bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
Authors: Fan Jiajun , Zhang Xuyao , Wang Shaofei , Chen Wei , Li Yubin , Zeng Xian , Wang Yichen , Luan Jingyun , Li Li , Wang Ziyu , Sun Xilin , Shen Baozhong , Ju Dianwen 
Published: August 2019

AbstractLung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.
NudC-like protein 2 restrains centriole amplification by stabilizing HERC2
Authors: Li Min , Xu Xiaoyang , Zhang Jun , Liu Min , Wang Wei , Gao Ya , Sun Qiang , Zhang Jiayu , Lu Yunkun , Wang Fangwei , Liu Wei , Zhou Tianhua , Yang Yuehong 
Published: August 2019

AbstractCentriole duplication is tightly controlled to occur once per cell cycle, and disruption of this synchrony causes centriole amplification, which is frequently observed in many cancers. Our previous work showed that nuclear distribution gene C (NudC)-like protein 2 (NudCL2) localizes to centrosomes; however, little is known about the role of NudCL2 in the regulation of centrosome function. Here, we find that NudCL2 is required for accurate centriole duplication by stabilizing the E3 ligase HECT domain and RCC1-like domain-containing protein 2 (HERC2). Knockout (KO) of NudCL2 using CRISPR/Cas9-based genome editing or depletion of NudCL2 using small interfering RNA causes significant centriole amplification. Overexpression of NudCL2 significantly suppresses hydroxyurea-induced centriole overduplication. Quantitative proteomic analysis reveals that HERC2 is downregulated in NudCL2 KO cells. NudCL2 is shown to interact with and stabilize HERC2. Depletion of HERC2 leads to the similar defects to that in NudCL2-downregulated cells, and ectopic expression of HERC2 effectively rescues the centriole amplification caused by the loss of NudCL2, whereas the defects induced by HERC2 depletion cannot be reversed by exogenous expression of NudCL2. Either loss of NudCL2 or depletion of HERC2 leads to the accumulation of ubiquitin-specific peptidase 33 (USP33), a centrosomal protein that positively regulates centriole duplication. Moreover, knockdown of USP33 reverses centriole amplification in both NudCL2 KO and HERC2-depleted cells. Taken together, our data suggest that NudCL2 plays an important role in maintaining the fidelity of centriole duplication by stabilizing HERC2 to control USP33 protein levels, providing a previously undescribed mechanism restraining centriole amplification.
Tuning the activity and selectivity of electroreduction of CO2 to synthesis gas using bimetallic catalysts
Authors: Lee Ji Hoon , Kattel Shyam , Jiang Zhao , Xie Zhenhua , Yao Siyu , Tackett Brian M. , Xu Wenqian , Marinkovic Nebojsa S. , Chen Jingguang G. 
Published: August 2019

AbstractThe electrochemical carbon dioxide reduction reaction to syngas with controlled CO/H2 ratios has been studied on Pd-based bimetallic hydrides using a combination of in situ characterization and density functional theory calculations. When compared with pure Pd hydride, the bimetallic Pd hydride formation occurs at more negative potentials for Pd-Ag, Pd-Cu, and Pd-Ni. Theoretical calculations show that the choice of the second metal has a more significant effect on the adsorption strength of *H than *HOCO, with the free energies between these two key intermediates (i.e., ΔG(*H)–ΔG(*HOCO)) correlating well with the carbon dioxide reduction reaction activity and selectivity observed in the experiments, and thus can be used as a descriptor to search for other bimetallic catalysts. The results also demonstrate the possibility of alloying Pd with non-precious transition metals to promote the electrochemical conversion of CO2 to syngas.
Comprehensive characterization of RAS mutations in colon and rectal cancers in old and young patients
Authors: Serebriiskii Ilya G. , Connelly Caitlin , Frampton Garrett , Newberg Justin , Cooke Matthew , Miller Vince , Ali Siraj , Ross Jeffrey S. , Handorf Elizabeth , Arora Sanjeevani , Lieu Christopher , Golemis Erica A. , Meyer Joshua E. 
Published: August 2019

