bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling
Authors: Stoner Samuel A. , Liu Katherine Tin Heng , Andrews Elizabeth T. , Liu Mengdan , Arimoto Kei-Ichiro , Yan Ming , Davis Amanda G. , Weng Stephanie , Dow Michelle , Xian Su , DeKelver Russell C. , Carter Hannah , Zhang Dong-Er 
Published: February 2020

AbstractLarge-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.
Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells
Authors: Varikuti Sanjay , Singh Bhawana , Volpedo Greta , Ahirwar Dinesh K. , Jha Bijay K. , Saljoughian Noushin , Viana Agostinho G. , Verma Chaitenya , Hamza Omar , Halsey Gregory , Holcomb Erin A. , Maryala Ritvik J. , Oghumu Steve , Ganju Ramesh K. , Satoskar Abhay R. 
Published: February 2020

Abstract
Background
Ibrutinib is a Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible kinase (ITK) inhibitor used for treating chronic lymphocytic leukaemia (CLL) and other cancers. Although ibrutinib is known to inhibit the growth of breast cancer cell growth in vitro, its impact on the treatment and metastasis of breast cancer is unclear.

Methods
Using an orthotopic mouse breast cancer model, we show that ibrutinib inhibits the progression and metastasis of breast cancer.

Results
Ibrutinib inhibited proliferation of cancer cells in vitro, and Ibrutinib-treated mice displayed significantly lower tumour burdens and metastasis compared to controls. Furthermore, the spleens and tumours from Ibrutinib-treated mice contained more mature DCs and lower numbers of myeloid-derived suppressor cells (MDSCs), which promote disease progression and are linked to poor prognosis. We also confirmed that ex vivo treatment of MDSCs with ibrutinib switched their phenotype to mature DCs and significantly enhanced MHCII expression. Further, ibrutinib treatment promoted T cell proliferation and effector functions leading to the induction of antitumour TH1 and CTL immune responses.

Conclusions
Ibrutinib inhibits tumour development and metastasis in breast cancer by promoting the development of mature DCs from MDSCs and hence could be a novel therapeutic agent for the treatment of breast cancer.
Bone-derived mesenchymal stem cells alleviate compression-induced apoptosis of nucleus pulposus cells by N6 methyladenosine of autophagy
Authors: Li Gaocai , Song Yu , Liao Zhiwei , Wang Kun , Luo Rongjin , Lu Saideng , Zhao Kangcheng , Feng Xiaobo , Liang Hang , Ma Liang , Wang Bingjin , Ke Wencan , Yin Huipeng , Zhan Shengfeng , Li Shuai , Wu Xinghuo , Zhang Yukun , Yang Cao 
Published: February 2020

AbstractN6 methyladenosine (m6A) is one of the most prevalent epitranscriptomic modifications of mRNAs, and plays a critical role in various bioprocesses. Bone-derived mesenchymal stem cells (BMSCs) can attenuate apoptosis of nucleus pulposus cells (NPCs) under compression; however, the underlying mechanisms are poorly understood. This study showed that the level of m6A mRNA modifications was decreased, and the autophagic flux was increased in NPCs under compression when they were cocultured with BMSCs. We report that under coculture conditions, RNA demethylase ALKBH5-mediated FIP200 mRNA demethylation enhanced autophagic flux and attenuated the apoptosis of NPCs under compression. Specific silencing of ALKBH5 results in impaired autophagic flux and a higher proportion of apoptotic NPCs under compression, even when cocultured with BMSCs. Mechanistically, we further identify that the m6A “reader” YTHDF2 is likely to be involved in the regulation of autophagy, and lower m6A levels in the coding region of FIP200 lead to a reduction in YTHDF2-mediated mRNA degradation of FIP200, a core molecular component of the ULK1 complex that participates in the initiating process of autophagy. Taken together, our study reveals the roles of ALKBH5-mediated FIP200 mRNA demethylation in enhancing autophagy and reducing apoptosis in NPCs when cocultured with BMSCs.
Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss
Authors: Herranen Anni , Ikäheimo Kuu , Lankinen Tuuli , Pakarinen Emmi , Fritzsch Bernd , Saarma Mart , Lindahl Maria , Pirvola Ulla 
Published: February 2020

