimmy Tsz Hang , Hemberg Martin 
Published: August 2023

AbstractSingle-cell RNA-seq is widely used for transcriptome profiling, but most analyses have focused on gene-level events, with much less attention devoted to alternative splicing. Here, we present scASfind, a novel computational method to allow for quantitative analysis of cell type-specific splicing events. scASfind utilizes an efficient data structure to store the percent spliced-in value for each splicing event. This makes it possible to exhaustively search for patterns among all differential splicing events, allowing us to identify marker events, mutually exclusive events, and large blocks of exons that are specific to one or more cell types. These methods allow researchers to compare cells based on isoforms rather than genes, thereby enabling more nuanced characterization of cell types and states. We demonstrate the advantages of scASfind on two mouse and one human datasets, identifying differences across the several key genes that cannot be detected using gene expression alone.
Combined Mek inhibition andPpargactivation Eradicates Muscle Invasive Bladder cancer in a Mouse Model of BBN-induced Carcinogenesis
Authors: Tate Tiffany , Plumber Sakina A , Al-Ahmadie Hikmat , Chen Xiao , Choi Woonyoung , Lu Chao , Viny Aaron , Batourina Ekatherina , Gartensson Krisjian , Alija Besmira , Molotkov Andrei , Wiessner Gregory , McKiernan James , McConkey David , Dinney Colin , Czerniak Bogdan , Mendelsohn Cathy Lee 
Published: August 2023

AbstractBladder cancers (BCs) can be divided into 2 major subgroups displaying distinct clinical behaviors and mutational profiles: basal/squamous (BASQ) tumors that tend to be muscle invasive, and luminal/papillary (LP) tumors that are exophytic and tend to be non-invasive.Ppargis a likely driver of LP BC and has been suggested to act as a tumor suppressor in BASQ tumors, where it is likely suppressed by MEK-dependent phosphorylation. Here we tested the effects of rosiglitazone, aPpargagonist, in a mouse model of BBN-induced muscle invasive BC. Rosiglitazone activatedPpargsignaling in suprabasal epithelial layers of tumors but not in basal-most layers containing highly proliferative invasive cells, reducing proliferation but not affecting tumor survival. Addition of trametinib, a MEK inhibitor, inducedPpargsignaling throughout all tumor layers, and eradicated 91% of tumors within 7-days of treatment. The 2-drug combination also activated a luminal differentiation program, reversing squamous metaplasia in the urothelium of tumor-bearing mice. Paired ATAC-RNA-seq analysis revealed that tumor apoptosis was most likely linked to down-regulation of Bcl-2 and other pro-survival genes, while the shift from BASQ to luminal differentiation was associated with activation of the retinoic acid pathway and upregulation of Kdm6a, a lysine demethylase that facilitates retinoid-signaling. Our data suggest that rosiglitazone, trametinib, and retinoids, which are all FDA approved, may be clinically active in BASQ tumors in patients. That muscle invasive tumors are populated by basal and suprabasal cell types with different responsiveness toPPARGagonists will be an important consideration when designing new treatments.
Tag attachment reduces the initiation of recruitment in the rock ant,Temnothorax rugatulus
Authors: Taylor Benjamin Z. , Rajagopal Supraja , Sasaki Takao 
Published: August 2023

AbstractTechnological advances continue to push the boundaries of scientific inquiry in animal behavior. One such development is the emergence of automated tracking systems, which enable the collection of high-resolution spatio-temporal information for animals. Although tag-based tracking systems provide valuable insights into animal movement and collective behavior, the attachment of devices can have detrimental effects in some cases. Here, we investigated the effects of recently developed miniature tracking tags using the rock ant,Temnothorax rugatulus, as a model system. To do so, we compared the foraging activities of tagged and untagged ants within partially tagged colonies. Additionally, we compared the foraging activities of these tagged colonies with those of untagged control colonies. We found that tags did not reduce individual activity, with tagged ants visiting the food source as frequently as untagged ants. However, our analysis revealed a marked difference in recruitment behavior—tagged ants were significantly less likely to participate in tandem runs. This study demonstrates, for the first time, that tracking tags can negatively impact ant behavior. Although tracking devices are powerful tools for understanding complex behavioral patterns, it is crucial to carefully consider their potential impact on animal behavior to ensure accurate conclusions.
BundleCleaner: Unsupervised Denoising and Subsampling of Diffusion MRI-Derived Tractography Data
Authors: Feng Yixue , Chandio Bramsh Q. , Villalón-Reina Julio E. , Thomopoulos Sophia I. , Joshi Himanshu , Nair Gauthami , Joshi Anand A. , Venkatasubramanian Ganesan , John John P. , Thompson Paul M. 
Published: August 2023

AbstractWe presentBundleCleaner, an unsupervised multi-step frame-work that can filter, denoise and subsample bundles derived from diffusion MRI-based whole-brain tractography. Our approach considers both the global bundle structure and local streamline-wise features. We applyBundleCleanerto bundles generated from single-shell diffusion MRI data in an independent clinical sample of older adults from India using probabilistic tractography and the resulting ‘cleaned’ bundles can better align with the atlas bundles with reduced overreach. In a downstream tractometry analysis, we show that the cleaned bundles, represented with less than 20% of the original set of points, can robustly localize along-tract microstructural differences between 32 healthy controls and 34 participants with Alzheimer’s disease ranging in age from 55 to 84 years old. Our approach can help reduce memory burden and improving computational efficiency when working with tractography data, and shows promise for large-scale multi-site tractometry.
An ancient role for theCYP73gene family int-cinnamic acid 4-hydroxylation, phenylpropanoid biosynthesis and embryophyte development
Authors: Knosp Samuel , Kriegshauser Lucie , Tatsumi Kanade , Malherbe Ludivine , Wiedemann Gertrud , Bakan Bénédicte , Kohchi Takayuki , Reski Ralf , Renault Hugues 
Published: August 2023

ABSTRACTThe phenylpropanoid pathway is a plant metabolism intimately linked to the transition to terrestrial life. It produces phenolic compounds that play essential roles in stress mitigation and ecological interactions. The pathway also provides the building blocks for hydrophobic polymers that form apoplastic diffusion barriers and make up a significant fraction of the land plant biomass. Despite its significance in embryophytes (i.e., land plants), the origin and evolutionary history of the phenylpropanoid pathway remain poorly understood. In particular, little is known about the organization and function of the pathway in bryophytes, the non-vascular embryophytes. In this study, we conducted a multidisciplinary analysis of theCYP73gene family that encodest-cinnamic acid 4-hydroxylase (C4H), the first plant-specific enzyme in the pathway. Our results indicate that C4H activity originated with the emergence of theCYP73gene family in an ancestor of land plants and was supported by an arginine residue that stabilizes its substrate in the active site. C4H deficiency in the mossPhyscomitrium patens, the liverwortMarchantia polymorphaand the hornwortAnthoceros agrestisresulted in a shortage of phenylpropanoids and abnormal plant development. The latter could be rescued in the moss by the exogenous supply ofp-coumaric acid, the product of C4H. Our findings establish the emergence of theCYP73gene family as a foundational event for the development of the canonical plant phenylpropanoid pathway and underscores the deep-rooted conservation of the C4H enzyme function in embryophyte biology.