bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Metabolic dysregulations of cancer cells with metastatic potential”
Authors: Kader Sara Abdul , Dib Shaima , Achkar Iman W. , Thareja Gaurav , Suhre Karsten , Rafii Arash , Halama Anna 
Published: June 2021

AbstractMetastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies, given their vital role in cancer cell responses to multiple challenges, including nutrient and oxygen availability. However, the metabolic signatures of metastatic cells remain vastly elusive. We conducted untargeted metabolic profiling of cells and growth media of five selected triple negative breast cancer cell lines with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and low metastatic potential (LMP) (BT549, HCC1143). We identified 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve in the future as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.
The Mechanism of Replication Stalling and Recovery within Repetitive DNA
Authors: Casas-Delucchi Corella S , Daza-Martin Manuel , Williams Sophie L , Coster Gideon 
Published: June 2021

SUMMARYAccurate chromosomal DNA replication is essential to maintain genomic stability. Genetic evidence suggests that certain repetitive sequences impair replication, yet the underlying mechanism is poorly defined. Replication could be directly inhibited by the DNA template or indirectly, for example by DNA-bound proteins. Here, we reconstituted replication of mono-, di- and trinucleotide repeats in vitro using eukaryotic replisomes assembled from purified proteins. We found that structure-prone repeats are sufficient to impair replication. Whilst template unwinding was unaffected, leading strand synthesis was inhibited, leading to fork uncoupling. Synthesis through hairpin-forming repeats relied on replisome-intrinsic mechanisms, whereas synthesis of quadruplex-forming repeats required an extrinsic accessory helicase. DNA-induced fork stalling was mechanistically similar to that induced by leading strand DNA lesions, highlighting structure-prone repeats as an important potential source of replication stress. Thus, we propose that our understanding of the cellular response to replication stress also applies to stalling induced by repetitive sequences.
Antibacterial Activity and Acute Toxicity Testing of Biosynthesized Silver Nanoparticles against Methicilin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa
Authors: Olobayotan Ifeyomi Wilfred , Akin-Osanaiye Bukola Catherine , Onuh Olukemi A. 
Published: June 2021

ABSTRACTAntibacterial activity of biosynthesized silver nanoparticles was studied using the macrobroth dilution technique. The silver nanoparticles was significantly active (p > 0.05) against the test organisms at an extract concentration of 75 µg/ml. Concentrations ≤ 50 µg/ml were not as effective as the colony forming units at this concentration, 1.61 × 106 for methicillin-resistant Staphylococcus aureus and concentrations ≤ 25 µg/ml 1.45 × 106 for Pseudomonas aeruginosa respectively, were about the same range as the colony forming units of the controls. The silver nanoparticles inhibited Methicillin-Resistant S. aureus more (MIC of 75 µg/ml and MBC of 100 µg/ml) than they inhibited P. aeruginosa (both MIC and MBC was 100 µg/ml). The LD50 of the synthesized silver nanoparticles after oral administration was seen to be greater than 5000 mg/kg body weight and is therefore thought to be safe. This study supports the use of silver nanoparticles as therapeutic agents.
Mycobacterium tuberculosis H2S functions as a sink to modulate central metabolism, bioenergetics, and drug susceptibility
Authors: Kunota Tafara T.R. , Rahman Md. Aejazur , Truebody Barry E. , Mackenzie Jared S. , Saini Vikram , Lamprecht Dirk A. , Adamson John H. , Sevalkar Ritesh R. , Lancaster Jack R. , Berney Michael , Glasgow Joel N. , Steyn Adrie J.C. 
Published: June 2021

AbstractH2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.
The BLENDS Method for Data Augmentation of 4-Dimensional Brain Images
Authors: Nguyen Kevin P. , Raval Vyom , Minhajuddin Abu , Carmody Thomas , Trivedi Madhukar H. , Dewey Richard B. , Montillo Albert A. 
Published: June 2021

