bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner
Authors: Bayik Defne , Zhou Yadi , Park Chihyun , Hong Changjin , Vail Daniel , Silver Daniel J. , Lauko Adam J. , Roversi Gustavo A. , Watson Dionysios C. , Lo Alice , Alban Tyler J. , McGraw Mary , Sorensen Mia D. , Grabowski Matthew M. , Otvos Balint , Vogelbaum Michael A. , Horbinski Craig M. , Kristensen Bjarne Winther , Khalil Ahmad M. , Hwang Tae Hyun , Ahluwalia Manmeet S. , Cheng Feixiong , Lathia Justin D. 
Published: February 2020

AbstractMyeloid-derived suppressor cells (MDSCs) that block anti-tumor immunity are elevated in glioblastoma (GBM) patients. However, the distinct contribution of monocytic (mMDSC) versus granulocytic (gMDSC) subsets has yet to be determined. We observed that mMDSCs were enriched in the male tumor microenvironment, while gMDSCs were elevated in the circulation of female GBM models. Depletion of peripheral gMDSCs extended the survival only in female mice. Using gene expression signatures coupled with network medicine analysis, we demonstrated in pre-clinical models that mMDSCs could be targeted with anti-proliferative agents in males, whereas gMDSC function in females could be inhibited by IL-1β blockade. Analysis of patient data confirmed that proliferating mMDSCs were the predominant population in male tumors, and that a high gMDSC/IL-1β gene signature correlated with poor prognosis of female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM.Statement of SignificanceSexual dimorphism at the level of MDSC subset prevalence, localization and gene expression profile comprises a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSC in males, while IL-1 pathway inhibitors can provide benefit to females through blockade of gMDSC function.
Ras-GRF1 in CRF Cells Controls the Early Adolescent Female Response to Repeated Stress
Authors: Jin Shan-xue , Dickson David A. , Maguire Jamie , Feig Larry A. 
Published: February 2020

ABSTRACTRas-GRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates Ras and Rac GTPases. In hippocampal neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed that GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after exposure to 7-days of restraint-stress (7DRS) (30 min/day) elevation of serum CORT levels are suppressed in early adolescent (EA) female, but not EA male or adult female GRF1 knockdown mice. Here, we show that this phenotype is due, at least in part, to the loss of GRF1 expression in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockdown specifically in these cells also reduces serum CORT response to 7DRS in EA females, but not EA males or adult females. Moreover, it reduces females CORT levels to those to found in comparably stressed control male mice. GRF1 knockdown in CRF cells also blocks the anxiolytic phenotype normally found in EA females 24 hrs after 7DRS. Interestingly, loss of GRF1 in these cells has no effect after only 3 exposures to restraint stress, revealing a role for GRF1 in repeated stress-induced CRF cell plasticity that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response early-adolescent female display to repeated stress.
Fast retrograde access to projection neuron circuits underlying vocal learning in songbirds
Authors: Düring DN , Dittrich F , Rocha MD , Tachibana RO , Mori C , Okanoya K , Boehringer R , Ehret B , Grewe BF , Rauch M , Paterna JC , Kasper R , Gahr M , Hahnloser RHR 
Published: February 2020

SummaryUnderstanding the structure and function of neural circuits underlying speech and language is a vital step towards better treatments for diseases of these systems. Songbirds, among the few animal orders that share with humans the ability to learn vocalizations from a conspecific, have provided many insights into the neural mechanisms of vocal development. However, research into vocal learning circuits has been hindered by a lack of tools for rapid genetic targeting of specific neuron populations to meet the quick pace of developmental learning. Here, we present a new viral tool that enables fast and efficient retrograde access to projection neuron populations. In zebra finches, Bengalese finches, canaries, and mice, we demonstrate fast retrograde labeling of cortical or dopaminergic neurons. We further demonstrate the suitability of our construct for detailed morphological analysis, forin vivoimaging of calcium activity, and for multicolor brainbow labeling.
Portuguese wild grapevine genome re-sequencing (Vitis vinifera sylvestris)
Authors: Ramos Miguel J N , Coito João L , Silva David F , Cunha Jorge , Costa M Manuela R , Amâncio Sara , Rocheta Margarida 
Published: February 2020

