julilili42/papers huggingface dataset:
Constitutions as Intergenerational Contracts: Flexible or fixed?
2017-08-04

Abstract: Constitutions enshrine the fundamental values of a people and build a framework for a state’s public policy. With regard to intergenerational justice, their endurance gives rise to two concerns: the (forgone) welfare concern and the sovereignty concern. In this paper, I outline a procedure for constitution- amending that is intergenerationally just. In its line of reasoning, the paper debates ideas such as perpetual constitutions, sunset constitutions, constitutional reform commissions and constitutional conventions both historically and analytically. It arrives at the conclusion that recurrent constitutional reform commissions in fixed time intervals strike the best balance between the necessary rigidity and the necessary flexibility of constitutions.
Cover Picture: Modular Synthesis of Triazole‐Based Chiral Iodoarenes for Enantioselective Spirocyclizations (Adv. Synth. Catal. 17/2017)
2017-08-04

The inside cover picture, provided by Pericàs and Nachtsheim, illustrates the development of novel C1-symmetric iodoarenes as precursors for chiral aryl-λ3-iodanes. The synthesis of these structures is highly modular and allows easy modification on all major substituents, namely the arene, the alkyl ether and the terminal triazole. This is not only the first example for a triazole-based chiral iodoarene but also the so far most efficient C1-symmetric catalyst for the oxidative enantioselective spirocyclization of 1-naphtholcarboxylic acids to spirolactones. Details can be found in the full paper on pages 2931–2941 (C. Hempel, C. Maichle-Moessmer, M. A. Pericàs, B. J. Nachtsheim, Adv. Synth. Catal. 2017, 359, 2931–2941; DOI: 10.1002/adsc.201700246).
Long-term Trends in the Transition to the Labour Market in Germany
2017-08-04

Successful transitions from school to work are decisive for success later in life. The situation of young people at this stage is therefore an issue not only for scientific research, but also for public discussion. A high level of institutionalised coordination has traditionally been a core element of the German institutional system, not least with regard to education, training and employment, and this has been associated with comparatively smooth transition patterns. Discussion in recent years has, however, increasingly focused on the problems occurring at these transitions. When assessing this situation, it is not only important to know how many people finally make successful transitions, but also how extended and complex transitions are. Against this background, this paper asks whether and to what extent there has been a de-structuring of the transition to the labour market in Germany – and, linked with it, of the transition to adulthood – as it has been proposed by theories of individualisation. Possible indicators of such a de-structuring would be a de-standardisation of transition patterns, a decreasing social differentiation and a declining significance of school-to-work transitions for other domains of life.
Self‐regulated learning from illustrated text: Eye movement modelling to support use and regulation of cognitive processes during learning from multimedia
2017-08-07

Background When learning with text and pictures, learners often fail to adequately process the materials, which can be explained as a failure to self‐regulate one's learning by choosing adequate cognitive learning processes. Eye movement modelling examples ( EMME ) showing how to process multimedia instruction have improved elementary school children's learning from text and pictures in previous studies. Aims We tested whether the positive effects of EMME for improving self‐regulated multimedia learning extend to university students and teaching of more comprehensive processing strategies. Moreover, we investigated whether EMME 's effectiveness depends upon a learner's cognitive prerequisites. Sample Participants were 50 university students (38 female; M = 26.88 years) with different study majors. Methods Different prior knowledge aspects were assessed as cognitive prerequisites. Before learning about mitosis from a multimedia instruction, students either received no intervention or saw EMME demonstrating various multimedia learning processes. Learning outcomes and eye movements served as dependent variables. Results Learners in the EMME group showed more intense processing of pictures and more frequent transitions between text and pictures. Weaker learners showed poorer recall performance after having studied EMME , whereas EMME had no effect on stronger students. In the forced‐choice verification task, stronger students benefitted from EMME , whereas no effect occurred for weaker students. The picture‐processing time was suited to explain the positive effects of EMME for stronger students. Conclusions Our results indicate that EMME illustrating a comprehensive set of cognitive processes support multimedia learning for stronger university students.
Crenolanib is a type I tyrosine kinase inhibitor that inhibits mutant KIT D816 isoforms prevalent in systemic mastocytosis and core binding factor leukemia
2017-08-07

