bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microwell array based opto-electrochemical detections revealing co-adaptation of rheological properties and oxygen metabolism in budding yeast
Authors: Vajrala Venkata Suresh , Alric Baptiste , Laborde Adrian , Colin Camille , Suraniti Emmanuel , Temple-Boyer Pierre , Arbault Stephane , Delarue Morgan , Launay Jérome 
Published: January 2021

AbstractMicrodevices composed of microwell arrays integrating nanoelectrodes (OptoElecWell) were developed to achieve dual high-resolution optical and electrochemical detections on singleSaccharomyces cerevisiaebudding yeast cells. Each array consists in 1.6 × 105microwells of 8 µm diameter and 5 µm height, with a platinum nanoring electrode for in-situ electrochemistry, all integrated on a transparent thin wafer for further high-resolution live-cell imaging. After optimizing the filling rate, 32% of cells were effectively trapped within microwells. This allowed to analyseS. cerevisiaemetabolisms associated with basal respiration while simultaneously measuring optically other cellular parameters. In this study, we focused on the impact of glucose concentration on respiration and intracellular rheology. We found that while oxygen uptake rate decreased with increasing glucose concentration, diffusion of tracer nanoparticles increased. Our OptoElecWell based respiration methodology provided similar results compared to the commercial gold-standard Seahorse XF analyser, while using 20 times lesser biological samples, paving the way to achieve single cell metabolomics. In addition, it facilitates an optical route to monitor the contents within single cells. The proposed device, in combination with the dual detection analysis, opens up new avenues for measuring cellular metabolism, and relating it to various cellular physiological and rheological indicators at single cell level.
Multiomics Integration Elucidates Metabolic Modulators of Drug Resistance in Lymphoma
Authors: Choueiry Fouad , Singh Satishkumar , Sun Xiaowei , Zhang Shiqi , Sircar Anuvrat , Amber Hart , Alinari Lapo , Narendranath Epperla , Baiocchi Robert , Zhu Jiangjiang , Sehgal Lalit 
Published: January 2021

AbstractBackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Bruton’s tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug tolerant form. The drug tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug resistant tumor is poorly understood.MethodsIn this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a ‘multi-omics’ analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation and pharmaceutical inhibition, were further used to identify the key players that contribute to the metabolic reprograming of the drug resistant clone.ResultsGene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that drug resistant clones undergo metabolic reprogramming from glycolysis towards oxidative phosphorylation & is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically.ConclusionsOur report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained Oxidative phosphorylation, additionally we outline the compensatory, pathway that regulates this metabolic reprogramming in the drug resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells.
Antibiotic treatment increases yellowness of carotenoid feather coloration in greenfinches (Chloris chloris)
Authors: Lind Mari-Ann , Sepp Tuul , Štšeglova Kristiina , Hõrak Peeter 
Published: January 2021

AbstractCarotenoid plumage coloration is an important signal of quality, and plays an important role in mate choice in many bird species. However, it remains unclear what mechanism makes carotenoids an honest signal. Here, we test the hypothesis that carotenoid plumage coloration might indicate gut health. Parasitic and microbial infections can affect nutrient absorption due to decreased gut surface or by altered gut microbiome. We took an advantage of a naturally occurring coinfection of parasites inhabiting the upper and lower portions of the digestive track to distinguish between the direct and indirect effects of parasites on carotenoid acquisition. Protozoan coccidian intestinal parasites are widespread in greenfinches (Chloris chloris) and the majority of greenfinches are infected in nature. Trichomonosis is an emerging disease of the upper digestive track that causes high mortality among greenfinches. We captured wild greenfinches (N=71) and administered anticoccidial medication toltrazuril (TOLTRA) to one group, antibiotic metronidazole (METRO) that is also effective for treatingTrichomonas gallinea, to the second group, and third group received no medication. In the METRO group, feathers grown during the experiment had significantly higher chroma of yellow parts, but there was no effect of TOLTRA on feather chroma. These results suggest that METRO increased the efficiency of carotenoid modification or deposition to the feathers rather than nutrient acquisition, and/or freed energy resources that could be invested in coloration. Alternatively, in accordance with shared pathway hypothesis, increase in efficiency of vital cellular processes might have occurred, as many microbial metabolites can modulate mitochondrial and immune function.
Sexually Transmitted Infections Select for Different Levels of Immunocompetence And Reproductive Efforts in The Two Sexes
Authors: Aldakak Lafi , Rühli Frank , Bender Nicole 
Published: January 2021