ABSTRACTVitisis a relevant genus worldwide. The genome of aVitis viniferarepresentative (PN40024) published in 2007 boosted grapevine related studies. While this reference genome is a suitable tool for the overall studies in the field, it lacks the ability to unveil changes accumulated duringV. viniferadomestication. Considering that grapevines for wine production (V. v. vinifera, hereaftervinifera) have evolved fromV. v. sylvestris(hereaftersylvestris), or from a shared no-longer existing ancestor, both subspecies are quite close, butsylvestrishas not been domesticated and still exist nowadays, preserving wild characteristics, making it a good material to provide insights intoviniferadomestication. The difference in the reproductive strategy between both subspecies is one of the characteristics that sets them apart. Whileviniferaflowers are hermaphrodite with functional male and female organs,sylvestrisis mostly dioecious. Male plants present flowers lacking functional carpels unable to produce grapes and female individuals have flowers with reflexed stamens producing infertile pollen but able to exhibit small and acidic grapes. In this paper, we describe the re-sequencing of the genomes from a male and a female individual of the wildsylvestrisand its comparison against the referenceviniferagenome.
Simple models including energy and spike constraints reproduce complex activity patterns and metabolic disruptions
Authors: Fardet Tanguy , Levina Anna 
Published: February 2020

AbstractIn this work, we introduce new phenomenological neuronal models (eLIF and mAdExp) that account for energy supply and demand in the cell as well as the inactivation of spike generation how these interact with subthreshold and spiking dynamics. Including these constraints, the new models reproduce a broad range of biologically-relevant behaviors that are identified to be crucial in many neurological disorders, but were not captured by commonly used phenomenological models. Because of their low dimensionalityeLIF and mAdExp open the possibility of future large-scale simulations for more realistic studies of brain circuits involved in neuronal disorders. The new models enable both more accurate modeling and the possibility to study energy-associated disorders over the whole time-course of disease progression instead of only comparing the initially healthy status with the final diseased state. These models, therefore, provide new theoretical and computational methods to assess the opportunities of early diagnostics and the potential of energy-centered approaches to improve therapies.Author summaryNeurons, even “at rest”, require a constant supply of energy to function. They cannot sustain high-frequency activity over long periods because of regulatory mechanisms, such as adaptation or sodium channels inactivation, and metabolic limitations. These limitations are especially severe in many neuronal disorders, where energy can become insufficient and make the neuronal response change drastically, leading to increased burstiness, network oscillations, or seizures. Capturing such behaviors and impact of energy constraints on them is an essential prerequisite to study disorders such as Parkinson’s disease and epilepsy. However, energy and spiking constraints are not present in any of the standard neuronal models used in computational neuroscience. Here we introduce models that provide a simple and scalable way to account for these features, enabling large-scale theoretical and computational studies of neurological disorders and activity patterns that could not be captured by previously used models. These models provide a way to study energy-associated disorders over the whole time-course of disease progression, and they enable a better assessment of energy-centered approaches to improve therapies.
Prediction of Essential Binding Domains for the Endocannabinoid N-Arachidonoylethanolamine (AEA) in the Brain Cannabinoid CB1 receptor
Authors: Shim Joong-Youn 
Published: February 2020

