julilili42/papers huggingface dataset:
Attenuated and Protease-Profile Modified Sendai Virus Vectors as a New Tool for Virotherapy of Solid Tumors
2014-03-05

Multiple types of oncolytic viruses are currently under investigation in clinical trials. To optimize therapeutic outcomes it is believed that the plethora of different tumor types will require a diversity of different virus types. Sendai virus (SeV), a murine parainfluenza virus, displays a broad host range, enters cells within minutes and already has been applied safely as a gene transfer vector in gene therapy patients. However, SeV spreading naturally is abrogated in human cells due to a lack of virus activating proteases. To enable oncolytic applications of SeV we here engineered a set of novel recombinant vectors by a two-step approach: (i) introduction of an ubiquitously recognized cleavage-motive into SeV fusion protein now enabling continuous spreading in human tissues, and (ii) profound attenuation of these rSeV by the knockout of viral immune modulating accessory proteins. When employing human hepatoma cell lines, newly generated SeV variants now reached high titers and induced a profound tumor cell lysis. In contrast, virus release from untransformed human fibroblasts or primary human hepatocytes was found to be reduced by about three log steps in a time course experiment which enables the cumulation of kinetic differences of the distinct phases of viral replication such as primary target cell infection, target cell replication, and progeny virus particle release. In a hepatoma xenograft animal model we found a tumor-specific spreading of our novel recombinant SeV vectors without evidence of biodistribution into non-malignant tissues. In conclusion, we successfully developed novel tumor-selective oncolytic rSeV vectors, constituting a new tool for virotherapy of solid tumors being ready for further preclinical and clinical development to address distinct tumor types.
Two-Page Book Embeddings of 4-Planar Graphs
2014-03-05

Back in the eighties, Heath showed that every 3-planar graph is subhamiltonian and asked whether this result can be extended to a class of graphs of degree greater than three. In this paper we affirmatively answer this question for the class of 4-planar graphs. Our contribution consists of two algorithms: The first one is limited to triconnected graphs, but runs in linear time and uses existing methods for computing hamiltonian cycles in planar graphs. The second one, which solves the general case of the problem, is a quadratic-time algorithm based on the book embedding viewpoint of the problem.
FGF21 inhibits adiponectin secretion in human adipocytes
2014-03-05

Differentiating murine subcutaneous preadipocytes express and secrete FGF21 which acts in an autocrine way to enhance differentiation and browning. We asked if (i) differentiating human subcutaneous preadipocytes express and release FGF21, (ii) recombinant human FGF21 (rhFGF21) influences the expression of white and brown adipocyte markers and insulin signaling components, and (iii) differences exist in responses to rhFGF21 between cells from insulin-sensitive (IS) and insulin-resistant (IR) donors. Preadipocytes were obtained from 10 IS and 10 IR participants of the TÜF study, matched for gender, age, and body fat. Cells were differentiated in the presence or absence of rhFGF21. RNA, cell lysates, and conditioned media were analyzed. FGF21 expression was very low in preadipocytes and undetectable in differentiated adipocytes, both in the presence or absence of rhFGF21. The FGF21 receptor FGFR1 and its cofactor KLB were well expressed during the whole differentiation period. RhFGF21 significantly decreased KLB expression (p < 0.05). The expression levels of the white adipocyte markers PPARG, ADIPOQ, and LEP increased independently of rhFGF21. By contrast, expression of UCP1, a brown adipocyte marker, was significantly increased by rhFGF21 from undetectable to very low levels (p < 0.01). RhFGF21 did not affect the expression of INSR, IRS1, AKT1/2, or SLC2A4, but significantly increased SLC2A1 (p < 0.05). RhFGF21 significantly reduced adiponectin release by hSUB (p < 0.01) and significantly increased leptin release (in hSUB from IR donors, p < 0.05). Concomitantly, IL-6 expression and release were also significantly increased by rhFGF21 (p < 0.05). No major differences in rhFGF21 effects were seen in cells from IR versus IS donors. Our data show that FGF21 treatment of human adipocytes has outcomes opposite to those of murine cells. FGF21 may exert insulin-desensitizing actions by potently inhibiting adiponectin release, an effect possibly mediated by IL-6.
Microarray based comparative genome-wide expression profiling of major subtypes of leukemia
2014-03-05

