bluuebunny/crossref_metadata_2025_split huggingface dataset:
SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology
Authors: Shen Wei-Bin , Elahi Montasir , Logue James , Yang Penghua , Baracco Lauren , Reece E. Albert , Wang Bingbing , Li Ling , Blanchard Thomas G , Han Zhe , Rissman Robert A , Frieman Matthew B , Yang Peixin 
Published: February 2022

AbstractThe neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still in debate. Long COVID manifests with “brain diseases” and the cause of these brain dysfunction is mysterious. Here, we analyze 34 age- and underlying disease-matched COVID-19 or non-COVID-19 human brains. SARS-CoV-2 RNA, nucleocapsid, and spike proteins are present in neurons of the cognitive centers of all COVID-19 patients, with its non-structural protein NSF2 detected in adult cases but not in the infant case, indicating viral replications in mature neurons. In adult COVID-19 patients without underlying neurodegeneration, SARS-CoV-2 infection triggers Aβ and p-tau deposition, degenerating neurons, microglia activation, and increased cytokine, in some cases with Aβ plaques and p-tau pretangles. The number of SARS-CoV-2+ cells is higher in patients with neurodegenerative diseases than in those without such conditions. SARS-CoV-2 further activates microglia and induces Aβ and p-tau deposits in non-Alzheimer’s neurodegenerative disease patients. SARS-CoV-2 infects mature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s disease (AD) individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers AD-like gene programs in healthy neurons and exacerbates AD neuropathology. An AD infectious etiology gene signature is identified through SARS-CoV-2 infection and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, our data suggest that SARS-CoV-2 invades the brain and activates an AD-like program.
Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries
Authors: Arhontoulis Dimitrios C , Kerr Charles , Richards Dylan , Tjen Kelsey , Hyams Nathaniel , Jones Jefferey A. , Deleon-Pennell Kristine , Menick Donald , Lindner Diana , Westermann Dirk , Mei Ying 
Published: February 2022

AbstractAcute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1βis an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1 β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1β treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1β treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.
Growth cone macropinocytosis of neurotrophin receptor and neuritogenesis are regulated by Neuron Navigator 1
Authors: Powers Regina M. , Daza Ray , Koehler Alanna E. , Julien  , Calabrese Barbara , Hevner Robert F. , Halpain Shelley 
Published: February 2022

ABSTRACTNeuron Navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone, and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin BDNF (brain-derived neurotropic factor). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.
PDX models of relapsed pediatric AML preserve global gene expression patterns and reveal therapeutic targets
Authors: Wunderlich Mark , Chen Jing , Sexton Christina , Manning Nicole , Byerly Luke , O’Brien Eric , Perentesis John P. , Mulloy James C. , Mizukawa Benjamin 
Published: February 2022

AbstractAs patient-derived xenograft (PDX) models of acute myeloid leukemia (AML) become increasingly common tools for preclinical evaluation of targeted therapies it becomes important to consider the fidelity with which this system recapitulates the disease state found in patients. Gene expression profiling of patient blasts has been successfully used to identify distinct subtypes of AML to uncover sub-type specific vulnerabilities and to predict response to therapy and outcomes. Currently, there is little information regarding how well PDX models of AML mimic global gene expression patterns found in patients. In order to address this point, we performed detailed RNA-Seq analysis of data obtained from a diverse series of pediatric AML PDXs, separately and compared to primary patient data. When unsupervised clustering was applied to the PDX sample dataset, we found grouping associated with KMT2A (MLL) gene status. Additionally, in combined analysis, PDX samples were found to align with primary patient samples harboring similar genetics. We found a strong correlation of expression levels of nearly all expressed transcripts in PDX and patient datasets thus demonstrating faithful recapitulation of gene expression signatures. Furthermore, paired patient/PDX samples showed strong concordance, suggesting retention of sample-specific gene expression in immune deficient mice. Comparisons of PDX models propagated in NOD/SCID/IL2rg-/-(NSG) mice compared to NSG mice with transgenic expression of human SCF, GM-CSF, and IL-3 (NSGS) revealed minimal differences related to increased JAK/STAT and macrophage activation pathways in NSGS. Additionally, a unique RAM immunophenotype associated expression signature pointed to discovery of cryptic CBFA2T3-GLIS2 rearrangement as the mechanistic driver mutation in two PDX models. Based on the relatively high BCL2 mRNA in these models, we tested the efficacy of venetoclax in combination with CPX-351 which resulted in reduced leukemia burden and prolonged survival. These results validate the PDX system as surrogate of the molecular signatures in high-risk pediatric AML and highlight this system’s utility for pre-clinical therapeutic discovery, especially in very rare subtypes of disease.
Anti-seed PNAs targeting multiple oncomiRs for brain tumor therapy
Authors: Wang Yazhe , Malik Shipra , Suh Hee-Won , Xiao Yong , Deng Yanxiang , Fan Rong , Huttner Anita , Bindra Ranjit S , Saltzman W Mark , Bahal Raman 
Published: February 2022

