bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynasore suppresses cell proliferation, migration, and invasion and enhances the antitumor capacity of cisplatin via STAT3 pathway in osteosarcoma
Authors: Zhong Binlong , Shi Deyao , Wu Fashuai , Wang Shangyu , Hu Hongzhi , Cheng Cheng , Qing Xiangcheng , Huang Xin , Luo Xueying , Zhang Zhicai , Shao Zengwu 
Published: September 2019

AbstractOsteosarcoma (OS) is the most common malignant bone tumor. The prognosis of metastatic and recurrent OS patients still remains unsatisfactory. Cisplatin reveals undeniable anti-tumor effect while induces severe side effects that threatening patients’ health. Dynasore, a cell-permeable small molecule that inhibits dynamin activity, has been widely studied in endocytosis and phagocytosis. However, the anti-tumor effect of dynasore on OS has not yet been ascertained. In the present study, we suggested that dynasore inhibited cell proliferation, migration, invasion, and induced G0/G1 arrest of OS cells. Besides, dynasore repressed tumorigenesis of OS in xenograft mouse model. In addition, we demonstrated that dynasore improved the anti-tumor effect of cisplatin in vitro and in vivo without inducing nephrotoxicity and hepatotoxicity. Mechanistically, dynasore repressed the expression of CCND1, CDK4, p-Rb, and MMP-2. Furthermore, we found that dynasore exerts anti-tumor effects in OS partially via inhibiting STAT3 signaling pathway but not ERK-MAPK, PI3K-Akt or SAPK/JNK pathways. P38 MAPK pathway served as a negative regulatory mechanism in dynasore induced anti-OS effects. Taken together, our study indicated that dynasore does suppress cell proliferation, migration, and invasion via STAT3 signaling pathway, and enhances the antitumor capacity of cisplatin in OS. Our results suggest that dynasore is a novel candidate drug to inhibit the tumor growth of OS and enhance the anti-tumor effects of cisplatin.
ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation
Authors: Peñaranda-Fajardo Natalia M. , Meijer Coby , Liang Yuanke , Dijkstra Bianca M. , Aguirre-Gamboa Raul , den Dunnen Wilfred F. A. , Kruyt Frank A. E. 
Published: September 2019

AbstractPatients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.
A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms
Authors: Priem Dario , Devos Michael , Druwé Sarah , Martens Arne , Slowicka Karolina , Ting Adrian T. , Pasparakis Manolis , Declercq Wim , Vandenabeele Peter , van Loo Geert , Bertrand Mathieu J. M. 
Published: September 2019

AbstractThe cytokine TNF promotes inflammation either directly by activating the MAPK and NF-κB signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-κB-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-κB activation. Apart from acting as an NF-κB inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.
Long non-coding RNA SNHG3 promotes progression of gastric cancer by regulating neighboring MED18 gene methylation
Authors: Xuan Yi , Wang Yanong 
Published: September 2019

AbstractTo understand the mechanistic involvement of long non-coding RNA (lncRNA) SNHG3 in gastric cancer (GC), the relative abundance of SNHG3 was determined by real-time PCR. Overall and metastasis-free survival was analyzed by Kaplan–Meier’s plot. The potential impact of SNHG3 on tumor progression was evaluated both in vitro and in vivo. The in vivo metastasis was monitored in the tail vein-injected mice. Our data suggested that high SNHG3 associated with unfavorable prognosis in respect to overall and metastasis-free survival. SNHG3-deficiency significantly suppressed cell proliferation and cell viability in vitro and xenograft progression in vivo. In addition, ectopic overexpression of SNHG3 promoted cell migration and invasion in vitro and lung metastasis in vivo. Mechanistically, we uncovered SNHG3 associated with EZH2 and negatively regulated MED18 expression through methylation modulation. Transient knockdown of MED18 in SNHG3-deficient cells completely rescued the tumor suppressive phenotypes in GC cells. Our data unraveled the oncogenic properties of high SNHG3 in GC, which predominantly depended on epigenetically regulated MED18.
Reduced sleep efficiency, measured using an objective device, was related to an increased prevalence of home hypertension in Japanese adults
Authors: Hirata Takumi , Nakamura Tomohiro , Kogure Mana , Tsuchiya Naho , Narita Akira , Miyagawa Ken , Nochioka Kotaro , Uruno Akira , Obara Taku , Nakaya Naoki , Metoki Hirohito , Kikuya Masahiro , Sugawara Junichi , Kuriyama Shinichi , Tsuji Ichiro , Kure Shigeo , Hozawa Atsushi 
Published: September 2019

