bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced glutamate decarboxylase 1 underlies morphine-promoted lung metastasis of triple-negative breast cancer in mice
Authors: Chen Shih-Hong , Shih Chien-Hung , Ke Ting-Ling , Hsiung Chia-Ni , Chen Kuo-Chin , Huang Zi-Xuan , Chuang Tsung-Hsien , Chen Li-Kuei , Chen Linyi 
Published: September 2023

AbstractIntroductionMorphine is commonly used for cancer-related pain management. Long-term morphine use is not only addictive but also has been associated with risk factor for cancer.MethodsWe intraperitoneally administered morphine to mice for 14 days and then implanted EO771 cells, triple negative breast cancer cells, into their mammary fat pad. After primary tumors were removed on 38th day, a subset of mice were continuously giving saline or morphine until the 68th day. Tumor size, organ metastasis, and tumor RNA expression were analyzed.ResultsOur results revealed that long-term morphine treatment increased lung metastasis in the triple-negative breast cancer mouse model. To determine cellular pathways responsible for morphine-mediated metastasis, we performed RNA sequencing analysis to compare transcriptional profiles during metastasis. Transcriptional analysis revealed a significant number of genes down-regulated by morphine treatment. Based on pathway analysis, we focused on the novel effect of morphine on down-regulating taurine/hypotaurine biosynthesis. Considering that morphine, droperidol (dopamine receptor antagonist), and naloxone (opioid receptor antagonist) may act through opioid receptor or dopamine receptor, we further demonstrated that taurine reduced EO771 cell invasion caused by morphine, but not by droperidol, or naloxone treatment. In addition, morphine treatment significantly reduced the expression ofGAD1, one of the enzymes required for biosynthesis of taurine, whereas droperidol and naloxone did not.ConclusionThese novel findings of morphine reducesGAD1level and taurine reverses invasion suggest that taurine could potentially be employed as a supplement for triple negative breast cancer patients using morphine as pain management.Key MessagesMorphine usage has been implicated in modulating immune system and affecting cancer progression.Long-term usage of morphine promotes metastasis of triple negative breast cancer through reducing taurine biosynthesis.These novel findings of morphine reduces GAD1 level and taurine reverses invasion suggest that taurine could potentially be employed as a supplement for triple negative breast cancer patients using morphine as pain management.
Minute-timescale simulations of G Protein Coupled Receptor A2A activation mechanism reveal a receptor pseudo-active state
Authors: D’Amore Vincenzo Maria , Conflitti Paolo , Marinelli Luciana , Limongelli Vittorio 
Published: September 2023

ABSTRACTG protein coupled receptors (GPCRs) are membrane proteins of greatest pharmacological relevance, targeted by over one third of marketed drugs. These receptors are activated by orthosteric ligands and undergo large conformational changes that lead to coupling diverse effector proteins. To achieve a fine regulation of the drug pharmacological response, it is imperative to shed light on the yet poorly understood aspects of GPCRs activation. In this work, we elucidate the entire activation mechanism of the adenosine A2A receptor (A2AR), a class A GPCR, performing minute timescale molecular dynamics and free energy calculations. We have explored the entire conformational landscape of A2AR in its basal apo form and in differently ligated conditions, elucidating the ligand intrinsic activity and the receptor’s lowest energy functional states. Among these is a novel pseudo-active state (pAs) of the A2AR apo form stabilised by specific “microswitch” residues interactions, including the salt bridge between the class A conserved residues R5.66and E6.30. In the pAs state, A2AR is able to couple β-arrestin 1 over G proteins, providing unprecedented structural basis for receptor desensitization and G protein-alternative cellular pathways. Our simulation protocol is generalisable and can be applied to study the activation of any GPCR, resulting a precious tool for drug design and biased signaling studies.
Proteomic adaptations in the kidney reveal orchestration of local and secreted antimicrobial peptides in human pyelonephritis
Authors: Borgards Lars , Siebels Bente , Voss Hannah , Krisp Christoph , Schmitz Jessica , Schwarz Lisa , Siemes Devon , Spangenberg Philippa , Bräsen Jan H , von Vietinghoff Sibylle , Schlüter Hartmut , Wagenlehner Florian , Engel Daniel R. , Shevchuk Olga 
Published: September 2023

