bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced activity of Adenylyl Cyclase 1 Attenuates Morphine Induced Hyperalgesia and Inflammatory Pain in Mice
Authors: Johnson Kayla , Doucette Alexis , Edwards Alexis , Watts Val J. , Klein Amanda H. 
Published: December 2020

AbstractOpioid tolerance and opioid-induced hyperalgesia during repeated opioid administration and chronic pain are associated with upregulation of adenylyl cyclase activity. The objective of this study was to test the hypothesis that a reduction in adenylyl cyclase 1 (AC1) activity or expression would attenuate morphine tolerance and hypersensitivity, and inflammatory pain using murine models. To investigate opioid tolerance and opioid-induced hyperalgesia, mice were subjected to twice daily treatments of saline or morphine using either a static (15 mg/kg, 5 days) or an escalating tolerance paradigm (10-40 mg/kg, 4 days). Systemic treatment with an AC1 inhibitor, ST03437 (5 mg/kg, ip), reduced morphine tolerance and morphine hyperalgesia in mice. Lumbar intrathecal administration of a vector incorporating adeno-associated virus and short-hairpin RNA againstAdcy1reduced morphine induced hypersensitivity compared to control vector treated mice. In contrast, morphine antinociception, along with baseline thermal paw withdrawal latencies, motor performance, exploration in an open field test, and burrowing behaviors were not affected by intrathecalAdcy1knockdown. Knockdown ofAdcy1by intrathecal injection also attenuated inflammatory mechanical hyperalgesia after intraplantar administration of Complete Freund’s Adjuvant (CFA) after one week post injection. ThisAdcy1knockdown strategy also increased burrowing and nesting activity after CFA injection when compared to controls. Together, these data indicate targeting AC1 to mitigate opioid-induced adverse effects, or as a method to treat chronic pain, are appropriate as a clinical approach and further development into generating pharmaceuticals targeting these genes/proteins may prove beneficial in the future.
Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirozaku , Zhan Yingqian A. , Hasan Maysun M. , Meng Fanli , Uddin Fathema , Donoghue Mark , Won Helen H. , Chavan Shweta S. , Chan Joseph M. , Ciampricotti Metamia , Chow Andrew , Offin Michael , Chang Jason C. , Ray-Kirton Jordana , Egger Jacklynn , Bhanot Umesh K. , Silber Joachim , Iacobuzio-Donahue Christine A. , Roehrl Michael H. , Hollmann Travis J. , Yu Helena A. , Rekhtman Natasha , Poirier John T. , Houck-Loomis Brian , Koche Richard P. , Rudin Charles M. , Sen Triparna 
Published: December 2020

ABSTRACTLineage plasticity, a capacity to reprogram cell phenotypic identity under evolutionary pressure, is implicated in treatment resistance and metastasis in multiple cancers. In lung adenocarcinomas (LUADs) amenable to treatment with targeted inhibitors, transformation to an aggressive neuroendocrine (NE) carcinoma resembling small cell lung cancer (SCLC) is a recognized mechanism of acquired resistance. Defining molecular mechanisms of NE transformation in lung cancer has been limited by a paucity of well annotated pre- and post-transformation clinical samples. We hypothesized that mixed histology LUAD/SCLC tumors may capture cancer cells proximal to, and on either side of, histologic transformation. We performed detailed genomic, epigenomic, transcriptomic and proteomic characterization of combined LUAD/SCLC tumors as well as pre- and post-transformation clinical samples. Our data support that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm in pre-transformation LUADs. Consistent shifts in gene expression programs in NE transformation include induction of several stem/progenitor cell regulatory pathways, including upregulation of PRC2 and WNT signaling, and suppression of Notch pathway activity. We observe induction of PI3K/AKT and an immunosuppressive phenotype in NE transformation. Taken together our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.
Normalizing the brain connectome for communication through synchronization
Authors: Petkoski S. , Jirsa V.K. 
Published: December 2020