AbstractFew studies have reported the relationship between reduced sleep efficiency and the prevalence of hypertension independent of sleep duration in Japan. This study aimed to evaluate whether reduced sleep efficiency, measured using an objective device for >1 week, was related to an increased prevalence of hypertension independent of sleep duration in the general Japanese population. We conducted a cross-sectional study of 904 participants aged ≥20 years who lived in Miyagi Prefecture, Japan. Sleep efficiency was measured using a contactless biomotion sleep sensor for 10 continuous days. The participants were classified into two groups according to their sleep efficiency: reduced (<90%) or not reduced (≥90%). Hypertension was defined as morning home blood pressure ≥135/85 mmHg or self-reported treatment for hypertension. Multivariable logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between sleep efficiency and hypertension adjusted for potential confounders. The results showed that two hundred and ninety-four individuals (32.5%) had reduced sleep efficiency, and 331 (36.6%) had hypertension. Individuals with reduced sleep efficiency had a higher body mass index and shorter sleep duration. In the multivariable analysis, reduced sleep efficiency was significantly related to an increased prevalence of hypertension (OR, 1.62; 95% CI, 1.15–2.28). In conclusion, reduced sleep efficiency was significantly related to an increased prevalence of hypertension in Japanese adults. Improvements in sleep efficiency may be important to reduce blood pressure in Japanese adults.
Developmental cell death regulates lineage-related interneuron-oligodendroglia functional clusters and oligodendrocyte homeostasis
Authors: Orduz David , Benamer Najate , Ortolani Domiziana , Coppola Eva , Vigier Lisa , Pierani Alessandra , Angulo María Cecilia 
Published: September 2019

AbstractThe first wave of oligodendrocyte precursor cells (firstOPCs) and most GABAergic interneurons share common embryonic origins. Cortical firstOPCs are thought to be replaced by other OPC populations shortly after birth, maintaining a consistent OPC density and making postnatal interactions between firstOPCs and ontogenetically-related interneurons unlikely. Challenging these ideas, we show that a cortical firstOPC subpopulation survives and forms functional cell clusters with lineage-related interneurons. Favored by a common embryonic origin, these clusters display unexpected preferential synaptic connectivity and are anatomically maintained after firstOPCs differentiate into myelinating oligodendrocytes. While the concomitant rescue of interneurons and firstOPCs committed to die causes an exacerbated neuronal inhibition, it abolishes interneuron-firstOPC high synaptic connectivity. Further, the number of other oligodendroglia populations increases through a non-cell-autonomous mechanism, impacting myelination. These findings demonstrate unprecedented roles of interneuron and firstOPC apoptosis in regulating lineage-related cell interactions and the homeostatic oligodendroglia density.
Lung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury
Authors: Claser Carla , Nguee Samantha Yee Teng , Balachander Akhila , Wu Howland Shanshan , Becht Etienne , Gunasegaran Bavani , Hartimath Siddesh V. , Lee Audrey W. Q. , Theng Theng Ho Jacqueline , Bing Ong Chee , Newell Evan W. , Goggi Julian , Guan Ng Lai , Renia Laurent 
Published: September 2019

