bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of individual differences in response to methadone, buprenorphine, and naltrexone in animal models of opioid use disorder
Authors: Kallupi Marsida , de Guglielmo Giordano , Conlisk Dana , Brennan Molly , Tieu Lani , Sedighim Sharona , Boomhower Brent , Smith Lauren C , Shankar Kokila , Carrette Lieselot LG , Simpson Sierra , Avelar Alicia , Maturin Lisa , Martinez Angelica , Qiao Ran , Dirik Selen , Crook Caitlin , Bonnet-Zahedi Selene , Iyer Mohini R. , Blucher Corrine E. , Fannon McKenzie J , Woods Leah C. Solberg , Palmer Abraham A. , George Olivier 
Published: July 2022

AbstractRationaleCurrent medications for opioid use disorder include buprenorphine, methadone, and naltrexone. While these medications show significant efficacy in reducing craving and opioid use, there are substantial individual differences in response to these treatments in humans. The reason for such difference is poorly known.ObjectivesHere, we tested the hypothesis that similar individual differences may be observed in a large population of heterogenous stock rats, that have been bred to maximize genetic diversity, using a behavioral paradigm relevant to opioid use disorder.MethodsOver 500 rats were given intermittent (4d/week) and extended access (12h/day) to oxycodone self-administration for 14 sessions to establish oxycodone dependence and escalation of intake. We then measured the effect of buprenorphine (0.5mg/kg), methadone (3mg/kg) and naltrexone (3mg/kg) on the motivation to self-administer oxycodone by using a progressive ratio schedule of reinforcement.ResultsWe found that naltrexone and buprenorphine significantly decreased motivation to oxycodone rewards. While naltrexone reduced oxycodone intake in both males and females, systemic administration with buprenorphine reduced progressive ratio responses only in males. Methadone reduced motivation to oxycodone self-administration in nearly 25% of the population, without reaching statical significance. Our results showed that the efficacy of these medications depends on the severity of addiction like behaviors, indicated by the addiction index.ConclusionsThese results demonstrate individual differences in response to medications to treat opioid use disorder in a genetically diverse population of rats.
Differential effects of oxytocin receptor antagonist on social rank and other social behavior in male mice
Authors: Nasukawa Daiki , Yamada Kota , Ujihara Yusuke , Hirakata Haruka , Tamura Ryuto , Yatagai Saya , Hayashi Kazuko , Toda Koji 
Published: July 2022

AbstractSocial rank within a group is essential for survival in many animals. Rank in the community helps to avoid unnecessary conflicts and establish stable relationships with others. Oxytocin has received increasing attention for its function in social behavior. However, the causal relationship between oxytocin levels and social rank has remained unclear. Here, we examined the effects of intraperitoneal injection of the oxytocin receptor antagonist L-368-899 on (1) social rank, (2) sex preference, (3) social preference, and (4) dyadic interaction in male mice. In the tube test, injection of the oxytocin receptor antagonist had no effect on first-rank mice, but caused fluctuation of the rank in second-rank mice, suggesting that the function of oxytocin in the maintenance of the social rank is rank-dependent. Second, injection of the oxytocin receptor antagonist dose-dependently impaired the sex preference of the male mice, confirming that oxytocin is essential in sexual behavior. Third, injection of the oxytocin receptor antagonist had no effect on social preference and dyadic interaction between the male mice, suggesting that oxytocin is not necessary in direct social interaction. Taken together, these results demonstrate that the role of the oxytocin in male mice is limited to a specific context of social behavior.HighlightsThe stable social rank of the male mice in their cages was clearly observed in the tube test.Administration of an oxytocin receptor antagonist to first-rank mice caused no change in social rank.Administration of an oxytocin receptor antagonist to second-rank mice caused fluctuation of social rank.Sex preference, but not social preference and dyadic interactions, were impaired after the injection of the oxytocin receptor antagonist.
Sampling bias and the robustness of ecological metrics for plant-damage-type association networks
Authors: Swain Anshuman , Azevedo-Schmidt Lauren E. , Maccracken S. Augusta , Currano Ellen D. , Dunne Jennifer , Labandeira Conrad C. , Fagan William F. 
Published: July 2022