Abstract∆9-tetrahydrocannabinol (∆9-THC), the main active ingredient ofCannabis sativa(marijuana), interacts with the human brain cannabinoid (CB1) receptor and mimics pharmacological effects of endocannabinoids (eCBs)N-arachidonylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG). Given recent intriguing findings that some allosteric modulators can enhance selectively the AEA-activated CB1 receptor, it is imperative to determine the structure of the AEA-bound CB1 receptor. However, due to its highly flexible nature of AEA, establishing its binding mode to the CB1 receptor is elusive. The aim of the present study was to explore many possible binding conformations of AEA within the binding pocket of the CB1 receptor that is confirmed in the recently available X-ray crystal structures of the agonist-bound CB1 receptors and predict essential AEA binding domains. We performed long time molecular dynamics stimulations of plausible AEA docking poses until its receptor binding interactions became optimally established. Our simulation results revealed that AEA favors to bind to the hydrophobic channel of the CB1 receptor, suggesting that the hydrophobic channel holds essential significance in AEA binding to the CB1 receptor. Our results also suggest that the H2/H3 region of the CB1 receptor is an AEA binding subsite privileged possibly over the H7 region. The results of the present study contribute to identifying the (hidden) allosteric site(s) of the CB1 receptor in our immediate future study.
Endonuclease activity of RecJ from extremely alkaliphilic Bacillus alcalophilus
Authors: Zheng Minggang , Wang Wen , Ma Liya , Wang Ling , Qu Lingyun , Liu Xipeng , Liu Hailiang 
Published: February 2020

ABSTRACTAt present, all documented RecJs are exonucleases, degrading single-stranded nucleic acids. Here, we report a novel RecJ, from the extremely alkaliphilic bacteriumBacillus alcalophilus(BaRecJ), which possesses endonuclease activity and can cleave supercoiled DNA. BaRecJ contains the typical DHH and DHHA1 domains, which are conserved in all RecJs, and a functionally unknown PIWI-like domain at the C-terminus. The endonuclease activity originates from the C-terminal domain of BaRecJ which contains PIWI-like domain, and the exonuclease activity from the DHH and DHHA1 domains. Mutational analysis reveals that several important residues affect the endonuclease activity of BaRecJ. Moreover, BaRecJ cleaves specific target sequences at moderate temperature when directed by a phosphorothioate-modified single-stranded DNA (S-modified ssDNA) guide. These findings suggest that BaRecJ is substantially different from any reported RecJs and has the potential to be developed as a new gene editing tool.
A novel drug-combination screen in zebrafish identifies epigenetic small molecule candidates for Duchenne muscular dystrophy
Authors: Farr Gist H. , Morris Melanie , Gomez Arianna , Pham Thao , Parker Elizabeth U. , Kilroy Elisabeth , Said Shery , Henry Clarissa , Maves Lisa 
Published: February 2020

SummaryDuchenne muscular dystrophy (DMD) is a severe neuromuscular disorder and is one of the most common muscular dystrophies. There are currently few effective therapies to treat the disease, although many small-molecule approaches are being pursued. Specific histone deacetylase inhibitors (HDACi) can ameliorate DMD phenotypes in mouse and zebrafish animal models and have also shown promise for DMD in clinical trials. However, beyond these HDACi, other classes of epigenetic small molecules have not been broadly and systematically studied for their benefits for DMD. Here, we performed a novel chemical screen of a library of epigenetic compounds using the zebrafishdmdmodel. We identified candidate pools of epigenetic compounds that improve skeletal muscle structure indmdzebrafish. We then identified a specific combination of two drugs, oxamflatin and salermide, that significantly rescueddmdzebrafish skeletal muscle degeneration. Furthermore, we validated the effects of oxamflatin and salermide in an independent laboratory. Our results provide novel, effective methods for performing a combination small-molecule screen in zebrafish. Our results also add to the growing evidence that epigenetic small molecules may be promising candidates for treating DMD.
Sox17 and β-catenin co-occupy Wnt-responsive enhancers to govern the endodermal gene regulatory network
Authors: Mukherjee Shreyasi , Chaturvedi Praneet , Rankin Scott A. , Fish Margaret B. , Wlizla Marcin , Paraiso Kitt D. , MacDonald Melissa , Chen Xiaoting , Weirauch Matthew T. , Blitz Ira L. , Cho Ken W. Y. , Zorn Aaron M. 
Published: February 2020