AbstractMalaria-associated acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are life-threatening manifestations of severe malaria infections. The pathogenic mechanisms that lead to respiratory complications, such as vascular leakage, remain unclear. Here, we confirm that depleting CD8+T cells with anti-CD8β antibodies in C57BL/6 mice infected withP. bergheiANKA (PbA) prevent pulmonary vascular leakage. When we transfer activated parasite-specific CD8+T cells into PbA-infected TCRβ−/−mice (devoid of all T-cell populations), pulmonary vascular leakage recapitulates. Additionally, we demonstrate that PbA-infected erythrocyte accumulation leads to lung endothelial cell cross-presentation of parasite antigen to CD8+T cells in an IFNγ−dependent manner. In conclusion, pulmonary vascular damage in ALI is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+T cells induced during infection. The mechanistic understanding of the immunopathogenesis in malaria-associated ARDS and ALI provide the basis for development of adjunct treatments.
A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1
Authors: Zheng Xiao-Feng , Acharya Sanket S. , Choe Katherine N. , Nikhil Kumar , Adelmant Guillaume , Satapathy Shakti Ranjan , Sharma Samanta , Viccaro Keith , Rana Sandeep , Natarajan Amarnath , Sicinski Peter , Marto Jarrod A. , Shah Kavita , Chowdhury Dipanjan 
Published: September 2019

AbstractMitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3β, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3β phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.
MLL1 is required for PAX7 expression and satellite cell self-renewal in mice
Authors: Addicks Gregory C. , Brun Caroline E. , Sincennes Marie-Claude , Saber John , Porter Christopher J. , Francis Stewart A. , Ernst Patricia , Rudnicki Michael A. 
Published: September 2019

AbstractPAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.
Epigenome editing strategies for the functional annotation of CTCF insulators
Authors: Tarjan Daniel R. , Flavahan William A. , Bernstein Bradley E. 
Published: September 2019

AbstractThe human genome is folded into regulatory units termed ‘topologically-associated domains’ (TADs). Genome-wide studies support a global role for the insulator protein CTCF in mediating chromosomal looping and the topological constraint of TAD boundaries. However, the impact of individual insulators on enhancer-gene interactions and transcription remains poorly understood. Here, we investigate epigenome editing strategies for perturbing individual CTCF insulators and evaluating consequent effects on genome topology and transcription. We show that fusions of catalytically-inactive Cas9 (dCas9) to transcriptional repressors (dCas9-KRAB) and DNA methyltransferases (dCas9-DNMT3A, dCas9-DNMT3A3L) can selectively displace CTCF from specific insulators, but only when precisely targeted to the cognate motif. We further demonstrate that stable, partially-heritable insulator disruption can be achieved through combinatorial hit-and-run epigenome editing. Finally, we apply these strategies to simulate an insulator loss mechanism implicated in brain tumorigenesis. Our study provides strategies for stably modifying genome organization and gene activity without altering the underlying DNA sequence.
Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis
Authors: Kumari Rajni , Deshmukh Ruhi S. , Das Sanjeev 
Published: September 2019

AbstractCaspase-10 belongs to the class of initiator caspases and is a close homolog of caspase-8. However, the lack of caspase-10 in mice and limited substrate repertoire restricts the understanding of its physiological functions. Here, we report that ATP-citrate lyase (ACLY) is a caspase-10 substrate. Caspase-10 cleaves ACLY at the conserved Asp1026 site under conditions of altered metabolic homeostasis. Cleavage of ACLY abrogates its enzymatic activity and suppresses the generation of acetyl-CoA, which is critical for lipogenesis and histone acetylation. Thus, caspase-10-mediated ACLY cleavage results in reduced intracellular lipid levels and represses GCN5-mediated histone H3 and H4 acetylation. Furthermore, decline in GCN5 activity alters the epigenetic profile, resulting in downregulation of proliferative and metastatic genes. Thus caspase-10 suppresses ACLY-promoted malignant phenotype. These findings expand the substrate repertoire of caspase-10 and highlight its pivotal role in inhibiting tumorigenesis through metabolic and epigenetic mechanisms.
An aggregon in conductin/axin2 regulates Wnt/β-catenin signaling and holds potential for cancer therapy
Authors: Bernkopf Dominic B. , Brückner Martina , Hadjihannas Michel V. , Behrens Jürgen 
Published: September 2019

