bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prädiktive Biomarker für die Patientenselektion
Authors: Schmale Ine 
Published: September 2018

Zusammenfassung
Das adaptive Immunsystem gilt heute als „ideale“ Antitumortherapie, da mit T-Zellen und Antikörpern eine hohe Diversität gegeben ist, das Immunsystem kleinste chemische Alterationen unterscheidet und nach einem effektiven Antigen-Priming eine nachhaltige Wirkung erzielt wird. T-Zellen sind ideale Tumorkiller, sagte Prof. Andrea Tannapfel, Bochum, auf dem DKK in einer Keynote-Lecture.
Akute myeloische Leukämie bei Erwachsenen
Authors: Spiekermann Karsten , Shen Anne-Sophie 
Published: September 2018

AbstractThere are several changes in the revised WHO classification for acute leukemia. The latest version of the European Leukemia Network (ELN)-risk classification defines AML with mutations in RUNX1, ASXL1 or TP53 to fall in the unfavorable risk group. Consequently, the somatic molecular genetic testing at the time of initial diagnosis should encompass these before mentioned three genes next to the already routine testing of NPM1, CEBPA and FLT3-ITD. Several new innovative substances have been developed and approved for AML therapy. The multikinase inhibitor midostaurin is a new substance in the induction therapy for patients with FLT-3 mutated AML. CPX-351 (cytarabin and daunorubicin in liposomatic formulation in a defined molar relation) is a new option for therapy associated AML and AML with myelodysplastic changes. Enasidenib is a targeting drug for relapsed or refractory AML with IDH2 mutation. Gemtuzumab, a CD33 + antibody-drug-conjugate is approved for CD33 positive cases.
The culture of social comparison
Authors: Baldwin Matthew , Mussweiler Thomas 
Published: September 2018

Significance
Humans have the unique ability to coordinate behavior, economic exchange, political action, and social relationships across immense distances and times. To keep this level of coordination running smoothly, we often look to others as comparison standards for how to behave, think, and feel. A detailed understanding of the relation between social comparison and broad patterns of social life is lacking, however. The current research is a step in this direction—we show that social comparison is linked to cultural practices that promote strong norms and punishment for deviance (tightness) and those that promote relational self-construal (collectivism). These findings advance our understanding of the origins of social comparison and highlight the essential role of comparison for the development of social life.
The Role of Research in Attaining Sustainable Development Goals
Authors: Fayomi O.S.I. , Okokpujie I. P. , Udo Mfon 
Published: September 2018

Abstract
A study on the significant roles of research in the realization of the Sustainable Development Goals was carried out to analyze the facts and figures gotten through secondary information’s to determine the resultant effect of research in the pursuance of the SDGs. This research explores various opinions of several authors and researchers towards the concept of research in totality. This study gave clear indications that research as a full concept is not a cliché and it is revolving year-in year-out in our contemporary world of interest as the need for human survival on the planet earth gets more prioritized on the agenda of the various sustainability organizations like UNESCO, United Nations, UNEP, IISD. This is the present century’s goal and it is all NGOs and other private parastatals are enjoined to be part of this move as it is a collective effort to seeing its realizations.
Capital structure and corporate performance in late Imperial Russia
Authors: Gregg Amanda , Nafziger Steven 
Published: September 2018

AbstractThis article investigates the financing of corporations in industrialization’s early stages by examining new balance sheet data describing all Imperial Russian corporations in 1914. We emphasize differences between two Russian corporation types: share partnerships and A-corporations. Share partnerships issued greater dividends, were less likely to issue bonds, and had larger accounts payable. We find that capital structures varied with age, size, and sector according to modern corporate finance theories and that scaled profits did not demonstrate differential market power across corporation types. Thus, Russian corporations exhibited considerable financial flexibility, and reducing incorporation costs could have benefited the Imperial Russian economy.
Spousal Loss and Change in Cognitive Functioning: An Examination of Temporal Patterns and Gender Differences
Authors: Wörn Jonathan , Comijs Hannie , Aartsen Marja 
Published: September 2018

Abstract

Objectives
The study investigates whether the disadvantaged position of men in the adverse consequences of widowhood for health and mortality also exists for changes in cognitive health.

Methods
We used data of up to 1,269 men and women aged 65 years and older who participated in the Longitudinal Aging Study Amsterdam in 3-yearly assessments between 1992 and 2012 (5,123 person-observations). All were married and without cognitive impairment (Mini-Mental State Examination ≥ 24) at baseline and up to 419 lost their spouse. In fixed effects regression models, the effect of spousal loss on change in four domains of cognitive functioning was estimated independently of age-related cognitive change.

Results
For women, a robust temporary decrease was found in the second year after spousal loss in the reasoning domain, but not in global cognitive functioning, processing speed, or memory. No robust effects were found for men.

