bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel kinome profiling technology reveals drug treatment is patient and 2D/3D model dependent in GBM
Authors: Fabro Federica , Kannegieter Nynke M. , de Graaf Erik L. , Queiroz Karla , Lamfers Martine L.M. , Ressa Anna , Leenstra Sieger 
Published: July 2022

ABSTRACTGlioblastoma is the deadliest brain cancer. One of the main reasons for poor outcome resides in therapy resistance, which adds additional challenges in finding an effective treatment. Small protein kinase inhibitors are molecules that have become widely studied for cancer treatments, including glioblastoma. However, none of these drugs have demonstrated a therapeutic activity or brought more benefit compared to the current standard procedure in clinical trials. Hence, understanding the reasons of the limited efficacy and drug resistance is valuable to develop more effective strategies toward the future. To gain novel insights into the method of action and drug resistance in glioblastoma, we established in parallel two patient-derived glioblastoma 2D and 3D organotypic multicellular spheroids models, and exposed them to a prolonged treatment of three weeks with temozolomide or either the two small protein kinase inhibitors enzastaurin and imatinib. We coupled the phenotypic evidence of cytotoxicity, proliferation, and migration to a novel kinase activity profiling platform (QuantaKinome™) that measured the activities of the intracellular network of kinases affected by the drug treatments. The results revealed a heterogeneous inter-patient phenotypic and molecular response to the different drugs. In general, small differences in kinase activation were observed, suggesting an intrinsic low influence of the drugs to the fundamental cellular processes like proliferation and migration. The pathway analysis indicated that many of the endogenously detected kinases were associated with the ErbB signaling pathway. We showed the intertumoral variability in drug responses, both in terms of efficacy and resistance, indicating the importance of pursuing a more personalized approach. In addition, we observed the influence derived from the application of 2D or 3D models in in vitro studies of kinases involved in the ErbB signaling pathway. We identified in one 3D sample a new resistance mechanism derived from imatinib treatment that results in a more invasive behavior. The present study applied a new approach to detect unique and specific drug effects associated with pathways in in vitro screening of compounds, to foster future drug development strategies for clinical research in glioblastoma.
Multimodal electrocorticogram active electrode array based on zinc oxide-thin film transistors
Authors: Zhang Fan , Zhang Luxi , Xia Jie , Zhao Wanpeng , Dong Shurong , Ye Zhi , Pan Gang , Luo Jikui , Zhang Shaomin 
Published: July 2022

AbstractActive electrocorticogram (ECoG) electrodes can amplify the weak electrophysiological signals and improve the anti-interference ability, but the traditional active electrodes are so opaque that cannot realize photoelectric collaborative observation. Here an active and fully-transparent ECoG array based on zinc oxide-thin film transistors (ZnO-TFTs) was developed as the local neural signal amplifier for electrophysiological monitoring. The transparency of the proposed ECoG array was up to 85% which is superior to previous reported active electrode array. Various electrical characterizations demonstrated its ability of electrophysiological signal recording, with a higher signal-to-noise ratio of 19.9 dB compared to the Au grid one (13.2 dB). The high transparency of ZnO-TFT electrode array allowed the collecting electrophysiological signals under direct light stimulation on optogenetic mice brain concurrently. The ECoG array could also work under 7-Tesla magnetic resonance imaging to record local brain signal without affecting brain tissue imaging. As the most transparent active ECoG array to date, it provides a powerful multimodal tool for brain observation, including recording brain activity under synchronized optical modulation and 7-Tesla magnetic resonance imaging.
Self-organized anteroposterior regionalization of early midbrain and hindbrain using micropatterned human embryonic stem cells
Authors: Xie Tianfa , Brown Lauren E. , Pak ChangHui , Sun Yubing 
Published: July 2022