ABSTRACTGlioblastoma (GBM) is one of the most lethal malignancies in the United States with poor survival and high recurrence rates, suggesting the need for approaches targeting the most important molecular drivers of tumor growth. Here, we aimed to simultaneously target oncomiRs 10b and 21, which have been reported to drive the aggressive growth and invasiveness of GBM. We designed short (8-mer bases) gamma-(γ)-modified peptide nucleic acids (sγPNAs), which target the seed region of oncomiRs 10b and 21 with high affinity. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG); the NPs were also functionalized with aldehydes to produce bioadhesive NPs. We have previously shown that these bioadhesive NPs (BNPs) produce superior transfection efficiency, with a tropism for tumor cells. The sγPNA BNPs showed superior anti-miR efficacy in comparison to the regular full length PNA BNPs in vitro. When combined with temozolomide, sγPNA BNPs administered via convention-enhanced delivery (CED) inhibited the growth of intracranial tumors and significantly improved the survival of animals (>120 days). RNA sequencing analysis revealed the role of vascular endothelial growth factor A (VEGFA) and integrin beta 8 (ITGB8), direct targets of both miR-10b and miR-21, in mediating the tumor growth. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs is a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor specific oncomiRs.SummaryTargeting oncomiRs 21 and 10b to improve GBM survivalGlioblastoma (GBM) is an aggressive malignant disorder with high recurrence rates and poor survival. Here, we aimed to simultaneously inhibit two aberrant oncomiRs—miR 21 and miR 10b—which have been previously associated with GBM invasiveness and progression. We synthesized short, gamma-modified peptide nucleic acids (sγPNA) targeted to the miR seed regions and loaded the sγPNAs into bioadhesive nanoparticles (BNPs). When the sγPNA-BNPs were added to cultured tumor cells, we observed significant reduction of target oncomiRs and increase of apoptosis in vitro. When delivered in vivo by convection-enhanced delivery, sγPNA BNPs dramatically increased the survival in two orthotopic (intracranial) mouse models of GBM. Moreover, the combination of sγPNA BNPs with temozolomide (TMZ) increased the survival of mice with GBM beyond the planned endpoint (120 days) with significant improvements in histopathology. The proposed strategy of sγPNA BNP with TMZ provides an alternative, promising approach for treatment of GBM.
Vitamin D receptor cistrome-transcriptome analyses establishes quantitatively distinct receptor genomic interactions in African American prostate cancer regulated by BAZ1A
Authors: Siddappa Manjunath , Hussain Shahid , Wani Sajad A. , Tang Hancong , Gray Jaimie S. , Jafari Hedieh , Wu Hsuchang , Long Mark D. , Elhussin Isra , Karanam Balasubramanyam , Wang Honghe , Morgan Rebecca , Hardiman Gary , Adelani Isaacson B. , Rotimi Solomon O. , Murphy Adam R , Nonn Larisa , Davis Melissa B , Kittles Rick A , Halbert Chanita Hughes , Sucheston-Campbell Lara E. , Yates Clayton , Campbell Moray J. 
Published: February 2022

ABSTRACTBackgroundAfrican American (AA) prostate cancer (PCa) appears uniquely sensitive to 1α,25(OH)2D3 signaling, compared to European American (EA) PCa, but the extent and impact of vitamin D receptor genomic functions remain poorly defined.ResultsA panel of EA and AA prostate epithelial cells (EA: HPr1-AR, LNCaP, AA: RC43N, RC43T, RC77N, RC77T) were analyzed with RIME to reveal the cell-specific composition of the VDR- complex. 1α,25(OH)2D3-dependent ATAC-Seq revealed the greatest impact on nucleosome positioning in RC43N and RC43T, with gain of nucleosome-free at enhancer regions. VDR ChIP-Seq identified stronger and more frequent VDR binding in RC43N and RC43T that was enriched for a larger and distinct motif repertoire, than EA cells. VDR binding significantly overlapped with core circadian rhythm transcription factors in AA cell line models. RNA-Seq also revealed significantly stronger 1α,25(OH)2D3 dependent VDR transcriptional responses enriched for circadian rhythm and inflammation networks in AA cells. Whilst RC43N was most responsive, RC43T displayed distorted responses. Significantly reduced BAZ1A/SMARCA5 in AA PCa samples was identified, and restored BAZ1A expression uniquely and significantly increased 1α,25(OH)2D3-regulated VDR targets in AA cells. These VDR- dependent cistrome-annotated genes were also uniquely and most significantly identified in three cohorts of AA PCa patients.ConclusionThese data suggest VDR transcriptional control in the prostate is more potent and dynamic in AA men, and primed to govern inflammatory and circadian pathways. Reduced BAZ1A/SMARCA5 expression and/or reduced environmentally-regulated serum vitamin D3 levels suppress these actions. Therefore, the VDR axis lies at the cross-roads of biopsychosocial processes including stress responses, access to quality early detection and treatment, social determinants and that collectively contribute to PCa health disparities.
Striatal dopamine encodes the relationship between actions and reward
Authors: Hart G. , Burton T.J. , Nolan C.R. , Balleine B.W. 
Published: February 2022

