bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythromycin suppresses neutrophil extracellular traps in smoking-related chronic pulmonary inflammation
Authors: Zhang Hui , Qiu Shi-Lin , Tang Qi-Ya , Zhou Xiu , Zhang Jian-Quan , He Zhi-Yi , Bai Jing , Li Mei-Hua , Deng Jing-Min , Liang Yi , Zhong Xiao-Ning 
Published: September 2019

AbstractNeutrophil extracellular traps (NETs) may play a critical role in smoking-related chronic airway inflammation. However, the mechanism by which NETs induced by cigarette smoke initiate the adaptive immunity in chronic obstructive pulmonary disease (COPD) is not fully understood. In this study, we explored the effects of NETs induced by cigarette smoke on the myeloid dendritic cells (mDCs) and Th1 and Th17 cells. Additionally, we observed the inhibitory effect of erythromycin on NETs induced by cigarette smoke. We found that elevated NET levels in the sputum of COPD patients were correlated with the circulating Th1 response, mDC activation and airflow limitation. NETs induced by cigarette smoke extract (CSE) could activate monocyte-derived mDCs and promote Th1 and Th17 differentiation in vitro. Erythromycin effectively inhibited NET formation induced by CSE. In vivo, erythromycin decreased NETs in the airway and ameliorated emphysema with Th1 and Th17 cell down-regulation and CD40+ and CD86+ mDCs suppression in mice chronically exposed to cigarette smoke. These findings provide direct evidence that NETs promote the differentiation of Th1 and Th17 and play a role in the adaptive immunity of smoking-related chronic lung inflammation. Erythromycin is a potential therapeutic strategy for NETs inhibition in COPD.
ΔNp63α suppresses cells invasion by downregulating PKCγ/Rac1 signaling through miR-320a
Authors: Aljagthmi Amjad A. , Hill Natasha T. , Cooke Mariana , Kazanietz Marcelo G. , Abba Martín C. , Long Weiwen , Kadakia Madhavi P. 
Published: September 2019

AbstractΔNp63α, a member of the p53 family of transcription factors, is overexpressed in a number of cancers and plays a role in proliferation, differentiation, migration, and invasion. ΔNp63α has been shown to regulate several microRNAs that are involved in development and cancer. We identified miRNA miR-320a as a positively regulated target of ΔNp63α. Previous studies have shown that miR-320a is downregulated in colorectal cancer and targets the small GTPase Rac1, leading to a reduction in noncanonical WNT signaling and EMT, thereby inhibiting tumor metastasis and invasion. We showed that miR-320a is a direct target of ΔNp63α. Knockdown of ΔNp63α in HaCaT and A431 cells downregulates miR-320a levels and leads to a corresponding elevation in PKCγ transcript and protein levels. Rac1 phosphorylation at Ser71 was increased in the absence of ΔNp63α, whereas overexpression of ΔNp63α reversed S71 phosphorylation of Rac1. Moreover, increased PKCγ levels, Rac1 phosphorylation and cell invasion observed upon knockdown of ΔNp63α was reversed by either overexpressing miR-320a mimic or Rac1 silencing. Finally, silencing PKCγ or treatment with the PKC inhibitor Gö6976 reversed increased Rac1 phosphorylation and cell invasion observed upon silencing ΔNp63α. Taken together, our data suggest that ΔNp63α positively regulates miR-320a, thereby inhibiting PKCγ expression, Rac1 phosphorylation, and cancer invasion.
Long noncoding RNA BFAL1 mediates enterotoxigenic Bacteroides fragilis-related carcinogenesis in colorectal cancer via the RHEB/mTOR pathway
Authors: Bao Yujie , Tang Jiayin , Qian Yun , Sun Tiantian , Chen Huimin , Chen Zhaofei , Sun Danfeng , Zhong Ming , Chen Haoyan , Hong Jie , Chen Yingxuan , Fang Jing-Yuan 
Published: September 2019