SUMMARYTo develop into the central nervous system, neuroepithelial cells must first form a neural tube consisting of a series of patterned neural progenitor cells along the anterior-posterior (AP) axis. Based on studies using model organisms, it has been revealed that AP spatial regionalization is dominated by gradients of morphogens that regulate retinoic acid (RA), sonic hedgehog (SHH), bone morphogenetic proteins (BMPs), and Wingless/int1 (WNT) signaling pathways. Recently, human pluripotent stem cells (hPSCs) were successfully induced into a patterned neural tissue with differential AP gene expression levels by a gradient of WNT activity controlled by a microfluidic device. However, the midbrain and hindbrain boundaries were not as sharp as observed in vivo, likely due to the lack of additional important morphogenic factors, such as RA and SHH. Here, we induced micropatterned hPSCs into AP patterned neural tissue by activating not only WNT but also RA and SHH signals under fully defined culture conditions. We found that hPSCs self-organized into spatially patterned midbrain (FOXG1-OTX2+) and hindbrain (HOXB4+) progenitors with a sharp boundary after 6 days of induction. Following the initial induction, the cells with midbrain identities near the pattern boundary folded inwardly to form a 3D structure, maintaining a distinct boundary between OTX2+ and HOXB4+ zones. To investigate the mechanism of cell fates patterning, we found that the reaction-diffusion of BMP/Noggin played a role in AP regionalization, while differential mechanical stress and cell sorting were unlikely to be involved. Then, we validated our model by investigating the effects of exposure to two known teratogens including valproic acid and isotretinoin. Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while isotretinoin disrupts the normal AP patterning of the midbrain and hindbrain. In conclusion, by integrating engineering approaches and chemically defined culture conditions, we have developed an in vitro AP patterned model of early human midbrain and hindbrain development, and we have revealed its potential to be employed as a high throughput drug discovery system.
DrosOmics: a comparative genomics browser to explore omics data in natural populations ofD. melanogaster
Authors: Coronado-Zamora Marta , Salces-Ortiz Judit , González Josefa 
Published: July 2022

AbstractThe advent of long-read sequencing technologies has allowed the generation of multiple high-quality de novo genome assemblies for multiple species, including well-known model species such asDrosophila melanogaster. Genome assemblies for multiple individuals of the same species are key to discover the genetic diversity present in natural populations, especially the one generated by transposable elements, the most common type of structural variant. Despite the availability of multiple genomic datasets forD. melanogasterpopulations, we lack an efficient visual tool to display different genomes assemblies simultaneously. In this work, we present DrosOmics, a comparative genomics-oriented browser for 52 high-quality reference genomes ofD. melanogaster, including annotations from a highly reliable set of transposable elements, and functional transcriptomics and epigenomics data for half the populations. DrosOmics is based on JBrowse 2, which allows the visualization of multiple assemblies at once, key to unraveling structural and functional features ofD. melanogasternatural populations.
Grain filling leads to backflow of surplus water in maize grain via the xylem to the cob and plant
Authors: Zhang Gui-Ping , Marasini Mukti , Li Wei-Wei , Zhang Feng-Lu 
Published: July 2022

AbstractThe rapid dehydration rate of maize grain is one of the main characteristics of cultivar selection of mechanical grain harvest, but the dominant driving force and mechanism of grain dehydration before physiological maturity remains disputable and obscure, respectively. This study found that, from grain formation to 5-10 days before physiological maturity of early and middle maturity maize cultivars, the main driving force of grain dehydration is filling and then converts to surface evaporation, by comparing the grain moisture content and dehydration rate between grain coated treatment and control. In the dye movement experiment, xylem-mobile dye movement into grain through pedicel xylem was observed during grain formation period, and declined and gradually not observed after grain formation. Xylem-mobile dye movement out of ear via cob, ear-pedicel and stem xylem was observed after grain formation. In addition, from grain formation to physiological maturity, there was a very significant positive correlation between grain filling rate and dehydration rate. According to these results, it is proposed here that in the grain dehydration phase driven by filling, the surplus water in grain flows back to cob via pedicel xylem, and some of it flows back to plant via cob and ear-pedicel xylem.HighlightThe surplus water in grain driven by grain filling flows back to the cob and plant for recyclingvia the xylem during the development of maize grain.
PD-L1ATTAC mice reveal the potential of targeting PD-L1 expressing cells in cancer therapy
Authors: Fueyo-Marcos Elena , Fustero-Torre Coral , Lopez Gema , Antón Marta Elena , Al-Shahrour Fátima , Fernández-Capetillo Oscar , Murga Matilde 
Published: July 2022

