bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of Data Acquisition and Phase Estimation for Quantitative Susceptibility Mapping with a Rotating-Tube Phantom
Authors: Keenan Kathryn E. , Berman Ben P. , Carnicka Slavka , Russek Stephen E. , Wang Wen-Tung , Butman John A. , Pham Dzung L. , Dagher Joseph 
Published: July 2021

AbstractPurposeQuantitative Susceptibility Mapping (QSM) is an MRI tool with the potential to reveal pathological changes from magnetic susceptibility measurements. Before phase data can be used to recover susceptibility (Δχ), the QSM process begins with two steps: data acquisition and phase estimation. We assess the performance of these steps, when applied without user intervention, on several variations of a phantom imaging task.ApproachWe used a rotating-tube phantom with five tubes ranging from Δχ=0.05 ppm to Δχ=0.336 ppm. MRI data was acquired at nine angles of rotation for four different pulse sequences. The images were processed by 10 phase estimation algorithms including Laplacian, region-growing, branch-cut, temporal unwrapping and maximum-likelihood methods. We analyzed errors between measured and expected phase using the probability mass function and Cumulative Distribution Function.ResultsRepeatable acquisition and estimation methods were identified based on the probability of relative phase errors. For single-echo GRE and segmented EPI sequences, a region-growing method was most reliable with Pr(relative error<0.1)=0.95 and 0.90 respectively. For multi-echo sequences, a Maximum-Likelihood method was most reliable with Pr(relative error<0.1)=0.97. The most repeatable multi-echo methods outperformed the most repeatable single-echo methods.ConclusionsWe found a wide range of repeatability and reproducibility for off-the-shelf MRI acquisition and phase estimation approaches. The error was dominated in many cases by spatially discontinuous phase unwrapping errors. Any post-processing applied on erroneous phase estimates, such as QSM’s background field removal and dipole inversion, would suffer from error propagation. Our paradigm identifies methods that yield consistent and accurate phase estimates that would ultimately yield consistent and accurate Δχ estimates.
A survey of optimal strategy for signature-based drug repositioning and an application to liver cancer
Authors: Yang Chen , Chen Mengnuo , Wang Siying , Qian Ruolan , Huang Xiaowen , Wang Jun , Liu Zhicheng , Qin Wenxin , Wang Cun , Hang Hualian , Wang Hui 
Published: July 2021

AbstractPharmacologic perturbation projects, such as Connectivity Map (CMap) and Library of Integrated Network-based Cellular Signatures (LINCS), have produced many perturbed expression data, providing enormous opportunities for computational therapeutic discovery. However, currently there is no consensus on which methodologies and parameters are the most optimal to conduct such analysis. Aiming to fill this gap, we developed new benchmarking standards for quantitatively estimating drug retrieval performance. Investigations of potential factors influencing drug retrieval were conducted based on these standards. As a result, we determined an optimal strategy for LINCS data-based therapeutic discovery. With this approach, we further identified new therapeutics for liver cancer of which the current treatment modalities remain imperfect. Both computational and experimental results demonstrated homoharringtonine (HHT) could be a promising anti-liver cancer agent. In summary, our findings will not only impact the future applications of LINCS data but also offer new opportunities for therapeutic intervention for liver cancer.
Small Vessel Diseases: 3D Characteristics of the Vasculature and White Matter
Authors: Saito Rie , Tainaka Kazuki , Nozaki Hiroaki , Uemura Masahiro , Toyoshima Yasuko , Suzuki Masahiro , Tanaka Masaharu , Hasegawa Arika , Abe Takashi , Sato Aki , Hashidate Hideki , Igarashi Shuichi , Koike Ryoko , Ueda Akihiko , Ueda Mitsuharu , Ando Yukio , Akazawa Kohei , Onodera Osamu , Kakita Akiyoshi 
Published: July 2021

