bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new experimental evidence-weighted signaling pathway resource in FlyBase
Authors: Attrill Helen , Antonazzo Giulia , Goodman Joshua L. , Thurmond Jim , Strelets Victor B , Brown Nicholas H. ,   the FlyBase Consortium
Published: August 2023

AbstractResearch in model organisms is central to the characterization of signaling pathways in multicellular organisms. Here, we present the systematic curation of 17 Drosophila signaling pathways using the Gene Ontology framework to establish a comprehensive and dynamic resource that has been incorporated into FlyBase, providing visualization and data integration tools to aid research projects. By restricting to experimental evidence reported in the research literature and quantifying the amount of such evidence for each gene in a pathway, we captured the landscape of empirical knowledge of signaling pathways inDrosophila.Summary statementComprehensive curation of Drosophila signaling pathways and new visual displays of the pathways provides a new FlyBase resource for researchers, and new insights into signaling pathway architecture.
Studies on the International Space Station to assess the effects of microgravity on iPSC-derived neural organoids
Authors: Marotta Davide , Ijaz Laraib , Barbar Lilianne , Nijsure Madhura , Stein Jason , Clements Twyman , Stoudemire Jana , Grisanti Paula , Noggle Scott A. , Loring Jeanne F. , Fossati Valentina 
Published: August 2023

AbstractExposure to microgravity in low-Earth orbit (LEO) has been shown to affect human cardiovascular, musculoskeletal, and immune systems. Post-flight brain imaging indicates that reports about astronauts and mouse models suggest that microgravity may cause intracranial fluid shifts and possibly alter white and gray matter of the brain [1]. To focus on the effects of microgravity on the brain, we used induced pluripotent stem cells (iPSCs) to produce three-dimensional (3D) human neural organoids as models of the nervous system. We studied iPSCs derived from four individuals, including people with the neurological diseases primary progressive multiple sclerosis (PPMS) and Parkinson’s disease (PD) and non-symptomatic controls. We patterned the organoids toward cortical and dopaminergic fates representing regions of the brain affected by MS and PD, respectively. Microglia were generated from the same cell lines and integrated into a portion of the organoids. The organoids were maintained for 30 days in a novel static culture system on the International Space Station (ISS) and live samples were returned to Earth. The post-flight samples were evaluated using histology, transcriptome and secretome analysis. Microglia-specific genes and secreted proteins were detectable in the microglia-containing organoid cultures. The gene expression analyses of individual organoids cultured in LEO and on Earth suggest that cell proliferation was lower and neural cells were more mature in samples that were cultured in LEO. These experiments lay the groundwork for further studies, including long term studies to investigate the effects of microgravity on the brain. With two more missions using similar cells, we are determining whether this effect of microgravity is consistent in separate experiments. Such studies may ultimately aid in developing countermeasures for the effects of microgravity on the nervous systems of astronauts during space exploration and suggest novel therapeutic interventions for neurological diseases on Earth.
Nuclear Transformation In Metalloenzyme. A Novel And High Potential Cancer Treatment Research
Authors: Van Luyen Tran , Tuan Truong Hoang 
Published: August 2023

AbstractIn this study, we have introduced a novel approach to cancer treatment involving the deactivation of metalloenzymes through the utilization of radioisotopes. The concept of leveraging radioisotopes to interact with metalloenzymes represents a groundbreaking theoretical advancement. Through simulations utilizing the MIRD code and based on the consistent concentration of stable Mg within stage 2A cancerous tissue, we have quantified the potential success rates.To conduct these simulations, we employed 0.1 nanograms (ng) of stable Mg, which corresponds to an activity of 19.7 MBq of Mg-28. This data was input into the MIRD calculations to estimate the absorbed doses within various organs, employing diverse methods of radioisotope administration into the body. Remarkably, even with a mere 1‰ probability of effectively reaching the intended cancerous tissues, this quantity of Mg-28 demonstrates the capability to render billions of Mg-containing metalloenzymes inactive.The remarkable efficiency achieved through precise radioisotope targeting underscores the promise of this methodology. Nevertheless, the findings underscore the necessity of undertaking both in vitro and in vivo research initiatives prior to embarking on clinical trials.
Meningeal CSF transport is primarily mediated by the arachnoid and pia maters during development
Authors: Pan Shelei , Koleske Joshua , Koller Gretchen M. , Halupnik Grace L. , Alli Abdul-Haq O. , Koneru Shriya , DeFreitas Dakota , Ramagiri uthi , Strahle Jennifer M. 
Published: August 2023