AbstractPlants and their insect herbivores have been a dominant component of the terrestrial ecological landscape for the past 410 million years and feature intricate evolutionary patterns and co-dependencies. A complex systems perspective allows for both detailed resolution of these evolutionary relationships as well as comparison and synthesis across systems. Using proxy data of insect herbivore damage (denoted by the damage type or DT) preserved on fossil leaves, functional bipartite network representations provide insights into how plant–insect associations depend on geological time, paleogeographical space, and environmental variables such as temperature and precipitation. However, the metrics measured from such networks are prone to sampling bias. Such sensitivity is of special concern for plant–DT association networks in paleontological settings where sampling effort is often severely limited. Here, we explore the sensitivity of functional bipartite network metrics to sampling intensity and identify sampling thresholds above which metrics appear robust to sampling effort. Across a broad range of sampling efforts, we find network metrics to be less affected by sampling bias and/or sample size than richness metrics, which are routinely used in studies of fossil plant–DT interactions. These results provide reassurance that cross-comparisons of plant–DT networks offer insights into network structure and function and support their widespread use in paleoecology. Moreover, these findings suggest novel opportunities for using plant–DT networks in neontological terrestrial ecology to understand functional aspects of insect herbivory across geological time, environmental perturbations, and geographic space.
Functional screening of lysosomal storage disorder genes identifies modifiers of alpha-synuclein mediated neurodegeneration
Authors: Yu Meigen , Ye Hui , De-Paula Ruth B. , Mangleburg Carl Grant , Wu Timothy , Li Yarong , Duong Duc , Allen Genevera I. , Seyfried Nicholas T. , Al-Ramahi Ismael , Botas Juan , Shulman Joshua M. 
Published: July 2022

ABSTRACTHeterozygous variants in the glucocerebrosidase (GBA) gene are common and potent risk factors for Parkinson’s disease (PD). GBA also causes the autosomal recessive lysosomal storage disorder (LSD), Gaucher disease, and emerging evidence from human genetics implicates many other LSD genes in PD susceptibility. We have systemically tested 88 conserved fly homologs of 38 human LSD genes for requirements in the aging adult Drosophila brain and for potential genetic interactions with neurodegeneration caused by α-synuclein (αSyn), which forms Lewy body pathology in PD. Our screen identifies 15 genetic enhancers of αSyn-induced progressive locomotor dysfunction, following knockdown of fly homologs of GBA and other LSD genes with independent support as PD susceptibility factors from human genetics (SCARB2, SMPD1, CTSD, GNPTAB, SLC17A5). For several genes, results from multiple alleles support dose-sensitivity and context-dependent pleiotropy in the presence or absence of αSyn. Homologs of 2 genes causing cholesterol storage disorders, Npc1a / NPC1 and Lip4 / LIPA, were independently confirmed as loss-of-function enhancers of αSyn-induced brain structural degeneration. The enzymes encoded by several modifier genes are upregulated in αSyn transgenic flies, based on unbiased proteomics, revealing a possible compensatory response. Overall, our results reinforce the important role of lysosomal genes in brain health and PD pathogenesis, and implicate several metabolic pathways, including cholesterol homeostasis, in αSyn-mediated neurodegeneration.
Identification of a microbial sub-community from the feral chicken gut that reducesSalmonellacolonization and improves gut health in a gnotobiotic chicken model
Authors: Wongkuna Supapit , Kumar Roshan , Ghimire Sudeep , Drescher Samara Mattiello , Maji Abhijit , Ambat Achuthan , Antony Linto , Chankhamhaengdecha Surang , Janvilisri Tavan , Nelson Eric , Doerner Kinchel C. , Behr Melissa , Scaria Joy 
Published: July 2022