Discussion
Considering that only one cognitive domain was affected and effects were temporary, cognitive functioning seems rather robust to the experience of spousal loss. Despite men having often been reported to be in a disadvantaged position in other health domains, our analyses indicate no such pattern for cognitive functioning.
Polycystin-1 regulates bone development through an interaction with the transcriptional coactivator TAZ
Authors: Merrick David , Mistry Kavita , Wu Jingshing , Gresko Nikolay , Baggs Julie E , Hogenesch John B , Sun Zhaoxia , Caplan Michael J 
Published: September 2018

Abstract
Polycystin-1 (PC1), encoded by the PKD1 gene that is mutated in the autosomal dominant polycystic kidney disease, regulates a number of processes including bone development. Activity of the transcription factor RunX2, which controls osteoblast differentiation, is reduced in Pkd1 mutant mice but the mechanism governing PC1 activation of RunX2 is unclear. PC1 undergoes regulated cleavage that releases its C-terminal tail (CTT), which translocates to the nucleus to modulate transcriptional pathways involved in proliferation and apoptosis. We find that the cleaved CTT of PC1 (PC1-CTT) stimulates the transcriptional coactivator TAZ (Wwtr1), an essential coactivator of RunX2. PC1-CTT physically interacts with TAZ, stimulating RunX2 transcriptional activity in pre-osteoblast cells in a TAZ-dependent manner. The PC1-CTT increases the interaction between TAZ and RunX2 and enhances the recruitment of the p300 transcriptional co-regulatory protein to the TAZ/RunX2/PC1-CTT complex. Zebrafish injected with morpholinos directed against pkd1 manifest severe bone calcification defects and a curly tail phenotype. Injection of messenger RNA (mRNA) encoding the PC1-CTT into pkd1-morphant fish restores bone mineralization and reduces the severity of the curly tail phenotype. These effects are abolished by co-injection of morpholinos directed against TAZ. Injection of mRNA encoding a dominant-active TAZ construct is sufficient to rescue both the curly tail phenotype and the skeletal defects observed in pkd1-morpholino treated fish. Thus, TAZ constitutes a key mechanistic link through which PC1 mediates its physiological functions.
Life Inside a Dinosaur Bone: a Thriving Microbiome
Authors: Saitta Evan T. , Liang Renxing , Lau Chui Y. , Brown Caleb M. , Longrich Nicholas R. , Kaye Thomas G. , Novak Ben J. , Salzberg Steven , Donohoe Paul , Dickinson Marc , Vinther Jakob , Bull Ian D. , Brooker Richard A. , Martin Peter , Abbott Geoffrey D. , Knowles Timothy D. J. , Penkman Kirsty , Onstott Tullis C. 
Published: September 2018

AbstractFossils were long thought to lack original organic material, but the discovery of organic molecules in fossils and sub-fossils, thousands to millions of years old, has demonstrated the potential of fossil organics to provide radical new insights into the fossil record. How long different organics can persist remains unclear, however. Non-avian dinosaur bone has been hypothesised to preserve endogenous organics including collagen, osteocytes, and blood vessels, but proteins and labile lipids are unstable during diagenesis or over long periods of time. Furthermore, bone is porous and an open system, allowing microbial and organic flux. Some of these organics within fossil bone have therefore been identified as either contamination or microbial biofilm, rather than original organics. Here, we use biological and chemical analyses of Late Cretaceous dinosaur bones and sediment matrix to show that dinosaur bone hosts a diverse microbiome. Fossils and matrix were freshly-excavated, aseptically-acquired, and then analysed using microscopy, spectroscopy, chromatography, spectrometry, DNA extraction, and 16S rRNA amplicon sequencing. The fossil organics differ from modern bone collagen chemically and structurally. A key finding is that 16S rRNA amplicon sequencing reveals that the subterranean fossil bones host a unique, living microbiome distinct from that of the surrounding sediment. Even in the subsurface, dinosaur bone is biologically active and behaves as an open system, attracting microbes that might alter original organics or complicate the identification of original organics. These results suggest caution regarding claims of dinosaur bone ‘soft tissue’ preservation and illustrate a potential role for microbial communities in post-burial taphonomy.
Alzheimer’s disease Phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
Authors: Magno Lorenza , Lessard Christian B , Martins Marta , Cruz Pedro , Katan Matilda , Bilsland Jamie , Chakrabaty Paramita , Golde Todd E , Whiting Paul J 
Published: September 2018

ABSTRACTRecent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.We confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.SUMMARYThePLCG2P522R variant is protective against Alzheimer’s disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.
Quantification of protein mobility and associated reshuffling of cytoplasm during chemical fixation
Authors: Huebinger Jan , Spindler Jessica , Holl Kristin J. , Koos Björn 
Published: September 2018