AbstractAlthough the role of striatal dopamine in Pavlovian conditioning and in habits has been reasonably well described, relatively little is known about its function in goal-directed action. In this study we trained hungry rats on two lever press actions for distinct food outcomes and recorded dopamine release in the dorsomedial striatum as these action-outcome associations were encoded and subsequently degraded. During initial training the lever press actions generated bilateral dopamine release that was found to reflect the predicted action value. This value was updated by the prediction error generated by the feedback produced by contact with the outcome, or its absence, after the press. Importantly, hemispheric dopamine release became increasingly lateralized across the course of training, with greater release in the hemisphere contralateral to the press. Using video analysis and multiple different measures, we could find no evidence that the degree of lateralized release was associated with movement; rather, we found that it tracked the strength of the action-outcome association, increasing and decreasing with increments and decrements in the contingency between specific actions and their consequences. Similar results emerged whether the rewards were delivered on ratio or interval schedules of reinforcement and whether we used unpaired outcome delivery or outcome-identity reversal to modify the specific contingencies. These findings suggest that, whereas moment-to-moment fluctuations in action value are reflected in bilateral dopamine release, a second signal broadcasts the overall strength of specific action-outcome relationships via the difference between contralateral and ipsilateral release during actions.
Profilin 1 deficiency drives mitotic defects and impairs genome stability
Authors: Scotto di Carlo Federica , Russo Sharon , Muyas Francesc , Mangini Maria , Pazzaglia Laura , Biamonte Flavia , De Luca Anna Chiara , Scotlandi Katia , Cortés-Ciriano Isidro , Gianfrancesco Fernando 
Published: February 2022

AbstractProfilin 1 –encoded by PFN1– is a small actin-binding protein with a tumour suppressive role in various adenocarcinomas and pagetic osteosarcomas. However, its contribution to tumour development is not fully understood. Using fix and live cell imaging, we report that Profilin 1 inactivation results in multiple mitotic defects, manifested prominently by anaphase bridges, multipolar spindles, misaligned and lagging chromosomes, and cytokinesis failures. Accordingly, next-generation sequencing technologies highlighted that Profilin 1 knock-out cells display extensive copy-number alterations, which are associated with complex genome rearrangements and chromothripsis events in primary pagetic osteosarcomas with Profilin 1 inactivation. Mechanistically, we show that Profilin 1 is recruited to the spindle midzone at anaphase, and its deficiency reduces the supply of actin filaments to the cleavage furrow during cytokinesis. The mitotic defects are also observed in mouse embryonic fibroblasts and mesenchymal cells deriving from a newly generated knock-in mouse model harbouring a Pfn1 loss-of-function mutation. Furthermore, nuclear atypia is also detected in histological sections of mutant femurs. Thus, our results indicate that Profilin 1 has a role in regulating cell division, and its inactivation triggers mitotic defects, one of the major mechanisms through which tumour cells acquire chromosomal instability.
Universal structural requirements for maximal robust perfect adaptation in biomolecular networks
Authors: Gupta Ankit , Khammash Mustafa 
Published: February 2022

AbstractConsider a biomolecular reaction network that exhibits robust perfect adaptation to disturbances from several parallel sources. The well-known Internal Model Principle of control theory suggests that such systems must include a subsystem (called the “internal model”) that is able to recreate the dynamic structure of the disturbances. This requirement poses certain structural constraints on the network which we elaborate in this paper for the scenario where constant-in-time disturbances maximally affect network interactions and there is model uncertainty and possible stochasticity in the dynamics. We prove that these structural constraints are primarily characterized by a simple linear-algebraic stoichiometric condition which remains the same for both deterministic and stochastic descriptions of the dynamics. Our results reveal the essential requirements for maximal robust perfect adaptation in biology, with important implications for both systems and synthetic biology. We exemplify our results through many known examples of robustly adapting networks and we construct new examples of such networks with the aid of our linear-algebraic characterization.
Keratin 8 is a scaffolding and regulatory protein of ERAD complexes
Authors: Pranke Iwona M. , Chevalier Benoit , Premchandar Aiswarya , Baatallah Nesrine , Tomaszewski Kamil F. , Bitam Sara , Tondelier Danielle , Golec Anita , Stolk Jan , Lukacs Gergely L. , Hiemstra Pieter S. , Dadlez Michal , Lomas David A. , Irving James A. , Delaunay-Moisan Agnes , van Anken Eelco , Hinzpeter Alexandre , Sermet-Gaudelus Isabelle , Edelman Aleksander 
Published: February 2022