ABSTRACTNetworks in neuroscience determine how brain function unfolds, and their perturbations lead to psychiatric disorders and brain disease. Brain networks are characterized by their connectomes, which comprise the totality of all connections, and are commonly described by graph theory. This approach is deeply rooted in a particle view of information processing, based on the quantification of informational bits such as firing rates. Oscillations and brain rhythms demand, however, a wave perspective of information processing based on synchronization. We extend traditional graph theory to a dual particle-wave-perspective, integrate time delays due to finite transmission speeds and derive a normalization of the connectome. When applied to the data base of the Human Connectome project, we explain the emergence of frequency-specific network cores including the visual and default mode networks. These findings are robust across human subjects (N=100) and are a fundamental network property within the wave picture. The normalized connectome comprises the particle view in the limit of infinite transmission speeds and opens the applicability of graph theory to a wide range of novel network phenomena, including physiological and pathological brain rhythms. These two perspectives are orthogonal, but not incommensurable, when understood within the novel here proposed generalized framework of structural connectivity.AUTHOR SUMMARYAll networks are composed of nodes and links, forming the structural frame, in which communication occurs. We demonstrate that graph theoretical tools make the implicit assumption of information transmission via exchange of bits, suggesting that the stronger connected nodes are more impactful upon the remainder of the network. This corollary does not extend to communication through oscillations, which is the prominent information carrier in brain networks. We extend traditional network analysis to the oscillatory domain and derive a novel network normalization including descriptive metrics. Along the prototypical example of the brain as a network, we illustrate the consequences of this novel approach and demonstrate that the normalization robustly explains the emergence of the prominent frequency-specific network cores, which cannot be understood within the traditional framework.
THE CIRCADIAN CLOCK IN THE RETINAL PIGMENT EPITHELIUM CONTROLS THE DIURNAL RHYTHM OF PHAGOCYTIC ACTIVITY
Authors: DeVera Christopher , Dixon Jendayi , Chrenek Micah A. , Baba Kenkichi , Iuvone P. Michael , Tosini Gianluca 
Published: December 2020

AbstractThe diurnal peak of phagocytosis by the retinal pigment epithelium (RPE) of photoreceptor outer segments (POS) is under circadian control, and it is believed that this process involves interactions from both the retina and RPE. Previous studies have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. Thereby, the aim of the current study was to determine whether the circadian clock in the retina and or RPE controls the diurnal phagocytic peak of photoreceptor outer segments and whether selective disruption of the circadian clock in the RPE would affect RPE cells function and the viability during aging. To that aim, we first generated and validated an RPE tissue-specific KO of the essential clock gene, Bmal1, and then we determined the daily rhythm in phagocytic activity by the RPE in mice lacking a functional circadian clock in the retina or RPE. Then using electroretinography, spectral domain-optical coherence tomography, and optomotor response measurements of visual function we determined the effect ofBmal1removal in young (6-month old) and old (18-month old) mice. RPE morphology and lipofuscin accumulation was also determined in young and old mice. Our data show that the circadian clock in the RPE controls the daily diurnal phagocytic peak of POS. Surprisingly, the lack of a functional RPE circadian clock or the diurnal phagocytic peak does not result in any detectable age-related degenerative phenotype in the retina or RPE. Thus, our results demonstrate that the loss of the circadian clock in the RPE or the lack of the daily peak in phagocytosis of POS does not result in deterioration of photoreceptors or the RPE during aging.
Early cis-regulatory events in the formation of retinal horizontal cells
Authors: Schick Estie , Gonzalez Kevin C. , Dutta Pooja , Hossain Kazi , Ghinia Tegla Miruna G. , Emerson Mark M. 
Published: December 2020

AbstractDuring retinal development, multipotent and restricted progenitor cells generate all of the neuronal cells of the retina. Among these are horizontal cells, which are interneurons that modulate the light-induced signal from photoreceptors. This study utilizes the identification of novel cis-regulatory elements as a method to examine the gene regulatory networks that direct the development of horizontal cells. Here we describe a screen for cis-regulatory elements, or enhancers, for the horizontal cell-associated genes PTF1A, ONECUT1 (OC1), TFAP2A (AP2A), and LHX1. The OC1ECR22 and Tfap2aACR5 elements were shown to be potential enhancers for OC1 and TFAP2A, respectively, and to be specifically active in developing horizontal cells. The OC1ECR22 element is activated by PTF1A and RBPJ, which translates to regulation of OC1 expression and suggests that PTF1A is a direct activator of OC1 expression in developing horizontal cells. The region within the Tfap2aACR5 element that is responsible for its activation was determined to be a 100 bp sequence named Motif 4. Both OC1ECR22 and Tfap2aACR5 are negatively regulated by the nuclear receptors THRB and RXRG, as is the expression of OC1 and AP2A, suggesting that nuclear receptors may have a role in the negative regulation of horizontal cell development.
LOCAL REGULATION AND FUNCTION OF IMPORTIN-β1 IN HIPPOCAMPAL NEURONS DURING TRANSCRIPTION-DEPENDENT PLASTICITY
Authors: Lee Yan Jun , Navakkode Sheeja , Tan Chee Fan , Sze Siu Kwan , Sajikumar Sreedharan , Ch’ng Toh Hean 
Published: December 2020

