bluuebunny/crossref_metadata_2025_split huggingface dataset:
Controls on fracture distribution in Cretaceous sedimentary rocks from the Isfahan region, Iran
Authors: SAEIN ALI FARZIPOUR , RIAHI ZAHRA TAJMIR 
Published: May 2017

AbstractIn this study, relationships between fracture patterns, lithology, thickness, diagenetic processes and grain size are evaluated within Cretaceous sediments in two sections of Dizlu and Kolah Ghazi of Isfahan. This study area was selected based on its outcrops of different rock units and its well-developed tectonic fractures. The fracture patterns within stratigraphic units of these sections are studied using geometrical and statistical analyses. This study finds that variable fracture spacing and fracture spacing ratios can be affected by lithology, thickness, grain size of sediments and diagenetic processes. A study of fracture stratigraphy based on fracture pattern evaluation within different cropped-out sedimentary rocks can be used to improve understanding of the same types of sedimentary rock units below the surface or throughout other sedimentary basins. Consequently, this could improve information regarding storage and fluid flow pattern throughout sedimentary rocks in different regions, even for subsurface purposes.
Is It Desirable to Be Able to Do the Undesirable? Moral Bioenhancement and the Little Alex Problem
Authors: HAUSKELLER MICHAEL 
Published: May 2017

Abstract:It has been argued that moral bioenhancement is desirable even if it would make it impossible for us to do what is morally required. Others find this apparent loss of freedom deplorable. However, it is difficult to see how a world in which there is no moral evil can plausibly be regarded as worse than a world in which people are not only free to do evil, but also where they actually do it, which would commit us to the seemingly paradoxical view that, under certain circumstances, the bad can be better than the good. Notwithstanding, this view is defended here.
Moral Bioenhancement and Free Will: Continuing the Debate
Authors: RAKIĆ VOJIN 
Published: May 2017

Abstract:This article continues and expands differences I have with Ingmar Persson and Julian Savulescu concerning issues of moral bioenhancement and free will. They have criticized my conception of voluntary moral bioenhancement, claiming that it ignores the extent to which freedom is a matter of degree. Here, I argue that freedom as a political concept (or as one that is analogous to a political concept) is indeed scalar in nature, but that freedom of the will is to be understood as a threshold concept and therefore not as subject to degree. Consequently, I contend, by asserting that freedom is a matter of degree, that Persson and Savulescu have not undermined my arguments favoring voluntary moral enhancement. In addition, I add three further arguments against compulsory moral bioenhancement.
Would We Even Know Moral Bioenhancement If We Saw It?
Authors: WISEMAN HARRIS 
Published: May 2017

Abstract:The term “moral bioenhancement” conceals a diverse plurality encompassing much potential, some elements of which are desirable, some of which are disturbing, and some of which are simply bland. This article invites readers to take a better differentiated approach to discriminating between elements of the debate rather than talking of moral bioenhancement “per se,” or coming to any global value judgments about the idea as an abstract whole (no such whole exists). Readers are then invited to consider the benefits and distortions that come from the usual dichotomies framing the various debates, concluding with an additional distinction for further clarifying this discourse qua explicit/implicit moral bioenhancement.
Imagining Moral Bioenhancement Practices: Drawing Inspiration from Moral Education, Public Health Ethics, and Forensic Psychiatry
Authors: SPECKER JONA , SCHERMER MAARTJE H.N. 
Published: May 2017

Abstract:In this article, we consider contexts or domains in which (future) moral bioenhancement interventions possibly or most likely will be implemented. By looking closely at similar or related existing practices and their relevant ethical frameworks, we hope to identify ethical considerations that are relevant for evaluating potential moral bioenhancement interventions. We examine, first, debates on the proper scope of moral education; second, proposals for identifying early risk factors for antisocial behaviour; and third, the difficult balancing of individual freedom and third party concerns in (forensic) psychiatry. In imagining moral bioenhancement in practice, we observe that unlike other forms of enhancement, moral enhancement fundamentally asks how the interests and preferences of the individual and the interests of others should be weighed (in view of public safety and managing public risk). Highly diverse domains such as education, mental health, and the judicial domain might be involved, and moral bioenhancement might challenge existing institutional settings. Given these highly varied contexts and domains, it appears unlikely that there will be a distinct set of practices that will be referred to as “moral bioenhancement.”
Inhibition of SDF-1 receptors CXCR4 and CXCR7 attenuates acute pulmonary inflammation via the adenosine A2B-receptor on blood cells
Authors: Konrad Franziska Magdalena , Meichssner Nadine , Bury Annette , Ngamsri Kristian-Christos , Reutershan Jörg 
Published: May 2017