The uncontrolled proliferation of hematopoietic cells with no capacity to differentiate into mature blood cells leads to leukemia. Though considerable amount of work has been done in understanding the molecular basis and gene expression profiles of hematologic malignancies viz., chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML), the role of various underlying genes and mechanisms predisposing the disease are poorly understood. To develop the early diagnosis, preventive and therapeutic strategies, identification of population specific novel mutations and candidate genes are required. Micro array based gene expression profiling was performed for total of 18 samples (4 from each subtype of leukemia that is, CLL, CML, ALL, AML and 2 controls) from Indian population using single color hybridization. The expression of all genes presented in terms of fold variation was subjected to F-test. The microarray data of genes showing differential regulation with respect to the control samples have been obtained from total 50, 238 probes covering 14,992 genes on Agilent&rsquo;s Human 8X60K Array. The experiment was conducted with expectation to have similar patterns of result in terms of gene expression but it demonstrates statistically significant relationship only among CML and ALL which are of myeloid and lymphoid origin, respectively, in contrast to other combinations. Gene expression profiles of four subtypes of leukemia were compared to each other to ascertain the overall association and significance of genes for occurrence of different types of leukemiawhich would guide in the development of common probable biomarkers for leukemias followed by effective diagnosis, prognosis and treatment. Based on their geomean fold values, the highly upregulated genes found in this study are listed. &nbsp; Keywords: Leukemia, microarray, gene expression profiling, fold variation, lymphoid, myeloid, geomean fold.
Personality traits in patients with active and controlled acromegaly: A cross sectional multi-center study
2014-03-05

Introduction: Acromegalic patients (AP) and patients with non-functioning pituitary adenomas display distinct personality patterns, with more pessimism, higher fear of uncertainty and asthenia. We aimed to investigate in more detail personality traits in AP, dependent on activity, age, gender and pituitary insufficiency (PI).
Acute effects of intranasal insulin on endogenous glucose production and hepatic energy metabolism in humans
2014-03-05

Evidence from rodent studies suggests that central delivery of insulin may regulate peripheral glucose metabolism through indirect cross-talk between brain and peripheral tissues. In the present study, we aimed to investigate the acute effects of intranasal insulin on endogenous (hepatic) glucose production (EGP) and hepatic energy metabolism in humans. Eight lean normoglycemic humans (age 26 ± 2yrs, BMI 23 ± 1 kg/m2, CON) and 8 patients with type 2 diabetes (age 61 ± 3yrs, BMI 27 ± 1 kg/m2, T2D) received intranasal insulin (160 IU; Actrapid, Novo-Nordisk, Denmark) or placebo in a randomized, single-blinded, cross-over trail. Rates of EGP were assessed by the isotopic dilution technique with [6,6-2H2]glucose and metabolic parameters were monitored with repeated blood sampling. Hepatic fat content (HCL) and adenosine triphosphate (ATP) concentrations were determined at baseline and three hours after intervention by magnetic resonance spectroscopy (31P/1H-MRS) on a 3T clinical MR scanner (Philips, Best, The Netherlands). Intranasal insulin caused a transient increase in serum insulin levels at 10 minutes in CON (Δ= 3.6 ± 0.8μU/ml, p = 0.01 vs. placebo). Blood glucose concentrations were not affected by either intranasal insulin or placebo and remained unchanged in both CON and T2D. The hepatic insulin sensitivity index, determined from EGP and insulin levels, was not changed after intranasal insulin in either group compared to placebo, but was lower in T2D for 180 min (9.7 ± 0.9 vs. 13.5 ± 0.7, p = 0.002). HCL decreased (Δ= 0.2 ± 0.1%, p = 0.04), whereas absolute concentrations of hepatic γ-ATP increased (Δ= 0.5 ± 0.2 mmol/l, p = 0.04) after intranasal insulin in CON, but not in T2D. In conclusion, central insulin has no acute effect on glucose production in humans, but associates with beneficial effects on hepatic lipid and energy metabolism, both of which are blunted in T2D. This could either result from greater insulinemia and/or higher insulin sensitivity in the normoglycemic humans.
The hepatokine fetuin-A associates with insulin resistance and induces inflammation but selectively improves cAMP-dependent insulin secretion of human islets
2014-03-05

Nonalcoholic fatty liver disease leads to an altered secretion of proteins, so called hepatokines. Previously, we found that increased plasma levels of the hepatokine fetuin-A strongly predicts the incidence of type-2 diabetes in humans. Fetuin-A inhibits insulin receptor signaling and augments inflammation. Interestingly, fatty acid-induced activation of TLR4 has been found to depend on fetuin-A. In humans with impaired glucose tolerance, plasma fetuin-A levels negatively correlate with insulin secretion. The present study aims to examine effects of fetuin-A in human islets.
The I148 M variant in PNPLA3 is associated with altered hepatic lipid composition in humans
2014-03-05

