bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic effects of combing proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers
Authors: Rykkelid Anne Marit , Sinha Priyanshu Manojkumar , Folefac Charlemagne Asonganyi , Horsman Michael Robert , Sørensen Brita Singers , Søland Tine Merete , Franciscus Schreurs Olaf Joseph , Malinen Eirik , Edin Nina Frederike J 
Published: September 2023

AbstractBackground and purposeCombining radiation therapy with immunotherapy may be beneficial in treatment of head and neck cancer (HNC), but the combined effect may depend on tumor characteristics and the type of radiation. The purpose was to compare responses for two syngeneic tumor models in mice following X-ray or proton irradiation with or without immune checkpoint inhibition (ICI).Materials and methodsMOC1 and MOC2 tumors were inoculated in the right hind leg of each mouse (C57BL/6J, n=159). Single-dose irradiation with X-rays or protons and administration of anti-PDL1 started when the tumors reached 200 mm3. Doses of 5-30 Gy were given. Time-dependent tumor volume data were analyzed with a regression model yielding the growth rate γ without irradiation and the reduction in growth rate per dose η. Relative biological effectiveness (RBE) was calculated as the ratio of η for X-rays to that of protons. Synergy between radiation and ICI was estimated as the ratio of η’s.ResultsMOC2 tumors grew faster and were more radioresistant than MOC1 tumors. ICI reduced the growth rate for MOC1 with 20±2% compared to controls, while no reduction was seen for MOC2. RBE for MOC1 wo/w ICI was 0.89±0.04 and 0.93±0.06, respectively, while it was 1.15±0.12 and 1.60±0.17, respectively, for MOC2. Combination synergy for X-rays was 1.22±0.08 and 0.96±0.11 in MOC1 and MOC2, respectively, while was it 1.27±0.06 and 1.33 ±0.13, respectively, for protons.ConclusionsRBE for protons was dependent on use of ICI and tumor type. A greater synergy may be achieved when combining protons with ICI compared to X-rays and ICI.
Exploring the metabolic profiling ofA. baumanniifor antimicrobial development using genome-scale modelling
Authors: Leonidou Nantia , Xia Yufan , Friedrich Lea , Schütz Monika S. , Dräger Andreas 
Published: September 2023

ABSTRACTWith the emergence of multidrug-resistant bacteria, the World Health Organization published a catalog of microorganisms urgently needing new antibiotics, with the carbapenem-resistantAcinetobacter baumanniidesignated as “critical”. Such isolates, frequently detected in healthcare settings, pose a global pandemic threat. One way to facilitate a systemic view of bacterial metabolism and allow the development of new therapeutics is to apply constraint-based modelling. Here, we developed a versatile workflow to build high-quality and simulation-ready genome-scale metabolic models. We applied our workflow to create a novel metabolic model forA. baumanniiand validated its predictive capabilities using experimental nutrient utilization and gene essentiality data. Our analysis showed that our modeliACB23LX could recapitulate cellular metabolic phenotypes observed duringin vitroexperiments, while positive biomass production rates were observed and experimentally validated in various growth media. We further defined a minimal set of compounds that increaseA. baumannii‘s cellular biomass and identified putative essential genes with no human counterparts, offering novel candidates for future antimicrobial development. Finally, we assembled and curated the first collection of reconstructions for distinctA. baumanniistrains and analysed their growth characteristics. The presented models are in a standardised and well-curated format, enhancing their usability for multi-strain network reconstruction.
Application of genome-scale models of metabolism and expression to the simulation and design of recombinant organisms
Authors: Oftadeh Omid , Hatzimanikatis Vassily 
Published: September 2023

AbstractThe production of recombinant proteins in a host using synthetic constructs such as plasmids comes at the cost of detrimental effects such as reduced growth, energetic inefficiencies, and other stress responses, collectively known as metabolic stress. Increasing the number of copies of the foreign gene increases the metabolic load but increases the expression of the foreign protein. Thus, there is a trade-off between biomass and product yield in response to changes in heterologous gene copy number. This work proposes a computational method, rETFL (recombinant Expression and Thermodynamic Flux), for analyzing and predicting the responses of recombinant organisms to the introduction of synthetic constructs. rETFL is an extension to the ETFL formulations designed to reconstruct models of metabolism and expression (ME-models). We have illustrated the capabilities of the method in four studies to (i) capture the growth reduction in plasmid-containingE. coliand recombinant protein production; (ii) explore the trade-off between biomass and product yield as plasmid copy number is varied; (iii) predict the emergence of overflow metabolism in recombinantE. coliin agreement with experimental data; and (iv) investigate the individual pathways and enzymes affected by the presence of the plasmid. We anticipate that rETFL will serve as a comprehensive platform for integrating available omics data for recombinant organisms and making context-specific predictions that can help optimize recombinant expression systems for biopharmaceutical production and gene therapy.
A cluster-randomized trial of client and provider-directed financial interventions to align incentives with appropriate case management in retail medicine outlets: results of the TESTsmART Trial in western Kenya
Authors: Laktabai J. , Kimachas E. , Kipkoech J. , Menya D. , Arthur D. , Zhou Y. , Chepkwony T. , Abel L. , Robie E. , Amunga M. , Ambani G. , Woldeghebriel M. , Garber E. , Eze Nwamaka , Mudabai Pamela , Gallis J.A. , Fashanu Chizoba , Saran I. , Woolsey A. , Visser T. , Turner E.L. , O’Meara W. Prudhomme 
Published: September 2023

AbstractACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years. These reductions would not have been possible without publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to their overconsumption. We test an innovative, scalable, and sustainable strategy to target ACT subsidies to clients with a confirmatory diagnosis. We supportead point-of-care malaria testing (mRDTs) in 39 retail medicine outlets in western Kenya and randomized them to three study arms; control arm offering subsidized RDT testing for 0.4USD, client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully subsidized) first-line ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions and resulted in targeting of ACTs to confirmed malaria cases – 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates (RD=0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients (RD=0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain.
Biomarkers for Identification of High-Risk Coronary Artery Plaques in Patients with Suspected Coronary Artery Disease
Authors: Pedersen Gitte , Dahl Jonathan Nørtoft , Rasmussen Laust Dupont , Blavnsfeldt Anne-Birgitte Garm , Böttcher Sidsel Hauge , Böttcher Matias Hauge , Nyegaard Mette , Nissen Louise , Winther Simon 
Published: September 2023

ABSTRACTBackgroundPatients with atherosclerotic plaques containing high-risk features have an increased likelihood of events and a worse prognosis. Whether increased levels of Troponin I (TnI) and C-reactive protein (CRP) are associated with the presence of high-risk coronary atherosclerotic plaques (HRP) is not well described. We assessed the association between 1) TnI and 2) CRP with quantified coronary plaque burden, luminal diameter stenosis, and HRP in patients with low/intermediate pre-test probability of obstructive coronary artery disease (CAD) referred for coronary computed tomography angiography (CCTA).MethodsThe CCTA from 1,615 patients were analyzed using a semiautomatic software for coronary artery plaque characterization. Patients with high TnI (>6 ng/L) and high CRP (>2 mg/L) were identified. Associations of TnI and CRP with plaque burden, stenosis (≥50% luminal diameter stenosis on CCTA), and HRP were investigated.ResultsTnI and CRP were both positively correlated with total plaque burden (TnI rs=0.14, p<0.001; CRP rs=0.08, p<0.001). In multivariate logistic regression analyses, high TnI was associated with stenosis (OR 1.43, 95% confidence interval (CI) 1.03-1.99, p=0.034), the presence of HRP (OR 1.79, 95% CI: 1.17– 2.74, p=0.008), and the subtypes of HRP; low attenuation plaque (OR 1.93, 95% CI: 1.24–3.00, p=0.003), and positive remodeling (OR 1.51, 95% CI: 1.07–2.13, p=0.018). For CRP, only stenosis and napkin ring sign correlated significantly.ConclusionIn patients with suspected CAD, TnI and CRP are associated with HRP features. These findings may suggest that inflammatory and particularly ischemic biomarkers might improve early risk stratification and affect patient management.ClinicalTrials.govidentifier:NCT02264717CLINICAL PERSPECTIVEUsing CCTA, our findings direct the focus toward plaque characteristics rather than just overall plaque burden, outlining that the presence of stenosis and specifically HRPs may be more important in CAD risk evaluation than the amount of atherosclerosis alone. Our findings suggest that biomarkers can help identify patients with HRP features, which previously were shown to increase the risk of future events. TnI may have a place in pre-test evaluation of patients with stable chest pain by introducing biomarkers to a pre-test clinical likelihood model, which may pave the way for more accurate risk stratification and, consequently, better-informed clinical decision-making. Still, trials on biomarker-guided diagnostic testing and medical therapy in de novo stable chest pain patients are warranted.
ReMIND: The Brain Resection Multimodal Imaging Database
Authors: Juvekar Parikshit , Dorent Reuben , Kögl Fryderyk , Torio Erickson , Barr Colton , Rigolo Laura , Galvin Colin , Jowkar Nick , Kazi Anees , Haouchine Nazim , Cheema Harneet , Navab Nassir , Pieper Steve , Wells William M. , Bi Wenya Linda , Golby Alexandra , Frisken Sarah , Kapur Tina 
Published: September 2023

