bluuebunny/crossref_metadata_2025_split huggingface dataset:
SWAN Identification of Common Aneuploidy-Based Oncogenic Drivers
Authors: Bowers Robert R. , Jones Christian M. , Paz Edwin A. , Barrows John K. , Armeson Kent E. , Long David T. , Delaney Joe R. 
Published: May 2021

SummaryHaploinsufficiency drives Darwinian evolution. Siblings, while alike in many aspects, differ due to monoallelic differences inherited from each parent. In cancer, solid tumors exhibit aneuploid genetics resulting in hundreds to thousands of monoallelic gene-level copy-number alterations (CNAs) in each tumor. Aneuploidy patterns are heterogeneous, posing a challenge to identify drivers in this high-noise genetic environment. Here, we developed Shifted Weighted Annotation Network (SWAN) analysis to assess biology impacted by cumulative monoallelic changes. SWAN enables an integrated pathway-network analysis of CNAs, RNA expression, and mutations via a simple web platform. SWAN is optimized to best prioritize known and novel tumor suppressors and oncogenes, thereby identifying drivers and potential druggable vulnerabilities within cancer CNAs. Protein homeostasis, phospholipid dephosphorylation, and ion transport pathways are commonly suppressed. An atlas of CNA pathways altered in each cancer type is released. These CNA network shifts highlight new, attractive targets to exploit in solid tumors.HighlightsCopy-number alteration pathways define solid tumor biologySWAN is released as an integrative point-and-click pathway analysis toolModerate impact drivers highlighted by SWAN validatedin vitroCopy-number altered pathways associate with mutations and survival
The self-regulated response of the Wnt pathway to an oncogenic mutation in β-catenin
Authors: Moshkovsky Ana R , Ma Wenzhe , Kirschner Marc W 
Published: May 2021

ABSTRACTOncogenic mutations in β-catenin can inhibit degradation of β-catenin by preventing phosphorylation of its degron. Degron phosphorylation is mediated by the Axin scaffold, Casein Kinase 1α (CK1α) and Glycogen Synthase Kinase 3 (GSK3). We studied an oncogenic form of β-catenin with a deletion of serine 45 (S45), a site that is phosphorylated by the kinase CK1α. When the S45 site is phosphorylated, it promotes the GSK3-mediated phosphorylations of the β-catenin degron. Deletion of S45 would be expected to prevent GSK3-mediated phosphorylation of the mutant protein and thus block degradation. We found that the S45 mutant was still phosphorylatable by GSK3, and its expression increased the concentration of Axin, restoring the rate of GSK3-mediated phosphorylation to levels comparable to those observed for the wild-type β-catenin. We conclude that there is one core mechanism for creating the phosphodegron for both primed and unprimed β-catenin, which involves the generation of an Axin-GSK3 complex.SIGNIFICANCEUnderstanding how the Wnt pathway responds to mutations in β-catenin phosphodegron can reveal important properties of the pathway in normal and cancer cells and is valuable for the design of more effective therapeutic strategies.
One Scaffold – Different Organelles Sensors: pH-Activable Fluorescent Probes for Targeting Live Primary Microglial Cell Organelles
Authors: Jethava Krupal P. , Prakash Priya , Manchanda Palak , Arora Harshit , Chopra Gaurav 
Published: May 2021