The common sequence variant I148 M in patatin-like phospholipase domain 3 (PNPLA3) is associated with increased hepatic triacylglyceride (TAG) content but not with insulin resistance or diabetes in humans. In vitro data and a transgenic mouse model demonstrated that PNPLA3 I148 M not only increases hepatic lipid content, but also confers qualitative changes in hepatic lipid composition which may contribute to the metabolic consequences. Therefore we hypothesised that PNPLA3 I148 M impacts the hepatic lipid composition also in humans and analyzed the fatty acid composition of 5 lipid fractions in liver biopsies from 47 human subjects including 18 carriers of the PNPLA3 I148 M variant. PNPLA3 I148 M was associated with a strong increase (1.7-fold) in liver TAG but not other lipid fractions. The relative fatty acid composition of the TAGs showed a distinct pattern with significantly increased content of the n-3 polyunsaturated fatty acid (PUFA) alpha-linolenic acid (18:3 n-3) by 44% and decreased fatty acids of the n-6 series: eicosatrienoic acid (20:3) by 34%, arachidonic acid (20:4) by 44%, docosatetraenoic acid (22:4) by 50% and the end product docosapentaenoic acid (22:5) by 39%. These results are in part concordant with the changes detected in mouse livers overexpressing human PNPLA3 I148 M. Noteworthy, most PUFAs also showed an inverse correlation with TAG content independent of the PNPLA3 genotype. In a multivariate model including liver fat content, PNPLA3 genotype and fatty acid composition, two significant changes remained: reduced stearate and increased alpha-linoleate content in hepatic TAG. These two changes in fatty acid composition can be exclusively attributed to the PNPLA3 I148 M mutation and not general steatosis. Since stearate can induce insulin resistance and alpha-linoleate can protect from it, these changes may be part of the mechanism how PNPLA3 I148 M increases liver fat content without causing insulin resistance.
5-Azacytidine Improves the Osteogenic Differentiation Potential of Aged Human Adipose-Derived Mesenchymal Stem Cells by DNA Demethylation
2014-03-06

The therapeutic value of adipose-derived mesenchymal stem cells (Ad-MSCs) for bone regeneration is critically discussed. A possible reason for reduced osteogenic potential may be an age-related deterioration of the Ad-MSCs. In long term in vitro culture, epigenomic changes in DNA methylation are known to cause gene silencing, affecting stem cell growth as well as the differentiation potential. In this study, we observed an age-related decline in proliferation of primary human Ad-MSCs. Decreased Nanog, Oct4 and Lin28A and increased Sox2 gene-expression was accompanied by an impaired osteogenic differentiation potential of Ad-MSCs isolated from old donors (>60 a) as compared to Ad-MSCs isolated from younger donors (<45 a). 5-hydroxymethylcytosine (5 hmC) and 5-methylcytonsine (5 mC) distribution as well as TET gene expression were evaluated to assess the evidence of active DNA demethylation. We observed a decrease of 5 hmC in Ad-MSCs from older donors. Incubation of these cells with 5-Azacytidine induced proliferation and improved the osteogenic differentiation potential in these cells. The increase in AP activity and matrix mineralization was associated with an increased presence of 5 hmC as well as with an increased TET2 and TET3 gene expression. Our data show, for the first time, a decrease of DNA hydroxymethylation in Ad-MSCs which correlates with donor-age and that treatment with 5-Azacytidine provides an approach which could be used to rejuvenate Ad-MSCs from aged donors.
The Individual Therapy Process Questionnaire: Development and Validation of a Revised Measure to Evaluate General Change Mechanisms in Psychotherapy
2014-03-06

There is a dearth of measures specifically designed to assess empirically validated mechanisms of therapeutic change. To fill in this research gap, the aim of the current study was to develop a measure that covers a large variety of empirically validated mechanisms of change with corresponding versions for the patient and therapist. To develop an instrument that is based on several important change process frameworks, we combined two established change mechanisms instruments: the Scale for the Multiperspective Assessment of General Change Mechanisms in Psychotherapy (SACiP) and the Scale of the Therapeutic Alliance—Revised (STA‐R). In our study, 457 psychosomatic inpatients completed the SACiP and the STA‐R and diverse outcome measures in early, middle and late stages of psychotherapy. Data analyses were conducted using factor analyses and multilevel modelling. The psychometric properties of the resulting Individual Therapy Process Questionnaire were generally good to excellent, as demonstrated by (a) exploratory factor analyses on both patient and therapist ratings, (b) CFA on later measuring times, (c) high internal consistencies and (d) significant outcome predictive effects. The parallel forms of the ITPQ deliver opportunities to compare the patient and therapist perspectives for a broader range of facets of change mechanisms than was hitherto possible. Consequently, the measure can be applied in future research to more specifically analyse different change mechanism profiles in session‐to‐session development and outcome prediction. Copyright © 2014 John Wiley &amp; Sons, Ltd. Key Practitioner Message This article describes the development of an instrument that measures general mechanisms of change in psychotherapy from both the patient and therapist perspectives. Post‐session item ratings from both the patient and therapist can be used as feedback to optimize therapeutic processes. We provide a detailed discussion of measures developed to evaluate therapeutic change mechanisms.
Slowness and Sparseness Have Diverging Effects on Complex Cell Learning
2014-03-06