AbstractLong noncoding RNAs (lncRNAs) contribute to many steps in carcinogenesis and often serve as biomarkers or therapeutic targets for tumor diagnosis and therapy. Although the role of lncRNAs in tumor formation is becoming clear, whether lncRNAs mediate gut microbiota-induced colorectal cancer (CRC) is largely unknown. Enterotoxigenic Bacteroides fragilis (ETBF) is a well-known tumor-inducing bacterium in the human gut; however, its tumorigenic effect remains to be explored. In the present study, we revealed the mechanism by which a lncRNA participates in gut bacteria-induced carcinogenesis: Bacteroides fragilis-associated lncRNA1 (BFAL1) in CRC tissues mediates ETBF carcinogenesis. BFAL1 was highly expressed in CRC tissues compared with that in adjacent normal tissues. In vitro, BFAL1 was upregulated in ETBF-treated CRC cells. Mechanistically, ETBF promoted tumor growth via BFAL1 by activating the Ras homolog, which is the MTORC1 binding/mammalian target of the rapamycin (RHEB/mTOR) pathway. Furthermore, BFAL1 regulated RHEB expression by competitively sponging microRNAs miR-155-5p and miR-200a-3p. Clinically, both high expression of BFAL1 and high abundance of ETBF in CRC tissues predicted poor outcomes for patients with CRC. Thus, BFAL1 is a mediator of ETBF-induced carcinogenesis and may be a potential therapeutic target for ETBF-induced CRC.
Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading
Authors: Gilbert Hamish T. J. , Mallikarjun Venkatesh , Dobre Oana , Jackson Mark R. , Pedley Robert , Gilmore Andrew P. , Richardson Stephen M. , Swift Joe 
Published: September 2019

AbstractStudies of cellular mechano-signaling have often utilized static models that do not fully replicate the dynamics of living tissues. Here, we examine the time-dependent response of primary human mesenchymal stem cells (hMSCs) to cyclic tensile strain (CTS). At low-intensity strain (1 h, 4% CTS at 1 Hz), cell characteristics mimic responses to increased substrate stiffness. As the strain regime is intensified (frequency increased to 5 Hz), we characterize rapid establishment of a broad, structured and reversible protein-level response, even as transcription is apparently downregulated. Protein abundance is quantified coincident with changes to protein conformation and post-translational modification (PTM). Furthermore, we characterize changes to the linker of nucleoskeleton and cytoskeleton (LINC) complex that bridges the nuclear envelope, and specifically to levels and PTMs of Sad1/UNC-84 (SUN) domain-containing protein 2 (SUN2). The result of this regulation is to decouple mechano-transmission between the cytoskeleton and the nucleus, thus conferring protection to chromatin.
GSTA4 mediates reduction of cisplatin ototoxicity in female mice
Authors: Park Hyo-Jin , Kim Mi-Jung , Rothenberger Christina , Kumar Ashok , Sampson Edith M. , Ding Dalian , Han Chul , White Karessa , Boyd Kevin , Manohar Senthilvelan , Kim Yong-Hwan , Ticsa Maria S. , Gomez Aaron S. , Caicedo Isabela , Bose Upal , Linser Paul J. , Miyakawa Takuya , Tanokura Masaru , Foster Thomas C. , Salvi Richard , Someya Shinichi 
Published: September 2019

AbstractCisplatin is one of the most widely used chemotherapeutic drugs for the treatment of cancer. Unfortunately, one of its major side effects is permanent hearing loss. Here, we show that glutathione transferase α4 (GSTA4), a member of the Phase II detoxifying enzyme superfamily, mediates reduction of cisplatin ototoxicity by removing 4-hydroxynonenal (4-HNE) in the inner ears of female mice. Under cisplatin treatment, loss ofGsta4results in more profound hearing loss in female mice compared to male mice. Cisplatin stimulates GSTA4 activity in the inner ear of female wild-type, but not male wild-type mice. In femaleGsta4−/−mice, cisplatin treatment results in increased levels of 4-HNE in cochlear neurons compared to maleGsta4−/−mice. In CBA/CaJ mice, ovariectomy decreases mRNA expression ofGsta4, and the levels of GSTA4 protein in the inner ears. Thus, our findings suggest that GSTA4-dependent detoxification may play a role in estrogen-mediated neuroprotection.
An in vitro model maintaining taxon-specific functional activities of the gut microbiome
Authors: Li Leyuan , Abou-Samra Elias , Ning Zhibin , Zhang Xu , Mayne Janice , Wang Janet , Cheng Kai , Walker Krystal , Stintzi Alain , Figeys Daniel 
Published: September 2019