ABSTRACTLineage specification is governed by gene regulatory networks (GRNs) that integrate the activity of signaling effectors and transcription factors (TFs) on enhancers. Sox17 is a key transcriptional regulator of definitive endoderm development, and yet, its genomic targets remain largely uncharacterized. Here, using genomic approaches and epistasis experiments, we define the Sox17-governed endoderm GRN inXenopusgastrulae. We show that Sox17 functionally interacts with the canonical Wnt pathway to specify and pattern the endoderm while repressing alternative mesectoderm fates. Sox17 and β-catenin co-occupy hundreds of key enhancers. In some cases, Sox17 and β-catenin synergistically activate transcription independent of Tcfs, whereas on other enhancers, Sox17 represses ß-catenin/Tcf-mediated transcription to spatially restrict gene expression domains. Our findings establish Sox17 as a tissue-specific modifier of Wnt responses and point to a novel paradigm where genomic specificity of Wnt/ß-catenin transcription is determined through functional interactions between lineage-specific Sox TFs and ß-catenin/Tcf transcriptional complexes. Given the ubiquitous nature of Sox TFs and Wnt signaling, this mechanism has important implications across a diverse range of developmental and disease contexts.Key findingsSox17 regulates germ layer segregation by promoting endoderm differentiation while simultaneously repressing mesectoderm fates.Functional interactions between Sox17 and canonical Wnt-signaling is a major feature of the GRN controlling endoderm specification and patterning.Sox17 and β-catenin co-occupy a subset of enhancers to synergistically stimulate transcription in the absence of Tcfs.Sox17 regulates the spatial expression domains of Wnt/β-catenin-responsive transcription in the gastrula.
C. elegansnuclear RNAi factor SET-32 deposits the transgenerational heritable histone modification, H3K23me3
Authors: Schwartz-Orbach Lianna , Zhang Chenzhen , Sidoli Simone , Amin Richa , Kaur Diljeet , Zhebrun Anna , Ni Julie , Gu Sam 
Published: February 2020

AbstractNuclear RNAi provides a highly tractable system to study RNA-mediated chromatin changes and epigenetic inheritance. Recent studies have indicated that the regulation and function of nuclear RNAi-mediated heterochromatin are highly complex. Our knowledge of histone modifications and the corresponding histone modifying enzymes involved in the system remains limited. In this study, we show that the heterochromatin mark, H3K23me3, is induced by nuclear RNAi at both exogenous and endogenous targets inC. elegans. In addition, dsRNA-induced H3K23me3 can be inherited for four generations. We demonstrate that the histone methyltransferase SET-32, methylates H3K23in vitro. Bothset-32and the germline nuclear RNAi Argonaute,hrde-1, are required for nuclear RNAi-induced H3K23me3in vivo. Our data poise H3K23me3 as an additional chromatin modification in the nuclear RNAi pathway and provides the field with a new target for uncovering the role of heterochromatin in transgenerational epigenetic silencing.
Units of motor production: Bengalese finches interrupt song within syllables
Authors: Riedner D. , Adam I. 
Published: February 2020

AbstractBirdsong consists of syllables that are separated by silent intervals. Previous work in zebra finches showed that syllables correspond to the smallest motor production units (Cynx, 1990; Franz and Goller, 2002) by inducing song stops using strobe light. In this study, we interrupted the song of six Bengalese finches experimentally with the bird’s own song as auditory stimulus using an interactive playback approach. Five of the tested males interrupted their ongoing vocalizations within syllables (16 instances of induced interrupted syllables) in response to the playback. Additionally, we observed 9 spontaneous interruptions in our control recordings. This study establishes that birds can interrupt ongoing syllables within extremely short latencies in response to an auditory stimulus, and that auditory stimuli interrupt syllables more effectively than visual stimuli. Even if syllables are the functionally stable production units, the ability to disrupt those units differs between species and individuals, indicating various degrees of vocal control.
Quantitative dialing of gene expression via precision targeting of KRAB repressor
Authors: Wilken Matthew S. , Ciarlo Christie , Pearl Jocelynn , Schanzer Elaine , Liao Hanna , Biber Benjamin Van , Queitsch Konstantin , Bloom Jordan , Federation Alexander , Acosta Reyes , Vong Shinny , Otterman Ericka , Dunn Douglass , Wang Hao , Zrazhevskiy Pavel , Nandakumar Vivek , Bates Daniel , Sandstrom Richard , Urnov Fyodor D. , Funnell Alister , Green Shon , Stamatoyannopoulos John A. 
Published: February 2020