AbstractColorectal cancer (CRC) is increasingly appreciated as a heterogeneous disease, with factors such as microsatellite instability (MSI), cancer subsite within the colon versus rectum, and age of diagnosis associated with specific disease course and therapeutic response. Activating oncogenic mutations in KRAS and NRAS are common in CRC, driving tumor progression and influencing efficacy of both cytotoxic and targeted therapies. The RAS mutational spectrum differs substantially between tumors arising from distinct tissues. Structure-function analysis of relatively common somatic RAS mutations in G12, Q61, and other codons is characterized by differing potency and modes of action. Here we show the mutational profile of KRAS, NRAS, and the less common HRAS in 13,336 CRC tumors, comparing the frequency of specific mutations based on age of diagnosis, MSI status, and colon versus rectum subsite. We identify mutation hotspots, and unexpected differences in mutation spectrum, based on these clinical parameters.
Modelling the ultra-strongly coupled spin-boson model with unphysical modes
Authors: Lambert Neill , Ahmed Shahnawaz , Cirio Mauro , Nori Franco 
Published: August 2019

AbstractA quantum system weakly coupled to a zero-temperature environment will relax, via spontaneous emission, to its ground-state. However, when the coupling to the environment is ultra-strong the ground-state is expected to become dressed with virtual excitations. This regime is difficult to capture with some traditional methods because of the explosion in the number of Matsubara frequencies, i.e., exponential terms in the free-bath correlation function. To access this regime we generalize both the hierarchical equations of motion and pseudomode methods, taking into account this explosion using only a biexponential fitting function. We compare these methods to the reaction coordinate mapping, which helps show how these sometimes neglected Matsubara terms are important to regulate detailed balance and prevent the unphysical emission of virtual excitations. For the pseudomode method, we present a general proof of validity for the use of superficially unphysical Matsubara-modes, which mirror the mathematical essence of the Matsubara frequencies.
AAV-ie enables safe and efficient gene transfer to inner ear cells
Authors: Tan Fangzhi , Chu Cenfeng , Qi Jieyu , Li Wenyan , You Dan , Li Ke , Chen Xin , Zhao Weidong , Cheng Cheng , Liu Xiaoyi , Qiao Yunbo , Su Bing , He Shuijin , Zhong Chao , Li Huawei , Chai Renjie , Zhong Guisheng 
Published: August 2019

AbstractHearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.
MICU1 controls cristae junction and spatially anchors mitochondrial Ca2+ uniporter complex
Authors: Gottschalk Benjamin , Klec Christiane , Leitinger Gerd , Bernhart Eva , Rost René , Bischof Helmut , Madreiter-Sokolowski Corina T. , Radulović Snježana , Eroglu Emrah , Sattler Wolfgang , Waldeck-Weiermair Markus , Malli Roland , Graier Wolfgang F. 
Published: August 2019

AbstractRecently identified core proteins (MICU1, MCU, EMRE) forming the mitochondrial Ca2+ uniporter complex propelled investigations into its physiological workings. Here, we apply structured illumination microscopy to visualize and localize these proteins in living cells. Our data show that MICU1 localizes at the inner boundary membrane (IBM) due to electrostatic interaction of its polybasic domain. Moreover, this exclusive localization of MICU1 is important for the stability of cristae junctions (CJ), cytochrome c release and mitochondrial membrane potential. In contrast to MICU1, MCU and EMRE are homogeneously distributed at the inner mitochondrial membrane under resting conditions. However, upon Ca2+ elevation MCU and EMRE dynamically accumulate at the IBM in a MICU1-dependent manner. Eventually, our findings unveil an essential function of MICU1 in CJ stabilization and provide mechanistic insights of how sophistically MICU1 controls the MCU-Complex while maintaining the structural mitochondrial membrane framework.
Comprehensive analysis of syndromic hearing loss patients in Japan
Authors: Ideura Michie , Nishio Shin-ya , Moteki Hideaki , Takumi Yutaka , Miyagawa Maiko , Sato Teruyuki , Kobayashi Yumiko , Ohyama Kenji , Oda Kiyoshi , Matsui Takamichi , Ito Tsukasa , Suzumura Hiroshi , Nagai Kyoko , Izumi Shuji , Nishiyama Nobuhiro , Komori Manabu , Kumakawa Kozo , Takeda Hidehiko , Kishimoto Yoko , Iwasaki Satoshi , Furutate Sakiko , Ishikawa Kotaro , Fujioka Masato , Nakanishi Hiroshi , Nakayama Jun , Horie Rie , Ohta Yumi , Naito Yasushi , Kakudo Mariko , Sakaguchi Hirofumi , Kataoka Yuko , Sugahara Kazuma , Hato Naohito , Nakagawa Takashi , Tsuchihashi Nana , Kanda Yukihiko , Kihara Chiharu , Tono Tetsuya , Miyanohara Ikuyo , Ganaha Akira , Usami Shin-ichi 
Published: August 2019

