bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis
Authors: Buccarelli Mariachiara , Marconi Matteo , Pacioni Simone , De Pascalis Ivana , D’Alessandris Quintino Giorgio , Martini Maurizio , Ascione Barbara , Malorni Walter , Larocca Luigi Maria , Pallini Roberto , Ricci-Vitiani Lucia , Matarrese Paola 
Published: August 2018

AbstractThe role of autophagy in cancer onset and progression appears still controversial. On one hand, autophagy allows cancer cell to survive in unfavorable environmental conditions, on the other hand, once internal energy resources are exhausted, it leads to cell death. In addition, autophagy interpheres with cell cycle progression, de facto exerting a cytostatic activity. Hence, it represents an important target for anticancer therapy. For example, temozolomide (TMZ), of use for glioblastoma (GBM) treatment, appears as capable of inducing autophagy partially inhibiting cancer cell proliferation. However, GBM, a very aggressive brain tumor with poor prognosis even after surgery and radio-chemotherapy, invariably recurs and leads to patient death. Since cancer stem cells have been hypothesized to play a role in refractory/relapsing cancers, in the present work we investigated if autophagy could represent a constitutive cytoprotection mechanism for glioblastoma stem-like cells (GSCs) and if the modulation of autophagic process could affect GBM growth and survival. Thus, in the present study we first evaluated the relevance of autophagy in GBM tumor specimens, then its occurrence in GSCs and, finally, if modulation of autophagy could influence GSC response to TMZ. Our results suggested that, in vitro, the impairing autophagic process with quinacrine, a compound able to cross the blood-brain barrier, increased GSC susceptibility to TMZ. Death of GSCs was apparently due to the iron dependent form of programmed cell death characterized by the accumulation of lipid peroxides called ferroptosis. These results underscore the relevance of the modulation of autophagy in the GSC survival and death and suggest that triggering of ferroptosis in GSCs could represent a novel and important target for the management of glioblastoma.
DBC1 regulates Wnt/β-catenin-mediated expression of MACC1, a key regulator of cancer progression, in colon cancer
Authors: Kim Hwa Jin , Moon Sue Jin , Kim Seok-Hyung , Heo Kyu , Kim Jeong Hoon 
Published: August 2018

AbstractMetastasis-associated in colon cancer 1 (MACC1) has been reported to be overexpressed in multiple cancers and promote proliferation, metastasis, cancer stem cell-like properties, and drug resistance of cancer cells. Despite its significance and the considerable knowledge accumulated on the function of MACC1 in various types of human malignancies, regulatory mechanisms underlying MACC1 expression remain unclear. Here we report that MACC1 is a direct target of Wnt/β-catenin signaling pathway in colon cancer cells and that DBC1 functions as a coactivator for Wnt-mediated MACC1 expression by promoting the activity of a LEF1/β-catenin-dependent enhancer located in intron 1 of MACC1 gene. DBC1 is required for LEF1/β-catenin complex formation on the MACC1 enhancer and for long-distance enhancer-promoter interaction of the MACC1 locus. MACC1 expression was increased in colonosphere cells compared to adherent colon cancer cells, and DBC1 overexpression further increased MACC1 expression in colonospheres and promoted sphere-forming abilities of colon cancer cells and drug resistance of colonospheres. Importantly, expressions of MACC1 and DBC1 are positively correlated with each other, upregulated in high-risk groups of colorectal cancer patients, and associated with poor survival. Our results establish MACC1 as a transcriptional target of Wnt/β-catenin signaling and suggest that DBC1 plays a key role in colorectal cancer progression through Wnt/β-catenin-MACC1 signaling axis.
Notch3/VEGF-A axis is involved in TAT-mediated proliferation of pulmonary artery smooth muscle cells: Implications for HIV-associated PAH
Authors: Guo Ming-Lei , Kook Yeon Hee , Shannon Callen E. , Buch Shilpa 
Published: August 2018