ABSTRACTThe standard of care for brain tumors is maximal safe surgical resection. Neuronavigation augments the surgeon’s ability to achieve this but loses validity as surgery progresses due to brain shift. Moreover, gliomas are often indistinguishable from surrounding healthy brain tissue. Intraoperative magnetic resonance imaging (iMRI) and ultrasound (iUS) help visualize the tumor and brain shift. iUS is faster and easier to incorporate into surgical workflows but offers a lower contrast between tumorous and healthy tissues than iMRI. With the success of data-hungry Artificial Intelligence algorithms in medical image analysis, the benefits of sharing well-curated data cannot be overstated. To this end, we provide the largest publicly available MRI and iUS database of surgically treated brain tumors, including gliomas (n=92), metastases (n=11), and others (n=11). This collection contains 369 preoperative MRI series, 320 3D iUS series, 301 iMRI series, and 356 segmentations collected from 114 consecutive patients at a single institution. This database is expected to help brain shift and image analysis research and neurosurgical training in interpreting iUS and iMRI.
Universal preprocessing of single-cell genomics data
Authors: Booeshaghi A. Sina , Sullivan Delaney K. , Pachter Lior 
Published: September 2023

AbstractWe describe a workflow for preprocessing a wide variety of single-cell genomics data types. The approach is based on parsing of machine-readableseqspecassay specifications to customize inputs forkb-python, which useskallistoandbustoolsto catalog reads, error correct barcodes, and count reads. The universal preprocessing method is implemented in the Python packagecellatlasthat is available for download at:https://github.com/cellatlas/cellatlas/.
A novel vaccine strategy using quick and easy conversion of bacterial pathogens to unnatural amino acid-auxotrophic suicide derivatives
Authors: Nagasawa Yuya , Nakayama Momoko , Kato Yusuke , Ogawa Yohsuke , Aribam Swarmistha Devi , Tsugami Yusaku , Iwata Taketoshi , Mikami Osamu , Sugiyama Aoi , Onishi Megumi , Hayashi Tomohito , Eguchi Masahiro 
Published: September 2023

AbstractWe propose a novel strategy for quick and easy preparation of suicide live vaccine candidates against bacterial pathogens. This method requires only the transformation of one or more plasmids carrying genes encoding for two types of biological devices, an unnatural amino acid (uAA) incorporation system and toxin-antitoxin systems in which translation of the antitoxins requires the uAA incorporation.Escherichia coliBL21-AI laboratory strains carrying the plasmids were viable in the presence of the uAA, whereas the free toxins killed these strains after removal of the uAA. The survival time after uAA removal could be controlled by the choice of uAA incorporation system and toxin-antitoxin systems. Multilayered toxin-antitoxin systems suppressed escape frequency to less than 1 escape per 109generations in the best case. This conditional suicide system also worked inSalmonella entericaandE. coliclinical isolates. TheS. entericavaccine strains were attenuated with a >105-fold lethal dose. Serum IgG response and protection against the parental pathogenic strain were confirmed. In addition, the liveE. colivaccine strain was significantly more immunogenic and provided greater protection than a formalin-inactivated vaccine. The liveE. colivaccine was not detected after inoculation, presumably because the uAA is not present in the host animals or in the natural environment. These results suggest that this strategy provides a novel way to rapidly produce safe and highly immunogenic live bacterial vaccine candidates.SignificanceLive vaccines are the oldest vaccines with a history of more than 200 years. Due to their strong immunogenicity, live vaccines are still an important category of vaccines today. However, the development of live vaccines has been challenging due to the difficulties in achieving a balance between safety and immunogenicity. In recent decades, the frequent emergence of various new and old pathogens at risk of causing pandemics has highlighted the need for rapid vaccine development processes. We have pioneered the use of unnatural amino acids to control gene expression and to conditionally kill host bacteria as a biological containment system. This report highlights a quick and easy conversion of bacterial pathogens into live vaccine candidates using this containment system.
Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells
Authors: Gabele Anna , Sprang Maximilian , Cihan Mert , Dietzen Sarah , Klein Matthias , Harms Gregory , Ziesmann Tanja , Pape Katrin , Wasser Beatrice , Gomez-Zepeda David , Braband Kathrin , Delacher Michael , Lemmermann Niels , Bittner Stefan , Andrade-Navarro Miguel A. , Tenzer Stefan , Bopp Tobias , Distler Ute 
Published: September 2023