AbstractMore than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.
Fault stress inversion reveals seismogenic asperity of the 2011 Mw 9.0 Tohoku-Oki earthquake
Authors: Xie Zhoumin , Cai Yongen , Wang Chi-yuen , Yoshioka Shoichi , Tanaka Momo 
Published: August 2019

AbstractWe predict, with a model (earthquake stress model) that inverts the displacements documented at 163 GNSS onshore stations of the GEONET, the change of shear and normal stresses on the megathrust near the Japan Trench over the seven years before the 2011 Mw 9.0 Tohoku-Oki earthquake. We find three areas on the megathrust with greater accumulations of shear and normal stresses before the earthquake, which match the ruptured areas of the mainshock and two largest aftershocks (Mw 7.8 and 7.4) that occurred within half an hour after the mainshock. We also find that the change of normal stress on the fault before the earthquake is not uniform but increases in the up-dip portion (shallower depth) of the fault from the hypocenter and decreases in the down-dip portion. We infer that the occurrence of the giant earthquake at the shallow portion of the megathrust may be attributed to the increase of the normal stress there, which leads to an increase of fault shear strength and allows more elastic strain energy to accumulate to prepare for the next big earthquake. Based on these results we propose a new concept of the seismogenic asperity as the area of greater accumulations of shear and normal stresses. The method presented here may be useful for predicting the rupture zone of future large earthquakes.
Examination of molecular space and feasible structures of bioactive components of humic substances by FTICR MS data mining in ChEMBL database
Authors: Orlov Alexey A. , Zherebker Alexander , Eletskaya Anastasia A. , Chernikov Viktor S. , Kozlovskaya Liubov I. , Zhernov Yury V. , Kostyukevich Yury , Palyulin Vladimir A. , Nikolaev Eugene N. , Osolodkin Dmitry I. , Perminova Irina V. 
Published: August 2019

AbstractHumic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a ‘biological activity black-box’ due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.
Regulation of gene expression by altered promoter methylation using a CRISPR/Cas9-mediated epigenetic editing system
Authors: Kang Jeong Gu , Park Jin Suk , Ko Jeong-Heosn , Kim Yong-Sam 
Published: August 2019

AbstractDespite the increased interest in epigenetic research, its progress has been hampered by a lack of satisfactory tools to control epigenetic factors in specific genomic regions. Until now, many attempts to manipulate DNA methylation have been made using drugs but these drugs are not target-specific and have global effects on the whole genome. However, due to new genome editing technologies, potential epigenetic factors can now possibly be regulated in a site-specific manner. Here, we demonstrate the utility of CRISPR/Cas9 to modulate methylation at specific CpG sites and to elicit gene expression. We targeted the murine Oct4 gene which is transcriptionally locked due to hypermethylation at the promoter region in NIH3T3 cells. To induce site-specific demethylation at the Oct4 promoter region and its gene expression, we used the CRISPR/Cas9 knock-in and CRISPR/dCas9-Tet1 systems. Using these two approaches, we induced site-specific demethylation at the Oct4 promoter and confirmed the up-regulation of Oct4 expression. Furthermore, we confirmed that the synergistic effect of DNA demethylation and other epigenetic regulations increased the expression of Oct4 significantly. Based on our research, we suggest that our proven epigenetic editing methods can selectively modulate epigenetic factors such as DNA methylation and have promise for various applications in epigenetics.
In vitro spleen cell cytokine responses of adult mice immunized with a recombinant PorA (major outer membrane protein [MOMP]) from Campylobacter jejuni
Authors: Albert M. John , Raghupathy Raj , Khan Islam , Azizieh Fawaz Y. 
Published: August 2019