AbstractAcute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils into the different compartments of the lung. Recent studies showed evidence that the chemokine stromal cell-derived factor (SDF)-1 and its receptors CXCR4 and CXCR7 influence migration of immune cells and their activity was linked to adenosine concentrations. We investigated the particular role of CXCR4- and CXCR7-inhibition and the potential link to the adenosine A2B-receptor, which plays an important anti-inflammatory role in the lung. After LPS-inhalation for 45 minutes, administration of the CXCR4-inhibitor (AMD3100) decreased transendothelial and transepithelial migration, whereas CXCR7-antagonism influenced epithelial migration exclusively. In A2B−/− mice, no anti-inflammatory effects were detectible through either one of the agents. Using chimeric mice, we identified A2Bon hematopoietic cells to be crucial for these anti-inflammatory effects of CXCR4/7-inhibition. Both inhibitors decreased TNFα, IL6, CXCL1 and CXCL2/3 levels in the bronchoalveolar lavage of wild type mice, while not influencing the chemokine release in A2B−/− mice. Inflammation augmented the expression of both receptors and their inhibition increased A2B-levels upon inflammation.In vitroassays with human epithelium/endothelium confirmed ourin vivofindings. During inflammation, inhibition of CXCR4- and CXCR7-receptors prevented microvascular permeability in wild type but not in A2B−/− mice, highlighting the pivotal role of an active A2B-receptor in this setting. The combination of both inhibitors had a synergistic effect in preventing capillary leakage. In conclusion, we determined the pivotal role of CXCR4- and CXCR7-inhibition in acute pulmonary inflammation, which depended on A2B-receptor signalling.
Deletion of Pdcd5 in mice led to the deficiency of placenta development and embryonic lethality
Authors: Li Ge , Xu Chentong , Lin Xin , Qu Liujing , Xia Dan , Hongdu Beiqi , Xia Yan , Wang Xiaokun , Lou Yaxin , He Qihua , Ma Dalong , Chen Yingyu 
Published: May 2017

AbstractProgrammed cell death 5 (PDCD5) is an apoptosis promoter molecule that displays multiple biological activities. However, the function of PDCD5 in vivo has not yet been investigated. Here, we generated a Pdcd5 knockout mouse model to study the physiological role of PDCD5 in vivo. Knockout of the Pdcd5 gene resulted in embryonic lethality at mid-gestation. Histopathological analysis revealed dysplasia in both the LZs and JZs in Pdcd5–/– placentas with defects in spongiotrophoblasts and trophoblast giant cells. Furthermore, Pdcd5–/– embryos had impaired transplacental passage capacity. We also found that Pdcd5–/– embryos exhibited cardiac abnormalities and defective liver development. The growth defect is linked to impaired placental development and may be caused by insufficient oxygen and nutrient transfer across the placenta. These findings were verified in vitro in Pdcd5 knockout mouse embryonic fibroblasts, which showed increased apoptosis and G0/G1 phase cell cycle arrest. Pdcd5 knockout decreased the Vegf and hepatocyte growth factor (Hgf) levels, downregulated the downstream Pik3ca–Akt–Mtor signal pathway and decreased cell survival. Collectively, our studies demonstrated that Pdcd5 knockout in mouse embryos results in placental defects and embryonic lethality.
Protein disulfide isomerase-mediated apoptosis and proliferation of vascular smooth muscle cells induced by mechanical stress and advanced glycosylation end products result in diabetic mouse vein graft atherosclerosis
Authors: Ping Suning , Liu Shuying , Zhou Yuhuan , Li Ziqing , Li Yuhuang , Liu Kefeng , Bardeesi Adham SA , Wang Linli , Chen Jingbo , Deng Lie , Wang Jingjing , Wang Hong , Chen Dadi , Zhang Zhengyu , Sheng Puyi , Li Chaohong 
Published: May 2017

AbstractProtein disulfide isomerase (PDI) involves cell survival and death. Whether PDI mediates mechanical stretch stress (SS) and/or advanced glycosylation end products (AGEs) -triggered simultaneous increases in proliferation and apoptosis of vascular smooth muscle cells (VSMCs) is unknown. Here, we hypothesized that different expression levels of PDI trigger completely opposite cell fates among the different VSMC subtypes. Mouse veins were grafted into carotid arteries of non-diabetic and diabetic mice for 8 weeks; the grafted veins underwent simultaneous increases in proliferation and apoptosis, which triggered vein graft arterializations in non-diabetic or atherosclerosis in diabetic mice. A higher rate of proliferation and apoptosis was seen in the diabetic group. SS and/or AGEs stimulated the quiescent cultured VSMCs, resulting in simultaneous increases in proliferation and apoptosis; they could induce increased PDI activation and expression. Both in vivo and in vitro, the proliferating VSMCs indicated weak co-expression of PDI and SM-α-actin while apoptotic or dead cells showed strong co-expression of both. Either SS or AGEs rapidly upregulated the expression of PDI, NOX1 and ROS, and their combination had synergistic effects. Inhibiting PDI simultaneously suppressed the proliferation and apoptosis of VSMCs, while inhibition of SM-α-actin with cytochalasin D led to increased apoptosis and cleaved caspases-3 but had no effect on proliferation. In conclusion, different expression levels of PDI in VSMCs induced by SS and/or AGEs triggered a simultaneous increase in proliferation and apoptosis, accelerated vein graft arterializations or atherosclerosis, leading us to propose PDI as a novel target for the treatment of vascular remodeling and diseases.
HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival
Authors: Lacher Sonja M , Bruttger Julia , Kalt Bettina , Berthelet Jean , Rajalingam Krishnaraj , Wörtge Simone , Waisman Ari 
Published: May 2017

AbstractStatins are a well-established family of drugs that lower cholesterol levels via the competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). In addition, the pleiotropic anti-inflammatory effects of statins on T cells make them attractive as therapeutic drugs in T-cell-driven autoimmune disorders. Since statins do not exclusively target HMGCR and thus might have varying effects on different cell types, we generated a new mouse strain allowing for the tissue-specific deletion of HMGCR. Deletion of HMGCR expression in T cells led to a severe decrease in their numbers with the remaining cells displaying an activated phenotype, with an increased proportion of regulatory T cells (Tregs) in particular. However, deletion of HMGCR specifically in Tregs resulted in severe autoimmunity, suggesting that this enzyme is also essential for the maintenance of Tregs. We were able to prevent the death of HMGCR-deficient lymphocytes by the addition of either the direct metabolite of HMGCR, namely mevalonate, or the downstream metabolite geranylgeranyl pyrophosphate, which is essential for protein prenylation. However, the addition of cholesterol, which is the final product of the mevalonate pathway, did not inhibit cell death, indicating that protein prenylation rather than the cholesterol biosynthesis pathway is indispensible for T-cell survival.
DNA damage and S phase-dependent E2F1 stabilization requires the cIAP1 E3-ubiquitin ligase and is associated with K63-poly-ubiquitination on lysine 161/164 residues
Authors: Glorian Valérie , Allègre Jennifer , Berthelet Jean , Dumetier Baptiste , Boutanquoi Pierre-Marie , Droin Nathalie , Kayaci Cémile , Cartier Jessy , Gemble Simon , Marcion Guillaume , Gonzalez Daniel , Boidot Romain , Garrido Carmen , Michaud Olivier , Solary Eric , Dubrez Laurence 
Published: May 2017

AbstractThe E2F transcription factor 1 is subtly regulated along the cell cycle progression and in response to DNA damage by post-translational modifications. Here, we demonstrated that the E3-ubiquitin ligase cellular inhibitor of apoptosis 1 (cIAP1) increases E2F1 K63-poly-ubiquitination on the lysine residue 161/164 cluster, which is associated with the transcriptional factor stability and activity. Mutation of these lysine residues completely abrogates the binding of E2F1 to CCNE, TP73 and APAF1 promoters, thus inhibiting transcriptional activation of these genes and E2F1-mediated cell proliferation control. Importantly, E2F1 stabilization in response to etoposide-induced DNA damage or during the S phase of cell cycle, as revealed by cyclin A silencing, is associated with K63-poly-ubiquitinylation of E2F1 on lysine 161/164 residues and involves cIAP1. Our results reveal an additional level of regulation of the stability and the activity of E2F1 by a non-degradative K63-poly-ubiquitination and uncover a novel function for the E3-ubiquitin ligase cIAP1.
Activation of transient receptor potential vanilloid 4 involves in hypoxia/reoxygenation injury in cardiomyocytes
Authors: Wu Qiong-Feng , Qian Cheng , Zhao Ning , Dong Qian , Li Jing , Wang Bin-Bin , Chen Lei , Yu Lixiu , Han Bing , Du Yi-Mei , Liao Yu-Hua 
Published: May 2017