Activating D816 mutations of the class III receptor tyrosine kinase <i>KIT</i> are associated with the majority of patients with systemic mastocytosis (SM), but also core binding factor (CBF) AML, making <i>KIT</i> mutations attractive therapeutic targets for the treatment of these cancers. Crenolanib is a potent and selective inhibitor of wild-type as well as mutant isoforms of the class III receptor tyrosine kinases FLT3 and PDGFRα/β. Notably, crenolanib inhibits constitutively active mutant-FLT3 isoforms resulting from amino acid substitutions of aspartic acid at codon 835, which is homologous to codon 816 in the <i>KIT</i> gene - suggesting sensitivity against mutant-KIT D816 isoforms as well. Here we demonstrate that crenolanib targets KIT D816 in SM and CBF AML models: crenolanib inhibits cellular proliferation and initiates apoptosis of mastocytosis cell lines expressing these mutations. Target-specificity was confirmed using an isogenic cell model. In addition, we demonstrate that KIT D816 mutations are targetable with clinically achievable doses of crenolanib. Further, a rationale to combine cladribine (2-CDA), the therapeutic standard in SM, with crenolanib is provided. In conclusion, we demonstrate that crenolanib is an inhibitor of mutant-KIT D816 isoforms at clinically achievable concentrations, and thus may be a potential treatment for SM and CBF AML as a monotherapy or in combination approaches.
C–H Bond Activation and Isoprene Polymerization by Lutetium Alkylaluminate/gallate Complexes Bearing a Peripheral Boryl and a Bulky Hydrotris(pyrazolyl)borate Ligand
2017-08-07

The bimetallic lutetium alkylaluminate complex [(Tp t Bu,Me )Lu(Me)(AlMe 3 {B(NDippCH) 2 })] {Tp t Bu,Me = hydrotris(3‐Me‐5‐ t Bu‐pyrazolyl)borate} formed readily upon addition of 0.5 equivalents of the organoaluminum boryl compound [Me 2 Al{B(NDippCH) 2 }] 2 (Dipp = C 6 H 3 i Pr 2 ‐2,6) to [(Tp t Bu,Me )LuMe 2 ] in n ‐hexane solution. Thermally induced cyclometalative C–H bond activation of this compound led to the formation of [(Tp ( t Bu–H)2/ t Bu,Me )Lu(AlMe 2 {B(NDippCH) 2 })] {Tp ( t Bu–H)2/ t Bu,Me = hydro(3‐Me‐5‐ t Bu‐pyrazolyl)bis[μ‐(3‐Me‐5‐Me 2 CCH 2 ‐pyrazolyl)]borate} in quantitative yields. The latter complex bears an unusual κ 5 coordination mode of the activated tris(pyrazolyl)borate ligand. Additionally, one Lu–CH 2 (R) moiety is coordinated by a “neutral” [Me 2 Al{B(NDippCH) 2 }] unit, which can be separated off by addition of THF or trimethylaluminum. The gallium analogue of complex [(Tp t Bu,Me )Lu(Me)(AlMe 3 {B(NDippCH) 2 })] could not be isolated from the respective reaction of monomeric [Me 2 Ga{B(NDippCH) 2 }] with [(Tp t Bu,Me )LuMe 2 ], but the C–H bond activated gallate complex [(Tp ( t Bu–H)2/ t Bu,Me )Lu(GaMe 2 {B(NDippCH) 2 })] was obtained instead following a prolonged mild thermal treatment. The performance of the new lutetium complexes as precatalysts in the polymerization of isoprene was assessed and possible activation and deactivation scenarios were studied by NMR spectroscopy.
Epigallocatechin-3-gallate (EGCG) up-regulates miR-15b expression thus attenuating store operated calcium entry (SOCE) into murine CD4+ T cells and human leukaemic T cell lymphoblasts
2017-08-08