AbstractCerebral small vessel disease (SVD) is associated with white matter hyperintensities (WMHs), thereby contributing to vascular dementia and movement disorder. However, the pathomechanisms responsible for WMH-related small vessel degeneration remain poorly understood due to the technical limitations of current methods. The aim of this study was to clarify the 2- and 3-dimensional (2D and 3D) pathological features of small vessels and white matter (WM) in the brains of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), HTRA1-autosomal dominant disease (HTRA1-AD) and sporadic SVD (sSVD). From a cohort of 86 consecutive autopsied patients with SVDs, we retrieved those with genetically confirmed CADASIL and HTRA1-AD (three and three, respectively), and four with sSVD. We quantitatively evaluated WM and vascular changes in the frontal portion of the centrum semiovale and temporal lobe using conventional 2D and chemically cleared 3D analytical methods with light-sheet fluorescence microscopy. Quantitatively, the WM pathology, including the density of myelin, axons and gliosis, was most severe in CADASIL, but unexpectedly sSVD was second in order of severity, followed by HTRA1-AD. The density of clasmatodendrocytes, known to be irreversibly injured astrocytes, was considerably highest in HTRA1-AD. The vascular pathology, including arteriole and capillary sclerosis and the extent of the perivascular space, was most severe in CADASIL, whereas the density of smooth muscle actin (SMA) positivity was most decreased in HTRA1-AD. 3D immunohistochemistry for SMA demonstrated two distinct patterns of SMA loss within the vessels: (1) CADASIL and sSVD: diffuse loss, being prominent in small branches, (2) HTRA1-AD: selective loss in main branches. Overall, the extent of WM and vascular degeneration is most severe in CADASIL, whereas SMA loss is most evident in HTRA1-AD. These differences in the size and distribution of affected vessels may be related to the heterogeneous WM pathology and underlying pathomechanisms of SVD.
Antimicrobial activity of a repurposed harmine-derived compound on extensively drug-resistantAcinetobacter baumanniiclinical isolates
Authors: Breine Anke , Van Gysel Mégane , Elsocht Mathias , Whiteway Clémence , Philippe Chantal , Quinet Théo , Valcek Adam , Wouters Johan , Ballet Steven , Van der Henst Charles 
Published: July 2021

SynopsisObjectivesThe spread of antibiotic resistant bacteria is an important threat for human healthcare.Acinetobacter baumanniibacteria impose one of the major issues, as multidrug- to pandrug-resistant strains have been found, rendering some infections untreatable. In addition,A. baumanniiis a champion in surviving in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found inA. baumanniiisolates, the search for new antibacterials is challenging. Here, we screened a compound library to identify compounds active against recent isolates ofA. baumanniibacteria.MethodsA repurposing drug screen was undertaken to identifyA. baumanniigrowth inhibitors. One hit was further characterized by determining its IC50and testing its activity on 43 recent clinicalA. baumanniiisolates, amongst which 40 are extensively drug- and carbapenem-resistant strains.ResultsThe repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proved to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC50of 48.23 µM. In addition, HDC1 impairs growth of all 43 recent clinicalA. baumanniiisolates.ConclusionsWe identified a compound with inhibitory activity on all tested, extensively drug-resistant clinicalA. baumanniiisolates.
Deciphering the tumor-specific immunopeptidome in vivo with genetically engineered mouse models
Authors: Jaeger Alex M. , Stopfer Lauren E. , Sanders Emma A. , Sandel Demi A. , Freed-Pastor William A. , Rideout William M. , Naranjo Santiago , Fessenden Tim , Winter Peter S. , Kohn Ryan E. , Schenkel Jason , Shanahan Sean-Luc , Shalek Alex K. , Spranger Stefani , White Forest M. , Jacks Tyler 
Published: July 2021