AbstractIn vitro gut microbiome models could provide timely and cost-efficient solutions to study microbiome responses to drugs. For this purpose, in vitro models that maintain the functional and compositional profiles of in vivo gut microbiomes would be extremely valuable. Here, we present a 96-deep well plate-based culturing model (MiPro) that maintains the functional and compositional profiles of individual gut microbiomes, as assessed by metaproteomics, while allowing a four-fold increase in viable bacteria counts. Comparison of taxon-specific functions between pre- and post-culture microbiomes shows a Pearson’s correlation coefficient r of 0.83 ± 0.03. In addition, we show a high degree of correlation between gut microbiome responses to metformin in the MiPro model and those in mice fed a high-fat diet. We propose MiPro as an in vitro gut microbiome model for scalable investigation of drug-microbiome interactions such as during high-throughput drug screening.
Differentiation but not ALS mutations in FUS rewires motor neuron metabolism
Authors: Vandoorne Tijs , Veys Koen , Guo Wenting , Sicart Adria , Vints Katlijn , Swijsen Ann , Moisse Matthieu , Eelen Guy , Gounko Natalia V. , Fumagalli Laura , Fazal Raheem , Germeys Christine , Quaegebeur Annelies , Fendt Sarah-Maria , Carmeliet Peter , Verfaillie Catherine , Van Damme Philip , Ghesquière Bart , De Bock Katrien , Van Den Bosch Ludo 
Published: September 2019

AbstractEnergy metabolism has been repeatedly linked to amyotrophic lateral sclerosis (ALS). Yet, motor neuron (MN) metabolism remains poorly studied and it is unknown if ALS MNs differ metabolically from healthy MNs. To address this question, we first performed a metabolic characterization of induced pluripotent stem cells (iPSCs) versus iPSC-derived MNs and subsequently compared MNs from ALS patients carrying FUS mutations to their CRISPR/Cas9-corrected counterparts. We discovered that human iPSCs undergo a lactate oxidation-fuelled prooxidative metabolic switch when they differentiate into functional MNs. Simultaneously, they rewire metabolic routes to import pyruvate into the TCA cycle in an energy substrate specific way. By comparing patient-derived MNs and their isogenic controls, we show that ALS-causing mutations in FUS did not affect glycolytic or mitochondrial energy metabolism of human MNs in vitro. These data show that metabolic dysfunction is not the underlying cause of the ALS-related phenotypes previously observed in these MNs.
Experimental demonstration of quantum advantage for one-way communication complexity surpassing best-known classical protocol
Authors: Kumar Niraj , Kerenidis Iordanis , Diamanti Eleni 
Published: September 2019

AbstractDemonstrating a quantum advantage with currently available experimental systems is of utmost importance in quantum information science. While this remains elusive for quantum computation, the field of communication complexity offers the possibility to already explore and showcase this advantage for useful tasks. Here, we define such a task, the Sampling Matching problem, which is inspired by the Hidden Matching problem and features an exponential gap between quantum and classical protocols in the one-way communication model. Our problem allows by its conception a photonic implementation based on encoding in the phase of coherent states of light, the use of a fixed size linear optic circuit, and single-photon detection. This enables us to demonstrate in a proof-of-principle experiment an advantage in the transmitted information resource over the best known classical protocol, something impossible to reach for the original Hidden Matching problem. Our demonstration has implications in quantum verification and cryptographic settings.
Autoinhibition and activation mechanisms of the eukaryotic lipid flippase Drs2p-Cdc50p
Authors: Bai Lin , Kovach Amanda , You Qinglong , Hsu Hao-Chi , Zhao Gongpu , Li Huilin 
Published: September 2019

AbstractThe heterodimeric eukaryotic Drs2p-Cdc50p complex is a lipid flippase that maintains cell membrane asymmetry. The enzyme complex exists in an autoinhibited form in the absence of an activator and is specifically activated by phosphatidylinositol-4-phosphate (PI4P), although the underlying mechanisms have been unclear. Here we report the cryo-EM structures of intact Drs2p-Cdc50p isolated from S. cerevisiae in apo form and in the PI4P-activated form at 2.8 Å and 3.3 Å resolution, respectively. The structures reveal that the Drs2p C-terminus lines a long groove in the cytosolic regulatory region to inhibit the flippase activity. PIP4 binding in a cytosol-proximal membrane region triggers a 90° rotation of a cytosolic helix switch that is located just upstream of the inhibitory C-terminal peptide. The rotation of the helix switch dislodges the C-terminus from the regulatory region, activating the flippase.
The EYA3 tyrosine phosphatase activity promotes pulmonary vascular remodeling in pulmonary arterial hypertension
Authors: Wang Yuhua , Pandey Ram Naresh , York Allen J. , Mallela Jaya , Nichols William C. , Hu Yueh-Chiang , Molkentin Jeffery D. , Wikenheiser-Brokamp Kathryn A. , Hegde Rashmi S. 
Published: September 2019

