bluuebunny/crossref_metadata_2025_split huggingface dataset:
Linkage of a plasma zinc signature and impaired insulin receptor activation: Implications for the mechanism of type 2 diabetes mellitus
Authors: Prabhakar Shashidhar M. 
Published: December 2019

AbstractType 2 diabetes mellitus (T2DM) is characterized by decreased plasma zinc levels and hyperzincuria, yet the underlying cause of these zinc disturbances is unknown. In this study, we compared postprandial plasma zinc levels in samples from T2DM and healthy control subjects to determine whether zinc is associated with a different set of proteins. We found that in T2DM a considerable amount of zinc remained following albumin/Ig depletion. A discrepancy in total amount of zinc in the remaining set of zinc-associated proteins identified and estimated by protein analysis as alpha-2 macroglobulin (A2M), and in T2DM alone some bacterial proteinases as well, indicated that the likely source of this discrepancy was from bacterial zinc proteinases trapped by A2M that obscured the high levels of these proteinases. Furthermore, an insulin receptor assay examined whether activated A2M (A2MFF) affected insulin receptor activation. The results showed a significant decrease in insulin receptor activation following repeated treatments with A2MFF but not after a single treatment with A2MFF. Our findings suggest that in T2DM, A2MFF likely arises from the trapping of zinc-dependent bacterial proteinases and impairs insulin receptor activation from a prolonged presence, which may result in a “receptor-protective” effect manifested as insulin resistance.
The CDK8 inhibitor DCA promotes a tolerogenic chemical immunophenotype in CD4+ T cells via a novel CDK8-GATA3-FOXP3 pathway
Authors: Arnett Azlann , Moo Keagan G , Flynn Kaitlin J , Sundberg Thomas B , Johannessen Liv , Shamji Alykhan F , Gray Nathanael S , Decker Thomas , Zheng Ye , Gersuk Vivian H , Levy David E , Marié Isabelle J , Rahman Ziaur S , Linsley Peter S , Xavier Ramnik J , Khor Bernard 
Published: December 2019

AbstractImmune health requires innate and adaptive immune cells to engage precisely balanced pro- and anti-inflammatory forces. We employ the concept of chemical immunophenotypes to classify small molecules functionally or mechanistically according to their patterns of effects on primary innate and adaptive immune cells. The high-specificity, low-toxicity cyclin dependent kinase 8 (CDK8) inhibitor DCA exerts a distinct tolerogenic profile in both innate and adaptive immune cells. DCA promotes Treg and Th2 differentiation, while inhibiting Th1 and Th17 differentiation, in both murine and human cells. This unique chemical immunophenotype led to mechanistic studies showing that DCA promotes Treg differentiation in part by regulating a previously undescribed CDK8-GATA3-FOXP3 pathway that regulates early pathways of Foxp3 expression. These results highlight previously unappreciated links between Treg and Th2 differentiation and extend our understanding of the transcription factors that regulate Treg differentiation and their temporal sequencing. These findings have significant implications for future mechanistic and translational studies of CDK8 and CDK8 inhibitors.
Improving source modeling of auditory steady-state responses with frequency-specific brain maps
Authors: Farahani Ehsan Darestani , Wouters Jan , van Wieringen Astrid 
Published: December 2019

AbstractAuditory steady-state responses (ASSRs) are evoked brain responses to modulated or repetitive acoustic stimuli. Due to a wide range of clinical and research applications, there is a great (clinical) interest to investigate the underlying neural generators of ASSRs. The cortical sources of ASSRs mostly are located in the auditory cortex (AC), although some studies avoiding prior assumptions regarding the number and location of the sources have also reported activity of sources outside of the AC. However, little is known about the number and location of these sources. In this study, we present a novel extension to minimum-norm imaging (MNI) which facilitates ASSR source reconstruction and provides a comprehensive and consistent picture of sources in response to low- as well as high modulation frequencies, monaurally presented to the left and right ears.Results demonstrate that the proposed MNI approach is successful in reconstructing sources located both within (primary) and outside (non-primary) of the AC. The locations of the non-primary sources are consistent with the literature. Primary sources are detected in every experimental condition, thereby corroborating the robustness of the approach. Moreover, we show that the MNI approach is capable of reconstructing the subcortical activities of ASSRs. In summary, the results indicate that the MNI approach outperforms the previously used method of group-ICA, in terms of detection of sources in the AC, reconstructing the subcortical activities and reducing computational load.
Mining Archive.org’s Twitter Stream Grab for Pharmacovigilance Research Gold
Authors: Tekumalla Ramya , Asl Javad Rafiei , Banda Juan M. 
Published: December 2019