AbstractPyelonephritis (PN) is a frequent bacterial infection of the kidney and is often associated with severe diseases, organ loss and sepsis. Antibiotics are the cornerstone of therapy, however, increasing antibiotic resistance threatens therapy success and necessitates novel treatment strategies. Various proteins, such as antimicrobial peptides (AMPs), are key molecules of the innate immune response and insights into their regulation may help overcome multi-drug resistance and severe diseases. Using label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), several cellular, biological, and metabolic processes important for the antimicrobial response were identified, including a significant increase in previously undescribed proteins in human PN with antimicrobial function. Among others, we observed elevation of AMPs, such as calprotectin, azurocidin-1, and cathepsin G in the kidney, which we validated in the urine. Additionally, we observed a negative correlation of azurocidin-1 with plasma levels of C-reactive protein suggesting that the presence in the kidney may protect from severe diseases and systemic inflammation. This study represents the first renal proteomic dataset of human PN, enabling novel insights into the expression of AMPs in the context of PN.Lay SummaryGrowing antimicrobial resistance necessitates a better understanding of the expression of proteins that are critical for the immune response. Using mass spectrometry we identified AMPs in the kidney and urine of PN patients. Elevated levels of the AMP azurocidin-1 was associated with reduced systemic inflammation, indicated by lower C-reactive protein. Overall, this study identified expression of previously undescribed AMPs in the context of human PN. These proteins may play a pivotal role in protection from severe diseases and systemic inflammation.
Acute and sub-chronic toxicity of aqueous stem-bark extract ofAnnickia polycarpa
Authors: Lartey Nathaniel Lartey , Nyarko Eric Nana Yaw , Asare-Anane Henry , Antwi Stephen , Okine Laud Kenneth 
Published: September 2023

ABSTRACTBackground and aimThe lack of standardization and scientific validation of the use of most plant extracts leads to toxicity problems. The stem bark extract ofAnnickia polycarpahas been shown to possess antioxidant, antidiabetic, analgesic, and anti-colitis effects. However, nothing is known about the effects of the prolonged use of the extract. Thus, we investigated the acute and sub-chronic toxicity of the aqueous stem bark extract of (APE) in Sprague-Dawley rats.Experimental procedureThe LD50 and sub-chronic toxicity of APE (20 mg/kg, 100 mg/kg, and 500 mg/kg) was studied over 3 months in Sprague-Dawley rats. Serum alkaline phosphatase (ALP), alanine transaminase (ALT), direct bilirubin and creatinine were measured after 3 months of treatment. Hematological analysis and urinalysis were also performed. Also, the effect of APE on blood clotting time and pentobarbital-induced sleeping time were determined at the termination of treatment. Finally, histological analysis was done on liver, kidney, lung, and heart after hematoxylin-eosin staining of tissue cross-sections at the termination of treatment.Results and conclusionThe LD50 of APE in rats was higher than 5000 mg/kg with no observable signs of toxicity. APE also showed no hematotoxic effect when used consistently for 3 months. Additionally, APE had no adverse effect on the liver and kidney evidenced by a lack of effect on serum biochemical parameters (ALP, ALT, direct bilirubin, and creatinine), urinalysis as well as the tissue morphology of these organs. No adverse morphological effects were also observed with the heart muscle cells. However, APE showed mild selective toxicity to the lung characterized by alveolar space closing and interstitial fibrosis and alveolar septa thickening. These results indicate that APE is generally non-toxic at the tested doses but shows mild selective pneumotoxicity when used over a long period of time.
EquiPNAS: improved protein-nucleic acid binding site prediction using protein-language-model-informed equivariant deep graph neural networks
Authors: Roche Rahmatullah , Moussad Bernard , Shuvo Md Hossain , Tarafder Sumit , Bhattacharya Debswapna 
Published: September 2023