AbstractThe incidence of pulmonary arterial hypertension (PAH) is a significant co-morbidity observed in HIV (+) individuals. Pulmonary artery smooth muscle cells (PASMCs)—key components of the arterial vessel wall that regulate vessel diameter, demonstrate increased proliferation and hypertrophy in the lungs of HIV infected individuals, underscoring the role of these cells in the pathogenesis of HIV-associated PAH. While several pathways have been implicated in enhanced proliferation of PASMCs, detailed molecular mechanism(s) underlying HIV-associated PASMC proliferation still remain elusive. In the current study, we sought to investigate the effects HIV protein transactivator of transcription (TAT)-mediated proliferation on PASMCs. In agreement with earlier findings, our results also demonstrated TAT-mediated proliferation of human PASMCs. We identified activation of a novel Notch3 signaling pathway in TAT-mediated proliferation of PASMCs. Further validation of the Notch 3 pathway was demonstrated using both pharmacological (γ-secretase inhibitor, DAPT), as well as genetic approaches (Notch3 siRNA). Vascular endothelial growth factor A (VEGF-A) was identified as a novel downstream molecule that was induced following Notch activation. Findings from in vitro studies were further validated in archived simian immunodeficiency virus (SIV)-infected monkey lung tissues. There was increased activation of Notch3 signaling as well as enhanced expression of VEGF-A in the lungs of SIV-infected macaques compared with the lungs of SIV(−) controls. Taken together, we demonstrated that HIV-TAT increased the proliferation of PASMCs via the Notch3/VEGF-A axis. Targeting the Notch3/VEGF-A axis could thus be considered a potential therapeutic approach for the treatment of HIV-associated PAH.
Notch3-dependent β-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
Authors: Arasada Rajeswara Rao , Shilo Konstantin , Yamada Tadaaki , Zhang Jianying , Yano Seiji , Ghanem Rashelle , Wang Walter , Takeuchi Shinji , Fukuda Koji , Katakami Nobuyuki , Tomii Keisuke , Ogushi Fumitaka , Nishioka Yasuhiko , Talabere Tiffany , Misra Shrilekha , Duan Wenrui , Fadda Paolo , Rahman Mohammad A. , Nana-Sinkam Patrick , Evans Jason , Amann Joseph , Tchekneva Elena E. , Dikov Mikhail M. , Carbone David P. 
Published: August 2018

AbstractEGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
Fossil lemurs from Egypt and Kenya suggest an African origin for Madagascar’s aye-aye
Authors: Gunnell Gregg F. , Boyer Doug M. , Friscia Anthony R. , Heritage Steven , Manthi Fredrick Kyalo , Miller Ellen R. , Sallam Hesham M. , Simmons Nancy B. , Stevens Nancy J. , Seiffert Erik R. 
Published: August 2018

AbstractIn 1967 G.G. Simpson described three partial mandibles from early Miocene deposits in Kenya that he interpreted as belonging to a new strepsirrhine primate, Propotto. This interpretation was quickly challenged, with the assertion that Propotto was not a primate, but rather a pteropodid fruit bat. The latter interpretation has not been questioned for almost half a century. Here we re-evaluate the affinities of Propotto, drawing upon diverse lines of evidence to establish that this strange mammal is a strepsirrhine primate as originally suggested by Simpson. Moreover, our phylogenetic analyses support the recognition of Propotto, together with late Eocene Plesiopithecus from Egypt, as African stem chiromyiform lemurs that are exclusively related to the extant aye-aye (Daubentonia) from Madagascar. Our results challenge the long-held view that all lemurs are descended from a single ancient colonization of Madagascar, and present an intriguing alternative scenario in which two lemur lineages dispersed from Africa to Madagascar independently, possibly during the later Cenozoic.
Commensal microflora-induced T cell responses mediate progressive neurodegeneration in glaucoma
Authors: Chen Huihui , Cho Kin-Sang , Vu T. H. Khanh , Shen Ching-Hung , Kaur Mandeep , Chen Guochun , Mathew Rose , McHam M. Lisa , Fazelat Ahad , Lashkari Kameran , Au Ngan Pan Bennett , Tse Joyce Ka Yu , Li Yingqian , Yu Honghua , Yang Lanbo , Stein-Streilein Joan , Ma Chi Him Eddie , Woolf Clifford J. , Whary Mark T. , Jager Martine J. , Fox James G. , Chen Jianzhu , Chen Dong F. 
Published: August 2018