ABSTRACTPurposeData augmentation improves the accuracy of deep learning models when training data is scarce by synthesizing additional samples. This work addresses the lack of validated augmentation methods specific for synthesizing anatomically realistic 4D (3D+time) images for neuroimaging, such as fMRI, by proposing a new augmentation method.Materials and MethodsThe proposed method, BLENDS, generates new nonlinear warp fields by combining intersubject coregistration maps, computed using symmetric normalization, through spatial blending. These new warp fields can be applied to existing 4D fMRI to create new augmented images. BLENDS is tested on two neuroimaging problems using de-identified datasets: 1) the prediction of antidepressant response from task-based fMRI in the EMBARC dataset (n = 163), and 2) the prediction of Parkinson’s Disease symptom trajectory from baseline resting-state fMRI regional homogeneity in the PPMI dataset (n = 43).ResultsBLENDS readily generates hundreds of new fMRI from existing images, with unique anatomical variations from the source images, that significantly improve prediction performance. For antidepressant response prediction, augmenting each original image once (2x the original training data) significantly increased prediction R2 from 0.055 to 0.098 (p < 1e-6), while at 10x augmentation R2 increased to 0.103. For the prediction of Parkinson’s Disease trajectory, 10x augmentation R2 increased from 0.294 to 0.548 (p < 1e-6).ConclusionAugmentation of fMRI through nonlinear transformations with BLENDS significantly improves the performance of deep learning models on clinically relevant predictive tasks. This method will help neuroimaging researchers overcome dataset size limitations and achieve more accurate predictive models.
Enriched sleep environments lengthen lemur sleep duration
Authors: Vining Alexander Q. , Nunn Charles L. , Samson David R. 
Published: June 2021

AbstractCharacteristics of the sleep-site are thought to influence the quality and duration of primate sleep, yet only a handful of studies have investigated these links experimentally. Using actigraphy and infrared videography, we quantified sleep in four lemur species (Eulemur coronatus, Lemur catta, Propithecus coquereli, and Varecia rubra) under two different experimental conditions at the Duke Lemur Center (DLC) in Durham, NC, USA. Individuals from each species underwent three weeks of simultaneous testing to investigate the hypothesis that comfort level of the sleep-site influences sleep. We obtained baseline data on normal sleep, and then, in a pair-wise study design, we compared the daily sleep times of individuals in simultaneous experiments of sleep-site enrichment and sleep-site impoverishment. Over 163 24-hour periods from 8 individuals (2 of each species), we found strong evidence that enriched sleep-sites increased daily sleep times of lemurs, with an average increase of thirty-one minutes. The effect of sleep-site impoverishment was small and not statistically significant. We conclude that properties of a sleep-site enhancing softness or insulation, more than the factors of surface area or stability, influence lemur sleep, with implications regarding the importance of nest building in primate evolution and the welfare and management of captive lemurs.
Targeted degradation of the oncogenic phosphatase SHP2
Authors: Vemulapalli Vidyasiri , Donovan Katherine A. , Seegar Tom C.M. , Rogers Julia M. , Bae Munhyung , Lumpkin Ryan J. , Cao Ruili , Henke Matthew T. , Fischer Eric S. , Cuny Gregory D. , Blacklow Stephen C. 
Published: June 2021

AbstractSHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras/MAPK pathway upon stimulation of receptor tyrosine kinases (RTKs), which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at sub-micromolar concentration, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.
Localization of TRP channels in healthy oral mucosa from human donors
Authors: Moayedi Yalda , Michlig Stephanie , Park Mark , Koch Alia , Lumpkin Ellen A 
Published: June 2021

AbstractThe oral cavity is exposed to a remarkable range of noxious and innocuous conditions, including temperature fluctuations, mechanical forces, inflammation and environmental and endogenous chemicals. How such changes in the oral environment are sensed by oral cells and tissues is not completely understood. Transient receptor potential (TRP) ion channels are a diverse family of molecular receptors that are activated by chemicals, temperature changes, and tissue damage. In non-neuronal cells, TRP channels play roles in inflammation, as well as tissue development and maintenance. In somatosensory neurons, TRP channels mediate nociception, thermosensation and chemosensation. To assess whether TRP channels might be involved in environmental sensing in the human oral cavity, we investigated the distribution of TRP channels in human tongue and hard palate. Oral biopsies were collected from volunteers and underwent fluorescent immunohistochemistry followed by confocal imaging. We analyzed immunoreactivity of TRP channels in human oral epithelia including TRPV3, TRPV4, TRPV1, TRPM8, and TRPA1. TRPV3 and TRPV4 were expressed in epithelial cells with inverse expression patterns where they are likely to contribute to epithelial development and integrity. TRPA1 immunoreactivity was found in fibroblasts, subsets immune cells, and neurons, consistent with known roles of TRPA1 in sensory transduction, as well as in response to damage and inflammation. TRPM8 immunoreactivity was found in lamina propria cells and some neuronal subpopulations including some neurons within the end bulbs of Krause, consistent with a role in thermal sensation. TRPV1 immunoreactivity was identified in intraepithelial nerve fibers, in some end bulbs of Krause, and in epithelial cells, consistent with roles in nociception and thermosensation. Immunoreactivity of TRPM8 and TRPV1 in end bulbs of Krause suggest that these structures contain a variety of neuronal afferents, including those that mediate nociception, thermosensation and mechanotransduction. Collectively, these studies support the role of TRP channels in oral environmental surveillance and response.
Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes
Authors: Postigo-Fernandez Jorge , Creusot Rémi J. 
Published: June 2021