AbstractProtein language models (pLMs) trained on a large corpus of protein sequences have shown unprecedented scalability and broad generalizability in a wide range of predictive modeling tasks, but their power has not yet been harnessed for predicting protein-nucleic acid binding sites, critical for characterizing the interactions between proteins and nucleic acids. Here we present EquiPNAS, a new pLM-informed E(3) equivariant deep graph neural network framework for improved protein-nucleic acid binding site prediction. By combining the strengths of pLM and symmetry-aware deep graph learning, EquiPNAS consistently outperforms the state-of-the-art methods for both protein-DNA and protein-RNA binding site prediction on multiple datasets across a diverse set of predictive modeling scenarios ranging from using experimental input to AlphaFold2 predictions. Our ablation study reveals that the pLM embeddings used in EquiPNAS are sufficiently powerful to dramatically reduce the dependence on the availability of evolutionary information without compromising on accuracy, and that the symmetry-aware nature of the E(3) equivariant graph-based neural architecture offers remarkable robustness and performance resilience. EquiPNAS is freely available athttps://github.com/Bhattacharya-Lab/EquiPNAS.
Rapid optogenetic clustering of a cytoplasmic BcLOV4 variant
Authors: Huang Zikang , Benman William , Dong Liang , Bugaj Lukasz J. 
Published: September 2023

AbstractProtein clustering is a powerful form of optogenetic control, yet there is currently only one protein —Cry2—whose light-induced clustering has been harnessed for these purposes. Recently, the photoreceptor BcLOV4 was found to form protein clusters in mammalian cells in response to blue light, although clustering coincided with its translocation to the plasma membrane, potentially constraining its application as an optogenetic clustering module. Herein we identify key amino acids that couple clustering to membrane binding, allowing us to engineer a variant of BcLOV4 that clusters in the cytoplasm and does not associate with the membrane in response to blue light. This variant, BcLOVclust, clustered over many cycles with dramatically faster clustering and de-clustering kinetics compared to Cry2. The magnitude of BcLOVclust clustering could be strengthened by appending an intrinsically disordered region from the fused in sarcoma (FUS) protein, or by optimizing the fluorescent protein to which it was fused. BcLOVclust retained the temperature sensitivity of BcLOV4 such that light induced clustering was transient, and the rate of spontaneous declustering increased with temperature. At low temperatures, BcLOVclust and Cry2 could be multiplexed in the same cells, allowing light control of independent protein condensates. BcLOVclust could also be applied to control signaling proteins and stress granules in mammalian cells. Thus BcLOVclust provides an alternative to Cry2 for optogenetic clustering and a method for multiplexed clustering. While its usage is currently suited for organisms that can be cultured below ∼30 °C, a deeper understanding of BcLOVclust thermal response will further enable its use at physiological mammalian temperatures.Graphical abstractHighlightsLight-responsive clustering of BcLOV4 can be decoupled from its membrane associationBcLOVclust clusters in the cytoplasm with faster ON and OFF kinetics than Cry2BcLOVclust and Cry2 can be multiplexed in the same cellBcLOVclust can control RhoA activity and stress granule formation
Gene regulatory network that shaped the evolution of larval sensory organ in Cnidaria
Authors: Gilbert Eleanor , Craggs Jamie , Modepalli Vengamanaidu 
Published: September 2023

AbstractAmong non-bilaterian animals, a larval apical sensory organ with integrated neurons is only found in cnidarians. Within cnidarians, an apical organ with a ciliary tuft is mainly found in Actiniaria. Whether this apical tuft has evolved independently in Actiniaria or alternatively originated in the common ancestor of Cnidaria and Bilateria and was lost in specific groups is uncertain. We generated transcriptomes of the apical domain during the planula stage of four species representing three key groups of cnidarians:Aurelia aurita(Scyphozoa),Nematostella vectensis(Actiniaria), andAcropora millepora&Acropora tenuis(Scleractinia). We showed that the canonical genes implicated in patterning the apical domain ofNematostellaare largely absent inAurelia, indicating that scyphozoans and anthozoans do not share apical organ homology. In contrast, the apical domain of the scleractinian planula shares gene expression pattern withNematostella. By comparing the larval single-cell transcriptomes, we revealed the apical organ cell type of Scleractinia and confirmed its homology to Actiniaria. However,Fgfa2, a vital regulator of the regionalisation of theNematostellaapical organ, is absent in the scleractinian genome. Likewise, we found thatFoxJ1and 245 genes associated with cilia are exclusively expressed in theNematostellaapical domain, which is in line with the presence of ciliary apical tuft in Actiniaria and its absence in Scleractinia and Scyphozoa. Our findings suggest that the common ancestor of cnidarians and bilaterians lacked an apical organ with a ciliary tuft, and it could have evolved independently in several clades of cnidarians and bilaterians.
Patterns of genomic variation reveal a single evolutionary origin of the wild allotetraploidMimulus sookensis
Authors: Whitener Makenzie R. , Mangelson Hayley , Sweigart Andrea L. 
Published: September 2023