CD4<sup>+</sup> T cells are key elements in immune responses and inflammation. Activation of T cell receptors in CD4<sup>+</sup> T cells triggers cytosolic Ca<sup>2+</sup> release with subsequent store operated Ca<sup>2+</sup> entry (SOCE), which is accomplished by the pore forming Ca<sup>2+</sup> release activated Ca<sup>2+</sup> (CRAC) channel Orai1 and its regulator stromal cell-interaction molecule 2 (STIM2). Green tea polyphenol epigallocatechin-3-gallate (EGCG) acts as a potent anti-inflammatory and anti-oxidant agent for various types of cells including immune cells. However, how post-transcriptional gene regulators such as miRNAs are involved in the regulation of Ca<sup>2+</sup> influx into murine CD4<sup>+</sup> T cells and human Jurkat T cells through EGCG is not defined. EGCG treatment of murine CD4<sup>+</sup> T cells significantly down-regulated the expression of STIM2 and Orai1 both at mRNA and protein levels. Furthermore, EGCG significantly decreased SOCE in both murine and human T cells. EGCG treatment increased miRNA-15b (miR-15b) abundance in both murine and human T cells. Bioinformatics analysis reveals that miR-15b, which has a STIM2 binding site, is involved in the down-regulation of SOCE. Overexpression of miR-15b significantly decreased the mRNA and protein expression of STIM2 and Orai1 in murine T cells. Treatment of Jurkat T cells with 10 μM EGCG further decreased mTOR and PTEN protein levels. EGCG decreased mitochondrial membrane potential (MMP) in both human and murine T cells. In conclusion, the observations suggest that EGCG inhibits the Ca<sup>2+</sup> entry into murine and human T cells, an effect accomplished at least in part by up-regulation of miR-15b.
Comment: Affective Control of Action
2017-08-08

This commentary challenges Railton’s claim that the affective system is the key source of control of action. Whilst the affective system is important for understanding how acting for a reason is possible, we argue that there are many levels of control of action and adaptive behaviour and that the affective system is only one source of control. Such a model seems to be more in line with the emerging picture from affective and movement neuroscience.
The planar tree packing theorem
2017-08-08

Packing graphs is a combinatorial problem where several given graphs are being mapped into a common host graph such that every edge is used at most once. In the planar tree packing problem we are given two trees and on vertices and have to find a planar graph on vertices that is the edge-disjoint union of and . A clear exception that must be made is the star which cannot be packed together with any other tree. But according to a conjecture of García et al. from 1997 this is the only exception, and all other pairs of trees admit a planar packing. Previous results addressed various special cases, such as a tree and a spider tree, a tree and a caterpillar, two trees of diameter four, two isomorphic trees, and trees of maximum degree three. Here we settle the conjecture in the affirmative and prove its general form, thus making it the planar tree packing theorem. The proof is constructive and provides a polynomial time algorithm to obtain a packing for two given nonstar trees.
ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage
2017-08-09

Abstract Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576–90. ©2017 AACR.
Evolutionarily diverse SYP1 Qa‐SNAREs jointly sustain pollen tube growth in Arabidopsis
2017-08-09

Summary Intracellular membrane fusion is effected by SNARE proteins that reside on adjacent membranes and form bridging trans ‐ SNARE complexes. Qa‐ SNARE members of the Arabidopsis SYP 1 family are involved in membrane fusion at the plasma membrane or during cell plate formation. Three SYP 1 family members have been classified as pollen‐specific as inferred from gene expression profiling studies, and two of them, SYP 124 and SYP 125 , are confined to angiosperms. The SYP 124 gene appears genetically unstable, whereas its sister gene SYP 125 shows essentially no variation among Arabidopsis accessions. The third pollen‐specific member SYP 131 is sister to SYP 132, which appears evolutionarily conserved in the plant lineage. Although evolutionarily diverse, the three SYP 1 proteins are functionally overlapping in that only the triple mutant syp124 syp125 syp131 shows a specific and severe male gametophytic defect. While pollen development and germination appear normal, pollen tube growth is arrested during passage through the style. Our results suggest that angiosperm pollen tubes employ a combination of ancient and modern Qa‐ SNARE proteins to sustain their growth‐promoting membrane dynamics during the reproductive process.
Liver cyst gene knockout in cholangiocytes inhibits cilium formation and Wnt signaling
2017-08-09

Mutations in the PRKCSH, SEC63 and LRP5 genes cause autosomal dominant polycystic liver disease (ADPLD). The proteins products of PRKCSH (alias GIIB) and SEC63 function in protein quality control and processing in the endoplasmic reticulum (ER), while LRP5 is implicated in Wnt/β-catenin signaling. To identify common denominators in the PLD pathogenesis, we mapped the PLD interactome by affinity proteomics, employing both HEK293T cells and H69 cholangiocytes. Identification of known complex members, such as glucosidase IIA (GIIA) for PRKCSH, and SEC61A1 and SEC61B for SEC63, confirmed the specificity of the analysis. GANAB, encoding GIIA, was very recently identified as an ADPLD gene. The presence of GIIA in the LRP5 complex pinpoints a potential functional connection with PRKCSH. Interestingly, all three PLD-associated protein complexes included filamin A (FLNA), a multifunctional protein described to play a role in ciliogenesis as well as canonical Wnt signalling. As ciliary dysfunction may also contribute to hereditary liver cyst formation, we evaluated the requirement of PRKCSH and SEC63 for ciliogenesis and Wnt signaling. By CRISPR/Cas9 induced knockdown of both ADPLD genes in HEK293T cells and H69 cholangiocytes, we identified that their depletion results in defective ciliogenesis. However, only H69 knockouts displayed reduced Wnt3a activation. Our results suggest that loss of PRKCSH and SEC63 leads to general defects in ciliogenesis, while quenching of the Wnt signaling cascade is cholangiocyte-restricted. Interactions of all three PLD-associated protein complexes with FLNA may mark a common link between the ADPLD proteins and the cystogenic processes driving this disease.
CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients
2017-08-10

Achromatopsia is a rare autosomal recessive cone disorder characterized by color vision defects, photophobia, nystagmus, and severely reduced visual acuity. The disease is caused by mutations in genes encoding crucial components of the cone phototransduction cascade (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) or in ATF6, involved in the unfolded protein response. CNGB3 encoding the beta subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors is the major achromatopsia gene. Here, we present a comprehensive spectrum of CNGB3 mutations and their prevalence in a cohort of 1074 independent families clinically diagnosed with achromatopsia. Of these, 485 (45.2%) carried mutations in CNGB3. We identified a total of 98 different potentially disease-causing CNGB3 variants, 58 of which are novel. About 10% of patients with CNGB3 mutations only harbored a single heterozygous variant. Therefore, we performed quantitative real-time PCR in 43 of such single heterozygotes in search of the missing allele, followed by microarray-based comparative genomic hybridization and breakpoint mapping. We discovered nine different heterozygous copy number variations encompassing one to 10 consecutive exons in 16 unrelated patients. Moreover, one additional patient with a homozygous CNGB3 deletion encompassing exons 4-18 was identified, highlighting the importance of CNV analysis for this gene.
Simultaneous quantification of DNA damage and mitochondrial copy number by long-run DNA-damage quantification (LORD-Q)
2017-08-10

DNA damage and changes in the mitochondrial DNA content have been implicated in ageing and cancer development. To prevent genomic instability and tumorigenesis, cells must maintain the integrity of their nuclear and mitochondrial DNA. Advances in the research of DNA damage protection and genomic stability, however, also depend on the availability of techniques that can reliably quantify alterations of mitochondrial DNA copy numbers and DNA lesions in an accurate high-throughput manner. Unfortunately, no such method has been established yet. Here, we describe the high-sensitivity long-run real-time PCR technique for DNA-damage quantification (LORD-Q) and its suitability to simultaneously measure DNA damage rates and mitochondrial DNA copy numbers in cultured cells and tissue samples. Using the LORD-Q multiplex assay, we exemplarily show that the mitochondrial DNA content does not directly affect DNA damage susceptibility, but influences the efficacy of certain anticancer drugs. Hence, LORD-Q provides a fast and precise method to assess DNA lesions, DNA repair and mtDNA replication as well as their role in a variety of pathological settings.
Coi1 is a novel assembly factor of the yeast complex III–complex IV supercomplex
2017-08-10