AbstractHuman genes are regulated quantitatively, yet the ability to specify the expression level of a native gene accurately and specifically using a defined reagent has remained elusive. Here we show that precise targeting of KRAB repressive domain within regulatory DNA unlocks an endogenous quantitative ‘dial’ that can be engaged at nucleotide resolution to program expression levels across a wide physiologic range, with single-gene specificity and high reproducibly in primary cells.
Assessment of mitochondrial physiology of murine white adipose tissue by mechanical permeabilization and lipid depletion
Authors: Romeiro Natália C. , Ferreira Caroline M. , Oliveira Marcus F. 
Published: February 2020

AbstractWhite adipose tissue (WAT) is classically associated with energy storage in the form of triacylglycerol and is directly associated with metabolic disorders, including obesity. Mitochondria regulates cellular expenditure and are active in WAT. Although isolated mitochondria have been classically used to assess their functions, several artifacts can be introduced by this approach. Although methods to assess mitochondrial physiology in permeabilized WAT were proposed, important limitations that affect organelle function exist. Here, we established and validated a method for functional evaluation of mice mesenteric WAT (mWAT) mitochondria by using mechanical permeabilization in combination with lipid depletion and high-resolution respirometry. We observed that mild stirring of mWAT for 20 minutes at room temperature with 4% fatty acid-free albumin selectively permeabilized white adipocytes plasma membrane. In these conditions, mWAT mitochondria were intact and coupled, exhibiting succinate-induced respiratory rates that were sensitive to classical modulators of oxidative phosphorylation. Finally, the respiratory capacity of mWAT in females was significantly higher than in males, an observation that agrees with reported data using isolated mitochondria. The functional assessment of mWAT mitochondria through mild mechanical permeabilization, lipid depletion and high resolution respirometry proposed here will contribute to a better understanding of WAT biology in several pathophysiological contexts.
Long non-coding RNALINC00152plays an oncogenic role via targeting STAT3 and c-MYC signaling in esophageal adenocarcinoma
Authors: Zhao Honglin , Xiao Matthew , Zhao Huijie , Wang Zhuwen , Nancarrow Derek , Chen Guoan 
Published: February 2020

AbstractObjectiveEsophageal cancer remains a threat to public health with an increasing incidence and low survival rate worldwide. In the past thirty years the rates for esophageal adenocarcinoma (EAC) have increased over 500%. Prior studies have linked Barret’s esophagus (BE), Low grade dysplasia (LGD), and High grade dysplasia (HGD) as general precursors to EAC. However, the exact pathways by which EAC occurs have not been uncovered. Recent genomic studies have discovered a new family of active RNA species named long non-coding RNAs (lncRNAs). Of which,LINC00152has been linked to several human cancers and shown to promote cell proliferation in lung, gastric, hepatocellular, colorectal, and clear cell renal carcinoma. This study is to investigate the roles ofLINC00152in EAC using EAC patient data and EAC cell lines.MethodsWe usedLINC00152specific siRNAs to knockdownLINC00152and used the Gateway cloning method to generate stable overexpression ofLINC00152in Flo, OE19, and OE33 cell lines forin vitrostudy. The cells were tested for changes in cell proliferation, colony formation, invasion and migration. Real-time PCR assay was used for detecting mRNA expression and Western blot was used for examining altered protein expressions affected byLINC00152. Data analysis were performed using excel and Prism. Statistical differences were assessed using the Student’s T-test. Survival analysis was done using Kaplan–Meier estimates.ResultsThis study found that high levels ofLINC00152correlated positively with tumor progression, invasive potential, and TNM stage advancement in EAC.LINC00152knockdown could inhibit cell proliferation, colony formation, and cell invasion. Western blot and Real-time PCR results suggests thatLINC00152may active via STAT3 and c-MYC signaling as both demonstrated changes following knockdown and overexpression experiments.ConclusionsThis study indicated thatLINC00152might be used as both a biomarker and a novel therapeutic target to improve the outcome for EAC patients. Further characterization ofLINC00152as a novel therapeutic target for EAC is warranted.