ABSTRACTAntigen-specific immunotherapy involves the delivery of self-antigens as proteins or peptides (or using nucleic acids encoding them) to be presented with the goal of inducing tolerance. Approaches employing specific epitopes restricted to the subject’s MHC haplotypes have multiplied and offer a more focused and tailored way of targeting autoreactive T cells. In addition, the Endotope platform allows endogenously expressed epitopes to be processed and presented on appropriate MHC class I and II molecules. Here, we evaluated the efficacy of a DNA vaccine encoding epitopes selected and tailored for the non-obese diabetic (NOD) mouse compared to the expression of the proinsulin protein, one of the most successful antigens in prevention of NOD disease, and we assessed the influence of several parameters (e.g. route, dosing frequency) on preventing diabetes onset at normoglycemic and dysglycemic stages. First, encoded peptides should be secreted for effective disease prevention. Furthermore, short weekly treatments with Endotope and proinsulin DNA vaccines delay disease onset, but sustained treatments are required for long-term protection, which was more significant with intradermal delivery. Although epitopes can be presented for at least two weeks, reducing the frequency of antigen administration from weekly to every other week reduced efficacy. Finally, both Endotope and proinsulin DNA vaccines were effective in the dysglycemic stage of disease, but proinsulin provided better protection, particularly in subjects with slower progression of disease. Thus, our data support the possibility of applying a precision medicine approach based on tailored epitopes for the treatment of tissue-specific autoimmune diseases with DNA vaccines.SIGNIFICANCE STATEMENTAntigen-specific immunotherapy is a targeted approach to treat autoimmune diseases by turning off responses to disease-relevant antigens only, leaving the rest of the immune system unaffected. Protein antigens contain many epitopes, but only a fraction of them can be presented on a specific HLA haplotype and the relative importance of different antigens vary between patients due to disease heterogeneity. Strategies based on specific epitopes do not only consider the HLA haplotype and immune profile of groups of patients but can also include important neoepitopes not present in protein antigens. Here, we provide proof-of-principle that such strategy applied to tolerogenic DNA vaccination is effective in a preclinical model of autoimmune diabetes, paving the way for precision medicine using endogenously encoded epitopes.
Efficient discovery of potently neutralizing SARS-CoV-2 antibodies using LIBRA-seq with ligand blocking
Authors: Shiakolas Andrea R. , Johnson Nicole , Kramer Kevin J. , Suryadevara Naveenchandra , Wrapp Daniel , Periasamy Sivakumar , Pilewski Kelsey A. , Raju Nagarajan , Nargi Rachel , Sutton Rachel E. , Walker Lauren , Setliff Ian , Crowe James E. , Bukreyev Alexander , Carnahan Robert H. , McLellan Jason S. , Georgiev Ivelin S. 
Published: June 2021

ABSTRACTSARS-CoV-2 therapeutic antibody discovery efforts have met with notable success but have been associated with a generally inefficient process, requiring the production and characterization of exceptionally large numbers of candidates for the identification of a small set of leads. Here, we show that incorporating antibody–ligand blocking as part of LIBRA-seq, the high-throughput sequencing platform for antibody discovery, results in efficient identification of ultra-potent neutralizing antibodies against SARS-CoV-2. LIBRA-seq with ligand blocking is a general platform for functional antibody discovery targeting the disruption of antigen–ligand interactions.
An image reconstruction framework for characterizing initial visual encoding
Authors: Zhang Ling-Qi , Cottaris Nicolas P. , Brainard David H. 
Published: June 2021

AbstractWe developed an image-computable observer model of the initial visual encoding that operates on natural image input, based on the framework of Bayesian image reconstruction from the excitations of the retinal cone mosaic. Our model extends previous work on ideal observer analysis and evaluation of performance beyond psychophysical discrimination, takes into account the statistical regularities of the visual environment, and provides a unifying framework for answering a wide range of questions regarding the visual front end. Using the error in the reconstructions as a metric, we analyzed variations of the number of different photoreceptor types on human retina as an optimal design problem. In addition, the reconstructions allow both visualization and quantification of information loss due to physiological optics and cone mosaic sampling, and how these vary with eccentricity. Furthermore, in simulations of color deficiencies and interferometric experiments, we found that the reconstructed images provide a reasonable proxy for modeling subjects’ percepts. Lastly, we used the reconstruction-based observer for the analysis of psychophysical threshold, and found notable interactions between spatial frequency and chromatic direction in the resulting spatial contrast sensitivity function. Our method is widely applicable to experiments and applications in which the initial visual encoding plays an important role.
Anal skin-like epithelium mediates colonic wound healing
Authors: Liu Cambrian Y. , Girish Nandini , Gomez Marie L. , Dubé Philip E. , Washington M. Kay , Simons Benjamin D. , Polk D. Brent 
Published: June 2021