AbstractIn the last few years Twitter has become an important resource for the identification of Adverse Drug Reactions (ADRs), monitoring flu trends, and other pharmacovigilance and general research applications. Most researchers spend their time crawling Twitter, buying expensive pre-mined datasets, or tediously and slowly building datasets using the limited Twitter API. However, there are a large number of datasets that are publicly available to researchers which are underutilized or unused. In this work, we demonstrate how we mined over 9.4 billion Tweets from archive.org’s Twitter stream grab using a drug-term dictionary and plenty of computing power. Knowing that not everything that shines is gold, we used pre-existing drug-related datasets to build machine learning models to filter our findings for relevance. In this work we present our methodology and the 3,346,758 identified tweets for public use in future research.
CD42b immunostaining as a marker for placental fibrinoid in normal pregnancy and complications
Authors: Zhang Peilin 
Published: December 2019

AbstractBackgroundThere are two types of the fibrinoid deposits within the placenta, and the nature of these fibrinoid are poorly understood in clinical setting.DesignFibrinoid deposits within normal pregnancy and the pregnancy related complications are studied using the routine hematoxylin and eosin stain and immunostaining for CD42b as a marker for platelet aggregates and fibrin.ResultsFibrin-like fibrinoid is associated with platelet aggregates characterized by the positive immunostaining for CD42b and coagulatory cascade activation with blood flow changes in the circulation and intervillous spaces. Matrix-type fibrinoid is not associated with platelet aggregates and coagulation and its pathogenesis is unknown.ConclusionFibrinoid deposits within the intervillous spaces are mostly from maternal circulation and these fibrinoids are likely the result of the laminar blood flow change at specific anatomic locations, leading to activation of coagulatory cascade. The pathogenesis of matrix-like fibrinoid is unclear. CD42b immunostaining is helpful in difficult cases.
Interrogating mechanisms of ssDNA binding to a viral HUH-endonuclease by alanine scanning of an electrostatic patch
Authors: Nelson Andrew , Tompkins Kassidy , Ramirez Maria Paz , Gordon Wendy R. 
Published: December 2019

AbstractHUH endonucleases (dubbed “HUH-tags”) are small protein domains capable of forming covalent adducts with ssDNA in a sequence-specific manner. Because viral HUH-tags are relatively small, react quickly, and require no chemical modifications to their ssDNA substrate, they have great value as protein fusion tags in biotechnologies ranging from genetic engineering to single-molecule studies. One of the greatest assets of these tags is sequence-specificity to their unique, native Ori sequence in vivo, introducing the possibility of using multiple HUH-tags in multiplexed “one-pot” reactions. However, their mechanism of ssDNA sequence binding and specificity is poorly understood, and there is noted cross-reactivity between tags of closely related species. In order to understand the mechanism of ssDNA binding, we performed an alanine scan along a positively-charged patch of one such HUH-tag, replication-associated protein from Wheat Dwarf Virus (WDV Rep), and characterized the enzymatic activity in both the rate and extent of the reaction. In molecular beacon Stopped-Flow experiments, single point mutants of WDV showed a more than 60% decrease in reaction rate constant, and gel shift assays showed an almost complete lack of activity for some variants for single nucleotide ssDNA substitutions. In all, these findings help allow us to highlight key interactions in WDV-ssDNA binding, and we gain further insight into potential rational engineering of HUH-endonucleases to bind desired sequences of DNA.
Direct therapeutic targeting of SWI/SNF induces epigenetic reprogramming and durable tumor regression in rhabdoid tumor
Authors: Chasse Maggie H. , Johnson Benjamin K. , Boguslawski Elissa A. , Sorensen Katie M. , Heo Lyong , Madaj Zachary B. , Beddows Ian , Foxa Gabrielle E. , Kitchen-Goosen Susan M. , Williams Bart O. , Triche Timothy J. , Grohar Patrick J. 
Published: December 2019

ABSTRACTPurposeRhabdoid tumor is a pediatric cancer characterized by the biallelic inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. SMARCB1 inactivation leads to SWI/SNF redistribution to favor a proliferative dedifferentiated cellular state. Although this deletion is the known oncogenic driver, SWI/SNF therapeutic targeting remains a challenge.Experimental DesignWe define a novel epigenetic mechanism for mithramycin using biochemical fractionation, chromatin immunoprecipitation sequencing (ChIP-seq), and a dual spike-in assay for transposase accessible chromatin sequencing (ATAC-seq). We correlate epigenetic reprogramming with changes with chromatin A/B compartments and promoter accessibility with chromHMM models and RNA-seq. Finally, we demonstrate durable, marked tumor response in an intramuscular rhabdoid tumor xenograft model.ResultsHere we show mithramycin and a second-generation analogue EC8042 evict mutated SWI/SNF from chromatin and are effective in rhabdoid tumor. SWI/SNF blockade triggers chromatin compartment remodeling and promoter reprogramming leading to differentiation and amplification of H3K27me3, the catalytic mark of PRC2. Treatment of rhabdoid rumor xenografts with EC8042 leads to marked, durable tumor regression and differentiation of the tumor tissue into benign mesenchymal tissue, including de novo bone formation.ConclusionOverall, this study identifies a novel therapeutic candidate for rhabdoid tumor and an approach that may be applicable to the 20% of cancers characterized by mutated SWI/SNF.STATEMENT OF TRANSLATIONAL RELEVANCEThere is a tremendous need for novel therapeutic approaches for rhabdoid tumor and the more than 20% of human cancers characterized by dysregulation of the SWI/SNF chromatin remodeling complex. While approaches to target associated complexes, such as PRC2, known to be influenced by dysregulated SWI/SNF are currently being evaluated in the clinic, the direct therapeutic targeting of SWI/SNF has not been explored. Here we identify an inhibitor of SWI/SNF and thoroughly explore the therapeutic development of this compound from a mechanistic and translational perspective thus providing insight into the targeting of this complex as well as a dose, schedule, and biomarker of target inhibition that is immediately clinically translatable.
Transient disruption of the inferior parietal lobule impairs action mindreading
Authors: Patri Jean-François , Koul Atesh , Soriano Marco , Valente Martina , Avenanti Alessio , Cavallo Andrea , Panzeri Stefano , Becchio Cristina 
Published: December 2019

AbstractAlthough it is well established that fronto-parietal regions are active during action observation, whether they play a causal role in the ability to “mindread” others’ actions remains controversial. In experiments reported here, we combined offline continuous theta-burst stimulation (cTBS) with computational modeling to reveal single-trial computations in the inferior parietal lobule (IPL) and inferior frontal gyrus (IFG). Participants received cTBS over the left IPL and IFG, in separate sessions, before completing an intention discrimination task or a kinematic discrimination task unrelated to intention. We found that transient disruption of activity of the IPL, but not the IFG, specifically impaired the observer’s ability to judge intention from movement kinematics. Kinematic discrimination unrelated to intention, in contrast, was largely unaffected. Computational analyses revealed that IPL cTBS did not impair the ability to ‘see’ changes in movement kinematics, nor did it alter the weight given to informative versus non-informative kinematic features. Rather, it selectively impaired the ability to link variations in informative features to the correct intention. These results provide the first causal evidence that IPL maps kinematics to intentions.
Beta 1 Integrin Signaling Mediates Pancreatic Ductal Adenocarcinoma Resistance to MEK Inhibition
Authors: Brannon Arthur , Drouillard Donovan , Steele Nina , Sutherland Shadae , Crawford Howard C. , di Magliano Marina Pasca 
Published: December 2019

AbstractPancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. The high mortality rate can be attributed to multiple factors, including late diagnosis and lack of effective therapies.KRASis the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer using primary mouse and human 3D organoid cultures. We optimized the culture of pancreatic tumor organoids that utilized Matrigel as a basement membrane mimetic, facilitating polarized growth. Pancreatic tumor organoids recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the organoids with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.
Systemic Brain Tumor Delivery of Synthetic Protein Nanoparticles for Glioblastoma Therapy
Authors: Gregory Jason V. , Kadiyala Padma , Doherty Robert , Cadena Melissa , Habeel Samer , Ruoslahti Erkki , Lowenstein Pedro R. , Castro Maria G. , Lahann Joerg 
Published: December 2019

AbstractGlioblastoma multiforme (GBM), the most aggressive form of brain cancer, has witnessed very little clinical progress over the last decades, in parts, due to the absence of effective drug delivery strategies. Intravenous injection is the least invasive delivery route to the brain, but has been severely limited by the blood-brain barrier (BBB). Inspired by the capacity of natural proteins and viral particulates to cross the BBB, we engineered a synthetic protein nanoparticle (SPNP) based on polymerized human serum albumin (HSA) equipped with the cell-penetrating peptide iRGD. SPNPs containing siRNA against Signal Transducer and Activation of Transcription 3 factor (STAT3i) result inin vitroandin vivodownregulation of STAT3, a central hub associated with GBM progression. When combined with the standard of care, ionized radiation, STAT3iSPNPs result in tumor regression and long-term survival in 87.5% of GBM bearing mice and primes the immune system to develop anti-GBM immunological memory.
Neural Fragility as an EEG Marker of the Seizure Onset Zone
Authors: Li Adam , Huynh Chester , Fitzgerald Zachary , Cajigas Iahn , Brusko Damian , Jagid Jonathan , Claudio Angel , Kanner Andres , Hopp Jennifer , Chen Stephanie , Haagensen Jennifer , Johnson Emily , Anderson William , Crone Nathan , Inati Sara , Zaghloul Kareem , Bulacio Juan , Gonzalez-Martinez Jorge , Sarma Sridevi V. 
Published: December 2019