AbstractAntibodies targeting the PD-1 receptor and its ligand PD-L1 have shown impressive responses in some tumors of bad prognosis. We hypothesized that the selective elimination of PD-L1 expressing cells could similarly have antitumoral effects. To address this question, we developed an inducible suicidal knock-in mouse allele of Pd-l1 (PD-L1ATTAC) which allows for the tracking and specific elimination of PD-L1-expressing cells in adult tissues. Elimination of PD-L1 expressing cells from the mouse peritoneum increased the septic response to lipopolysaccharide (LPS), due to an exacerbated inflammatory response to the endotoxin. In addition, mice depleted of PD-L1+ cells were resistant to colon cancer peritoneal allografts, which was associated with a loss of immunosuppresive B cells and macrophages, concomitant with an increase in activated cytotoxic CD8 T cells. Collectively, these results illustrate the usefulness of PD-L1ATTAC mice and provide genetic support to the concept of targeting PD-L1 expressing cells in cancer therapy.
Dynamicin vivomapping of the methylproteome using a chemoenzymatic approach
Authors: Farhi Jonathan , Emenike Benjamin , Lee Richard S. , Beusch Christian M. , Jones Robert B. , Verma Ashish K. , Jones Celina Y. , Foroozani Maryam , Reeves Monica , Sad Kirti , Parwani Kiran K. , Bagchi Pritha , Deal Roger B. , Katz David J. , Corbett Anita H. , Gordon David E. , Raj Monika , Spangle Jennifer M. 
Published: July 2022

AbstractDynamic protein post-translation methylation is essential for cellular function, highlighted by the essential role of methylation in transcriptional regulation and its aberrant dysregulation in diseases including cancer. This underscores the importance of cataloging the cellular methylproteome. However, comprehensive analysis of the methylproteome remains elusive due to limitations in current enrichment and analysis pipelines. Here, we employ an L-Methionine analogue, ProSeMet, that is chemoenzymatically converted to the SAM analogue ProSeAM in cells andin vivoto tag proteins with a biorthogonal alkyne that can be directly detected via LC-MS/MS, or functionalized for subsequent selective enrichment and LC-MS/MS identification. Without enrichment, we identify lysine mono-, di-, and trimethylation, histidine methylation, and arginine methylation with site specific resolution on proteins including heat shock protein HSPA8, for which methylation is implicated in human disease. With enrichment, we identify 486 proteins known to be methylated and 221 proteins with novel methylation sites encompassing diverse cellular functions. Systemic ProSeMet delivery in mice pseudomethylates proteins across organ systems with blood-brain barrier penetrance and identifies site-specific pseudomethylationin vivowith LC-MS/MS. Leveraging these pipelines to define the cellular methylproteome may have broad applications for understanding the methylproteome in the context of disease.
Tauopathy and alcohol consumption interact to alter locus coeruleus excitatory transmission and excitability in male and female mice
Authors: Downs Anthony M. , Catavero Christina M , Kasten Michael R. , McElligott Zoé A. 
Published: July 2022

ABSTRACTAlcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimer’s Disease and Frontal-Temporal Dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nuclei in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than WT males. At the end of the drinking study, LC function was assessed usingex vivowhole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype., We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than WT. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol and tauopathy related dementia.
A novel biopolymer synergizes type I IFN and IL-1β production through STING
Authors: Hoover Ashley R. , Liu Kaili , Kit Lam Samuel Siu , Wong Chun Fung , Medcalf Alexandra D. , Sun Xiao-Hong , Hode Tomas , Alleruzzo Lu , Furrer Coline , Valerio Trisha I. , Chen Wei R. 
Published: July 2022

AbstractN-dihydrogalactochitosan (GC) is developed for inducing immune responses. Synthesized from chitosan and galactose, GC is a new chemical entity that significantly enhances the immune-stimulating properties of its parental material, chitosan, making it a promising therapeutic agent. When used in combination with antigenic material, GC stimulates innate and adaptive antitumor and antiviral immunities. However, the mechanism of GC has not been fully investigated. Herein we demonstrate that GC drives type I IFN production and IFN responses in antigen presenting cells (APCs) and has superior potency compared to its corresponding chitosan. More importantly, GC drives alternative activation of STING leading to inflammatory cell death that enhances dendritic cell (DC) activation, which triggers a variety of nucleic acid sensing pattern recognition receptors (PRRs) and IL-1β production.In vivo, GC induced a potent response of type I IFN and upregulated genes associated with STING signaling within the tumor microenvironment (TME). Moreover, intratumoral delivery of GC reduced the numbers of M2-like macrophages residing within the TME, while subsequently increasing the number of DCs. Our findings demonstrate GC’s unique ability to activate STING and stimulate a broad type I IFN response which holds therapeutic promise in generating antitumor and antiviral immunities.
PD-1 and CTLA-4 exert additive control of effector regulatory T cells
Authors: Perry Joseph A. , Lanzar Zachary , Clark Joseph T. , Hart Andrew P. , Douglas Bonnie B. , Shallberg Lindsey , O’Dea Keenan , Christian David A. , Hunter Christopher A. 
Published: July 2022