AbstractEarly recognition and enhanced degradation of misfolded proteins by the endoplasmic reticulum (ER) quality control and ER-associated degradation (ERAD) cause defective protein secretion and membrane targeting, as exemplified for Z-alpha 1 antitrypsin (Z-A1AT), responsible for alpha-1-antitrypsin deficiency (A1ATD) and F508del-CFTR (cystic fibrosis transmembrane conductance regulator) responsible for cystic fibrosis (CF).Prompted by our previous observation that decreasing Keratin 8 (K8) expression increased trafficking of F508del-CFTR to the plasma membrane, we investigated whether K8 impacts trafficking of soluble misfolded Z-A1AT protein. The subsequent goal of this study was to elucidate the mechanism underlying the K8-dependent regulation of protein trafficking, focusing on the ERAD pathway.The results show that diminishing K8 concentration in HeLa cells enhances secretion of both Z-A1AT and wild type (WT) A1AT with a 13-fold and 4-fold increase, respectively. K8 down-regulation triggers ER failure and cellular apoptosis when ER stress is jointly elicited by conditional expression of the μsheavy chains, as previously shown for Hrd1 knock-out. Simultaneous K8 silencing and Hrd1 knock-out did not show any synergistic effect, consistent with K8 acting in the Hrd1-governed ERAD step. Fractionation experiments reveal that K8 is recruited to ERAD complexes containing Derlin2, Sel1 and Hrd1 proteins upon expression of Z/WT-A1AT and F508del-CFTR. Treatment of the cells with c407, a small molecule inhibiting K8 interaction, decreases K8 and Derlin2 recruitment to high-order ERAD complexes. This was associated with increased Z-A1AT secretion in both HeLa and Z-homozygous A1ATD patients’ respiratory cells. Overall, we provide evidence that K8 acts as an ERAD modulator. It may play a scaffolding protein role for early-stage ERAD complexes, regulating Hrd1-governed retrotranslocation initiation/ubiquitination processes. Targeting K8-containing ERAD complexes is an attractive strategy for the pharmacotherapy of A1ATD.
Evidence for close molecular proximity between reverting and undifferentiated cells
Authors: Zreika Souad , Fourneaux Camille , Vallin Elodie , Modolo Laurent , Seraphin Rémi , Moussy Alice , Ventre Elias , Bouvier Matteo , Ozier-Lafontaine Anthony , Bonnaffoux Arnaud , Picard Franck , Gandrillon Olivier , Giraud Sandrine 
Published: February 2022

AbstractAccording to Waddington’s epigenetic landscape concept, the differentiation process can be illustrated by a cell akin to a ball rolling down from the top of a hill (proliferation state) and crossing furrows before stopping in basins or “attractor states” to reach its stable differentiated state. However, it is now clear that some committed cells can retain a certain degree of plasticity and reacquire phenotypical characteristics of a more pluripotent cell state. In line with this dynamic model, we have previously shown that differentiating cells (chicken erythrocytic progenitors (T2EC)) retain for 24 hours the ability to self-renew when transferred back in self-renewal conditions. Despite those intriguing and promising results, the underlying molecular state of those “reverting” cells remains unexplored. The aim of the present study was therefore to molecularly characterize the T2EC reversion process by combining advanced statistical tools to make the most of single cell transcriptomic data. For this purpose, T2EC, initially maintained in a self-renewal medium (0H), were induced to differentiate for 24h (24H differentiating cells); then a part of these cells was transferred back to the self-renewal medium (48H reverting cells) and the other part was maintained in the differentiation medium for another 24h (48H differentiating cells). For each time point, cell transcriptomes were generated using scRT-qPCR and scRNAseq. Our results showed a strong overlap between 0H and 48H reverting cells when applying dimensional reduction. Moreover, the statistical comparison of cell distributions and differential expression analysis indicated no significant differences between these two cell groups. Interestingly, gene pattern distributions highlighted that, while 48H reverting cells have gene expression pattern more similar to 0H cells, they retained traces of their engagement in the differentiation process. Finally, Sparse PLS analysis showed that only the expression of 3 genes discriminates 48H reverting and 0H cells. Altogether, we show that reverting cells return to an earlier molecular state almost identical to undifferentiated cells and demonstrate a previously undocumented physiological and molecular plasticity during the differentiation process, which most likely results from the dynamic behavior of the underlying molecular network.