ABSTRACTTargeting live cell organelles is important for imaging and to understand and control specific biochemical processes. Typically, fluorescent probes with distinct structural scaffolds have been used for targeting specific cell organelle. Herein, we aimed to design modular one-step synthetic strategies using a common reaction intermediate to develop new lysosomal, mitochondrial and nucleus targeting pH-activable fluorescent probes that are all based on a single boron dipyrromethane analogs. The divergent cell organelle targeting was achieved by synthesizing pH-activable fluorescent probes with specific functional groups changes to the main scaffold resulting in differential fluorescence and pKa. Specifically, we show that the functional group transformation of the same scaffold influences cellular localization and specificity of pH-activable fluorescent probes in live primary microglial cells with pKa’s ranging from ~4.5-6.0. We introduce a structure-organelle-relationship (SOR) framework targeting the nucleus (NucShine), lysosomes (LysoShine) and mitochondria (MitoShine) in primary mouse microglial cells. This work will result in future applications of SOR beyond imaging to target and control organelle-specific biochemical processes in disease-specific models.
The petrosal and basicranial morphology ofProtoceras celer
Authors: Robson Selina Viktor , Seale Brendon , Theodor Jessica M. 
Published: May 2021

AbstractProtoceratids are an extinct family of endemic North American artiodactyls. The phylogenetic position of protoceratids in relation to camelids and ruminants has been contentious for over a century. The petrosal morphology of basal (Leptotragulus) and derived (Syndyoceras) protoceratids has suggested that protoceratids are closely related to ruminants, whereas a prior description of a disarticulated intermediate protoceratid petrosal (Protoceras celer) indicated that protoceratids were closely related to camelids. This contradictory evidence implied that there were several character reversals within the protoceratid lineage and brought into question the utility of basicranial characters in artiodactyl phylogenetics. Here, we provide descriptions of an additionalP. celerpetrosal. The descriptions are based on data produced by computed tomography scans, which allowed us to image the petrosalin situin the skull. Our results indicate that the petrosal morphology ofP. celeris similar to that of other protoceratids, implying that, contrary to previous evidence, petrosal morphology is conserved within the Protoceratidae.
Visualization of lake succession as indicated by macrophyte species composition and trophic levels in lakes subdivided by volcanic eruption at Akan Caldera, Hokkaido, Japan
Authors: Wakana Isamu , Kadono Yasuro , Urabe Jotaro , Tamura Yuki , Suzuki Yoshifusa , Yamada Hiroyuki , Oyama Yoichi , Wada Keiji , Hasegawa Takeshi , Ohara Masashi 
Published: May 2021

AbstractIt is not feasible to continuously observe ecological succession in lakes because of the long time-scales generally involved. Thus, the process has been inductively deduced by comparing many lakes with different succession states, or indirectly simulated by tracking studies of smaller water bodies, experiments using microcosms or mesocosms, and reconstruction of lake history by sediment analysis. However, the reality of succession processes in large lakes with slow succession is not well understood, and new approaches are needed. Theoretically, in a group of large and small lakes of similar ages and with similar initial and watershed environments, the rate of nutrient accumulation in each lake depends on the ratio of watershed area to lake size, and the lakes are predicted to evolve to different trophic levels over time. Here, we tested this hypothesis on the 10 lakes of varying sizes in Akan Caldera, Japan, which were formed thousands of years ago by fragmentation due to volcanic eruptions within the caldera. Topographic and water quality studies showed that the ratio of accumulated watershed area to lake size (area and volume), expressed logarithmically, had a positive linear regression with the total phosphorus concentration, an indicator of trophic level. The trophic levels of the lakes were diverse, including oligotrophic, mesotrophic, and eutrophic types in the traditional “lake type” classification based on total phosphorus and chlorophyll-a concentrations. Furthermore, 21 species of aquatic macrophytes were observed by a diving survey, and the plant species composition was classified into five groups corresponding to the trophic status of the lakes, indicating a conventional “hydrarch succession”. The diversity of water quality and aquatic vegetation in a group of lakes with similar origins paves the way for new comparative studies of lakes, including large lakes.
Network Pharmacology Integrated Molecular Docking Based Prediction of Active Compounds and Potential Targets inTinospora crispaLinn. as Insulin Sensitizer
Authors: Zuhri Ummu Mastna , Purwaningsih Erni Hernawati , Fadilah  , Yuliana Nancy Dewi 
Published: May 2021