AbstractThere is no information on cytokine profiles for use as markers of protection in Campylobacter jejuni infection. To study this, we used outer membrane protein (MOMP [PorA]) as the vaccine for protection and spleen cell cytokines as markers of protection. We cloned and expressed porA from C. jejuni111 and immunized mice by the intraperitoneal route. Subsequently, mice were orally challenged with live C. jejuni 111. The vaccine induced protection as evidenced by reduced fecal excretion of C. jejuni111. Cytokines were measured in vitro after stimulation of spleen cells with MOMP. The levels of pro-inflammatory cytokines, IL-12, TNF-α, IL-17A and IL-17F were similar in control and test mice. The levels of pro-inflammatory cytokines, IL-2 and IFN-γ were higher in control mice than in test mice, and the levels of pro-inflammatory cytokines, IL-8 and IL-1β were higher in test mice than in control mice. Among the two anti-inflammatory cytokines, the levels were similar for IL-10 but higher for IL-4 in test mice than in control mice. Ratios of pro-inflammatory to anti-inflammatory cytokines showed a bias towards an anti-inflammatory response in favor of antibody production reflecting the role of antibodies in immunity. Cytokine production patterns by spleen cells may be used as markers of protection in the mouse model.
Adsorption of 1,4-phenylene diisothiocyanate onto the graphene oxide sheets functionalized with polydiphenylamine in doped state
Authors: Baibarac M. , Daescu M. , Fejer S. N. 
Published: August 2019

AbstractAdsorption processes of 1,4-phenylene diisothiocyanate (PDITC) on two new platforms of the type graphene oxide (GO) sheets and GO layers functionalization with polydiphenylamine (PDPA) are studied by Raman scattering and photoluminescence (PL). An interaction in solid state phase of the two constituents, i.e. PDITC and GO sheets, and a deposition of PDITC onto the PDPA functionalized GO layers, respectively, by the drop casting method, were performed. In the first case, it is shown that interaction in solid state phase of GO with PDITC leads to an intercalation of the organic compound between GO sheets simultaneously with the appearance of the o-thiocarbamate groups, that induces: (i) an enhancement of the PDITC Raman lines situated in the 400–800 and 1000–1300 cm−1 spectral ranges, (ii) a change in the ratio between the relative intensities of the two Raman lines peaked at 1585 and 1602 cm−1 accompanied by an up-shift in the case of the second line and (iii) a down-shift of the PDTIC PL band from 502 to 491 nm. Using cyclic voltammetry, an electrochemical functionalization of the GO layers with PDPA doped with H3PMo12O40 heteropolyanions takes place, as demonstrated by Raman scattering and FTIR spectroscopy. The presence of the amine groups in the molecular structure of the doped PDPA functionalized GO layers induces a chemical adsorption of PDITC on this platform, when the thiourea groups appear simultaneously with o-thiocarbamate groups. A chemical mechanism is proposed to take place at the interface of the GO sheets and the doped PDPA functionalized GO layers, respectively, with PDITC.
Tissue-specific progesterone receptor-chromatin binding and the regulation of progesterone-dependent gene expression
Authors: Dinh D. T. , Breen J. , Akison L. K. , DeMayo F. J. , Brown H. M. , Robker R. L. , Russell D. L. 
Published: August 2019

AbstractProgesterone receptor (PGR) co-ordinately regulates ovulation, fertilisation and embryo implantation through tissue-specific actions, but the mechanisms for divergent PGR action are poorly understood. Here we characterised PGR activity in mouse granulosa cells using combined ChIP-seq for PGR and H3K27ac and gene expression microarray. Comparison of granulosa, uterus and oviduct PGR-dependent genes showed almost complete tissue specificity in PGR target gene profiles. In granulosa cells 82% of identified PGR-regulated genes bound PGR within 3 kb of the gene and PGR binding sites were highly enriched in proximal promoter regions in close proximity to H3K27ac-modified active chromatin. Motif analysis showed highly enriched PGR binding to the PGR response element (GnACAnnnTGTnC), but PGR also interacted significantly with other transcription factor binding motifs. In uterus PGR showed far more tendency to bind intergenic chromatin regions and low evidence of interaction with other transcription factors. This is the first genome-wide description of PGR action in granulosa cells and systematic comparison of diverse PGR action in different reproductive tissues. It clarifies finely-tuned contextual PGR-chromatin interactions with implications for more targeted reproductive medicine.