ABSTRACTThe transcription factor interferon regulatory factor 4 (IRF4) is crucial for the differentiation and fate determination of pro-inflammatory T helper (Th)17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. To unveil IRF4-driven lineage determination in Th17 and Treg cells, we integrated data derived from affinity-purification and full mass spectrometry-based proteome analysis with chromatin immune precipitation sequencing (ChIP-Seq). This allowed the characterization of subtype-specific molecular programs and the identification of novel, previously unknown IRF4 interactors in the Th17/Treg context, such as RORγt, AHR, IRF8, BACH2, SATB1, and FLI1. Moreover, our data reveal that most of these transcription factors are recruited to IRF composite elements for the regulation of cell type-specific transcriptional programs providing a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.
Song distinguishability predicts reproductive isolation between subspecies of the dark-eyed junco
Authors: Hourihan Sarah , Hudson Emily , Du’Mottuchi Ximena León , Beach Emily , Smith Sydnie , Creanza Nicole 
Published: September 2023

ABSTRACTThe dark-eyed junco (Junco hyemalis) has experienced rapid phenotypic diversification within the last 18,000 years, resulting in several subspecies that reside in partially overlapping regions across North America. These subspecies have distinct plumage and morphology. If members of a subspecies disproportionately mate with one another, we would expect genetic differences to accumulate between the subspecies. In parallel, their learned songs could also accumulate changes. If song is used by individuals to recognize members of their own subspecies during mate selection, which would prevent the production of less fit hybrid offspring between subspecies, then song differences might co-localize with subspecies boundaries. Here, we quantify 10 song features to explore subspecies-level song variation using song recordings from community-science databases. We build a machine learning classifier to measure how accurately the subspecies’ songs can be distinguished from one another. Here, we show that songs of dark-eyed junco subspecies exhibit significant song-feature differences. However, these differences do not necessarily lead to distinguishability between subspecies. Notably, we find that subspecies pairs with adjacent ranges that do not hybridize have much more distinguishable songs, and also more evidence for genetic differentiation, than pairs that are known to hybridize. Thus, song distinguishability appears to have predictive power about which subspecies will hybridize, suggesting that song might play a role in reinforcing certain subspecies boundaries more than others. Finally, we analyze subspecies-level song differences alongside available genetic data and geographic coordinates to characterize the current evolutionary landscape of the dark-eyed junco subspecies complex. We observe geographic signal in the song and genetic data, indicating that individuals who share a range are more likely to share song characteristics and be genetically similar. This study illuminates the existence of subspecies-level song differences in the dark-eyed junco and provides further clarity on the role learned song plays in reinforcing reproductive boundaries between dark-eyed junco subspecies.
maskNMF: A denoise-sparsen-detect approach for extracting neural signals from dense imaging data
Authors: Pasarkar Amol , Kinsella Ian , Zhou Pengcheng , Wu Melissa , Pan Daisong , Fan Jiang Lan , Wang Zhen , Abdeladim Lamiae , Peterka Darcy S. , Adesnik Hillel , Ji Na , Paninski Liam 
Published: September 2023

AbstractA number of calcium imaging methods have been developed to monitor the activity of large populations of neurons. One particularly promising approach, Bessel imaging, captures neural activity from a volume by projecting within the imaged volume onto a single imaging plane, therefore effectively mixing signals and increasing the number of neurons imaged per pixel. These signals must then be computationally demixed to recover the desired neural activity. Unfortunately, currently-available demixing methods can perform poorly in the regime of high imaging density (i.e., many neurons per pixel). In this work we introduce a new pipeline (maskNMF) for demixing dense calcium imaging data.The main idea is to first denoise and temporally sparsen the observed video; this enhances signal strength and reduces spatial overlap significantly. Next we detect neurons in the sparsened video using a neural network trained on a library of neural shapes. These shapes are derived from segmented electron microscopy images input into a Bessel imaging model; therefore no manual selection of “good” neural shapes from the functional data is required here. After cells are detected, we use a constrained non-negative matrix factorization approach to demix the activity, using the detected cells’ shapes to initialize the factorization. We test the resulting pipeline on both simulated and real datasets and find that it is able to achieve accurate demixing on denser data than was previously feasible, therefore enabling faithful imaging of larger neural populations. The method also provides good results on more “standard” two-photon imaging data. Finally, because much of the pipeline operates on a significantly compressed version of the raw data and is highly parallelizable, the algorithm is fast, processing large datasets faster than real time.
Differential effects of acute and prolonged morphine withdrawal on motivational and goal-directed control over reward-seeking behavior
Authors: Halbout Briac , Hutson Collin , Agrawal Stuti , Springs Zachary A. , Ostlund Sean B. 
Published: September 2023

AbstractOpioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational, and cognitive processes involved in regulating the pursuit and consumption of natural food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically-driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened emotional reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal also disrupted their ability to exert flexible goal-directed control over their reward-seeking behavior. Specifically, morphine-withdrawn rats displayed insensitivity to reward devaluation both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case insensitivity to reward devaluation was only observed in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.