AbstractInsulin resistance is a metabolic disorder characterized by the decreased response to insulin in muscle, liver, and adipose cells. The normal insulin levels are unable to control glucose, lipids, and energy homeostasis. This condition remains a complex phenomenon that involves several genetic defects and environmental stresses, such as obesity. A full understanding is required to understand the entire itinerary and functional consequences of the occurrence of insulin resistance to develop a potent drug in diabetes management. In the present study, we investigated the mechanism of known phytochemical constituents ofTinospora crispaand its interaction with insulin resistant target proteins by using network pharmacology and molecular docking. The insulin sensitizer activities ofTinospora crispamay be associated with the inhibition of the activation of the inflammatory pathway and the activation of insulin signaling. Tinoscorside A, Makisterone C, Borapetoside A and B, and β sitosterol consider the main phytoconstituents ofTinospora crispaby its binding with active sites of main protein targets of insulin resistance potential therapy. In conclusion,Tinospora crispawas one of the promising therapeutic agent in type 2 diabetes mellitus management. Regulation in glucose homeostasis, adipolysis, cell proliferation, and antiapoptosis may be the critical mechanism ofTinospora crispaas an insulin sensitizer.
XENet: Using a new graph convolution to accelerate the timeline for protein design on quantum computers
Authors: Maguire Jack B. , Grattarola Daniele , Klyshko Eugene , Mulligan Vikram Khipple , Melo Hans 
Published: May 2021

AbstractGraph representations are traditionally used to represent protein structures in sequence design protocols where the folding pattern is known. This infrequently extends to machine learning projects: existing graph convolution algorithms have shortcomings when representing protein environments. One reason for this is the lack of emphasis on edge attributes during massage-passing operations. Another reason is the traditionally shallow nature of graph neural network architectures. Here we introduce an improved message-passing operation that is better equipped to model local kinematics problems such as protein design. Our approach, XENet, pays special attention to both incoming and outgoing edge attributes.We compare XENet against existing graph convolutions in an attempt to decrease rotamer sample counts in Rosetta’s rotamer substitution protocol. This use case is motivating because it allows larger protein design problems to fit onto near-term quantum computers. XENet outperformed competing models while also displaying a greater tolerance for deeper architectures. We found that XENet was able to decrease rotamer counts by 40% without loss in quality. This decreased the problem size of our use case by more than a factor of 3. Additionally, XENet displayed an ability to handle deeper architectures than competing convolutions.Author summaryGraphs data structures are ubiquitous in the field of protein design and are at the core of the recent advances in artificial intelligence brought forth by graph neural networks (GNNs). GNNs have led to some impressive results in modeling protein interactions, but are not as common as other tensor representations.Most GNN architectures tend to put little to no emphasis on the information stored on edges; however, protein modeling tools often use edges to represent vital geometric relationships about residue pair interactions. In this paper, we show that a more advanced processing of edge attributes can lead to considerable benefits when modeling chemical data.We introduce XENet, a new member of the GNN family that is shown to have improved ability to model protein residue environments based on chemical and geometric data. We use XENet to intelligently simplify the optimization problem that is solved when designing proteins. This task is important to us and others because it allows larger proteins to be designed on near-term quantum computers. We show that XENet is able to train on our protein modeling data better than existing methods, successfully resulting in a dramatic decrease in protein design sample space with no loss in quality.
Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium
Authors: Sha Zhiqiang , van Rooij Daan , Anagnostou Evdokia , Arango Celso , Auzias Guillaume , Behrmann Marlene , Bernhardt Boris , Bolte Sven , Busatto Geraldo F. , Calderoni Sara , Calvo Rosa , Daly Eileen , Deruelle Christine , Duan Meiyu , Souza Duran Fabio Luis , Durston Sarah , Ecker Christine , Ehrlich Stefan , Fair Damien , Fedor Jennifer , Fitzgerald Jacqueline , Floris Dorothea L. , Franke Barbara , Freitag Christine M. , Gallagher Louise , Glahn David C , Haar Shlomi , Hoekstra Liesbeth , Jahanshad Neda , Jalbrzikowski Maria , Janssen Joost , King Joseph A. , Lazaro Luisa , Luna Beatriz , McGrath Jane , Medland Sarah E. , Molloy Ciara , Muratori Filippo , Murphy Declan G.M. , Neufeld Janina , O’Hearn Kirsten , Oranje Bob , Parellada Mara , Pariente Jose C. , Postema Merel C. , Remnelius Karl Lundin , Retico Alessandra , Penteado Rosa Pedro Gomes , Rubia Katya , Shook Devon , Tammimies Kristiina , Taylor Margot J. , Tosetti Michela , Wallace Gregory L. , Zhou Fengfeng , Thompson Paul M. , Fisher Simon E. , Buitelaar Jan K. , Francks Clyde 
Published: May 2021