AbstractBackgroundThe recent characterization of the glymphatic system and meningeal lymphatics has re-emphasized the role of the meninges in facilitating CSF transport and clearance. Here, we characterize small and large CSF solute distribution patterns along the intracranial and surface meninges in neonatal rodents and compare our findings to a rodent model of intraventricular hemorrhage-posthemorrhagic hydrocephalus. We also examine CSF interactions with the tela choroidea and its pial invaginations into the choroid plexuses of the lateral, third, and fourth ventricles.Methods1.9-nm gold nanoparticles, 15-nm gold nanoparticles, or 3 kDa Red Dextran Tetramethylrhodamine constituted in aCSF were infused into the right lateral ventricle of P7 rats to track CSF circulation. 10 minutes post-1.9-nm gold nanoparticle and Red Dextran Tetramethylrhodamine injection and 4 hours post-15-nm gold nanoparticle injection, animals were sacrificed and brains harvested for histologic analysis to identify CSF tracer localization in the cranial and spine meninges and choroid plexus. Spinal dura and leptomeninges (arachnoid and pia) wholemounts were also performed.ResultsThere was significantly less CSF tracer distribution in the dura compared to the arachnoid and pia maters in neonatal rodents. Both small and large CSF tracers were transported intracranially to the arachnoid and pia mater of the perimesencephalic cisterns and tela choroidea, but not the dura mater of the falx cerebri. CSF tracers followed a similar distribution pattern in the spinal meninges. In the choroid plexus, there was large CSF tracer distribution in the apical surface of epithelial cells, and small CSF tracer along the basolateral surface. There were no significant differences in tracer intensity in the intracranial meninges of control vs. intraventricular hemorrhage-posthemorrhagic hydrocephalus (PHH) rodents, indicating preserved meningeal transport in the setting of PHH.ConclusionsDifferential CSF tracer handling by the leptomeninges suggests that there are distinct roles for CSF handling between the arachnoid-pia and dura maters in the developing brain. Similarly, differences in apical vs. luminal choroid plexus CSF handling may provide insight into particle-size dependent CSF transport at the CSF-choroid plexus border.
Long-Term Exposure of Cells to Cdk4 Inhibitor Palbociclib Leads to Chromosomal Aberrations
Authors: Kaulich Manuel , Dowdy Steven F. 
Published: August 2023

AbstractBreast cancers are often driven by mutations, alterations and activation of cell cycle regulatory proteins, including the retinoblastoma tumor suppressor protein (Rb), cyclin E and cyclin-dependent kinases (Cdks), especially cyclin D:Cdk4/6 complexes. There are currently three FDA approved Cdk4/6 inhibitors (Cdk4i) for treating breast cancer. The standard treatment protocol is 21 days of continuous Cdk4i treatment, followed by a 7 day cessation period and then repeating the 28 day protocol. We asked the question of what happens to cells that reenter the cell cycle during the 7 day Cdk4i cessation period. Using RPE1 cells containing visual reporter endogenous histone 2B and p27 genes tagged with eGFP and mCherry, we treated the cells with a Cdk4i, Palbociclib for 1 to 42 days that spanned the clinical exposure, followed by drug release (washout) and video microscopic analysis. Surprisingly, we found that as little as 4 days of Cdk4i treatment and release resulted in a significant increase in micronuclei and multinucleated cells that had reentered the cell cycle. The peak chromosomal aberration occurred between 14 and 35 days, a timing that spans the clinical dosing regimen.These observations raise questions concerning the potential that cycling patients on and off of Cdk4 inhibitors may generate gross chromosomal changes to tumor cells that reenter the cell cycle during the 7 day clinical cessation (washout) period and thereby increase the potential to initiate secondary oncogenic events.
Probing for Intentions: The Early Readiness Potential Does Not Reflect Awareness of Motor Preparation
Authors: Gavenas Jake , Schurger Aaron , Maoz Uri 
Published: August 2023