AbstractThe non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.
Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease
Authors: Han Mei , Piorońska Weronika , Wang Sai , Nwosu Zeribe Chike , Sticht Carsten , Wang Shanshan , Gao Yan , Ebert Matthias Philip , Dooley Steven , Meyer Christoph 
Published: February 2020

AbstractCaveolin-1 (CAV1) is a crucial regulator of lipid accumulation and metabolism. Previous studies have shown that global Cav1 deficiency affects lipid metabolism and hepatic steatosis. We aimed to analyze the consequences of hepatocyte-specific Cav1 knockout under healthy conditions and upon non-alcoholic fatty liver disease (NAFLD) development. Male and female hepatocyte-specific Cav1 knockout (HepCAV1ko) mice were fed a methionine/choline (MCD) deficient diet for 4 weeks. MCD feeding caused severe hepatic steatosis and slight fibrosis. In addition, liver function parameters, i.e., ALT, AST, and GLDH, were elevated, while cholesterol and glucose level were reduced upon MCD feeding. These differences were not affected by hepatocyte-specific Cav1 knockout. Microarray analysis showed strong differences in gene expression profiles of livers from HepCAV1ko mice compared those of global Cav1 knockout animals. Pathway enrichment analysis identified that metabolic alterations were sex-dimorphically regulated by hepatocyte-specific CAV1. In male HepCAV1ko mice, metabolic pathways were suppressed in NAFLD, whereas in female knockout mice induced. Moreover, gender-specific transcription profiles were modulated in healthy animals. In conclusion, our results demonstrate that hepatocyte-specific Cav1 knockout significantly altered gene profiles, did not affect liver steatosis and fibrosis in NAFLD and that gender had severe impact on gene expression patterns in healthy and diseased hepatocyte-specific Cav1 knockout mice.
Nogo-A-targeting antibody promotes visual recovery and inhibits neuroinflammation after retinal injury
Authors: Baya Mdzomba Julius , Joly Sandrine , Rodriguez Léa , Dirani Ali , Lassiaz Patricia , Behar-Cohen Francine , Pernet Vincent 
Published: February 2020

AbstractN-Methyl-D-aspartate (NMDA)-induced neuronal cell death is involved in a large spectrum of diseases affecting the brain and the retina such as Alzheimer’s disease and diabetic retinopathy. Associated neurological impairments may result from the inhibition of neuronal plasticity by Nogo-A. The objective of the current study was to determine the contribution of Nogo-A to NMDA excitotoxicity in the mouse retina. We observed that Nogo-A is upregulated in the mouse vitreous during NMDA-induced inflammation. Intraocular injection of a function-blocking antibody specific to Nogo-A (11C7) was carried out 2 days after NMDA-induced injury. This treatment significantly enhanced visual function recovery in injured animals. Strikingly, the expression of potent pro-inflammatory molecules was downregulated by 11C7, among which TNFα was the most durably decreased cytokine in microglia/macrophages. Additional analyses suggest that TNFα downregulation may stem from cofilin inactivation in microglia/macrophages. 11C7 also limited gliosis presumably via P.Stat3 downregulation. Diabetic retinopathy was associated with increased levels of Nogo-A in the eyes of donors. In summary, our results reveal that Nogo-A-targeting antibody can stimulate visual recovery after retinal injury and that Nogo-A is a potent modulator of excitotoxicity-induced neuroinflammation. These data may be used to design treatments against inflammatory eye diseases.
Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia
Authors: Li Yang , Gruber Joshua J. , Litzenburger Ulrike M. , Zhou Yiren , Miao Yu Rebecca , LaGory Edward L. , Li Albert M. , Hu Zhen , Yip Michaela , Hart Lori S. , Maris John M. , Chang Howard Y. , Giaccia Amato J. , Ye Jiangbin 
Published: February 2020