AbstractOver 15 million epilepsy patients worldwide do not respond to drugs. Successful surgical treatment requires complete removal, or disconnection of the seizure onset zone (SOZ), brain region(s) where seizures originate. Unfortunately, surgical success rates vary between 30%-70% because no clinically validated biological marker of the SOZ exists. We develop and retrospectively validate a new EEG marker - neural fragility - in a retrospective analysis of 91 patients by using neural fragility of the annotated SOZ as a metric to predict surgical outcomes. Fragility predicts 43/47 surgical failures with an overall prediction accuracy of 76%, compared to the accuracy of clinicians being 48% (successful outcomes). In failed outcomes, we identify fragile regions that were untreated. When compared to 20 EEG features proposed as SOZ markers, fragility outperformed in predictive power and interpretability suggesting neural fragility as an EEG biomarker of the SOZ.
QAlign: Aligning nanopore reads accurately using current-level modeling
Authors: Joshi Dhaivat , Mao Shunfu , Kannan Sreeram , Diggavi Suhas 
Published: December 2019

AbstractMotivationEfficient and accurate alignment of DNA / RNA sequence reads to each other or to a reference genome / transcriptome is an important problem in genomic analysis. Nanopore sequencing has emerged as a major sequencing technology and many long-read aligners have been designed for aligning nanopore reads. However, the high error rate makes accurate and efficient alignment difficult. Utilizing the noise and error characteristics inherent in the sequencing process properly can play a vital role in constructing a robust aligner. In this paper, we design QAlign, a pre-processor that can be used with any long-read aligner for aligning long reads to a genome / transcriptome or to other long reads. The key idea in QAlign is to convert the nucleotide reads into discretized current levels that capture the error modes of the nanopore sequencer before running it through a sequence aligner.ResultsWe show that QAlign is able to improve alignment rates from around 80% up to 90% with nanopore reads when aligning to the genome. We also show that QAlign improves the average overlap quality by 9.2%, 2.5% and 10.8% in three real datasets for read-to-read alignment. Read-to-transcriptome alignment rates are improved from 51.6% to 75.4% and 82.6% to 90% in two real datasets.Availabilityhttps://github.com/joshidhaivat/QAlign.git
WHISKiT Physics: A three-dimensional mechanical model of the rat vibrissal array
Authors: Zweifel Nadina O. , Bush Nicholas E. , Abraham Ian , Murphey Todd D. , Hartmann Mitra J.Z. 
Published: December 2019

AbstractRodents tactually explore the environment using ~62 whiskers (vibrissae), regularly arranged in arrays on both sides of the face. The rat vibrissal system is one of the most commonly used models to study how the brain encodes and processes somatosensory information. To date, however, researchers have been unable to quantify the mechanosensory input at the base of each whisker, because the field lacks accurate models of three-dimensional whisker dynamics. To close this gap, we developed WHISKiT Physics, a simulation framework that incorporates realistic morphology of the full rat whisker array to predict time-varying mechanical signals for all whiskers. The dynamics of single whiskers were optimized based on experimental data, and then validated against free tip oscillations and the dynamic response to collision. The model is then extrapolated to include all whiskers in the array, taking into account each whisker’s individual geometry. Simulations of first mode resonances across the array approximately match previous experimental results and fall well within the range expected from biological variability. Finally, we use WHISKiT Physics to simulate mechanical signals across the array during three distinct behavioral conditions: passive whisker stimulation, active whisking against two pegs, and active whisking in a natural environment. The results demonstrate that the simulation system can be used to predict input signals during a variety of behaviors, something that would be difficult or impossible in the biological animal. In all behavioral conditions, interactions between array morphology and individual whisker geometry shape the tactile input to the whisker system.
DomainScope: A disease network based on protein domain connections
Authors: Voskanian-kordi Alin , Funai Ashley , Kann Maricel G. 
Published: December 2019

AbstractProtein domains are highly conserved functional units of proteins. Because they carry functionally significant information, the majority of the coding disease variants are located on domains. Additionally, domains are specific units of the proteins that can be targeted for drug delivery purposes. Here, using information about variants sites associated with diseases, a disease network was built, based on their sharing the same domain and domain variation site. The result was 49,990 disease pairs linked by domain variant site and 533,687 disease pairs that share the same mutated domain. These pairs were compared to disease pairs made using previous methods such as gene identity and gene variant site identity, which revealed that over 8,000 of these pairs were not only missing from the gene pairings but also not found commonly together in literature. The disease network was analyzed from their disease subject categories, which when compared to the gene-based disease network revealed that the domain method results in higher number of connections across disease categories versus within a disease category. Further, a study into the drug repurposing possibilities of the disease network created using domain revealed that 16,902 of the disease pairs had a drug reported for one disease but not the other, highlighting the drug repurposing potential of this new methodology.