AbstractGlaucoma is the most prevalent neurodegenerative disease and a leading cause of blindness worldwide. The mechanisms causing glaucomatous neurodegeneration are not fully understood. Here we show, using mice deficient in T and/or B cells and adoptive cell transfer, that transient elevation of intraocular pressure (IOP) is sufficient to induce T-cell infiltration into the retina. This T-cell infiltration leads to a prolonged phase of retinal ganglion cell degeneration that persists after IOP returns to a normal level. Heat shock proteins (HSP) are identified as target antigens of T-cell responses in glaucomatous mice and human glaucoma patients. Furthermore, retina-infiltrating T cells cross-react with human and bacterial HSPs; mice raised in the absence of commensal microflora do not develop glaucomatous T-cell responses or the associated neurodegeneration. These results provide compelling evidence that glaucomatous neurodegeneration is mediated in part by T cells that are pre-sensitized by exposure to commensal microflora.
Growth tradeoffs produce complex microbial communities on a single limiting resource
Authors: Manhart Michael , Shakhnovich Eugene I. 
Published: August 2018

AbstractThe relationship between the dynamics of a community and its constituent pairwise interactions is a fundamental problem in ecology. Higher-order ecological effects beyond pairwise interactions may be key to complex ecosystems, but mechanisms to produce these effects remain poorly understood. Here we model microbial growth and competition to show that higher-order effects can arise from variation in multiple microbial growth traits, such as lag times and growth rates, on a single limiting resource with no other interactions. These effects produce a range of ecological phenomena: an unlimited number of strains can exhibit multistability and neutral coexistence, potentially with a single keystone strain; strains that coexist in pairs do not coexist all together; and a strain that wins all pairwise competitions can go extinct in a mixed competition. Since variation in multiple growth traits is ubiquitous in microbial populations, our results indicate these higher-order effects may also be widespread, especially in laboratory ecology and evolution experiments.
A balance between aerodynamic and olfactory performance during flight in Drosophila
Authors: Li Chengyu , Dong Haibo , Zhao Kai 
Published: August 2018

AbstractThe ability to track odor plumes to their source (food, mate, etc.) is key to the survival of many insects. During this odor-guided navigation, flapping wings could actively draw odorants to the antennae to enhance olfactory sensitivity, but it is unclear if improving olfactory function comes at a cost to aerodynamic performance. Here, we computationally quantify the odor plume features around a fruit fly in forward flight and confirm that the antenna is well positioned to receive a significant increase of odor mass flux (peak 1.8 times), induced by wing flapping, vertically from below the body but not horizontally. This anisotropic odor spatial sampling may have important implications for behavior and the algorithm during plume tracking. Further analysis also suggests that, because both aerodynamic and olfactory functions are indispensable during odor-guided navigation, the wing shape and size may be a balance between the two functions.
Nuclear-resident RIG-I senses viral replication inducing antiviral immunity
Authors: Liu GuanQun , Lu Yao , Thulasi Raman Sathya N. , Xu Fang , Wu Qi , Li Zhubing , Brownlie Robert , Liu Qiang , Zhou Yan 
Published: August 2018