SUMMARYActivity-dependent transcription is critical for the encoding of long-term memories. Regulated nuclear entry of soluble proteins is one method to relay synaptic signals to the nucleus to couple neuronal excitation with transcription. To date, the role of importin-β1 in nuclear shuttling of proteins during activity-dependent transcription has always been inferred but not directly investigated. In this study, we demonstrate activity-dependent nuclear accumulation of importin-β1 from the soma and the synapto-dendritic compartments. Importantly, inhibition of importin-β1 mediated nuclear import during synaptic stimulation impairs long-term plasticity. We show evidence that importin-β1 mRNA-ribosome complex is distributed throughout the synapto-dendritic compartment and synaptic stimulation induces importin-β1 local protein synthesis. Finally, we identified candidate proteins that associate with importin-β1 at the synapse and characterize NDRG1 as an importin-β1 interactor that undergoes activity-dependent translocation into the nucleus. Collectively, our results highlight the crucial role of importin-β1 in the nuclear import of soluble proteins during long-term plasticity.
Mapping genetic effects on cell type-specific chromatin accessibility and annotating complex trait variants using single nucleus ATAC-seq
Authors: Benaglio Paola , Newsome Jacklyn , Han Jee Yun , Chiou Joshua , Aylward Anthony , Corban Sierra , Okino Mei-Lin , Kaur Jaspreet , Gorkin David U , Gaulton Kyle J 
Published: December 2020

AbstractGene regulation is highly cell type-specific and understanding the function of non-coding genetic variants associated with complex traits requires molecular phenotyping at cell type resolution. In this study we performed single nucleus ATAC-seq (snATAC-seq) and genotyping in peripheral blood mononuclear cells from 10 individuals. Clustering chromatin accessibility profiles of 66,843 total nuclei identified 14 immune cell types and sub-types. We mapped chromatin accessibility QTLs (caQTLs) in each immune cell type and sub-type which identified 6,248 total caQTLs, including those obscured from assays of bulk tissue such as with divergent effects on different cell types. For 3,379 caQTLs we further annotated putative target genes of variant activity using single cell co-accessibility, and caQTL variants were significantly correlated with the accessibility level of linked gene promoters. We fine-mapped loci associated with 16 complex immune traits and identified immune cell caQTLs at 517 candidate causal variants, including those with cell type-specific effects. At the 6q15 locus associated with type 1 diabetes, in line with previous reports, variant rs72928038 was a naïve CD4+ T cell caQTL linked toBACH2and we validated the allelic effects of this variant on regulatory activity in Jurkat T cells. These results highlight the utility of snATAC-seq for mapping genetic effects on accessible chromatin in specific cell types and provide a resource for annotating complex immune trait loci.
Evolutionary Emergence of First Animal Organisms Triggered by Environmental Mechano-Biochemical Marine Stimulation
Authors: Nguyen Ngoc Minh , Merle Tatiana , Broders Florence , Brunet Anne-Christine , Sarron Florian , Jha Aditya , Genisson Jean-Luc , Rottinger Eric , Farge Emmanuel 
Published: December 2020