AbstractVoluntary actions are typically preceded by the Readiness Potential (RP), a negative midfrontal EEG deflection that begins ∼2 seconds before movement. What cognitive and neural process the RP reflects and how it relates to conscious intention remain unclear due to conflicting findings. We investigated the neural basis and cognitive significance of the RP in a novel probe-based paradigm. Contrary to prior reports, we found that pre-probe RP buildups were not related to reported awareness of motor preparation. Computational modeling suggested that the best explanation for these results is via metacognitive access to stochastic accumulation. Reported preparation was also related to beta desynchronization over contralateral motor cortex shortly before probe onset. We conclude that the RP may be metacognitively accessible in response to external task demands but does not reflect the onset of a conscious intention. We discuss implications of these findings for voluntary action initiation and intention awareness.HighlightsWe investigate the mechanisms underlying voluntary action initiation in a new probe paradigm.Contrary to prior results, the readiness does not reflect reported awareness of motor preparation.Computational modeling supports stochastic accumulation over linear ballistic accumulation and classic RP models.Reported awareness of motor preparation may emerge from metacognitive access to stochastic accumulation.Time-frequency analysis suggests reported awareness may also relate to pre-probe beta desynchronization.
Modulation of Viability, Proliferation, and Stemness by Rosmarinic Acid in Medulloblastoma Cells: Involvement of HDACs and EGFR
Authors: Herlinger Alice Laschuk , Michaelsen Gustavo Lovatto , Sinigaglia Marialva , Fratini Lívia , Debom Gabriela Nogueira , Braganhol Elizandra , de Farias Caroline Brunetto , Brunetto Algemir Lunardi , Brunetto André Tesainer , Jaeger Mariane da Cunha , Roesler Rafael 
Published: August 2023

AbstractMedulloblastoma (MB) is a heterogeneous group of malignant pediatric brain tumors, divided into molecular groups with distinct biological features and prognosis. Currently available therapy often results in poor long-term quality of life for patients, which will be afflicted by neurological, neuropsychiatric, and emotional sequelae. Identifying novel therapeutic agents capable of targeting the tumors without jeopardizing patients’ quality of life is imperative. Rosmarinic acid (RA) is a plant-derived compound whose action against a series of diseases including cancer has been investigated, with no side effects reported so far. Previous studies have not examined whether RA has effects in MB. Here, we show RA is cytotoxic against human Daoy (IC50= 168 μM) and D283 (IC50= 334 μM) MB cells. Exposure to RA for 48 h reduced histone deacetylase 1 (HDAC1) expression while increasing H3K9 hyperacetylation, reduced epidermal growth factor (EGFR) expression, and inhibited EGFR downstream targets extracellular-regulated kinase (ERK)1/2 and AKT in Daoy cells. These modifications were accompanied by increased expression ofCDKN1A/p21, reduced expression ofSOX2, and a decrease in proliferative rate. Treatment with RA also reduced cancer stem cell markers expression and neurosphere size. Taken together, our findings indicate that RA can reduce cell proliferation and stemness and induce cell cycle arrest in MB cells. Mechanisms mediating these effects may include targeting HDAC1, EGFR, and ERK signaling, and promoting p21 expression, possibly through an increase in H3K9ac and AKT deactivation. RA should be further investigated as a potential anticancer agent in experimental MB.
IL-1Ra and CCL5, but not IL-10, are promising targets for treating SMA astrocyte-driven pathology
Authors: Allison Reilly L. , Suneja Mya , LaCroix Megan , Harmelink Matthew , Ebert Allison D. 
Published: August 2023