AbstractThe nucleus represents a cellular compartment where the discrimination of self from non-self nucleic acids is vital. While emerging evidence establishes a nuclear non-self DNA sensing paradigm, the nuclear sensing of non-self RNA, such as that from nuclear-replicating RNA viruses, remains unexplored. Here, we report the identification of nuclear-resident RIG-I actively involved in nuclear viral RNA sensing. The nuclear RIG-I, along with its cytoplasmic counterpart, senses influenza A virus (IAV) nuclear replication leading to a cooperative induction of type I interferon response. Its activation signals through the canonical signaling axis and establishes an effective antiviral state restricting IAV replication. The exclusive signaling specificity conferred by nuclear RIG-I is reinforced by its inability to sense cytoplasmic-replicating Sendai virus and appreciable sensing of hepatitis B virus pregenomic RNA in the nucleus. These results refine the RNA sensing paradigm for nuclear-replicating viruses and reveal a previously unrecognized subcellular milieu for RIG-I-like receptor sensing.
Elongator mutation in mice induces neurodegeneration and ataxia-like behavior
Authors: Kojic Marija , Gaik Monika , Kiska Bence , Salerno-Kochan Anna , Hunt Sarah , Tedoldi Angelo , Mureev Sergey , Jones Alun , Whittle Belinda , Genovesi Laura A. , Adolphe Christelle , Brown Darren L. , Stow Jennifer L. , Alexandrov Kirill , Sah Pankaj , Glatt Sebastian , Wainwright Brandon J. 
Published: August 2018

AbstractCerebellar ataxias are severe neurodegenerative disorders with an early onset and progressive and inexorable course of the disease. Here, we report a single point mutation in the gene encoding Elongator complex subunit 6 causing Purkinje neuron degeneration and an ataxia-like phenotype in the mutant wobbly mouse. This mutation destabilizes the complex and compromises its function in translation regulation, leading to protein misfolding, proteotoxic stress, and eventual neuronal death. In addition, we show that substantial microgliosis is triggered by the NLRP3 inflammasome pathway in the cerebellum and that blocking NLRP3 function in vivo significantly delays neuronal degeneration and the onset of ataxia in mutant animals. Our data provide a mechanistic insight into the pathophysiology of a cerebellar ataxia caused by an Elongator mutation, substantiating the increasing body of evidence that alterations of this complex are broadly implicated in the onset of a number of diverse neurological disorders.
Isocorroles as Homoaromatic NIR-Absorbing Chromophores: A First Quantum Chemical Study
Authors: Foroutan-Nejad Cina , Larsen Simon , Conradie Jeanet , Ghosh Abhik 
Published: August 2018

AbstractDensity functional theory calculations of magnetically induced current densities have revealed high diatropic ring currents in unsubstituted isocorrole consistent with homoaromatic character. An examination of the Kohn-Sham molecular orbitals showed clear evidence of homoconjugative interactions in four occupied π-type molecular orbitals as well as in the LUMO. Remarkably, substituents at the saturated meso position were found to exert a dramatic influence on the overall current density pattern. Thus, whereas bis(trimethylsilyl)-substitution strongly enhanced the peripheral diatropic current (consistent with enhanced homoaromaticity), difluoro-substitution engendered a strong, net paratropic current (consistent with antihomoaromaticity). In this respect, isocorroles stand in sharp contrast to benzenoid aromatics, for which substituents typically exert a small influence on the current density distribution.
Enzyme-modified non-oxidized LDL (ELDL) induces human coronary artery smooth muscle cell transformation to a migratory and osteoblast-like phenotype
Authors: Chellan Bijoy , Rojas Elizabeth , Zhang Chunling , Hofmann Bowman Marion A. 
Published: August 2018

AbstractEnzyme modified non-oxidative LDL (ELDL) is effectively taken up by vascular smooth muscle cells (SMC) and mediates transition into foam cells and produces phenotypic changes in SMC function. Our data show that incubation of human coronary artery SMC (HCASMC) with low concentration of ELDL (10 μg/ml) results in significantly enhanced foam cell formation compared to oxidized LDL (200 μg/ml; p < 0.01) or native LDL (200 μg/ml; p < 0.01). Bioinformatic network analysis identified activation of p38 MAPK, NFkB, ERK as top canonical pathways relevant for biological processes linked to cell migration and osteoblastic differentiation in ELDL-treated cells. Functional studies confirmed increased migration of HCASMC upon stimulation with ELDL (10 μg/ml) or Angiopoietin like protein 4, (ANGPTL4, 5 μg/ml), and gain in osteoblastic gene profile with significant increase in mRNA levels for DMP-1, ALPL, RUNX2, OPN/SPP1, osterix/SP7, BMP and reduction in mRNA for MGP and ENPP1. Enhanced calcification of HCASMC by ELDL was demonstrated by Alizarin Red staining. In summary, ELDL is highly potent in inducing foam cells in HCASMC and mediates a phenotypic switch with enhanced migration and osteoblastic gene profile. These results point to the potential of ELDL to induce migratory and osteoblastic effects in human smooth muscle cells with potential implications for migration and calcification of SMCs in human atherosclerosis.
Millennial soil retention of terrestrial organic matter deposited in the Bengal Fan
Authors: French Katherine L. , Hein Christopher J. , Haghipour Negar , Wacker Lukas , Kudrass Hermann R. , Eglinton Timothy I. , Galy Valier 
Published: August 2018