1.AbstractSex differences in immunity have been described in humans and other mammal species. Females have a lower incidence of infections and non-reproductive malignancies and exhibit higher antibody levels after vaccination. Existing evolutionary explanations are based on differences in reproductive strategies and reaction to extrinsic differences in susceptibility and virulence between the sexes. Here, we test the hypothesis that known differences in the probability of transmission and outcome of sexually transmitted infections contribute to sex differences in immunocompetence. We modelled reproductive and immune investments against a fertility limiting Sexually Transmitted Infection (STI). We show that, in line with previous findings, increased susceptibility selects for tolerance to the parasite while increased virulence selects for resistance against it. Differences in reproductive strategies between the sexes lead to sex differences in immunocompetence, mostly with higher competence in females. Extrinsic differences in susceptibility and virulence between the sexes can augment or alleviate the evolutionary consequences of intrinsic differences depending on their direction and magnitude. This indicates that the selection of sex-specific immune strategies is less predictable than thought before and explains why sex differences in immunity have been found to be not universal and pervasive across animal species.
GLS-driven glutamine catabolism contributes to prostate cancer radiosensitivity by regulating the redox state, stemness and ATG5-mediated autophagy
Authors: Mukha Anna , Kahya Uğur , Linge Annett , Chen Oleg , Löck Steffen , Lukiyanchuk Vasyl , Richter Susan , Alves Tiago C. , Peitzsch Mirko , Telychko Vladyslav , Skvortsov Sergej , Negro Giulia , Aschenbrenner Bertram , Skvortsova Ira-Ida , Mirtschink Peter , Lohaus Fabian , Hölscher Tobias , Neubauer Hans , Rivandi Mahdi , Franken André , Behrens Bianca , Stoecklein Nikolas H. , Toma Marieta , Sommer Ulrich , Zschaeck Sebastian , Rehm Maximilian , Eisenhofer Graeme , Schwager Christian , Abdollahi Amir , Groeben Christer , Kunz-Schughart Leoni A. , Baretton Gustavo B. , Baumann Michael , Krause Mechthild , Peitzsch Claudia , Dubrovska Anna 
Published: January 2021

AbstractRadiotherapy is one of the curative treatment options for localized prostate cancer (PCa). The curative potential of radiotherapy is mediated by irradiation-induced oxidative stress and DNA damage in tumor cells. However, PCa radiocurability can be impeded by tumor resistance mechanisms and normal tissue toxicity. Metabolic reprogramming is one of the major hallmarks of tumor progression and therapy resistance. Here, we found that radioresistant PCa cells and prostate cancer stem cells (CSCs) have a high glutamine demand. Glutaminase (GLS)-driven catabolism of glutamine serves not only for energy production but also for the maintenance of the redox state. Consequently, glutamine depletion or inhibition of critical regulators of glutamine utilization, such as glutaminase (GLS) and the transcription factor MYC results in PCa radiosensitization. On the contrary, we found that a combination of glutamine metabolism inhibitors with irradiation does not cause toxic effects on nonmalignant prostate cells. Glutamine catabolism contributes to the maintenance of CSCs through regulation of the alpha-ketoglutarate (α-KG)-dependent chromatin-modifying dioxygenase. The lack of glutamine results in the inhibition of CSCs with a high aldehyde dehydrogenase (ALDH) activity, decreases the frequency of the CSC populationsin vivoand reduces tumor formation in xenograft mouse models. Moreover, this study shows that activation of the ATG5-mediated autophagy in response to a lack of glutamine is a tumor survival strategy to withstand radiation-mediated cell damage. In combination with autophagy inhibition, the blockade of glutamine metabolism might be a promising strategy for PCa radiosensitization. High blood levels of glutamine in PCa patients significantly correlate with a shorter prostate-specific antigen (PSA) doubling time. Furthermore, high expression of critical regulators of glutamine metabolism, GLS1 and MYC, is significantly associated with a decreased progression-free survival in PCa patients treated with radiotherapy. Our findings demonstrate that GLS-driven glutaminolysis is a prognostic biomarker and therapeutic target for PCa radiosensitization.
A Self-Supervised Machine Learning Approach for Objective Live Cell Segmentation and Analysis
Authors: Robitaille Michael C. , Byers Jeff M. , Christodoulides Joseph A. , Raphael Marc P. 
Published: January 2021