AbstractSpinal muscular atrophy (SMA) is a pediatric genetic disorder characterized by the loss of spinal cord motor neurons. Although the mechanisms underlying motor neuron loss are not clear, current data suggest that glial cells contribute to disease pathology. We have previously found that SMA astrocytes drive microglial activation and motor neuron loss potentially through the upregulation of NFkB-mediated pro-inflammatory cytokines. In this study, we tested the ability of increasing either interleukin 10 (IL-10) or IL-1 receptor antagonist (IL-1ra) while neutralizing C-C motif chemokine ligand 5 (CCL5) to reduce the pro-inflammatory phenotype of SMA astrocytes. While IL-10 was ineffective, IL-1ra ameliorated SMA astrocyte-driven glial activation and motor neuron loss in iPSC-derived culturesin vitro.In vivoAAV5 delivered IL-1ra overexpression and miR-30 shRNA knockdown of CCL5 had modest but significant improvements on lifespan, weight gain, and motor function of SMNΔ7 mice. Together these data identify IL-1ra and CCL5 as possible therapeutic targets for SMA and highlight the importance of glial-targeted therapeutics for neurodegenerative disease.
NUCLEOPORIN1 mediates proteasome-based degradation of ABI5 to regulateArabidopsisseed germination
Authors: Thapa Raj K , Tian Gang , Lu Qing Shi Mimmie , Yu Yaoguang , Shu Jie , Chen Chen , Song Jingpu , Xie Xin , Shan Binghui , Nguyen Vi , Li Chenlong , Bian Shaomin , Liu Jun , Kohalmi Susanne E , Cui Yuhai 
Published: August 2023

AbstractNUCLEOPORIN1 (NUP1), a member of the Nuclear Pore Complex (NPC), is located on the inner side of the nuclear membrane. It is highly expressed in seeds; however, its role in seeds including germination has not been explored yet. Here, we identified an abscisic acid (ABA) hypersensitive phenotype ofnup1during germination. ABA treatment drastically changes the expression pattern of thousands of genes innup1, including the major transcription factors (TFs) involved in germination,ABI3,ABI4, andABI5. Double mutant analysis ofNUP1and these ABA-related genes showed that mutations inABI5can rescue the phenotype ofnup1, suggesting thatNUP1acts upstream ofABI5to regulate seed germination. ABI5, a key negative regulator of germination, is abundant in dry seeds and rapidly degrades during germination. However, its spatiotemporal regulation and interaction with other molecular players during degradation remained to be fully elucidated. We found that NUP1 is physically associated with ABI5 and the 26S proteasome. Mutation inNUP1delayed ABI5 degradation through its post-translational retention in nucleolus under abiotic stress. Taken together, our findings suggest that NUP1 anchors the proteasome to NPC and modulates seed germination through proteasome-mediated degradation of ABI5 in the vicinity of NPC in the nucleoplasm.
Sex differences in seizure presentation in Dravet syndrome model mice,Scn1a+/-
Authors: Vermudez Sheryl Anne D. , Lin Rui , McGinty Gabrielle , Liebhardt Amanda , Choe Yongho , Hui Benjamin , Lubbers Ella , Dhamne Sameer C. , Hameed Mustafa Q. , Rotenberg Alexander 
Published: August 2023