AbstractTo understand cellular functionalities, it is essential to unravel spatio-temporal patterns of molecular distributions and interactions within living cells. The technological progress in fluorescence microscopy now allows in principle to measure these patterns with sufficient spatial resolution. However, high resolution imaging comes along with long acquisition times and high phototoxicity. Physiological live cell imaging is therefore often unfeasible and chemical fixation is employed. However, fixation methods have not been rigorously reviewed to preserve patterns at the resolution at which they can be nowadays imaged. A key parameter for this is the time span until fixation is completed. During this time, cells are under unphysiological conditions and patterns decay. We demonstrate here that formaldehyde fixation takes more than one hour for cytosolic proteins in cultured cells. Associated with this, we found a distinct displacement of proteins and lipids, including their loss from the cells. Other small aldehydes like glyoxal or acrolein showed inferior results. Fixations using glutaraldehyde were faster than four minutes and retained most cytoplasmic proteins. Surprisingly, autofluorescence produced by glutaraldehyde was almost completely antagonized by supplementary addition of formaldehyde without compromising fixation speed. These findings indicate, which cellular processes can actually be reliably imaged after a certain chemical fixation.
Comparative Performance of the Finite Element Method and the Boundary Element Fast Multipole Method for Problems Mimicking Transcranial Magnetic Stimulation (TMS)
Authors: Htet Aung Thu , Saturnino Guilherme B. , Burnham Edward H. , Noetscher Gregory M. , Nummenmaa Aapo , Makarov Sergey N. 
Published: September 2018

AbstractA study pertinent to the numerical modeling of cortical neurostimulation is conducted in an effort to compare the performance of the finite element method (FEM) and an original formulation of the boundary element fast multipole method (BEM-FMM) at matched computational performance metrics. We consider two problems: (i) a canonic multi-sphere geometry and an external magnetic-dipole excitation where the analytical solution is available and; (ii) a problem with realistic head models excited by a realistic coil geometry. In the first case, the FEM algorithm tested is a fast open-source getDP solver running within the SimNIBS 2.1.1 environment. In the second case, a high-end commercial FEM software package ANSYS Maxwell 3D is used. The BEM-FMM method runs in the MATLAB®2018a environment.In the first case, we observe that the BEM-FMM algorithm gives a smaller solution error for all mesh resolutions and runs significantly faster for high-resolution meshes when the number of triangular facets exceeds approximately 0.25 M. We present other relevant simulation results such as volumetric mesh generation times for the FEM, time necessary to compute the potential integrals for the BEM-FMM, and solution performance metrics for different hardware/operating system combinations. In the second case, we observe an excellent agreement for electric field distribution across different cranium compartments and, at the same time, a speed improvement of three orders of magnitude when the BEM-FMM algorithm used.This study may provide a justification for anticipated use of the BEM-FMM algorithm for high-resolution realistic transcranial magnetic stimulation scenarios.
Pituitary carcinoma: The University of Texas MD Anderson Cancer Center experience
Authors: Santos-Pinheiro Fernando , Penas-Prado Marta , Kamiya-Matsuoka Carlos , Waguespack Steven G , Mahajan Anita , Brown Paul D , Shah Komal B , Fuller Gregory N , McCutcheon Ian E 
Published: September 2018

AbstractBackground: Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and frequently recur. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits accurate assessment. Methods: We describe a single-center experience in managing PC over a 22-year period and review previously published PC series. Results: 17 patients were identified. Median age at PC diagnosis was 44 years (range 16-82), and the median PA-to-PC conversion time was 5 years (range 1-29). Median follow-up was 28 months (range 8-158) with 7 deaths. Most PC were hormone-positive based on immunohistochemistry (n=12): ACTH (n=5), PRL (n=4), LH/FSH (n=2), GH (n=1). All patients underwent at least one resection and one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had metastases only to the CNS, and 6 (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest period of disease control in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression in 8 (47%) cases. The 2, 3 and 5-year survival rate of the entire cohort was 71%, 59% and 35%, respectively. All patients surviving >5 years were treated with TMZ-based therapy. Conclusions: PC treatment requires a multidisciplinary approach and multimodality therapy including surgery, radiation and chemotherapy. TMZ-based therapy was associated with higher survival rates and longer disease control.PrecisWe describe 17 PC patients who were diagnosed and treated at MDACC over a 22-year period. We have found that TMZ-based therapy correlated with longer disease control and higher survival rate.
Evolution of Replication Origins in Vertebrate Genomes: Rapid Turnover Despite Selective Constraints
Authors: Massipa Florian , Laurent Marc , Brossas Caroline , Fernández-Justel José Miguel , Gómez María , Prioleau Marie-Noelle , Duret Laurent , Picardb Franck 
Published: September 2018

BackgroundThe replication programme of vertebrate genomes is driven by the chro-mosomal distribution and timing of activation of tens of thousands of replication origins. Genome-wide studies have shown the frequent association of origins with promoters and CpG islands, and their enrichment in G-quadruplex sequence motifs (G4). However, the genetic determinants driving their activity remain poorly understood. To gain insight on the functional constraints operating on replication origins and their spatial distribution, we conducted the first evolutionary comparison of genome-wide origins maps across vertebrates.ResultsWe generated a high resolution genome-wide map of chicken replication origins (the first of a bird genome), and performed an extensive comparison with human and mouse maps. The analysis of intra-species polymorphism revealed a strong depletion of genetic diversity on an ~ 40 bp region centred on the replication initiation loci. Surprisingly, this depletion in genetic diversity wasnotlinked to the presence of G4 motifs, nor to the association with promoters or CpG islands. In contrast, we also showed that origins experienced a rapid turnover during vertebrates evolution, since pairwise comparisons of origin maps revealed that only 4 to 24% of them were conserved between any two species.ConclusionsThis study unravels the existence of a novel genetic determinant of replication origins, the precise functional role of which remains to be determined. Despite the importance of replication initiation activity for the fitness of organisms, the distribution of replication origins along vertebrate chromosomes is highly flexible.
Dynamic Control of Ca2+Binding in the C2 Domains of Synaptotagmin 1
Authors: Rock Patrick J. , Meyer Austin G. , Evans Chantell S. , Chapman Edwin R. , Sutton R. Bryan 
Published: September 2018

AbstractSynaptotagmin senses fluctuations in the Ca2+environment of neurons near active zones and transduces a signal to the SNARE complex to initiate exocytosis at the presynaptic terminus. The 3D structures of the two tandem C2 domains of synaptotagmin have been determined to high resolution; however, it is currently unclear how each domain dynamically interacts with Ca2+at the atomic level. To study the mechanistic consequences of the lethal mutations at the AD3 locus, we introduced tyrosine to asparagine point mutations in both the C2A and C2B domains of synaptotagmin 1, and we have constructed a model that describes the relationship between Ca2+-binding and the structural changes within each C2 domain. We show that the mobility of loop 3 in the Ca2+binding pocket increases markedly in C2A, while the mobility of loop 1 changes in C2B with the AD3 mutation. This increase in loop mobility results in an increase in the average volume and variance of the Ca2+-binding pockets of C2A and C2B. The volume of the unbound Ca2+-binding pocket in C2A is usually restrained by intra-domain interactions between the tyrosine residue at the AD3 locus and residues on loop 3; however, the AD3 mutation decouples the restraint and results in a larger, more variable Ca2+-binding pocket in C2A. C2B maintains a more compact Ca2+-binding pocket; however, its volume also fluctuates significantly with the AD3 mutation. Changes in binding pocket volume that involve more variable Ca2+binding loops would likely affect Ca2+affinity in the neurons of the affected organism. Using molecular-dynamics simulations, we show that mutations at the AD3 locus alter the mobility of the Ca2+-binding loops by removing a key stabilization mechanism that is normally present in C2 domains. The lack of loop stabilization results in a net increase in the volume of the Ca2+-binding pocket and provides an explanation for the observed lethal phenotype.
The adequacy of tissue microarrays in the assessment of inter- and intra-tumoural heterogeneity of infiltrating lymphocyte burden in leiomyosarcoma
Authors: Lee ATJ , Chew W , Smith MJ , Strauss DC , Fisher C , Hayes AJ , Judson I , Thway K , Jones RL , Huang PH 
Published: September 2018

AbstractThe characterisation and clinical relevance of tumour-infiltrating lymphocytes (TILs) in leiomyosarcoma (LMS), a subtype of soft tissue sarcoma that exhibits histological heterogeneity, is not established. The use of tissue microarrays (TMA) in studies that profile TIL burden is attractive but given the potential for intra-tumoural heterogeneity to introduce sampling errors, the adequacy of this approach is undetermined. In this study, we assessed the histological inter-and intra-tumoural heterogeneity in TIL burden within a retrospective cohort of primary LMS specimens. Using a virtual TMA approach, we also analysed the optimal number of TMA cores required to provide an accurate representation of TIL burden in a full tissue section. We establish that LMS have generally low and spatially homogenous TIL burdens, although a small proportion exhibit higher levels and more heterogeneous distribution of TILs. We show that a conventional and practical number (1-3) of TMA cores is adequate for correct ordinal categorisation of tumours with high or low TIL burden, but that many more cores (≥ 11) is required to accurately estimate absolute TIL numbers. Our findings provide a benchmark for the design of future studies aiming to define the clinical relevance of the immune microenvironments of LMS and other sarcoma subtypes.