AbstractPolyploidy occurs across the tree of life and is especially common in plants. Because newly formed cytotypes are often incompatible with their progenitors, polyploidy is also said to trigger “instantaneous” speciation. If a polyploid can self-fertilize or reproduce asexually, it is even possible for one individual to produce an entirely new lineage. How often this extreme scenario occurs is unclear, with most studies of wild polyploids reporting multiple origins. Here, we explore the evolutionary history of the wild allotetraploidMimulus sookensis,which was formed through hybridization between self-compatible, diploid species in theMimulus guttatuscomplex. We generate a chromosome-scale reference assembly forM. sookensisand define its distinct subgenomes. Despite previous reports suggesting multiple origins of this highly selfing polyploid, we discover patterns of population genomic variation that provide unambiguous support for a single origin, which we estimate occurred ∼71,000 years ago. OneM. sookensissubgenome is clearly derived from the selferM. nasutus, which, based on organellar variation, also appears to be the maternal progenitor. The ancestor of the other subgenome is less certain, but it shares variation with bothM. decorusandM. guttatus, two outcrossing diploids that overlap broadly withM. sookensis. Whatever its precise ancestry, this study establishesM. sookensisas an example of instantaneous speciation, likely facilitated by the polyploid’s predisposition to self-fertilize. With a reference genome forM. sookensisnow available and its origin clarified, this wild tetraploid is poised to become a model for understanding the genetic and evolutionary mechanisms of polyploid persistence.
ONeSAMP 3.0: Effective Population Size via SNP Data for One Population Sample
Authors: Hong Aaron , Cheek Rebecca G. , Mukherjee Kingshuk , Yooseph Isha , Oliva Marco , Heim Mark , Funk W. Chris , Tallmon David , Boucher Christina 
Published: September 2023

AbstractThe genetic effective size (Ne) is arguably one of the most important characteristics of a population as it impacts the rate of loss of genetic diversity. Genetic estimators of (Ne) increasingly popular tools in population and conservation genetic studies. Yet there are very few methods that can estimate the Ne from data from a single population and without extensive information about the genetics of the population, such as a linkage map, or a reference genome of the species of interest.We present ONeSAMP 3.0, an algorithm for estimating Ne from single nucleotide polymorphism (SNP) data collected from a single population sample using Approximate Bayesian Computation and local linear regression.We demonstrate the utility of this approach using simulated Wright-Fisher populations, and empirical data from five endangered Channel Island fox (Urocyon littoralis) populations to evaluate the performance of ONeSAMP 3.0 compared to a commonly used Ne estimator. Our results show that ONeSAMP 3.0 is robust to the number of individual samples and number of loci included in and appears accurate even if the range of true Ne values is large.This method is broadly applicable to natural populations and is flexible enough that future versions could easily include summary statistics appropriate for a suite of biological and sampling conditions. ONeSAMP 3.0 is publicly available under the GNU license athttps://github.com/AaronHong1024/ONeSAMP_3and also available with Bioconda (https://bioconda.github.io/index.html).
CD39 expression by regulatory T cells drives CD8+ T cell suppression during experimentalTrypanosoma cruziinfection
Authors: Araujo Furlan Cintia L. , Boccardo Santiago , Rodriguez Constanza , Robson Simon C. , Gruppi Adriana , Montes Carolina L. , Acosta Rodríguez Eva V. 
Published: September 2023