AbstractA complex microbial community in the gut generally prevent the colonization of enteric pathogens such asSalmonella. Because of the high complexity, several species or combination of species in the gut can confer colonization resistance. To gain a better understanding of the colonization resistance againstSalmonella enterica, we isolated a library of 1,300 bacterial strains from feral chicken gut microbiota which represented a total of 51 species. Using a co-culture assay, we screened the representative species from this library and identified 30 species that inhibitedSalmonella entericaTyphimurium. To improve theSalmonellainhibition capacity, from a pool of fast-growing species, we formulated 66 bacterial blends, each of which composed of 10 species. Bacterial blends were more efficient in inhibitingSalmonellaas compared to individual species. The blend that showed maximum inhibition (Mix10) also inhibited other serotypes ofSalmonellafrequently found in poultry. Thein vivoeffect of Mix10 was examined in a gnotobiotic and conventional chicken model. The Mix10 consortium reducedSalmonellacolonization, intestinal tissue damage and inflammation in both models. Cell free supernatant of Mix10 did not showSalmonellainhibition, indicating that Mix10 inhibitsSalmonellathrough either nutritional competition or reinforcement of host immunity. Out of ten species, three species in Mix10 did not colonize while three species constituted more than 70% of the community. Two of these species represents previously uncultured bacteria. Our approach could be used as a high-throughput screening system to identify additional bacterial sub-communities that confer colonization resistance against enteric pathogens and its effect on the host.ImportanceSalmonellacolonization in chicken and human infections originating fromSalmonella-contaminated poultry is a significant problem. Poultry has been identified as the most common food linked to enteric pathogen outbreaks in the United States. Since multi-drug resistantSalmonellaoften colonize chicken and cause human infections, methods to controlSalmonellacolonization in poultry are needed. The method we describe here could form the basis of developing gut microbiota-derived bacterial blends as a microbial ecosystem therapeutic againstSalmonella.
Angiogenesis precedes myogenesis during regeneration following biopsy injury in skeletal muscle
Authors: Jacobsen Nicole L. , Morton Aaron B. , Segal Steven S. 
Published: July 2022

AbstractBackgroundAcute injury to skeletal muscle damages myofibers and fragments capillaries, impairing contractile function and local perfusion. Myofibers and microvessels regenerate from satellite cells and from surviving microvessel fragments, respectively, to restore intact muscle. However, it is unknown whether myofiber regeneration and microvascular regeneration reflect interdependent processes or may proceed sequentially.MethodsTo investigate the temporal relationship between myogenesis and angiogenesis during regeneration, a punch biopsy (diameter, 2 mm) was performed through the center of the gluteus maximus (GM) muscle. Complete removal of all tissue components created a void into which regeneration was evaluated through 21 days post injury (dpi). Confocal imaging and histological analyses of whole-mount GM preparations and GM cross sections assessed the growth of microvessels and myofibers into the wound. Regeneration of perfused microvessels was evaluated in vivo by injecting fluorescent dextran into the circulation during intravital imaging.ResultsA provisional matrix filled with PDGFRα+ and CD45+ cells spanned the wound within 1 dpi. Regenerating microvessels advanced into the matrix by 7 dpi. At 10 dpi, sprouting and intussusceptive angiogenesis produced disorganized microvascular networks and spanned the wound with perfusion by 14 dpi. In striking contrast, the wound remained devoid of myofibers at 7 and 10 dpi. Myogenesis into the wound began by 14 dpi with nascent myofibers traversing the wound by 21 dpi. Regenerating myofibers and microvessels were less well organized than in the surrounding (uninjured) muscle.ConclusionsAngiogenesis precedes myogenesis following punch biopsy injury of adult skeletal muscle. Regenerating microvessels encompass the wound and become perfused with blood prior to colocalization with regenerating myofibers. These findings infer that a microvascular supply supports the metabolic demands of regenerating skeletal muscle. Finding that regenerated microvascular networks and myofibers are disorganized within the biopsy site suggests that loss of guidance cues upon complete tissue removal impairs re-establishment of canonical skeletal muscle structure.
FHL5 controls vascular disease-associated gene programs in smooth muscle cells
Authors: Wong Doris , Auguste Gaëlle , Lino Cardenas Christian L. , Turner Adam W. , Chen Yixuan , Ma Lijiang , Perry R. Noah , Aherrahrou Redouane , Kuppusamy Maniselvan , Yang Chaojie , Mosquera Jose Verdezoto , Dube Collin J. , Khan Mohammad Daud , Palmore Meredith , Kavousi Maryam , Peyser Patricia A. , Matic Ljubica , Hedin Ulf , Manichaikul Ani , Sonkusare Swapnil K. , Civelek Mete , Kovacic Jason C. , Björkegren Johan L.M. , Malhotra Rajeev , Miller Clint L. 
Published: July 2022