AbstractEffective immunosurveillance of cancer requires the presentation of peptide antigens on major histocompatibility complex Class I (MHC-I). Recent developments in proteomics have improved the identification of peptides that are naturally presented by MHC-I, collectively known as the “immunopeptidome”. Current approaches to profile tumor immunopeptidomes have been limited to in vitro investigation, which fails to capture the in vivo repertoire of MHC-I peptides, or bulk tumor lysates, which are obscured by the lack of tumor-specific MHC-I isolation. To overcome these limitations, we report here the engineering of a Cre recombinase-inducible affinity tag into the endogenous mouse MHC-I gene and targeting of this allele to the KrasLSL-G12D/+; p53fl/fl (KP) mouse model (KP; KbStrep). This novel approach has allowed us to isolate tumor-specific MHC-I peptides from autochthonous pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) in vivo. With this powerful analytical tool, we were able to profile the evolution of the LUAD immunopeptidome through tumor progression and show that in vivo MHC-I presentation is shaped by post-translational mechanisms. We also uncovered novel, putative LUAD tumor associated antigens (TAAs). Many peptides that were recurrently presented in vivo exhibited very low expression of the cognate mRNA, provoking reconsideration of antigen prediction pipelines that triage peptides according to transcript abundance. Beyond cancer, the KbStrep allele is compatible with a broad range of Cre-driver lines to explore antigen presentation in vivo in the pursuit of understanding basic immunology, infectious disease, and autoimmunity.
Sleep deprivation reduces the density of individual spine subtypes in a branch-specific fashion in CA1 neurons
Authors: Bolsius Youri G , Meerlo Peter , Kas Martien J , Abel Ted , Havekes Robbert 
Published: July 2021

SummarySleep deprivation has a negative impact on hippocampus-dependent memory, which are thought to depend on cellular plasticity. We previously found that five hours of sleep deprivation robustly decreases dendritic spine density in the CA1 area of the hippocampus in adult male mice. However, recent work by others suggests that sleep deprivation increases the density of certain spine types on specific dendritic branches. Based on these recent findings and our previous work, we conducted a more in-depth analysis of different spine types on branches 1, 2 and 5 of both apical and basal dendrites to assess whether five hours of sleep deprivation may have previously unrecognized spine-type and branch-specific effects. This analysis shows no spine-type specific changes on branch 1 and 2 of apical dendrites after sleep deprivation. In contrast, sleep deprivation decreases the number of mushroom and branched spines on branch 5. Likewise, sleep deprivation reduces thin, mushroom, and filopodia spine density on branch 5 of the basal dendrites, without affecting spines on branch 1 and 2. Our findings indicate that sleep deprivation leads to local branch-specific reduction in the density of individual spine types, and that local effects might not reflect the overall impact of sleep deprivation on CA1 structural plasticity. Moreover, our analysis underscores that focusing on a subset of dendritic branches may lead to potential misinterpretation of the overall impact of in this case sleep deprivation on structural plasticity.
The MpsB protein contributes to both the toxicity and immune evasion capacity of Staphylococcus aureus
Authors: Douglas Edward J.A. , Duggan Seána , Brignoli Tarcisio , Massey Ruth C. 
Published: July 2021

AbstractUnderstanding the role specific bacterial factors play in the development of severe disease in humans is critical if new approaches to tackle such infections are to be developed. In this study we focus on genes we have found to be associated with patient outcome following bacteraemia caused by the major human pathogen Staphylococcus aureus. By examining the contribution these genes make to the ability of the bacteria to survive exposure to the antibacterial factors found in serum, we identify three novel serum resistance associated genes, mdeA, mpsB and yycH. Detailed analysis of an MpsB mutant supports its previous association with the slow growing SCV phenotype of S. aureus, and we demonstrate that the effect this mutation has on membrane potential prevents the activation of the Agr quorum sensing system, and as a consequence the mutant bacteria do not produce cytolytic toxins. Given the importance of both toxin production and immune evasion to the ability of S. aureus to cause disease, we believe these findings explain the role of the mpsB gene as a mortality-associate locus during human disease.
A Comprehensive Overview of the Physical Health of the Adolescent Brain Cognitive Development Study (ABCD) Cohort at Baseline
Authors: Palmer Clare E. , Sheth Chandni , Marshall Andrew T. , Adise Shana , Baker Fiona C. , Chang Linda , Clark Duncan B. , Dagher Rada K. , Dowling Gayathri J. , Gonzalez Marybel R. , Haist Frank , Herting Megan M. , Huber Rebekah S. , Jernigan Terry L. , LeBlanc Kimberly , Lee Karen , Lisdahl Krista M. , Neigh Gretchen , Patterson Megan W. , Renshaw Perry , Rhee Kyung E. , Tapert Susan , Thompson Wesley K. , Uban Kristina , Sowell Elizabeth R. , Yurgelun-Todd Deborah 
Published: July 2021