AbstractDespite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.
Therapeutic senescence via GPCR activation in synovial fibroblasts facilitates resolution of arthritis
Authors: Montero-Melendez Trinidad , Nagano Ai , Chelala Claude , Filer Andrew , Buckley Christopher D. , Perretti Mauro 
Published: February 2020

AbstractRheumatoid arthritis affects individuals commonly during the most productive years of adulthood. Poor response rates and high costs associated with treatment mandate the search for new therapies. Here we show that targeting a specific G-protein coupled receptor promotes senescence in synovial fibroblasts, enabling amelioration of joint inflammation. Following activation of the melanocortin type 1 receptor (MC1), synovial fibroblasts acquire a senescence phenotype characterized by arrested proliferation, metabolic re-programming and marked gene alteration resembling the remodeling phase of wound healing, with increased matrix metalloproteinase expression and reduced collagen production. This biological response is attained by selective agonism of MC1, not shared by non-selective ligands, and dependent on downstream ERK1/2 phosphorylation. In vivo, activation of MC1leads to anti-arthritic effects associated with induction of senescence in the synovial tissue and cartilage protection. Altogether, selective activation of MC1is a viable strategy to induce cellular senescence, affording a distinct way to control joint inflammation and arthritis.
Enhanced eddy activity in the Beaufort Gyre in response to sea ice loss
Authors: Armitage Thomas W. K. , Manucharyan Georgy E. , Petty Alek A. , Kwok Ron , Thompson Andrew F. 
Published: February 2020

AbstractThe Beaufort Gyre freshwater content has increased since the 1990s, potentially stabilizing in recent years. The mechanisms proposed to explain the stabilization involve either mesoscale eddy activity that opposes Ekman pumping or the reduction of Ekman pumping due to reduced sea ice–ocean surface stress. However, the relative importance of these mechanisms is unclear. Here, we present observational estimates of the Beaufort Gyre mechanical energy budget and show that energy dissipation and freshwater content stabilization by eddies increased in the late-2000s. The loss of sea ice and acceleration of ocean currents after 2007 resulted in enhanced mechanical energy input but without corresponding increases in potential energy storage. To balance the energy surplus, eddy dissipation and its role in gyre stabilization must have increased after 2007. Our results imply that declining Arctic sea ice will lead to an increasingly energetic Beaufort Gyre with eddies playing a greater role in its stabilization.
The role of side-branching in microstructure development in laser powder-bed fusion
Authors: Pham Minh-Son , Dovgyy Bogdan , Hooper Paul A. , Gourlay Christopher M. , Piglione Alessandro 
Published: February 2020

AbstractIn-depth understanding of microstructure development is required to fabricate high quality products by additive manufacturing (for example, 3D printing). Here we report the governing role of side-branching in the microstructure development of alloys by laser powder bed fusion. We show that perturbations on the sides of cells (or dendrites) facilitate crystals to change growth direction by side-branching along orthogonal directions in response to changes in local heat flux. While the continuous epitaxial growth is responsible for slender columnar grains confined to the centreline of melt pools, side-branching frequently happening on the sides of melt pools enables crystals to follow drastic changes in thermal gradient across adjacent melt pools, resulting in substantial broadening of grains. The variation of scan pattern can interrupt the vertical columnar microstructure, but promotes both in-layer and out-of-layer side-branching, in particular resulting in the helical growth of microstructure in a chessboard strategy with 67° rotation between layers.
The empirical basis for modelling glacial erosion rates
Authors: Cook Simon J. , Swift Darrel A. , Kirkbride Martin P. , Knight Peter G. , Waller Richard I. 
Published: February 2020