AbstractBackgroundGenome-wide association studies (GWAS) have identified hundreds of loci associated with common vascular diseases such as coronary artery disease (CAD), myocardial infarction (MI), and hypertension. However, the lack of mechanistic insights for a majority of these loci limits translation of these findings into the clinic. Among these loci with unknown functions is UFL1-FHL5 (chr6q16.1), a locus that reached genome-wide significance in a recent CAD/MI GWAS meta-analysis. In addition to CAD/MI, UFL1-FHL5 is also implicated to coronary calcium, intracranial aneurysm, and migraine risk, consistent with the widespread pleiotropy observed among other GWAS loci.MethodsWe apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and imaging of human coronary artery tissues to implicate Four-and-a-half LIM domain 5 (FHL5) as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments.ResultsWe prioritized FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through eQTL colocalization methods. FHL5 gene expression was enriched in the SMC and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating SMC contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream CAD/MI loci, such as FOXL1 and FN1 that have roles in vascular remodeling.ConclusionTaken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling loci. These trans-acting mechanisms may account for a portion of the heritable risk for complex vascular diseases.
Rapid BCMA downmodulation on myeloma cells upon CAR T cell contact is mediated by trogocytosis and BCMA internalization
Authors: Camviel Nicolas , Wolf Benita , Croce Giancarlo , Gfeller David , Zoete Vincent , Arber Caroline 
Published: July 2022

AbstractBackgroundChimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) on multiple myeloma (MM) produces fast but not long-lasting responses. Reasons for treatment failure are poorly understood. CARs simultaneously targeting two antigens may represent an alternative. Here, we (1) designed and characterized novel A proliferation inducing ligand (APRIL) based dual-antigen targeting CARs, and (2) investigated mechanisms of resistance to CAR T cells with three different BCMA-binding moieties (APRIL, single-chain-variable-fragment, heavy-chain-only).MethodsThree new APRIL-CARs were designed and characterized. Human APRIL-CAR T cells were evaluated for their cytotoxic function in vitro and in vivo, for their polyfunctionality, immune synapse formation, memory, exhaustion phenotype and tonic signaling activity. To investigate resistance mechanisms, we analyzed BCMA levels and cellular localization and quantified CAR T cell - target cell interactions by live microscopy. Impact on pathway activation and tumor cell proliferation was assessed in vitro and in vivo.ResultsAPRIL-BBζ CAR T cells in a trimeric ligand binding conformation conferred the best polyfunctionality, immune synapse formation and fast anti-tumor function in vivo in two different mouse xenograft models. Upon CAR T cell – myeloma cell contact, we found rapid BCMA downmodulation on target cells with all three evaluated binding moieties. CAR T cells acquired BCMA on their cell surface by trogocytosis, and BCMA on MM cells was rapidly internalized. Since trogocytosis can lead to CAR T cell exhaustion and presence of CAR T cells does not protect patients from relapse, we investigated whether non-functional CAR T cells play a role in tumor progression. While CAR T cell – MM cell interactions activated BCMA pathway, we did not find enhanced tumor growth in vitro or in vivo.ConclusionWe designed and characterized distinct APRIL-CAR T cells for dual-antigen targeting of MM. Rapid BCMA downmodulation occurred upon CAR T cell – tumor cell encounter independently of whether an APRIL or antibody-based binding moiety was used. BCMA internalization mostly contributed to this effect, but trogocytosis by CAR T cells was also observed. Our study sheds light on the mechanisms underlying CAR T cell failure in MM and can inform the development of improved treatment strategies.
Phosphorylation Determines Whether Neuroligin-3 is at Excitatory or Inhibitory Synapses in Different Regions of the Brain
Authors: Altas Bekir , Tuffy Liam P. , Patrizi Annarita , Dimova Kalina , Soykan Tolga , Romanowski Andrea J. , Robertson Colin D. , Khim Saovleak N. , Bunce Garrett W. , Ambrozkiewicz Mateusz C. , Yagensky Oleksandr , Krueger-Burg Dilja , Hammer Matthieu , Hsiao He-Hsuan , Laskowski Pawel R. , Dyck Lydia , Sassoè-Pognetto Marco , Chua John J.E. , Urlaub Henning , Jahn Olaf , Brose Nils , Poulopoulos Alexandros 
Published: July 2022

ABSTRACTNeuroligin-3 is a postsynaptic adhesion molecule involved in development, function, and pathologies of synapses in the brain. It is a genetic cause of autism and a potent component of the tumor microenvironment in gliomas. There are four Neuroligins that operate at distinct synapse types, selectively interacting with presynaptic adhesion and postsynaptic scaffold proteins. We investigated the subcellular localization and scaffold specificities of synaptic Neuroligin-3 and demonstrate an unexpected pattern of localization to excitatory synapses in cortical areas, and inhibitory synapses in subcortical areas. Using phosphoproteomics, we identify Neuroligin-3-specific serine phosphorylation in cortex and hippocampus that obstructs a key binding site for inhibitory synapse scaffolds. Using in utero CRISPR/Cas9 knockout and replacement with phosphomimetic mutants, we demonstrate that phosphorylation at this site determines excitatory versus inhibitory synapse localization of Neuroligin-3 in vivo. Our data reveal a mechanism that differentially regulates the balance of Neuroligin-3 between excitatory and inhibitory synapses, adding to our emerging understanding of their role in the development of brain connectivity and associated pathologies.
Ranking species based on sensitivity to perturbations under non-equilibrium community dynamics
Authors: Medeiros Lucas P. , Allesina Stefano , Dakos Vasilis , Sugihara George , Saavedra Serguei 
Published: July 2022

AbstractManaging ecological communities requires fast detection of species that are sensitive to perturbations. Yet, the focus on recovery to equilibrium has prevented us from assessing species responses to perturbations when abundances fluctuate over time. Here, we introduce two data-driven approaches (expected sensitivity and eigenvector rankings) based on the time-varying Jacobian matrix to rank species over time according to their sensitivity to perturbations on abundances. Using several population dynamics models, we demonstrate that we can infer these rankings from time-series data to predict the order of species sensitivities. We find that the most sensitive species are not always the ones with the most rapidly changing or lowest abundance, which are typical criteria used to monitor populations. Finally, using two empirical time series, we show that sensitive species tend to be harder to forecast. Our results suggest that incorporating information on species interactions can improve how we manage communities out of equilibrium.
Cell-free Trim-Away reveals the mechanism of antibody-mediated protein degradation by TRIM21
Authors: Mevissen Tycho E.T. , Prasad Anisa V. , Walter Johannes C. 
Published: July 2022

ABSTRACTTRIM21 is a cytosolic antibody receptor and E3 ubiquitin ligase that promotes destruction of a broad range of pathogens. TRIM21 also underlies the antibody-dependent protein targeting method Trim-Away. Current evidence suggests that TRIM21 binding to antibodies leads to formation of a self-anchored K63 ubiquitin chain on the N-terminus of TRIM21 that triggers the destruction of TRIM21, antibody, and target protein. Here, we report that addition of antibody and TRIM21 to Xenopus egg extracts promotes efficient degradation of endogenous target proteins, establishing cell-free Trim-Away as a powerful tool to interrogate protein function. Chemical methylation of TRIM21 had no effect on target proteolysis, whereas deletion of all lysine residues in targets abolished their ubiquitination and proteasomal degradation. These results demonstrate that target protein but not TRIM21 polyubiquitination is required for Trim-Away, and they suggest that current models of TRIM21 function should be fundamentally revised.
Predicting the specific substrate for transmembrane transport proteins using BERT language model
Authors: Ataei Sima , Butler Gregory 
Published: July 2022

AbstractTransmembrane transport proteins play a vital role in cells’ metabolism by the selective passage of substrates through the cell membrane. Metabolic network reconstruction requires transport reactions that describe the specific substrate transported as well as the metabolic reactions of enzyme catalysis. In this paper, we apply BERT (Bidirectional Encoder Representations from Transformers) language model for protein sequences to predict one of 12 specific substrates. Our UniProt-ICAT-100 dataset is automatically constructed from UniProt using the ChEBI and GO ontologies to identify 4,112 proteins transporting 12 inorganic anion or cation substrates. We classified this dataset using three different models including Logistic Regression with an MCC of 0.81 and accuracy of 97.5%; Feed-forward Neural Networks classifier with an MCC of 0.88 and accuracy of 98.5%. Our third model utilizes a Fine-tuned BERT language model to predict the specific substrate with an MCC of 0.95 and accuracy of 99.3% on an independent test set.