SummaryIntestinal epithelial wound healing, which is essential for health, is compromised and represents a therapeutic target in inflammatory bowel disease (IBD). While studies have elucidated important subpopulations of intestinal epithelial cells in repair, these have yet to translate to therapies. Here, in mouse models of acute colitis, we demonstrate a distinct and essential source of wound-healing cells that re-epithelialize the distal colon. Using 3-d imaging, lineage tracing, and single-cell transcriptomics, we show that neighboring skin-like (squamous) cells of the anus rapidly migrate into the injured colon and establish a permanent epithelium of crypt-like morphology. These squamous cells derive from a small unique transition zone, at the boundary of colonic and anal epithelium, that resists colitis. The cells of this zone have a pre-loaded program of colonic differentiation and further upregulate key aspects of colonic epithelium during repair. Thus, heterologous cell-types at tissue junctions represent unique reserve cells capable of repair and plasticity.
Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population
Authors: Ng Sherrianne , Chen Muxuan , Kundu Samit , Wang Xuefei , Zhou Zuyi , Zheng Zhongdaixi , Qing Wei , Sheng Huafang , Wang Yan , He Yan , Bennett Phillip R. , MacIntyre David A. , Zhou Hongwei 
Published: June 2021

AbstractVaginal microbiota-host interactions are linked to preterm birth (PTB), which continues to be the primary cause of global childhood mortality. Despite the majority of PTB occuring in Asia, studies of the pregnancy vaginal microbiota are largely limited to Northern American and European populations. Here, we characterised the vaginal microbiome of 2689 pregnant Chinese women using metataxonomics and in a subset (n=823), the relationship between vaginal microbiota composition, sialidase activity and leukocyte presence and pregnancy outcomes. Vaginal microbiota were most frequently dominated by Lactobacillus crispatus or L. iners, with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including Gardnerella, Atopobium and Prevotella. Vaginal microbiota composition, high sialidase activity and/or leukocyte presence was not associated with PTB risk suggesting underlying differences in the vaginal microbiota and/or host immune responses of Chinese women, possibly accounting for low PTB rates in this population.ImportanceSpecific vaginal microorganisms or ‘vaginal microbiota’, are associated with preterm birth, which is the primary cause of death in children under 5yrs of age worldwide. Despite most preterm births occuring in Asia, almost all studies of the pregnancy vaginal microbiota have been limited to Northern American and European women. Here, we studied the vaginal microbiota in a large cohort of 2689 pregnant Chinese women and showed that it was most frequently dominated by Lactobacillus crispatus or L. iners. The latter was associated with leukocyte infiltration of vaginal secretions. Women with high activity of the enzyme sialidase, were frequently colonised by species associated with the common condition bacterial vaginosis, including Gardnerella, Atopobium and Prevotella species. Vaginal microbiota, high sialidase activity and/or leukocyte presence was not associated with preterm birth risk indicating differences in the microbe-host immune responses of Chinese women, possibly explaining why preterm birth rates in this population are low.
The RNA helicase Ded1 regulates translation and granule formation during multiple phases of cellular stress responses
Authors: Aryanpur Peyman P. , Mittelmeier Telsa M. , Bolger Timothy A. 
Published: June 2021

AbstractDed1 is a conserved RNA helicase that promotes translation initiation in steady-state conditions. Ded1 has also been shown to regulate translation during cellular stress and affect the dynamics of stress granules (SGs), accumulations of RNA and protein linked to translation repression. To better understand its role in stress responses, we examined Ded1 function in two different models: DED1 overexpression and oxidative stress. DED1 overexpression inhibits growth and promotes the formation of SGs. A ded1mutant lacking the low-complexity C-terminal region (ded1-ΔCT), which mediates Ded1 oligomerization and interaction with the translation factor eIF4G, suppressed these phenotypes, consistent with other stresses. During oxidative stress, a ded1-ΔCT mutant was defective in growth and in SG formation compared to wild-type cells, although SGs were increased rather than decreased in these conditions. Unlike stress induced by direct TOR inhibition, the phenotypes in both models were only partially dependent on eIF4G interaction, suggesting an additional contribution from Ded1 oligomerization. Furthermore, examination of the growth defects and translational changes during oxidative stress suggested that Ded1 plays a role during recovery from stress. Integrating these disparate results, we propose that Ded1 controls multiple aspects of translation and RNP dynamics in both initial stress responses and during recovery.