AbstractThe abundance of organic carbon (OC) in vegetation and soils (~2,600 PgC) compared to carbon in the atmosphere (~830 PgC) highlights the importance of terrestrial OC in global carbon budgets. The residence time of OC in continental reservoirs, which sets the rates of carbon exchange between land and atmosphere, represents a key uncertainty in global carbon cycle dynamics. Retention of terrestrial OC can also distort bulk OC- and biomarker-based paleorecords, yet continental storage timescales remain poorly quantified. Using “bomb” radiocarbon (14C) from thermonuclear weapons testing as a tracer, we model leaf-wax fatty acid and bulk OC 14C signatures in a river-proximal marine sediment core from the Bay of Bengal in order to constrain OC storage timescales within the Ganges-Brahmaputra (G-B) watershed. Our model shows that 79–83% of the leaf-waxes in this core were stored in continental reservoirs for an average of 1,000–1,200 calendar years, while the remainder was stored for an average of 15 years. This age structure distorts high-resolution organic paleorecords across geologically rapid events, highlighting that compound-specific proxy approaches must consider storage timescales. Furthermore, these results show that future environmental change could destabilize large stores of old - yet reactive - OC currently stored in tropical basins.
Rapid and reversible impairment of episodic memory by a high-fat diet in mice
Authors: McLean Fiona H. , Grant Christine , Morris Amanda C. , Horgan Graham W. , Polanski Alex J. , Allan Kevin , Campbell Fiona M. , Langston Rosamund F. , Williams Lynda M. 
Published: August 2018

AbstractAlzheimer’s disease is a leading cause of morbidity and mortality with no cure and only limited treatment available. Obesity and type 2 diabetes are positively associated with the development of premature cognitive decline and Alzheimer’s disease, linking diet with these conditions. Here we demonstrate that in mice episodic memory, together with spatial and contextual associative memory, is compromised after only one day of high-fat diet. However, object memory remains intact. This shows not only a more rapid effect than previously reported but also that more complex memories are at higher risk of being compromised by a high-fat diet. In addition, we show that these memory deficits are rapidly reversed by switching mice from a high-fat diet back to a low-fat diet. These findings have important implications for the contribution of nutrition to the development of cognitive decline and Alzheimer’s disease.
Effect of patterned polyacrylamide hydrogel on morphology and orientation of cultured NRVMs
Authors: Sanzari I. , Humphrey E. J. , Dinelli F. , Terracciano C. M. , Prodromakis T. 
Published: August 2018

AbstractWe recently demonstrated that patterned Parylene C films could be effectively used as a mask for directly copolymerizing proteins on polyacrylamide hydrogel (PAm). In this work, we have proved the applicability of this technique for studying the effect such platforms render on neonatal rat ventricular myocytes (NRVMs). Firstly, we have characterised topographically and mechanically the scaffolds in liquid at the nano-scale level. We thus establish that such platforms have physical properties that closely mimics thein vivoextracellular environment of cells. We have then studied the cell morphology and physiology by comparing cultures on flat uniformly-covered and collagen-patterned scaffolds. We show that micro-patterns promote the elongation of cells along the principal axis of the ridges coated with collagen. In several cases, cells also tend to create bridges across the grooves. We have finally studied cell contraction, monitoring Ca2+cycling at a certain stimulation. Cells seeded on patterned scaffolds present significant responses in comparison to the isotropic ones.