AbstractSmall average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls. Although these alterations affect multiple and widespread cortical regional asymmetries, the extent to which specific structural networks might be affected remains unknown. Inter-regional morphological covariance analysis can capture network connectivity relations between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1,455 individuals with ASD and 1,560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered asymmetry of hemispheric networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, driven by shifts toward higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve working memory, executive functions, language, reading, and sensorimotor processes. Taken together, these findings provide new insights into how altered brain left-right asymmetry in ASD affects specific structural and functional brain networks. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations
Authors: Flaherty Samuel M. , Russell Ian J. , Lukashkin Andrei N. 
Published: May 2021

AbstractThe cochlea’s inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method of local drug delivery to the cochlea presented here could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.
Blood-based liquid biopsy for comprehensive cancer genomic profiling using next-generation sequencing: an emerging paradigm for noninvasive cancer detection and management in dogs
Authors: Kruglyak Kristina M , Chibuk Jason , McLennan Lisa , Nakashe Prachi , Hernandez Gilberto E , Motalli-Pepio Rita , Fath Donna M , Tynan John A , Holtvoigt Lauren E , Chorny Ilya , Grosu Daniel S , Tsui Dana WY , Flory Andi 
Published: May 2021

AbstractThis proof-of-concept study demonstrates that blood-based liquid biopsy using next generation sequencing of cell-free DNA can noninvasively detect multiple classes of genomic alterations in dogs with cancer, including alterations that originate from spatially separated tumor sites.Eleven dogs with a variety of confirmed cancer diagnoses (including localized and disseminated disease) who were scheduled for surgical resection, and 5 presumably cancer-free dogs, were enrolled. Blood was collected from each subject, and multiple spatially separated tumor tissue samples were collected during surgery from 9 of the cancer subjects.All samples were analyzed using an advanced prototype of a novel liquid biopsy test designed to noninvasively interrogate multiple classes of genomic alterations for the detection, characterization, and management of cancer in dogs.In 5 of the 9 cancer patients with matched tumor and plasma samples, pre-surgical liquid biopsy testing identified genomic alterations, including single nucleotide variants and copy number variants, that matched alterations independently detected in corresponding tumor tissue samples. Importantly, the pre-surgical liquid biopsy test detected alterations observed in spatially separated tissue samples from the same subject, demonstrating the potential of blood-based testing for comprehensive genomic profiling of heterogeneous tumors. Among the 3 patients with post-surgical blood samples, genomic alterations remained detectable in one patient with incomplete tumor resection, suggesting utility for noninvasive detection of minimal residual disease following curative-intent treatment.Liquid biopsy allows for noninvasive profiling of cancer-associated genomic alterations with a simple blood draw and has potential to overcome the limitations of tissue-based testing posed by tissue-level genomic heterogeneity.
Chemoproteomic-enabled characterization of small GTPase Rab1a as a target of anN-arylbenzdiimidazole ligand’s rescue of Parkinson’s-associated cell toxicity
Authors: Hatstat A. Katherine , Quan Baiyi , Bailey Morgan , Fitzgerald Michael C. , Reinhart Michaela C. , McCafferty Dewey G. 
Published: May 2021