AbstractMachine learning algorithms hold the promise of greatly improving live cell image analysis by way of (1) analyzing far more imagery than can be achieved by more traditional manual approaches and (2) by eliminating the subjective nature of researchers and diagnosticians selecting the cells or cell features to be included in the analyzed data set. Currently, however, even the most sophisticated model based or machine learning algorithms require user supervision, meaning the subjectivity problem is not removed but rather incorporated into the algorithm’s initial training steps and then repeatedly applied to the imagery. To address this roadblock, we have developed a self-supervised machine learning algorithm that recursively trains itself directly from the live cell imagery data, thus providing objective segmentation and quantification. The approach incorporates an optical flow algorithm component to self-label cell and background pixels for training, followed by the extraction of additional feature vectors for the automated generation of a cell/background classification model. Because it is self-trained, the software has no user-adjustable parameters and does not require curated training imagery. The algorithm was applied to automatically segment cells from their background for a variety of cell types and five commonly used imaging modalities - fluorescence, phase contrast, differential interference contrast (DIC), transmitted light and interference reflection microscopy (IRM). The approach is broadly applicable in that it enables completely automated cell segmentation for long-term live cell phenotyping applications, regardless of the input imagery’s optical modality, magnification or cell type.
Priming anodal transcranial direct current stimulation attenuates short interval intracortical inhibition and increases time to task failure of a constant workload cycling exercise
Authors: Sidhu Simranjit K 
Published: January 2021

ABSTRACTTranscranial direct current stimulation (tDCS), a non-invasive neuromodulatory technique has been shown to increase the excitability of targeted brain area and influence endurance exercise performance. However, tDCS-mediated interaction between corticospinal excitability, GABAAmediated intracortical inhibition and endurance exercise performance remains understudied. In two separate sessions, twelve subjects performed fatigue cycling exercise (80% peak power output) sustained to task failure in a double-blinded design, following either ten minutes of anodal tDCS (atDCS) or sham. Corticospinal excitability and short interval intracortical inhibition (SICI) were measured at baseline, post neuromodulation and post-exercise using paired-pulse transcranial magnetic stimulation (TMS) in a resting hand muscle. There was a greater a decrease in SICI (P< 0.05) post fatigue cycling with atDCS priming compared to sham. Time to task failure (TTF) was significantly increased following atDCS compared to sham (P< 0.05). These findings suggest that atDCS applied over the motor cortex can augment cycling exercise performance; and this outcome may be mediated via a decrease in the excitability of GABAAinhibitory interneurons.
Testing for phylogenetic signal in single-cell RNA-seq data
Authors: Moravec Jiří C. , Lanfear Rob , Spector David L. , Diermeier Sarah D. , Gavryushkin Alex 
Published: January 2021

AbstractPhylogenetic methods are emerging as a useful tool to understand cancer evolutionary dynamics, including tumor structure, heterogeneity, and progression. Most currently used approaches utilize either bulk whole genome sequencing (WGS) or single-cell DNA sequencing (scDNA-seq) and are based on calling copy number alterations and single nucleotide variants (SNVs). scRNA-seq is commonly applied to explore differential gene expression of cancer cells throughout tumor progression. The method exacerbates the single-cell sequencing problem of low yield per cell with uneven expression levels. This accounts for low and uneven sequencing coverage and makes SNV detection and phylogenetic analysis challenging. In this paper, we demonstrate for the first time that scRNA-seq data contains sufficient evolutionary signal and can also be utilized in phylogenetic analyses. We explore and compare results of such analyses based on both expression levels and SNVs called from scRNA-seq data. Both techniques are shown to be useful for reconstructing phylogenetic relationships between cells, reflecting the clonal composition of a tumor. Both standardized expression values and SNVs appear to be equally capable of reconstructing a similar pattern of phylogenetic relationship. This pattern is stable even when phylogenetic uncertainty is taken in account. Our results open up a new direction of somatic phylogenetics based on scRNA-seq data. Further research is required to refine and improve these approaches to capture the full picture of somatic evolutionary dynamics in cancer.
Neutralizing antibodies targeting the SARS-CoV-2 receptor binding domain isolated from a naïve human antibody library
Authors: Bell Benjamin N. , Powell Abigail E. , Rodriguez Carlos , Cochran Jennifer R. , Kim Peter S. 
Published: January 2021

AbstractInfection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS-CoV-2 neutralizing antibodies. Here, we used a yeast surface-display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS-CoV-2 spike-pseudotyped lentivirus with IC50values as low as 60 ng/mLin vitro. Using a biolayer interferometry-based binding competition assay, we determined that these antibodies have distinct but overlapping epitopes with antibodies elicited during natural COVID-19 infection. Taken together, these analyses highlight howin vitroselection of naïve antibodies can mimic the humoral responsein vivo, yielding neutralizing antibodies and various epitopes that can be effectively targeted on the SARS-CoV-2 RBD.
Targeted sequence capture ofOrientia tsutsugamushiDNA from chiggers and humans
Authors: Elliott Ivo , Thangnimitchok Neeranuch , de Cesare Mariateresa , Linsuwanon Piyada , Paris Daniel H. , Day Nicholas PJ , Newton Paul N. , Bowden Rory , Batty Elizabeth M. 
Published: January 2021