AbstractAn imbalance between suppressor and effector immune responses may preclude cure in chronic parasitic diseases. In the case ofTrypanosoma cruziinfection, specialized regulatory Foxp3+ T (Treg) cells suppress protective type-1 effector responses. Herein, we investigated the kinetics and underlying mechanisms behind the regulation of protective parasite-specific CD8+ T cell immunity during acuteT. cruziinfection. Using the DEREG mouse model, we found that Treg cells play a critical role during the initial stages afterT. cruziinfection, subsequently influencing CD8+ T cells. Early Treg cell depletion increased the frequencies of polyfunctional short-lived, effector T cell subsets, without affecting memory precursor cell formation or the expression of activation markers. In addition, Treg cell depletion during early infection minimally affected the antigen-presenting cell response but it boosted CD4+ T cell responses before the development of anti-parasite effector CD8+ T cell responses. Crucially, the absence of CD39 expression on Treg cells significantly bolstered effector parasite-specific CD8+ T cell responses, leading to improved parasite control duringT. cruziinfection. Our work underscores the crucial role of Treg cells in regulating protective anti-parasite immunity and provides evidence that CD39 expression by Treg cells represents a key immunomodulatory mechanism in this infection model.
Integration of Patient-Derived Organoids and Organ-on-Chip Systems: Investigating Colorectal Cancer Invasion within the Mechanical and GABAergic Tumor Microenvironment
Authors: Strelez Carly , Perez Rachel , Chlystek John S. , Cherry Christopher , Yoon Ah Young , Haliday Bethany , Shah Curran , Ghaffarian Kimya , Sun Ren X. , Jiang Hannah , Lau Roy , Schatz Aaron , Lenz Heinz-Josef , Katz Jonathan E. , Mumenthaler Shannon M. 
Published: September 2023

SummaryThree-dimensional (3D) in vitro models are essential in cancer research, but they often neglect physical forces. In our study, we combined patient-derived tumor organoids with a microfluidic organ-on-chip system to investigate colorectal cancer (CRC) invasion in the tumor microenvironment (TME). This allowed us to create patient-specific tumor models and assess the impact of physical forces on cancer biology. Our findings showed that the organoid-on-chip models more closely resembled patient tumors at the transcriptional level, surpassing organoids alone. Using ’omics’ methods and live-cell imaging, we observed heightened responsiveness of KRAS mutant tumors to TME mechanical forces. These tumors also utilized the γ-aminobutyric acid (GABA) neurotransmitter as an energy source, increasing their invasiveness. This bioengineered model holds promise for advancing our understanding of cancer progression and improving CRC treatments.HighlightsMicrofluidic organ-on-chip system integrated with patient-derived CRC organoidsPhysical forces influence invasion, particularly in KRAS mutant tumor cellsGABAergic signaling contributes to increased invasion within a dynamic TMEThis model explores patient heterogeneity, TME interactions, and cancer progressionGRAPHICAL ABSTRACT
Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides
Authors: Schofield James H. , Longo Joseph , Sheldon Ryan D. , Albano Emma , Hawk Mark A. , Murphy Sean , Duong Loan , Rahmy Sharif , Lu Xin , Jones Russell G. , Schafer Zachary T. 
Published: September 2023

AbstractTargeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8+T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.
Breeding for growth has resulted in increased tolerance to drought at the cost of genetic diversity in Scots pine
Authors: Gil-Muñoz Francisco , Hayatgheibi Haleh , Niemi Juha M , Östlund Lars , García-Gil M Rosario 
Published: September 2023

AbstractClimate change possess a threat to forests and forestry. Drought has been identified as a one of the main issues due to its interaction with other biotic and abiotic stresses. Few studies have been done regarding breeding effect on the adaptability to climate change. After a common garden experiment with seedling families of Scots pine from northern Sweden, we have found differences in drought tolerance between families of breeding and natural origin. We performed a high throughput analysis-based phenotyping on both canopy and root traits. Root architecture traits might be related to drought tolerance and show moderate to high heritability values. The heritability of root architecture traits can be useful not only for drought but also for adaptability to other abiotic stresses. Analysis on architecture traits show that, especially on canopy-traits, families from breeding origins show less phenotypic variance than the ones from natural origins. The methodology employed to evaluate drought tolerance and plant architecture might be useful for future research and forest management focused on climate change adaptability.