AbstractAt homeostasis, a substantial proportion of Foxp3+ T regulatory cells (Tregs) have an activated phenotype associated with enhanced TCR signals and these effector Treg cells (eTregs) co-express elevated levels of PD-1 and CTLA-4. Short term in vivo blockade of the PD-1 or CTLA-4 pathways results in increased eTreg populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in Treg cells which was associated with increased eTreg proliferation, enhanced production of IL-10, and altered dendritic cell expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eTreg function and the ability to target these pathways in Treg cells may be useful to modulate inflammation.
Context matters: Changes in memory over a period of sleep are driven by encoding context
Authors: Schechtman Eitan , Heilberg Julia , Paller Ken A. 
Published: July 2022

AbstractDuring sleep, recently acquired episodic memories (i.e., autobiographical memories for specific events) are strengthened and transformed, a process termed consolidation. These memories are contextual in nature, with details of specific features interwoven with more general properties such as the time and place of the event. In this study, we hypothesized that the context in which a memory is embedded would guide the process of consolidation during sleep. To test this idea, we employed a spatial memory task and considered changes in memory over a 10-hour period including either sleep or wake. In both conditions, participants (N = 62) formed stories that contextually bound four objects together, and then encoded the on-screen spatial position of all objects. Results showed that the changes in memory over the sleep period were correlated among contextually linked objects, whereas no such effect was identified for the wake group. These results suggest that contexts binding different memories together play an active role in consolidation during sleep.
Polishing de novo nanopore assemblies of bacteria and eukaryotes with FMLRC2
Authors: Mak Q. Charles , Wick Ryan R. , Holt James Matthew , Wang Jeremy R. 
Published: July 2022

AbstractAs accuracy and throughput of nanopore sequencing improves, it is increasingly common to perform long-read-first de novo genome assemblies followed by polishing with accurate short reads (Kim et al. 2021). We briefly introduce FMLRC2, the successor to the original FM-index Long Read Corrector (FMLRC), and illustrate its performance as a fast and accurate de novo assembly polisher for both microbial and eukaryotic genomes.
In silico-based screening for natural product’s structural analogs as new drugs candidate against leishmaniasis
Authors: Barazorda-Ccahuana Haruna Luz , Goyzueta-Mamani Luis Daniel , Candia-Puma Mayron Antonio , Freitas Camila Simões de , Vieria Tavares Grasiele de Sousa , Lage Daniela Pagliara , Ferraz Coelho Eduardo Antonio , Chávez-Fumagalli Miguel Angel 
Published: July 2022

AbstractLeishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Hence, this study aims to in silico screen for natural product’s structural analogs as new drugs candidate against leishmaniasis. We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation, and Molecular Mechanics-Generalized Born Surface Area MM/GBSA estimation aiming to select structural analogs from natural products that have shown antileishmanial activity against arginase (ARG) enzyme and that could bind selectively against Leishmania ARG. The compounds 2H-1-Benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), Echioidinin, and Malvidin showed good results against ARG targets from three parasite species and negative results for potential toxicities. The Malvidin ligand generated interactions in the active center at pH 2.0 conditions and hydrogen bonds enhancing receptor-ligand coupling. This work identified Malvidin as a potential drug candidate to treat leishmaniasis.
Oxytocin receptor is not required for social attachment in prairie voles
Authors: Berendzen Kristen M. , Sharma Ruchira , Mandujano Maricruz Alvarado , Wei YiChao , Rogers Forrest D. , Simmons Trenton C. , Seelke Adele H.M. , Bond Jessica M. , Larios Rose D. , Sherman Michael , Parthasarathy Srinivas , Espineda Isidero , Knoedler Joseph R. , Beery Annaliese , Bales Karen L. , Shah Nirao M. , Manoli Devanand S. 
Published: July 2022

SummaryPrairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (OxtR) is critical for the display of social monogamy in these animals. We used CRISPR-mutagenesis to independently generate three different OxtR null mutant prairie vole lines. OxtR mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex when assayed using different paradigms. Mothers lacking OxtR delivered viable pups, and parents displayed care of their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that OxtR-mediated signaling is genetically dispensable for social attachment, parturition, and parental behavior.