AbstractGlaciers are highly effective agents of erosion that have profoundly shaped Earth’s surface, but there is uncertainty about how glacial erosion should be parameterised in landscape evolution models. Glacial erosion rate is usually modelled as a function of glacier sliding velocity, but the empirical basis for this relationship is weak. In turn, climate is assumed to control sliding velocity and hence erosion, but this too lacks empirical scrutiny. Here, we present statistically robust relationships between erosion rates, sliding velocities, and climate from a global compilation of 38 glaciers. We show that sliding is positively and significantly correlated with erosion, and derive a relationship for use in erosion models. Our dataset further demonstrates that the most rapid erosion is achieved at temperate glaciers with high mean annual precipitation, which serve to promote rapid sliding. Precipitation has received little attention in glacial erosion studies, but our data illustrate its importance.
Integrative genomic study of Chinese clear cell renal cell carcinoma reveals features associated with thrombus
Authors: Wang Xiang-Ming , Lu Yang , Song Yi-Meng , Dong Jun , Li Ruo-Yan , Wang Guo-Liang , Wang Xu , Zhang Shu-Dong , Dong Zhou-Huan , Lu Min , Wang Shi-Yu , Ge Li-Yuan , Luo Guang-Da , Ma Run-Zhuo , George Rozen Steve , Bai Fan , Wu Di , Ma Lu-Lin 
Published: February 2020

AbstractClear cell renal cell carcinoma (ccRCC) is a heterogeneous disease with features that vary by ethnicity. A systematic characterization of the genomic landscape of Chinese ccRCC is lacking, and features of ccRCC associated with tumor thrombus (ccRCC-TT) remain poorly understood. Here, we applied whole-exome sequencing on 110 normal-tumor pairs and 42 normal-tumor-thrombus triples, and transcriptome sequencing on 61 tumor-normal pairs and 30 primary-thrombus pairs from 152 Chinese patients with ccRCC. Our analysis reveals that a mutational signature associated with aristolochic acid (AA) exposure is widespread in Chinese ccRCC. Tumors from patients with ccRCC-TT show a higher mutational burden and genomic instability; in addition, mutations in BAP1 and SETD2 are highly enriched in patients with ccRCC-TT. Moreover, patients with/without TT show distinct molecular characteristics. We reported the integrative genomic sequencing of Chinese ccRCC and identified the features associated with tumor thrombus, which may facilitate ccRCC diagnosis, prognosis and treatment.
Mechanistic insight into carbon-carbon bond formation on cobalt under simulated Fischer-Tropsch synthesis conditions
Authors: Weststrate C. J. , Sharma Devyani , Garcia Rodriguez Daniel , Gleeson Michael A. , Fredriksson Hans O. A. , Niemantsverdriet J. W. 
Published: February 2020

AbstractFacile C-C bond formation is essential to the formation of long hydrocarbon chains in Fischer-Tropsch synthesis. Various chain growth mechanisms have been proposed previously, but spectroscopic identification of surface intermediates involved in C-C bond formation is scarce. We here show that the high CO coverage typical of Fischer-Tropsch synthesis affects the reaction pathways of C2Hx adsorbates on a Co(0001) model catalyst and promote C-C bond formation. In-situ high resolution x-ray photoelectron spectroscopy shows that a high CO coverage promotes transformation of C2Hx adsorbates into the ethylidyne form, which subsequently dimerizes to 2-butyne. The observed reaction sequence provides a mechanistic explanation for CO-induced ethylene dimerization on supported cobalt catalysts. For Fischer-Tropsch synthesis we propose that C-C bond formation on the close-packed terraces of a cobalt nanoparticle occurs via methylidyne (CH) insertion into long chain alkylidyne intermediates, the latter being stabilized by the high surface coverage under reaction conditions.
Genetic screens in isogenic mammalian cell lines without single cell cloning
Authors: DeWeirdt Peter C. , Sangree Annabel K. , Hanna Ruth E. , Sanson Kendall R. , Hegde Mudra , Strand Christine , Persky Nicole S. , Doench John G. 
Published: February 2020

AbstractIsogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor-intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small-molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts.