bluuebunny/crossref_metadata_2025_split huggingface dataset:
Declines and pronounced state-level variation in tapentadol use in the US
Authors: Low Ching Y. , McCall Kenneth L. , Piper Brian J. 
Published: March 2022

AbstractBackgroundTapentadol is an opioid approved for the treatment of moderate-to-severe pain in the United States (US). Tapentadol is unique as it is the only Schedule II prescription drug that has dual modes of action as it combines agonist activity at the µ opioid receptor with norepinephrine reuptake inhibition. This descriptive study characterized tapentadol use in the US.MethodsDrug distribution data from 2010 to 2020 were extracted for each state from the Drug Enforcement Administration. Use per state, corrected for population, was analyzed. The percentage of distribution channels (pharmacies, hospitals, and providers), the distributed amount of tapentadol, and the final adjusted quota of tapentadol were obtained. Data on tapentadol use as reported by the Medicare and Medicaid programs for 2010 to 2020 were also analyzed.ResultsThe distributed amount of tapentadol was 3.5 tons in 2020 and on average, the final adjusted production quota was 207.2% greater than the distributed amount between 2010 and 2020. Distributed tapentadol was 1.3% of all Schedule II opioids distributed in 2020. Tapentadol use decreased by −53.8% between 2012 and 2020 in the US whereas New Hampshire was the only state that had a positive change (+13.1%). There were minor changes in the amounts of tapentadol distributed via various distribution channels (Pharmacies = 98.0%, hospitals = 1.9% in 2020). Tapentadol prescribed by Nurse Practitioners experienced the largest increase of +8.7% among all specialties to 18.0%, the highest percentage of Medicare claims of tapentadol in 2019. Diabetes prevalence was significantly correlated with tapentadol distribution in 2012 (r(50) = .44,p< .01) and 2020 (r(50) = .28,p< .05).DiscussionThere has been a substantial decline over the past decade in tapentadol distribution and prescribing to Medicaid patients. The unusual tapentadol prescribing pattern in New Hampshire may warrant investigation regarding differing prescribers’ attitudes towards tapentadol or the employment of tapentadol as part of a step-down therapy for opioid addiction.
Species invasiveness and community invasibility of US freshwater fish fauna revealed via trait-based analysis
Authors: Su Guohuan , Mertel Adam , Brosse Sébastien , Calabrese Justin M. 
Published: March 2022

AbstractWhile biological invasions are recognized as a major threat to global biodiversity, determining species’ abilities to invade new areas (species invasiveness) and the vulnerability of those areas to invasions (community invasibility) are still poorly understood. Here, we used trait-based analysis to profile invasive species and quantify the community invasibility for >1,800 North American freshwater fish communities. We show that species with higher reproduction rates, longer life spans and larger sizes tend to be more invasive. Community invasibility peaked when the functional distance among native species was high, leaving unoccupied functional space for the establishment of potential invaders. Invasion success is therefore governed by both the functional traits of non-native species determining their invasiveness, and by the functional characteristics of the invaded community determining its invasibility. Considering those two determinants together will allow better predictions of invasions.
The 13A4 monoclonal antibody to the mouse PROM1 protein recognizes a structural epitope
Authors: Matalkah Fatimah , Rhodes Scott , Ramamurthy Visvanathan , Stoilov Peter 
Published: March 2022

ABSTRACTPurposeWe endeavored to map the epitope of the rat monoclonal antibody mAB 13A4 to the mouse PROM1 (CD133, AC133) protein. mAB 13A4 is the main reagent used to detect the mouse PROM1 protein. PROM1 is required for the maintenance of primary cilia and mutations in the Prom1 gene are associated with retinal degeneration.MethodsEpitope tagged clones of splice variants and tiled deletion mutants were used to map the mAB 13A4 epitope and test the predicted tertiary structure of PROM1. The proteins were expressed in Neuro 2a cells and analyzed by Western blot with antibodies to PROM1 and the epitope tag.ResultsDeletions in the second and third extracellular domains of the PROM1 protein disrupted the mAB 13A4 epitope. Furthermore, the affinity of mAB 13A4 to the major PROM1 isoform in photoreceptor cells is significantly reduced due to the inclusion of a photoreceptor-specific alternative exon in the third extracellular domain. Interestingly, a deletion in the photoreceptor specific isoform of six amino acids adjacent to the alternative exon restored the affinity of mAB 13A4 to PROM1.ConclusionmAB 13A4 recognizes a structural epitope that is stabilized by two of the extracellular domains of PROM1. The results of our mutagenesis are consistent with the computationally predicted helical bundle structure of PROM1 and point to the utility of mAB 13A4 for evaluating the effect of mutations on the PROM1 structure. We show that the PROM1 isoform composition needs to be considered when interpreting tissue and developmental expression data produced by mAB 13A4.
Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation
Authors: Granade Mitchell E. , Hargett Stefan R. , Lemke Michael C. , Luse Melissa A. , Bochkis Irina M. , Linden Joel , Harris Thurl E. 
Published: March 2022

AbstractAdipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1−/−), where F designates a fat-specific deletion. Fadora1−/− mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1−/− mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.
PANDORA: a fast, anchor-restrained modelling protocol for peptide:MHC complexes
Authors: Parizi Farzaneh Meimandi , Marzella Dario F. , Tilborg Derek Van , Renaud Nicolas , Sybrandi Daan , Buzatu Rafaella , Xue Li C 
Published: March 2022

ABSTRACTDeeper understanding T-cell mediated adaptive immune responses bears important implications in designing cancer immunotherapies and antiviral vaccines against pandemic outbreaks. T cells fire when they recognize foreign peptides that are presented on the cell surface by Major Histocompatibility Complexes (MHC), forming peptide:MHC (pMHC) complexes. 3D structure of pMHC complexes provides fundamental insight of T-cell recognition mechanism and aids immunotherapy design. High MHC and peptide diversities necessitate efficient computational modelling to enable whole proteome structural analysis.Here we present PANDORA, a robust pMHC structure modelling pipeline. Given a query, PANDORA searches for structural templates in its extensive database and then applies anchor restraints to the modelling process. This restrained energy minimization ensures one of the fastest pMHC modelling pipelines so far. On a set of 835 pMHC-I complexes over 78 MHC types, PANDORA generated models with a median RMSD of 0.68 Å and achieved a 93% success rate in top 10 models. PANDORA performs competitively with three pMHC-I modelling state-of-the-art approaches and outperforms AlphaFold in terms of accuracy while being superior to it in speed. PANDORA is a modularized and user-configurable python package with easy installation. We envision PANDORA to fuel deep learning with large-scale high-quality 3D models to tackle long-standing immunology challenges.
Assembly of functional diversity in an oceanic island flora
Authors: Barajas-Barbosa Martha Paola , Craven Dylan , Weigelt Patrick , Denelle Pierre , Otto Rüdiger , Díaz Sandra , Price Jonathan , Fernández-Palacios José María , Kreft Holger 
Published: March 2022

AbstractOceanic island floras are well-known for their morphological peculiarities and exhibit striking examples of trait evolution1,2. These morphological shifts are commonly attributed to insularity and thought to be shaped by biogeographical processes and evolutionary histories of oceanic islands1,3. However, the mechanisms through which biogeography and evolution have shaped the distribution and diversity of plant functional traits remain unclear. Here, we describe the functional trait space of an oceanic island flora (Tenerife, Canary Islands, Spain) using extensive field and laboratory measurements, and relate it to global trade-offs in ecological strategies. We find that the island trait space is concentrated around a functional hotspot dominated by shrubs with a conservative life-history strategy. By dividing the island flora into species groups with distinct biogeographical distributions and diversification histories, our results reveal that long-distance dispersal, and the interplay between inter-island dispersal and archipelago-level speciation processes drive functional divergence and expand trait space. Conversely, speciation via cladogenesis has overall led to functional convergence, densely packing trait space around shrubbiness. Our approach combines ecology, biogeography and evolution and opens avenues for new trait-based insights into how dispersal and speciation shape the assembly of native island floras.
Robust differential composition and variability analysis for multisample cell omics
Authors: Mangiola S , Schulze A , Trussart M , Zozaya E , Ma M , Gao Z , Rubin AF , Speed TP , Shim H , Papenfuss AT 
Published: March 2022