AbstractThe evolutionary emergence of the first animals is thought to have been intimately associated to the formation of a primitive endomesodermal gut (i.egastrulation) from ancestral multi-cellular spheres, blastulae, more than 700 million years ago. However, the biochemical cues having been at the origin of endomesoderm formation remain a mystery.Here we find that hydrodynamic mechanical strains developed by sea wavelets on pre-bilaterianNematostella vectensisand pre-metazoanChoanoeca flexarepresentatives, which common ancestor dates back to more than 700 million years ago, can trigger gastrulation in a Myo-II dependent mechanotransductive process. Gastrulation in turn induces endomesoderm first biochemical specification through the mechanical activation of the βcat pathway in pre-bilaterianNematostella vectensis, like in Drosophila and zebrafish embryos, which common ancestor dates back to 600-700 million years ago.These observations converge to animal emergence that has been mechanotransductively triggered by wavelet mechanical strains on the sea-shore in multicellular choanoflagellates through Myo-II more than 700 million years ago, a process achieved in first metazoan through mechanosensitive Y654-containing βcat evolutionary emergence found as conserved in all metazoan.One sentence summaryMarine hydrodynamic strains have activated first gastric organ formation from ancestral pre-animal cell colonies.
Dietary restriction in the long-chain acyl-CoA dehydrogenase knockout mouse
Authors: F. Diekman Eugène , van Weeghel Michel , Suárez-Fariñas Mayte , Argmann Carmen , Ranea-Robles Pablo , Wanders Ronald J.A. , Visser Gepke , van der Made Ingeborg , Creemers Esther E. , Houten Sander M. 
Published: December 2020

AbstractPatients with a disorder of mitochondrial long-chain fatty acid β-oxidation (FAO) have reduced fasting tolerance and may present with hypoketotic hypoglycemia, hepatomegaly, (cardio)myopathy and rhabdomyolysis. Patients should avoid a catabolic state because it increases reliance on FAO as energy source. It is currently unclear whether weight loss through a reduction of caloric intake is safe in patients with a FAO disorder. We used the long-chain acyl-CoA dehydrogenase knockout (LCAD KO) mouse model to study the impact of dietary restriction (DR) on the plasma metabolite profile and cardiac function. For this, LCAD KO and wild type (WT) mice were subjected to DR (70% of ad libitum chow intake) for 4 weeks and compared to ad libitum chow fed mice. We found that DR had a relatively small impact on the plasma metabolite profile of WT and LCAD KO mice. Echocardiography revealed a small decrease in left ventricular systolic function of LCAD KO mice, which was most noticeable after DR, but there was no evidence of DR-induced cardiac remodeling. Our results suggest that weight loss through DR does not have acute and detrimental consequences in a mouse model for FAO disorders.
Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity
Authors: Madhavan Aparajita , Kok Bernard P. , Grandjean Julia M.D. , Albert Verena , Sukiasyan Ara , Rius Bibiana , Powers Evan T. , Galmozzi Andrea , Saez Enrique , Wiseman R. Luke 
Published: December 2020

ABSTRACTIn obesity, overexpression of the IRE1-regulated transcription factor XBP1s protects against metabolic dysfunction by stimulating adaptive remodeling of multiple tissues, most notably the liver.1–5This observation suggests that pharmacologically increasing IRE1/XBP1s signaling might be an attractive approach to mitigate pathologies in obesity and its associated complications.6–8Here, we tested this notion by treating diet-induced obese (DIO) mice with the pharmacologic IRE1/XBP1s activator IXA4.9We show that IXA4 treatment selectively activated protective IRE1/XBP1s signaling in livers of DIO mice without inducing obesity-linked pathologies associated with IRE1 hyperactivity, such as liver inflammation and fibrosis.10,11Chronic IXA4 treatment improved systemic glucose metabolism and feeding-induced insulin action in the liver of DIO mice. These improvements were linked to IRE1/XBP1s-induced remodeling of the liver transcriptome, which dampened glucose production and reduced hepatic steatosis. Further, we show that IXA4 treatment enhanced pancreatic β cell function and insulin homeostasis, indicating that systemic activation of IRE1/XBP1s signaling engendered multi-tissue benefits that integrated to mitigate systemic metabolic dysfunction in DIO mice. Our findings show that selective pharmacological activation of protective IRE1/XBP1s signaling reprograms multiple metabolic tissues, such as liver and pancreas, and represents a potential strategy to correct metabolic alterations in obesity.
A Complex Containing HNRNPA2B1 and N6-methyladenosine Modified Transcripts Mediates Actions of Toxic Tau Oligomers
Authors: Jiang Lulu , Lin Weiwei , Zhang Cheng , Verma Mamta , Kwan Julian , van Vliet Emily , Ash Peter E. A. , Cruz Anna Lourdes , Boudeau Samantha , Maziuk Brandon F. , Lei Shuwen , Song Jaehyup , Alvarez Victor E. , Kayed Rakez , Kanaan Nicholas , Murray Melissa E. , Crary Johnathan F. , Petrucelli Leonard , Li Hu , Emili Andrew , Wolozin Benjamin 
Published: December 2020