AbstractTransient receptor potential vanilloid 4 (TRPV4) is highly expressed in heart and vessels and can be activated during myocardial ischemia/reperfusion (I/R). Recently, we found that treatment with a selective TRPV4 antagonist HC-067047 significantly reduced infarct size, decreased troponin T levels and improved cardiac function in murine model myocardial I/R. This study was undertaken to investigate the mechanism underlying TRPV4-mediated myocardial I/R injury. To mimic myocardial I/R injury, we established a hypoxia/reoxygenation (H/R) model in H9C2 cells and neonatal rat ventricle myocytes (NRVMs) in vitro. TRPV4 mRNA and protein expression was confirmed in the H9C2 and NRVM, whereas functional TRPV4 activity was assessed from Ca2+ influx response to a TRPV4 agonist GSK1016790A. TRPV4 functional expression was significantly enhanced during H/R. Furthermore, H/R increased the intracellular Ca2+ concentration ([Ca2+]i) and induced cell injury, which were reversed by HC-067047 but was further aggravated by GSK1016790A. Moreover, HC-067047 treatment significantly alleviated the increase of reactive oxygen species (ROS) generation, the depolarization of mitochondrial membrane potential (Δψm) and the opening of mitochondrial permeability transition pore (mPTP) during H/R. On the contrary, GSK1016790A exacerbated those effects. Meanwhile, increase in [Ca2+]i and ROS induced by activation of TRPV4 was almost abolished when cells were cultured in Ca2+-free medium. In addition, ROS scavenger NAC obviously reversed activation of TRPV4-induced changes of Δψm and mPTP opening. Finally, we confirmed the direct roles of TRPV4 on cardiac injury and ROS generation in murine model myocardial I/R in vivo. In conclusion, activation of TRPV4 induces Ca2+ influx in cardiomyocytes, with subsequent ROS release, depolarizing of Δψm, opening mPTP, inducing injury and TRPV4 has key roles during I/R via these pathways.
The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion
Authors: Jiang Runqiu , Tang Junwei , Chen Yun , Deng Lei , Ji Jie , Xie Yu , Wang Ke , Jia Wei , Chu Wen-Ming , Sun Beicheng 
Published: May 2017

AbstractLong noncoding RNAs play a pivotal role in T-helper cell development but little is known about their roles in Treg differentiation and functions during the progression of hepatocellular carcinoma (HCC). Here, we show that lnc-epidermal growth factor receptor (EGFR) upregulation in Tregs correlates positively with the tumour size and expression of EGFR/Foxp3, but negatively with IFN-γ expression in patients and xenografted mouse models. Lnc-EGFR stimulates Treg differentiation, suppresses CTL activity and promotes HCC growth in an EGFR-dependent manner. Mechanistically, lnc-EGFR specifically binds to EGFR and blocks its interaction with and ubiquitination by c-CBL, stabilizing it and augmenting activation of itself and its downstream AP-1/NF-AT1 axis, which in turn elicits EGFR expression. Lnc-EGFR links an immunosuppressive state to cancer by promoting Treg cell differentiation, thus offering a potential therapeutic target for HCC.
Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations
Authors: Zhou Xiaolai , Sun Lirong , Bracko Oliver , Choi Ji Whae , Jia Yan , Nana Alissa L. , Brady Owen Adam , Hernandez Jean C. Cruz , Nishimura Nozomi , Seeley William W. , Hu Fenghua 
Published: May 2017

AbstractHaploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation. We found reduced levels of PSAP in neurons both in mice deficient in PGRN and in human samples from FTLD patients due to GRN mutations. Furthermore, mice with reduced PSAP expression demonstrated FTLD-like pathology and behavioural changes. Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations.
Tailing and degradation of Argonaute-bound small RNAs protect the genome from uncontrolled RNAi
Authors: Pisacane Paola , Halic Mario 
Published: May 2017