AbstractCell omics such as single-cell genomics, proteomics and microbiomics allow the characterisation of tissue and microbial community composition, which can be compared between conditions to identify biological drivers. This strategy has been critical to unveiling markers of disease progression such as cancer and pathogen infection. For cell omic data, no method for differential variability analysis exists, and methods for differential composition analysis only take a few fundamental data properties into account. Here we introduce sccomp, a generalised method for differential composition and variability analyses able to jointly model data count distribution, compositionality, group-specific variability and proportion mean-variability association, with awareness against outliers. Sccomp is an extensive analysis framework that allows realistic data simulation and cross-study knowledge transfer. Here, we demonstrate that mean-variability association is ubiquitous across technologies showing the inadequacy of the very popular Dirichlet-multinomial modelling and provide mandatory principles for differential variability analysis. We show that sccomp accurately fits experimental data, with a 50% incremental improvement over state-of-the-art algorithms. Using sccomp, we identified novel differential constraints and composition in the microenvironment of primary breast cancer.Significance statementDetermining the composition of cell populations is made possible by technologies like single-cell transcriptomics, CyTOF and microbiome sequencing. Such analyses are now widespread across fields (~800 publications/month, Scopus). However, existing methods for differential abundance do not model all data features, and cell-type/taxa specific differential variability is not yet possible. Increase in the variability of tissue composition and microbial communities is a well-known indicator of loss of homeostasis and disease. A suitable statistical method would enable new types of analyses to identify component-specific loss of homeostasis for the first time. This and other innovations are now possible through our discovery of the mean-variability association for compositional data. Based on this fundamental observation, we have developed a new statistical model, sccomp, that enables differential variability analysis for composition data, improved differential abundance analyses, with cross-sample information borrowing, outlier identification and exclusion, realistic data simulation, based on experimental datasets, cross-study knowledge transfer.
Towards resolution of the intron retention paradox in breast cancer
Authors: Shah Jaynish S. , Milevskiy Michael , Petrova Veronika , Au Amy YM , Wong Justin J.L. , Visvader Jane E. , Schmitz Ulf , Rasko John E.J. 
Published: March 2022

AbstractAfter many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue.In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR.Strikingly, we found that reduced IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA binding protein (RBP) expression and changes in tissue composition are among the causes of low IR in BrCa.Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.
Four tumor micro-environmental niches explain a continuum of inter-patient variation in the macroscopic cellular composition of breast tumors
Authors: Marrahi Anissa El , Lipreri Fabio , Alber David , Hausser Jean 
Published: March 2022

AbstractThe tumor microenvironment is a complex, self-organising tissue whose architecture determines prognostic and response to therapy. There is significant variation in the cellular and spatial architecture of the tumor-microenvironment within and across patients. Are there rules that constrain the architecture of the tumor-microenvironment?To find out, we develop a quantitative framework of tumor architecture inspired by ideas from satellite imaging, which we apply on deep single-cell profiling and multiplex imaging data in breast tumors. Data analysis shows that inter-patient variation in the macroscopic cellular composition of tumors is structured as a continuum explained by four tumor niches: cancer, inflammatory, tertiary lymphoid structure and fibrotic/necrotic. These niches have their origin in tumor micro-architecture and are shared across patients and tumor subtypes. Niche prevalence depends strongly on the patient, which constraints and explains inter-patient variation.The present framework will facilitate interpreting inter-patient variation in terms of a tractable number of micro-environmental niches which serve as organizational entities at the meso-scale to bridge the micro- and macro-scales of tumor architecture.
Developmental changes in cerebral NAD and neuroenergetics of an antioxidant compromised mouse model of schizophrenia
Authors: Skupienski Radek , Steullet Pascal , Do Kim Q. , Xin Lijing 
Published: March 2022

AbstractDefects in essential metabolic regulation for energy supply, increased oxidative stress promoting excitatory/inhibitory imbalance and phospholipid membrane dysfunction have been implicated in the pathophysiology of schizophrenia (SZ). The knowledge about the developmental trajectory of these key pathophysiological components and their interplay is important to develop new preventive and treatment strategies. However, this assertion is so far limited. To investigate the developmental regulations of these key components, we assessed, for the first time, in vivo redox state from the oxidized (NAD+) and reduced (NADH) form of Nicotinamide Adenine Dinucleotide (NAD), energy and membrane metabolites, neurotransmitters (γ-aminobutyrate and glutamate) by 31P and 1H MRS during the neurodevelopment of a SZ animal model with genetically compromised glutathione synthesis (gclm-KO mice). When compared to age-matched wild type (WT), an increase in NAD+/NADH redox ratio was found in gclm-KO mice until early adulthood, followed by a decrease in full adults as observed in patients. Especially, in early postnatal life (P20, corresponding to childhood), levels of several metabolites were altered in gclm-KO mice, including NAD+, ATP, phosphocreatine, intracellular pH, glutamine + glutamate and membrane phospholipids components, suggesting an interactive compensation for redox dysregulation between NAD, energy metabolism, and neurotransmission. The identified temporal neurometabolic regulations provide insights in preventive treatment targets for at-risk individuals, and other neurodevelopmental disorders involving oxidative stress and energetic dysfunction.
Genome Editing Is Induced in a Binary Manner in Single Human Cells
Authors: Takahashi Gou , Kondo Daiki , Maeda Minato , Morishita Yuji , Miyaoka Yuichiro 
Published: March 2022