AbstractDravet syndrome (DS) is an epileptic encephalopathy mostly due to haploinsufficiency of theSCN1Avoltagegated sodium channel subunit. Disease presentation (i.e., severe seizures and early life mortality) is highly recapitulated in mice haploinsufficient inScn1a(Scn1a+/-). However, phenotypic characterization inScn1a+/-mice in a sex and temporal manner is limited. Given the reliance of mouse models for studying disease pathophysiology and for the development of novel treatments, we tested whether mortality and seizure morbidity differed among young and adult male and femaleScn1a+/-animals in the F1 hybrid C57×129S6 background. We found increased mortality in femaleScn1a+/-mice regardless of age compared to their male counterparts (n = 120-125 mice/sex;p < 0.05). Interestingly, long-term video EEG recordings revealed the opposite for morbidity as seizure frequency and severity were escalated in adult maleScn1a+/-animals (n = 21-30 mice/sex;p < 0.05orp < 0.01). Adult femaleScn1a+/-mice, however, are more hyperactive (p < 0.05), which could be related to sleep impairment and contribute to the increased mortality despite decreased seizure morbidity. Overall, the phenotypic presentation ofScn1a+/-mice is sex-dependent and may have translational implications for therapeutic drug discovery and basic biology understanding in DS.Short SummarySex differences in mortality and seizure morbidity are discovered inScn1ahaploinsufficient mice,Scn1a+/-, which faithfully model the epileptic encephalopathy disorder, Dravet syndrome (DS). FemaleScn1a+/-mice die more across all ages, whereas adult maleScn1a+/-mice have more seizures that are of greater severity. Hyperactivity, as a proxy for sleep disruption, may contribute to the increased mortality in femaleScn1a+/-mice despite decreased seizure incidence and severity. These sex-specific findings may have considerable impact in therapeutic discovery and development for DS and otherSCN1A-related disorders.
Hippocampal-occipital connectivity reflects autobiographical memory deficits in aphantasia
Authors: Monzel Merlin , Leelaarporn Pitshaporn , Lutz Teresa , Schultz Johannes , Brunheim Sascha , Reuter Martin , McCormick Cornelia 
Published: August 2023

AbstractAphantasia refers to reduced or absent visual imagery. While most of us can readily recall decade-old personal experiences (autobiographical memories, AM) with vivid mental images, there is a dearth of information about whether the loss of visual imagery in aphantasics affects their AM retrieval. The hippocampus is thought to be a crucial hub in a brain-wide network underlying AM. One important question is whether this network, especially the connectivity of the hippocampus, is altered in aphantasia. In the current study, we tested 14 congenital aphantasics and 16 demographically matched controls in an AM fMRI task to investigate how key brain regions (i.e., hippocampus and visual-perceptual cortices) interact with each other during AM re-experiencing. All participants were interviewed regarding their autobiographical memory to examine their episodic and semantic recall of specific events. Aphantasics reported more difficulties in recalling AM, were less confident about their memories, and described less internal and emotional details than controls. Neurally, aphantasics displayed decreased hippocampal and increased visual-perceptual cortex activation during AM retrieval compared to controls. In addition, controls showed strong negative functional connectivity between the hippocampus and the visual cortex during AM and resting-state functional connectivity between these two brain structures predicted better visualization skills. Our results indicate that visual mental imagery plays an important role in detail-rich vivid AM, and that this type of cognitive function is supported by the functional connection between the hippocampus and the visual-perceptual cortex.
A developmental increase of inhibition promotes the emergence of hippocampal ripples
Authors: Pochinok Irina , Stöber Tristan M. , Triesch Jochen , Chini Mattia , Hanganu-Opatz Ileana L. 
Published: August 2023

AbstractSharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12 days-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of ChR2-transfected CA1 pyramidal neurons only from postnatal day (P) 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response then SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.
Marine heatwaves disrupt ecosystem structure and function via altered food webs and energy flux
Authors: Gomes Dylan G.E. , Ruzicka James J. , Crozier Lisa G. , Huff David D. , Brodeur Richard D. , Stewart Joshua D. 
Published: August 2023

AbstractThe prevalence and intensity of marine heatwaves is increasing globally, disrupting local environmental conditions. The individual and population-level impacts of prolonged heatwaves on marine species have recently been demonstrated, yet whole-ecosystem consequences remain unexplored. We leveraged time series abundance data of 361 taxa, grouped into 86 functional groups, from six long term surveys, diet information from a new diet database, and previous modeling efforts, to build two food web networks using an extension of the popular Ecopath ecosystem modeling framework, Ecotran. We compare ecosystem models parameterized before and after the onset of recent marine heatwaves to evaluate the cascading effects on ecosystem structure and function in the Northeast Pacific Ocean. While the ecosystem-level contribution (prey) and demand (predators) of most functional groups changed following the heatwaves, gelatinous taxa experienced the largest transformations, underscored by the arrival of northward-expanding pyrosomes. We show altered trophic relationships and energy flux have potentially profound consequences for ecosystem structure and function, and raise concerns for populations of threatened and harvested species.