AbstractThe development of phenotypic models of Parkinson’s disease (PD) has enabled screening and identification of phenotypically active small molecules that restore complex biological pathways affected by PD toxicity. While these phenotypic screening platforms are powerful, they do not inherently enable direct identification of the cellular targets of promising lead compounds. To overcome this, chemoproteomic platforms like Thermal Proteome Profiling (TPP) and Stability of Proteins from Rates of Oxidation (SPROX) can be implemented to reveal protein targets of biologically active small molecules. Here we utilize both of these chemoproteomic strategies to identify targets of anN-arylbenzdiimidazole compound, NAB2, which was previously identified for its ability to restore viability in cellular models of PD-associated α-synuclein toxicity. The combined results from our TPP and SPROX analyses of NAB2 and the proteins in a neuroblastoma-derived SHSY5Y cell lysate reveal a previously unrecognized protein target of NAB2. This newly recognized target, Rab1a, is a small GTPase that acts as a molecular switch to regulate ER-to-Golgi trafficking, a process that is disrupted by α-synuclein toxicity and restored by NAB2 treatment. Further validation reveals that NAB2 binds to Rab1a with selectivity for its GDP-bound form and that NAB2 treatment phenocopies Rab1a overexpression in alleviation of α-synuclein toxicity. Finally, we conduct a preliminary investigation into the relationship between Rab1a and the E3 ubiquitin ligase, Nedd4, a previously identified NAB2 target. Together, these efforts expand our understanding of the mechanism of NAB2 in the alleviation of α-synuclein toxicity and reinforce the utility of chemoproteomic identification of the targets of phenotypically active small molecules that regulate complex biological pathways.
Prior aerosol infection with lineage A SARS-CoV-2 variant protects hamsters from disease, but not reinfection with B.1.351 SARS-CoV-2 variant
Authors: Yinda Claude Kwe , Port Julia R. , Bushmaker Trenton , Fischer Robert J. , Schulz Jonathan E. , Holbrook Myndi G. , Shaia Carl , de Wit Emmie , van Doremalen Neeltje , Munster Vincent J. 
Published: May 2021

AbstractThe circulation of SARS-CoV-2 has resulted in the emergence of variants of concern (VOCs). It is currently unclear whether previous infection with SARS-CoV-2 provides protection against reinfection with VOCs. Here, we show that low dose aerosol exposure to hCoV-19/human/USA/WA-CDC-WA1/2020 (WA1, lineage A), resulted in a productive mild infection. In contrast, low dose of SARS-CoV-2 via fomites did not result in productive infection in the majority of exposed hamsters and these animals remained non-seroconverted. After recovery, hamsters were re-exposed to hCoV-19/South African/KRISP-K005325/2020 (VOC B.1.351) via an intranasal challenge. Seroconverted rechallenged animals did not lose weight and shed virus for 3 days. They had little infectious virus and no pathology in the lungs. In contrast, shedding, weight loss and extensive pulmonary pathology caused by B.1.351 replication was observed in the non-seroconverted animals. The rechallenged seroconverted animals did not transmit virus to naïve sentinels via direct contact transmission, in contrast to the non-seroconverted animals. Reinfection with B.1.351 triggered an anamnestic response that boosted not only neutralizing titers against lineage A, but also titers against B.1.351. Our results confirm that aerosol exposure is a more efficient infection route than fomite exposure. Furthermore, initial infection with SARS-CoV-2 lineage A does not prevent heterologous reinfection with B.1.351 but prevents disease and onward transmission. These data suggest that previous SARS-CoV-2 exposure induces partial protective immunity. The reinfection generated a broadly neutralizing humoral response capable of effectively neutralizing B.1.351 while maintaining its ability to neutralize the virus to which the initial response was directed against.