AbstractEven when precise nucleotide manipulations are intended, the outcomes of genome editing can be diverse, often including random insertions and deletions. The combinations and frequencies of these different outcomes in single cells are critical not only in the generation of genetically modified cell lines but also in the evaluation of the clinical effects of genome editing therapies. However, current methods only analyze cell populations, not single cells. Here, we utilized the Single Particle isolation System (SPiS) for the efficient isolation of single cells to systematically analyze genome editing results in individual human cultured cells. As a result, we discovered that genome editing induction has a binary nature, that is, the target alleles of cells tend to be all edited or not edited at all. This study enhances our understanding of the induction mechanism of genome editing and provides a new strategy to analyze genome editing outcomes in single cells.
Phenotypic Characterization of Liver Sinusoidal Endothelial Cells on the Human Liver-Chip for Potential in vitro Therapeutic Antibody Pharmacology Applications
Authors: Candarlioglu Pelin L. , Jadalannagari Sushma , Chaff Jake , Velez James , Joshipura Sannidhi R , Kanellias Marianne , Simpson Alexander P. , Kerns S. Jordan , Ewart Lorna , Hegde Manjunath , Ekert Jason 
Published: March 2022

AbstractLiver plays a vital role in the human immune system, in the internalization and catabolic clearance of therapeutic antibodies and antibody-bound immune complexes via Fc-receptor (FcR) binding on the hepatic reticuloendothelial system cells. This Fc portion of the antibody binding to FcR in the liver initiates the clearance of these antibodies or immune complexes, which is vital in the context of half-life, dosing interval, efficacy, and safety of therapeutic antibodies. The liver sinusoidal endothelial cells (LSECs) express scavenging receptors that recognize, bind, and internalize an enormous diversity of extracellular ligands. The Fc gamma receptor FcγRIIB or CD32B on LSECs is responsible for the clearance of a large majority of IgG-bound immune complexes in the liver. Investigating the pharmacological effects of antibody clearance via human liver in vitro has been challenging due to the lack of reliable long-term LSEC culture protocols. Human LSECs downregulate the expression of CD32B rapidly in vitro in traditional 2D LSEC mono- and co-cultures,. We describe a Liver-Chip model with a co-culture of primary human LSECs and hepatocytes to recreate the liver microenvironment and extend the viability and function of LSECs, including CD32B expression levels, for a duration that is relevant for assessing the pharmacokinetics (PK) of therapeutic antibodies. Our results show that the expression of CD32B can differ based on experimental variables such as the source of primary cells (donor), passage number or source of detection antibodies used to visualize CD32B and shear stress. The CD32B expression was maintained for 14 days on the Liver-Chip in a donor-dependent but passage number independent manner. The Scanning Electron Microscopy (SEM) imaging showed the presence of fenestrae structures - one of the hallmarks of LSEC function. Key LSEC markers, including CD32B expression, were validated through flow cytometry.
Pervasive impacts of climate change on the woodiness and ecological generalism of dry forest plant assemblages
Authors: Moura Mario R. , Nascimento Fellipe A. O. do , Paolucci Lucas N. , Silva Daniel P. , Santos Bráulio A. 
Published: March 2022

AbstractClimate emergency is a significant threat to biodiversity in the 21st century, but species will not be equally affected. In summing up different species’ responses at the local scale, we can assess changes in the species quantity and composition of biotic assemblages. Here we investigated climate change driven variation in species richness and spatial beta-diversity using modelled distributions of 2,841 plant species in Caatinga, the largest dry forest region of South America. More than 99% of plant assemblages were projected to lose species by 2060, with biotic homogenisation ─ the decrease in spatial beta-diversity forecasted in 40% of the Caatinga. Replacement of narrow-range woody species by wide-range non-woody ones should impact at least 85% of Caatinga plant assemblages. The future increase in aridity will change patterns of woodiness and ecological generalism of tropical dry forest plant assemblages, and ultimately erode ecosystem services linked to biomass productivity and carbon storage.