The yeast bc1 complex (complex III) and cytochrome oxidase (complex IV) are mosaics of core subunits encoded by the mitochondrial genome and additional nuclear-encoded proteins imported from the cytosol. Both complexes build various supramolecular assemblies in the mitochondrial inner membrane. The formation of the individual complexes and their supercomplexes depends on the activity of dedicated assembly factors. We identified a so far uncharacterized mitochondrial protein (open reading frame YDR381C-A) as an important assembly factor for complex III, complex IV, and their supercomplexes. Therefore we named this protein Cox interacting (Coi) 1. Deletion of COI1 results in decreased respiratory growth, reduced membrane potential, and hampered respiration, as well as slow fermentative growth at low temperature. In addition, coi1Δ cells harbor reduced steady-state levels of subunits of complexes III and IV and of the assembled complexes and supercomplexes. Interaction of Coi1 with respiratory chain subunits seems transient, as it appears to be a stoichiometric subunit neither of complex III nor of complex IV. Collectively this work identifies a novel protein that plays a role in the assembly of the mitochondrial respiratory chain.
Iron Kα line of Proca stars
2017-08-10

X-ray reflection spectroscopy can be a powerful tool to test the nature of\\nastrophysical black holes. Extending previous work on Kerr black holes with\\nscalar hair [1] and on boson stars [2], here we study whether astrophysical\\nblack hole candidates may be horizonless, self-gravitating, vector\\nBose-Einstein condensates, known as Proca stars [3]. We find that observations\\nwith current X-ray missions can only provide weak constraints and rule out\\nsolely Proca stars with low compactness. There are two reasons. First, at the\\nmoment we do not know the geometry of the corona, and therefore the uncertainty\\nin the emissivity profile limits the ability to constrain the background\\nmetric. Second, the photon number count is low even in the case of a bright\\nblack hole binary, and we cannot have a precise measurement of the spectrum.\\n
Severe neonatal hyperbilirubinemia in Crigler‐Najjar syndrome model mice can be reversed with zinc protoporphyrin
2017-08-10

Neurotoxic bilirubin is solely conjugated by UDP‐glucuronosyltransferase (UGT) 1A1. Due to an inadequate function of UGT1A1, human neonates develop mild to severe physiological hyperbilirubinemia. Accumulation of bilirubin in the brain leads to the onset of irreversible brain damage called kernicterus. Breastfeeding is one of the most significant factors that increase the risk of developing kernicterus in infants. Why does the most natural way of feeding increase the risk of brain damage or even death? This question leads to the hypothesis that breast milk‐induced neonatal hyperbilirubinemia might bring certain benefits to the body. One of the barriers to answering the above question is the lack of animal models that display mild to severe neonatal hyperbilirubinemia. A mouse model that develops neonatal hyperbilirubinemia was previously developed by a knockout of the Ugt1 locus. Deletion of Ugt1a1 results in neonatal lethality from bilirubin neurotoxicity. Bilirubin is the end product of heme catabolism in which heme oxygenase‐I is largely involved. When zinc protoporphyrin, an inhibitor of heme oxygenase I, was administered to newborn Ugt1 −/− mice, serum bilirubin levels dropped dramatically, rescuing the mice from bilirubin‐induced neonatal lethality. Zinc protoporphyrin‐treated Ugt1 −/− mice developed normally as adults capable of reproducing, but their newborns showed even more severe hyperbilirubinemia. Microarray analysis of the hyperbilirubinemic livers indicated that a number of genes associated with nucleotide, transport, and immune response were significantly down‐regulated in a serum bilirubin level‐dependent manner. Conclusion : Our study provides an opportunity to advance the development of effective therapeutics to effectively and rapidly prevent bilirubin‐induced toxicity. Neonatal hyperbilirubinemia has various impacts on the body that could be driven by the antioxidant property of bilirubin. ( Hepatology Communications 2017;1:792–802)
On Experiencing Meaning: Irreducible Cognitive Phenomenology and Sinewave Speech
2017-08-10

Upon first hearing sinewaves, all that can be discerned are beeps and whistles. But after hearing the original speech, the beeps and whistles sound like speech. The difference between these two episodes undoubtedly involves an alteration in phenomenal character. O’Callaghan (2011) argues that this alteration is non-sensory, but he leaves open the possibility of attributing it to some other source, e.g. cognition. I discuss whether the alteration in phenomenal character involved in sinewave speech provides evidence for cognitive phenomenology. I defend both the existence of cognitive phenomenology and the phenomenal contrast method, as each concerns the case presented here.