AbstractIn pulmonary hypertension vascular remodeling leads to narrowing of distal pulmonary arterioles and increased pulmonary vascular resistance. Vascular remodeling is promoted by the survival and proliferation of pulmonary arterial vascular cells in a DNA-damaging, hostile microenvironment. Here we report that levels of Eyes Absent 3 (EYA3) are elevated in pulmonary arterial smooth muscle cells from patients with pulmonary arterial hypertension and that EYA3 tyrosine phosphatase activity promotes the survival of these cells under DNA-damaging conditions. Transgenic mice harboring an inactivating mutation in the EYA3 tyrosine phosphatase domain are significantly protected from vascular remodeling. Pharmacological inhibition of the EYA3 tyrosine phosphatase activity substantially reverses vascular remodeling in a rat model of angio-obliterative pulmonary hypertension. Together these observations establish EYA3 as a disease-modifying target whose function in the pathophysiology of pulmonary arterial hypertension can be targeted by available inhibitors.
A global mass budget for positively buoyant macroplastic debris in the ocean
Authors: Lebreton Laurent , Egger Matthias , Slat Boyan 
Published: September 2019

AbstractPredicted global figures for plastic debris accumulation in the ocean surface layer range on the order of hundreds of thousands of metric tons, representing only a few percent of estimated annual emissions into the marine environment. The current accepted explanation for this difference is that positively buoyant macroplastic objects do not persist on the ocean surface. Subject to degradation into microplastics, the major part of the mass is predicted to have settled below the surface. However, we argue that such a simple emission-degradation model cannot explain the occurrence of decades-old objects collected by oceanic expeditions. We show that debris circulation dynamics in coastal environments may be a better explanation for this difference. The results presented here suggest that there is a significant time interval, on the order of several years to decades, between terrestrial emissions and representative accumulation in offshore waters. Importantly, our results also indicate that the current generation of secondary microplastics in the global ocean is mostly a result of the degradation of objects produced in the 1990s and earlier. Finally, we propose a series of future emission scenarios until 2050, discussing the necessity to rapidly reduce emissions and actively remove waste accumulated in the environment to mitigate further microplastic contamination in the global ocean.
An Investigation of Nanomechanical Properties of Materials using Nanoindentation and Artificial Neural Network
Authors: Lee Hyuk , Huen Wai Yeong , Vimonsatit Vanissorn , Mendis Priyan 
Published: September 2019

AbstractMechanical properties of materials can be derived from the force-displacement relationship through instrumented indentation tests. Complications arise when establishing the full elastic-plastic stress-strain relationship as the accuracy depends on how the material’s and indenter’s parameters are incorporated. For instance, the effect of the material work-hardening phenomenon such as the pile-up and sink-in effect cannot be accounted for with simplified analytical indentation solutions. Due to this limitation, this paper proposes a new inverse analysis approach based on dimensional functions analysis and artificial neural networks (ANNs). A database of the dimensional functions relating stress and strain parameters of materials has been developed. The database covers a wide range of engineering materials that have the yield strength-to-modulus ratio (σy/E) between 0.001 to 0.5, the work-hardening power (n) between 0–0.5, Poisson’s ratio (v) between 0.15–0.45, and the indentation angle (θ) between 65–80 degrees. The proposed algorithm enables determining the nanomechanical stress-strain parameters using the indentation force-displacement relationship, and is applicable to any materials that the properties are within the database range. The obtained results are validated with the conventional test results of steel and aluminum samples. To further demonstrate the application of the proposed algorithm, the nanomechanical stress-strain parameters of ordinary Portland cement phases were determined.
Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes
Authors: Choi Myeong A , Park Sun You , Chae Hye Yun , Song Yoojin , Sharma Chiranjeev , Seo Young Ho 
Published: September 2019

AbstractTo develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.
Aminopeptidase N-null neonatal piglets are protected from transmissible gastroenteritis virus but not porcine epidemic diarrhea virus
Authors: Luo Lei , Wang Shaohua , Zhu Lin , Fan Baochao , Liu Tong , Wang Lefeng , Zhao Panpan , Dang Yanna , Sun Pei , Chen Jianwen , Zhang Yunhai , Chang Xinjian , Yu Zhengyu , Wang Huanan , Guo Rongli , Li Bin , Zhang Kun 
Published: September 2019