AbstractPhysical health in childhood is crucial for neurobiological as well as overall development, and can shape long-term outcomes into adulthood. The landmark, longitudinal Adolescent Brain Cognitive Development StudySM (ABCD study®), was designed to investigate brain development and health in almost 12,000 youth who were recruited when they were 9-10 years old and will be followed through adolescence and early adulthood. The overall goal of this paper is to provide descriptive analyses of physical health measures in the ABCD study at baseline, including but not limited to sleep, physical activity and sports involvement, and body mass index, and how these measures vary across demographic groups. This paper outlines how the physical health of the ABCD sample corresponds with that of the US population and highlights important avenues for health disparity research. This manuscript will provide important information for ABCD users and help guide analyses investigating physical health as it pertains to adolescent and young adult development.
Long Term Study of Motivational and Cognitive Effects of Low-intensity Focused Ultrasound Neuromodulation in the Dorsal Striatum of Nonhuman Primates
Authors: Munoz F , Meaney A , Gross A , Liu K , Pouliopoulos AN , Liu D , Konofagou EE , Ferrera VP 
Published: July 2021

AbstractNoninvasive brain stimulation using focused ultrasound (FUS) has many potential applications as a research and clinical tool, including incorporation into neural prosthetics for cognitive rehabilitation. To develop this technology, it is necessary to evaluate the safety and efficacy of FUS neuromodulation for specific brain targets and cognitive functions. It is also important to test whether repeated long-term application of FUS to deep brain targets improves or degrades behavioral and cognitive function. To this end, we investigated the effects of FUS in the dorsal striatum of nonhuman primates (NHP) performing a visual-motor decision-making task for small or large rewards. Over the course of 2 years, we performed 129 and 147 FUS applications, respectively, in two NHP. FUS (0.5 MHz @ 0.2 – 0.8 MPa) was applied to the putamen and caudate in both hemispheres to evaluate the effects on movement accuracy, motivation, decision accuracy, and response time. Sonicating the caudate or the putamen unilaterally resulted in modest but statistically significant improvements in motivation and decision accuracy, but at the cost of slower reaction times. The effects were dose (i.e., FUS pressure) and reward dependent. There was no effect on reaching accuracy, nor was there long-term behavioral impairment or neurological trauma evident on T1-weighted, T2-weighted, or susceptibility-weighted MRI scans. Sonication also resulted in significant changes in resting state functional connectivity between the caudate and multiple cortical regions. The results indicate that applying FUS to the dorsal striatum can positively impact the motivational and cognitive aspects of decision making. The capability of FUS to improve motivation and cognition in NHPs points to its therapeutic potential in treating a wide variety of human neural diseases, and warrants further development as a novel technique for non-invasive deep brain stimulation.
Classic genome-wide association methods are unlikely to identify causal variants in strongly clonal microbial populations
Authors: Chen Peter E. , Shapiro B. Jesse 
Published: July 2021

AbstractSince the advent of genome-wide association studies (GWAS) in human genomes, an increasing sophistication of methods has been developed for more robust association detection. Currently, the backbone of human GWAS approaches is allele-counting-based methods where the signal of association is derived from alleles that are identical-by-state. Borrowing this approach from human GWAS, allele-counting-based methods have been popularized in microbial GWAS, notably the generalized linear model using either dimension reduction for fixed covariates and/or a genetic relationship matrix as a random effect in a mixed model to control for population stratification. In this work, we show how the effects of linkage disequilibrium (LD) can potentially obscure true-positive genotype-phenotype associations (i.e., genetic variants causally associated with the phenotype of interest) and also lead to unacceptably high rates of false-positive associations when applying these classical approaches to GWAS in weakly recombining microbial genomes. We developed a GWAS method called POUTINE (https://github.com/Peter-Two-Point-O/POUTINE), which relies on homoplastic mutation to both clarify the source of putative causal variants and reduce likely false-positive associations compared to traditional allele counting methods. Using datasets of M. tuberculosis genomes and antibiotic-resistance phenotypes, we show that LD can in fact render all association signals from allele counting methods to be fully indistinguishable from hundreds to thousands of sites scattered across an entire genome. These classic GWAS methods thus fail to pinpoint likely causal genotype-phenotype associations and separate them from background noise, even after applying methods to correct for population structure. We therefore urge caution when utilizing classical approaches, particularly in populations that are strongly clonal.
Antimicrobial activity of flavonoids glycosides and pyrrolizidine alkaloids from propolis of Scaptotrigona aff. postica
Authors: Cantero TM , da Silva Junior PI , Negri Giuseppina , Nascimento RM , Mendonça RZ 
Published: July 2021

AbstractStingless bees belonging to the Meliponinae subfamily, are known as meliponines. Scaptotrigona affinis postica Latreille, 1807 from northeast of Brazil is popularly known as ‘tubi’ in Maranhão State. Scaptotrigona, which is widely distributed in neotropical regions, includes species that build their hives in pre-existing cavities. Flavones di-C-glycosides, and the pyrrolizidine alkaloid 7-(3-methoxy-2-methylbutyryl)-9-echimidinylretronecine were reported previously in propolis from S. postica. Fractions 40 AEP and 40 MEP from ethanolic extract were analyzed by LC-MS. The chromatographic profile of fractions 40 AEP and 40 MEP revealed the presence of many pyrrolizidine alkaloids, among them, lithosenine (14), lithosenine arabinoside (19), 7-angeloyl-9-(2,3- dihydroxybutyryl) retronecine (1), 7-(2-methylbutyryl) retronecine (3), 9-sarracinoylretronecine (13) and viridinatine (8),besides the flavonoids schaftoside (15), aromadendrin-7-O-methyl ether (12), 7-methoxy-5,6,3’,4’,5’,6’-hexahydroxy-flavone-3-O-glucuronide (11), mangiferin (10) and 3-O-methyl mangiferin (17). Fractions 40 AEP and 40 MEP showed antimicrobial activity against Gram negative bacteria, including Escherichia coli D31-streptomycin resistant. Cell viability was expressed in terms of the relative absorbance of treated and untreated cells (control). There was no statistical difference between treated and untreated cells.
A novel α/β T-cell subpopulation defined by recognition of EPCR
Authors: Erausquin Elena , Morán-Garrido María , Saiz Jorge , Barbas Coral , Dichiara-Rodríguez Gilda , Ramírez Natalia , López-Sagaseta Jacinto 
Published: July 2021

AbstractT-cell self-recognition of antigen presenting molecules is led by antigen-dependent or independent mechanisms. The endothelial protein C receptor (EPCR) shares remarkable similarity with CD1d, including a lipid binding cavity. We have identified EPCR-specific α/β T-cells in the peripheral blood of healthy donors. The average frequency in the CD3+ leukocyte pool is comparable to other autoreactive T-cell subsets that specifically bind MHC-like receptors. Alteration of the EPCR lipid cargo, revealed by X-ray diffraction studies, points to a prevalent, yet not exclusive, lipid-independent self-recognition. In addition, we solve the EPCR lipidome, and detect species not yet described as EPCR ligands. These studies report, for the first time, novel recognition by circulating α/β T-cells and provide grounds for EPCR and lipid mediated T-cell restriction.
Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells
Authors: Shi Yuhao , Dolan Melissa , Mastri Michalis , Mckenery Amber , Hill James W. , Dommer Adam , Benzekry Sebastien , Long Mark , Abrams Scott , Puzanov Igor , Ebos John M.L. 
Published: July 2021

AbstractBackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) – a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance.MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression.ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFNα or IFNβ). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cellsex vivowhile diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplantedin vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling.In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing thatin vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients.ConclusionsThese results suggest that prolongedin vivoPD-L1 inhibition can ‘rewire’ type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.