AbstractRNAi is a conserved mechanism in which small RNAs induce silencing of complementary targets. How Argonaute-bound small RNAs are targeted for degradation is not well understood. We show that the adenyl-transferase Cid14, a member of the TRAMP complex, and the uridyl-transferase Cid16 add non-templated nucleotides to Argonaute-bound small RNAs in fission yeast. The tailing of Argonaute-bound small RNAs recruits the 3′–5′ exonuclease Rrp6 to degrade small RNAs. Failure in degradation of Argonaute-bound small RNAs results in accumulation of ‘noise’ small RNAs on Argonaute and targeting of diverse euchromatic genes by RNAi. To protect themselves from uncontrolled RNAi, cid14Δ cells exploit the RNAi machinery and silence genes essential for RNAi itself, which is required for their viability. Our data indicate that surveillance of Argonaute-bound small RNAs by Cid14/Cid16 and the exosome protects the genome from uncontrolled RNAi and reveal a rapid RNAi-based adaptation to stress conditions.
Synthesis of spiro quasi[1]catenanes and quasi[1]rotaxanes via a templated backfolding strategy
Authors: Steemers Luuk , Wanner Martin J. , Lutz Martin , Hiemstra Henk , van Maarseveen Jan H. 
Published: May 2017

AbstractDue to their well-defined three-dimensional geometry, spiro compounds are widely utilized in drug research. From the central tetrahedral carbon atom, besides the regular structure, an inverted spiro connectivity may be envisioned. Here we disclose the synthesis of this molecule class that we have coined quasi[1]catenanes. Next to their fascinating and aesthetic shape, the higher compactness as compared to regular spiro bicycles is noteworthy. To enable synthetic access to compact entangled multimacrocyclic molecules, we have developed a new strategy. The key element is a template, which is covalently connected to the linear precursors, and spatially directs the sterically congested backfolding macrocyclizations that are required to give quasi[1]catenanes. Similarly, quasi[1]rotaxanes are made.
Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve
Authors: Yang Bo , Zhou Wei , Jiao Jiao , Nielsen Jonas B. , Mathis Michael R. , Heydarpour Mahyar , Lettre Guillaume , Folkersen Lasse , Prakash Siddharth , Schurmann Claudia , Fritsche Lars , Farnum Gregory A. , Lin Maoxuan , Othman Mohammad , Hornsby Whitney , Driscoll Anisa , Levasseur Alexandra , Thomas Marc , Farhat Linda , Dubé Marie-Pierre , Isselbacher Eric M. , Franco-Cereceda Anders , Guo Dong-chuan , Bottinger Erwin P. , Deeb G. Michael , Booher Anna , Kheterpal Sachin , Chen Y. Eugene , Kang Hyun Min , Kitzman Jacob , Cordell Heather J. , Keavney Bernard D. , Goodship Judith A. , Ganesh Santhi K. , Abecasis Gonçalo , Eagle Kim A. , Boyle Alan P. , Loos Ruth J. F. , Eriksson Per , Tardif Jean-Claude , Brummett Chad M. , Milewicz Dianna M. , Body Simon C. , Willer Cristen J. 
Published: May 2017

AbstractBicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.
High pressure synthesis of a hexagonal close-packed phase of the high-entropy alloy CrMnFeCoNi
Authors: Tracy Cameron L. , Park Sulgiye , Rittman Dylan R. , Zinkle Steven J. , Bei Hongbin , Lang Maik , Ewing Rodney C. , Mao Wendy L. 
Published: May 2017

AbstractHigh-entropy alloys, near-equiatomic solid solutions of five or more elements, represent a new strategy for the design of materials with properties superior to those of conventional alloys. However, their phase space remains constrained, with transition metal high-entropy alloys exhibiting only face- or body-centered cubic structures. Here, we report the high-pressure synthesis of a hexagonal close-packed phase of the prototypical high-entropy alloy CrMnFeCoNi. This martensitic transformation begins at 14 GPa and is attributed to suppression of the local magnetic moments, destabilizing the initial fcc structure. Similar to fcc-to-hcp transformations in Al and the noble gases, the transformation is sluggish, occurring over a range of >40 GPa. However, the behaviour of CrMnFeCoNi is unique in that the hcp phase is retained following decompression to ambient pressure, yielding metastable fcc-hcp mixtures. This demonstrates a means of tuning the structures and properties of high-entropy alloys in a manner not achievable by conventional processing techniques.