AbstractThe paralogous scaffold proteins axin and conductin/axin2 are key factors in the negative regulation of the Wnt pathway transcription factor β-catenin, thereby representing interesting targets for signaling regulation. Polymerization of axin proteins is essential for their activity in suppressing Wnt/β-catenin signaling. Notably, conductin shows less polymerization and lower activity than axin. By domain swapping between axin and conductin we here identify an aggregation site in the conductin RGS domain which prevents conductin polymerization. Induction of conductin polymerization by point mutations of this aggregon results in enhanced inhibition of Wnt/β-catenin signaling. Importantly, we identify a short peptide which induces conductin polymerization via masking the aggregon, thereby enhancing β-catenin degradation, inhibiting β-catenin-dependent transcription and repressing growth of colorectal cancer cells. Our study reveals a mechanism for regulating signaling pathways via the polymerization status of scaffold proteins and suggests a strategy for targeted colorectal cancer therapy.
Vegetation structural change since 1981 significantly enhanced the terrestrial carbon sink
Authors: Chen Jing M. , Ju Weimin , Ciais Philippe , Viovy Nicolas , Liu Ronggao , Liu Yang , Lu Xuehe 
Published: September 2019

AbstractSatellite observations show that leaf area index (LAI) has increased globally since 1981, but the impact of this vegetation structural change on the global terrestrial carbon cycle has not been systematically evaluated. Through process-based diagnostic ecosystem modeling, we find that the increase in LAI alone was responsible for 12.4% of the accumulated terrestrial carbon sink (95 ± 5 Pg C) from 1981 to 2016, whereas other drivers of CO2 fertilization, nitrogen deposition, and climate change (temperature, radiation, and precipitation) contributed to 47.0%, 1.1%, and −28.6% of the sink, respectively. The legacy effects of past changes in these drivers prior to 1981 are responsible for the remaining 65.5% of the accumulated sink from 1981 to 2016. These results refine the attribution of the land sink to the various drivers and would help constrain prognostic models that often have large uncertainties in simulating changes in vegetation and their impacts on the global carbon cycle.
Martensitic phase transformation in TiNi
Authors: Sewak R. , Dey C. C. 
Published: September 2019

AbstractFrom temperature dependent perturbed angular correlation (PAC) measurements (77–873 K) in equiatomic TiNi intermetallic alloy, martensitic phase transformations have been observed. Three frequency components corresponding to three different phases of TiNi have been found in the temperature range 298–873 K. The results of quadrupole frequency and asymmetry parameters at room temperature are found to be: ωQ = 14(1) Mrad/s, η = 0 (33%), ωQ = 40.0(5) Mrad/s, η = 0.66(3) (52%) and ωQ = 56.7(3)Mrad/s, η = 0.39(2) (15%). The frequency component with η = 0 and which enhances to ~52% at 373 K can be attributed to the cubic austenite phase. The predominant component (~52%) found at room temperature has been attributed to monoclinic martensitic phase of TiNi and the third component with values of ωQ and η similar to those for the martensitic phase is attributed to the intermediate orthorhombic phase. At 77 K, no intermediate and austenite phases have been found but only the martensite phase is observed at this temperature. From XRD measurements at room temperature also, three phases of TiNi have been observed.
Visual dynamics cues in learning complex physical interactions
Authors: Hasson Christopher J. , Jalili Paneed F. 
Published: September 2019

AbstractThis study investigated the role of visual dynamics cues (VDCs) in learning to interact with a complex physical system. Manual gait training was used as an exemplary case, as it requires therapists to control the non-trivial locomotor dynamics of patients. A virtual analog was developed that allowed naïve subjects to manipulate the leg of a virtual stroke survivor (a virtual patient; VP) walking on a treadmill using a small robotic manipulandum. The task was to make the VP’s leg pass through early, mid, and late swing gait targets. One group of subjects (n = 17) started practice seeing the VP’s affected thigh and shank (i.e., VDCs); a second control group (n = 16) only saw the point-of-contact (VP ankle). It was hypothesized that, if seeing the VP’s leg provides beneficial dynamics information, the VDC group would have better task performance and generalization than controls. Results were not supportive. Both groups had similar task performance, and for the late swing gait target, a decrement in manipulative accuracy was observed when VDCs were removed in a generalization task. This suggests that when learning to manipulate complex dynamics, VDCs can create a dependency that negatively affects generalization if the visual context is changed.