AbstractSwine enteric diseases have caused significant economic loss and have been considered as the major threat to the global swine industry. Several coronaviruses, including transmissible gastroenteritis virus (TGEV) and porcine epidemic diarrhea virus (PEDV), have been identified as the causative agents of these diseases. Effective measures to control these diseases are lacking. The major host cells of transmissible gastroenteritis virus and porcine epidemic diarrhea virus have thought to be epithelial cells on small intestine villi. Aminopeptidase-N (APN) has been described as the putative receptor for entry of transmissible gastroenteritis virus and porcine epidemic diarrhea virus into cells in vitro. Recently, Whitworth et al. have reported that APN knockout pigs are resistant to TGEV but not PEDV after weaning. However, it remains unclear if APN-null neonatal pigs are protected from TGEV. Here we report the generation of APN-null pigs by using CRISPR/Cas9 technology followed by somatic cell nuclear transfer. APN-null pigs are produced with normal pregnancy rate and viability, indicating lack of APN is not embryonic lethal. After viral challenge, APN-null neonatal piglets are resistant to highly virulent transmissible gastroenteritis virus. Histopathological analyses indicate APN-null pigs exhibit normal small intestine villi, while wildtype pigs show typical lesions in small intestines. Immunochemistry analyses confirm that no transmissible gastroenteritis virus antigen is detected in target tissues in APN-null piglets. However, upon porcine epidemic diarrhea virus challenge, APN-null pigs are still susceptible with 100% mortality. Collectively, this report provides a viable tool for producing animals with enhanced resistance to TGEV and clarifies that APN is dispensable for the PEDV infection in pigs.
Activation of mucosal-associated invariant T cells in the lungs of sarcoidosis patients
Authors: Matsuyama Hisayo , Isshiki Takuma , Chiba Asako , Yamaguchi Tetsuo , Murayama Goh , Akasaka Yoshikiyo , Eishi Yoshinobu , Sakamoto Susumu , Homma Sakae , Miyake Sachiko 
Published: September 2019

AbstractAlthough the pathogenesis of sarcoidosis is not fully understood, immunological characterization has elucidated highly polarized expression of the type 1 T helper cell response. Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize bacterial riboflavin and rapidly produce cytokines such as interferon γ and tumor necrosis factor α. We prospectively evaluated the proportion of MAIT cells and the expression levels of cell surface markers in peripheral blood from 40 sarcoidosis patients and 28 healthy controls. MAIT cells in bronchoalveolar lavage fluid (BALF) were also examined in 12 sarcoidosis patients. In peripheral blood, the proportion of MAIT cells was lower (P = 0.0002), but the expression levels of CD69 and programmed death 1 on MAIT cells were higher in sarcoidosis patients than in healthy controls. Moreover, CD69 expression levels were significantly correlated with clinical biomarkers. Sarcoidosis patients with parenchymal infiltration in the lungs showed a significantly higher proportion and number of MAIT cells in BALF compared to patients without parenchymal infiltration. CD69 expression levels on MAIT cells in BALF were higher than levels in peripheral blood. The activation status of MAIT cells might reflect the disease activity of sarcoidosis. Therefore, it is a potential target for sarcoidosis treatment.
Predicting two-dimensional topological phases in Janus materials by substitutional doping in transition metal dichalcogenide monolayers
Authors: Maghirang Aniceto B. , Huang Zhi-Quan , Villaos Rovi Angelo B. , Hsu Chia-Hsiu , Feng Liang-Ying , Florido Emmanuel , Lin Hsin , Bansil Arun , Chuang Feng-Chuan 
Published: September 2019

AbstractUltrathin Janus two-dimensional (2D) materials are attracting intense interest currently. Substitutional doping of 2D transition metal dichalcogenides (TMDs) is of importance for tuning and possible enhancement of their electronic, physical and chemical properties toward industrial applications. Using systematic first-principles computations, we propose a class of Janus 2D materials based on the monolayers MX2 (M = V, Nb, Ta, Tc, or Re; X = S, Se, or Te) with halogen (F, Cl, Br, or I) or pnictogen (N, P, As, Sb, or Bi) substitution. Nontrivial phases are obtained on pnictogen substitution of group VB (V, Nb, or Ta), whereas for group VIIB (Tc or Re), the nontrivial phases are obtained for halogen substitution. Orbital analysis shows that the nontrivial phase is driven by the splitting of M-dyz and M-dxz orbitals. Our study demonstrates that the Janus 2D materials have the tunability and suitability for synthesis under various conditions.