AbstractScrub typhus is a febrile disease caused byOrientia tsutsugamushi, transmitted by larval stage Trombiculid mites (chiggers), whose primary hosts are small mammals. The phylogenomics ofO. tsutsugamushiin chiggers, small mammals and humans remains poorly understood. To combat the limitations imposed by the low relative quantities of pathogen DNA in typicalO. tsutsugamushiclinical and ecological samples, along with the technical, safety and cost limitations of cell culture, a novel probe-based target enrichment sequencing protocol was developed. The method was designed to capture variation among conserved genes and facilitate phylogenomic analysis at the scale of population samples. A whole-genome amplification step was incorporated to enhance the efficiency of sequencing by reducing duplication rates. This resulted in on-target capture rates of up to 93% for a diverse set of human, chigger, and rodent samples, with the greatest success rate in samples with real-time PCR Ctvalues below 35. Analysis of the best-performing samples revealed phylogeographic clustering at local, provincial and international scales. Applying the methodology to a comprehensive set of samples could yield a more complete understanding of the ecology, genomic evolution and population structure ofO. tsutsugamushiand other similarly challenging organisms, with potential benefits in the development of diagnostic tests and vaccines.
Therapeutic adenine base editing corrects nonsense mutation and improves visual function in a mouse model of Leber congenital amaurosis
Authors: Jo Dong Hyun , Jang Hyeon-Ki , Cho Chang Sik , Han Jun Hee , Ryu Gahee , Jung Youngri , Bae Sangsu , Kim Jeong Hun 
Published: January 2021

AbstractLeber congenital amaurosis (LCA) is an inherited retinal degeneration that causes severe visual dysfunction in children and adolescents. In patients with LCA, pathogenic variants are evident in specific genes, such as RPE65, which are related to the functions of retinal pigment epithelium and photoreceptors. Base editing confers a way to correct pathogenic substitutions without double-stranded breaks in contrast to the original Cas9. In this study, we prepared dual adeno-associated virus vectors containing the split adenine base editors with trans-splicing intein (AAV-ABE) for in vivo adenine base editing in retinal degeneration 12 (rd12) mice, an animal model of LCA, which possess a nonsense mutation of C to T transition in the Rpe65 gene (p.R44X). AAV-ABE induced an A to G transition in retinal pigment epithelial cells of rd12 mice when injected into the subretinal space. The on-target editing was sufficient to recover wild-type mRNA, RPE65 protein, and light-induced electrical responses of retinal tissues. We suggest adenine base editing to correct pathogenic variants in the treatment of LCA.
Surveillance of Shiga toxin-producingEscherichia coliassociated bloody diarrhea in Argentina
Authors: Rivas Marta , Pichel Mariana , Colonna Mariana , Casanello Adrián López , Alconcher Laura F. , Galavotti Jimena , Principi Iliana , Araujo Sofía Pérez , Ramírez Flavia B. , González Gladys , Pianciola Luis A. , Mazzeo Melina , Suarez Ángela , Oderiz Sebastián , Ghezzi Lidia F. R. , Arrigo Diego J. , Paladini José H. , Baroni María R. , Pérez Susana , Tamborini Ana , Chinen Isabel , Miliwebsky Elizabeth S. , Goldbaum Fernando , Muñoz Luciana , Spatz Linus , Sanguineti Santiago ,   the EPI-HUS Investigation Team
Published: January 2021

ABSTRACTIn Argentina, the hemolytic uremic syndrome associated with Shiga toxin-producingEscherichia coli(STEC-HUS) infection is endemic, and reliable data about prevalence and risk factors are available since 2000. However, information about STEC-associated bloody diarrhea (BD) cases is limited. A prospective study was carried out in seven tertiary-hospitals and 18 Referral Units from different regions, aiming to determine (i) STEC-positive BD cases frequency in 714 children aged 1 to 9 years old; and (ii) rate of progression to HUS. The number and regional distribution of STEC-HUS cases assisted in the same hospitals and period was also assessed. A total of 29 (4.1%) STEC-positive BD cases were confirmed by Shiga Toxin Quik Chek (STQC) and/or mPCR. The highest frequencies were found in the Southern region (Neuquén, 8.7%; Bahía Blanca, 7.9%), in children between 12 and 23 month of age (8.8%), during summertime. Four (13.8%) cases progressed to HUS, three to five days after BD onset. Twenty-seven STEC-HUS children mainly under 5 years old (77.8%) were enrolled, 51.9% were female; 44% were Stx-positive by STQC and all by mPCR. The most common serotypes were O157:H7 and O145:H28 and prevalent genotypes werestx2a-only or associated, both among BD and HUS cases. Considering the endemic behavior of HUS and its impact on public health, it is important to have updated information about the epidemiology of the diarrheal disease for early recognition of infected patients and initiation of supportive treatment. Finally, it also gives the opportunity to respond to outbreak situations effectively and in timely manner.