SummaryThe microtubule associated protein tau oligomerizes in response to stress and disease, but the function of oligomeric tau (oTau) and the ultimate mechanisms of toxicity are unknown. To gain insights, we have now used Cry2-based optogenetics to induce tau oligomers (oTau-c) in neuronal cultures. oTau-c can seed tau aggregation and biochemical fractionates in a manner similar to oTau. Optical induction of oTau elicits a translational stress response that includes cytoplasmic translocation of the TIA1, abundant stress granules (SGs) and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau. Imaging and immunoprecipitation verify the HNRNPA2B1 association with endogenous oTau in neurons, animal models and human Alzheimer brain tissue. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine modified transcripts (m6A). Knockdown of HNRNPA2B1 prevents oTau from associating with m6A, prevents oTau-induced reductions in protein synthesis and reduces oTau-induced toxicity. Finally, we show striking increases in m6A-oTau and -HNRNPA2B1 complexes in brains of Alzheimer subjects and P301S tau mice. These results reveal a novel complex containing oTau, HNRNPA2B1 and m6A that contributes to the integrated stress response of oTau.HighlightsDevelopment of a powerful method combining optical induction of tau oligomerization with precision mass spectrometry to obtain time resolved evolution of protein interaction networks.Demonstration of a tripartite complex that links tau oligomers with HNRNPA2B1 and N6-methyladenosine modified RNA in cytoplasmic stress granules.Knockdown of HNRNPA2B 1 abrogates the interactions of oTau with N6-methyladenosine modified RNA, as well as inhibits oTau-mediated neurodegeneration.Discovery that N6-methyladenosine modified RNA is significantly increased in the brains of P301S tau transgenic mice and in patients with Alzheimer’s disease.
Redox Imbalance and Biochemical Changes in Cancer by probing redox-sensitive mitochondrial cytochromes in label-free visible resonance Raman imaging
Authors: Abramczyk H. , Brozek-Pluska B. , Kopec M. , Błaszczyk M. , Radek M. 
Published: December 2020

AbstractBackgroundTo monitoring redox state changes and biological mechanisms occurring in mitochondrial cytochromes in cancers improving novel methods are required.MethodsWe used Raman spectroscopy and Raman imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo human brain and breast tissues at 532 nm, 633 nm, 785 nm.ResultsWe identified the oncogenic processes that characterize human infiltrating ductal carcinoma (IDC) and human brain tumors: gliomas; astrocytoma and medulloblastoma based on the quantification of cytochrome redox status by exploiting the resonance-enhancement effect of Raman scattering. We visualized localization of cytochromes by Raman imaging in the breast and brain tissues and analyzed cytochrome c vibrations at 750, 1126, 1337 and 1584 cm-1as a function of malignancy grade. We found that the concentration of reduced cytochrome c becomes abnormally high in human brain tumors and breast cancers and correlates with the grade of cancer aggressiveness.ConclusionsWe showed that Raman imaging provides additional insight into the biology of astrocytomas and breast ductal invasive cancer, which can be used for noninvasive grading, differential diagnosis, delineation of tumor extent, planning of surgery, and radiotherapy and post-treatment monitoring.Simple SummaryGliomas comprise around 30% of human brain tumors, while invasive ductal carcinoma (IDC) comprises around 80% of human breast cancers. The aim of our study was to show that cancerogenesis affects the redox status of mitochondrial cytochromes, which can be tracked by using Raman spectroscopy and imaging. We have shown the correlation between the intensity of cytochromes Raman bands at 750, 1126, 1337 and 1584 cm-1and malignancy grade for brain and breast cancers.Graphical Abstract