Following earlier studies which showed that a sparse coding principle may explain the receptive field properties of complex cells in primary visual cortex, it has been concluded that the same properties may be equally derived from a slowness principle. In contrast to this claim, we here show that slowness and sparsity drive the representations towards substantially different receptive field properties. To do so, we present complete sets of basis functions learned with slow subspace analysis (SSA) in case of natural movies as well as translations, rotations, and scalings of natural images. SSA directly parallels independent subspace analysis (ISA) with the only difference that SSA maximizes slowness instead of sparsity. We find a large discrepancy between the filter shapes learned with SSA and ISA. We argue that SSA can be understood as a generalization of the Fourier transform where the power spectrum corresponds to the maximally slow subspace energies in SSA. Finally, we investigate the trade-off between slowness and sparseness when combined in one objective function.
Coulomb Explosion Imaged Cryptochiral (R,R)‐2,3‐Dideuterooxirane: Unambiguous Access to the Absolute Configuration of (+)‐Glyceraldehyde
2014-03-06

Abstract The absolute configuration of ( R , R )‐2,3‐dideuterooxirane, which has been independently determined using Coulomb explosion imaging, has been unambiguously chemically correlated with the stereochemical key reference (+)‐glyceraldehyde. This puts the absolute configuration of D (+)‐glyceraldehyde on firm experimental grounds.
Creating cinematic wide gamut HDR-video for the evaluation of tone mapping operators and HDR-displays
2014-03-07

High quality video sequences are required for the evaluation of tone mapping operators and high dynamic range (HDR) displays. We provide scenic and documentary scenes with a dynamic range of up to 18 stops. The scenes are staged using professional film lighting, make-up and set design to enable the evaluation of image and material appearance. To address challenges for HDR-displays and temporal tone mapping operators, the sequences include highlights entering and leaving the image, brightness changing over time, high contrast skin tones, specular highlights and bright, saturated colors. HDR-capture is carried out using two cameras mounted on a mirror-rig. To achieve a cinematic depth of field, digital motion picture cameras with Super-35mm size sensors are used. We provide HDR-video sequences to serve as a common ground for the evaluation of temporal tone mapping operators and HDR-displays. They are available to the scientific community for further research.
Agreement and verb types in Kutchi Gujarati
2014-03-07

This paper explores the φ-agreement system in Kutchi Gujarati, focusing on canonical transitive cases and on non-canonical cases involving psych predicates and modal auxiliaries. Based on the agreement pattern in the future perfect, we argue that φ-agreement in Kutchi Gujarati involves two agreement probes, a higher (number/person) probe in T , and a lower (gender/number) probe in the v/Asp area. After showing how such a system derives the split-ergative agreement pattern in canonical transitive constructions (Section 2), we extend our analysis to other types of verbs, specifically to psych predicates (such as gam ‘like’) and to constructions that involve modal auxiliaries (such as par ‘have to’), both of which require a dative-marked subject (Section 3).
From dead leaf, to new life: TAL effectors as tools for synthetic biology
2014-03-07

Summary Whether rice, yeast or fly there is barely a model organism not yet reached by transcription activator‐like effectors ( TALE s) and their derivative fusion proteins. Insights into fundamental biology are now arriving on the back of work in recent years to develop these proteins as tools for molecular biology. This began with the publication of the simple cipher determining base‐specific DNA recognition by TALE s in 2009, and now encompasses a huge variety of established fusion proteins mediating targeted modifications to transcriptome, genome and, recently, epigenome. Straightforward design and exquisite specificity, allowing unique sites to be targeted even within complex eukaryote genomes, are key to the popularity of this system. Synthetic biology is one field that is just beginning to make use of these properties, with a number of recent publications demonstrating TALE ‐mediated regulation of synthetic genetic circuits. Intense interest has surrounded the CRISPR /Cas9 system within the last 12 months, and it is already proving its mettle as a tool for targeted gene modifications and transcriptional regulation. However, questions over off‐target activity and means for independent regulation of multiple Cas9‐guide RNA pairs must be resolved before this method can be included in the synthetic biology toolbox. TALE s are already showing promise as regulators of synthetic biological systems, a role that is likely to be developed further in the coming years.
WT1 expression increases with malignancy and indicates unfavourable outcome in astrocytoma
2014-03-07

Aims The zinc finger transcription factor WT1 is expressed in astrocytic neoplasms and therefore is a potential target of immunotherapy in brain tumours. Our aim was to further elucidate the role of WT1 as a diagnostic and prognostic marker in neuropathology, particularly as to the differentiation of astrocytoma from oligodendroglioma as well as to the dependency of WT1 expression on clinically relevant parameters. Methods 829 evaluable brain tumour samples were investigated by WT1 immunohistochemistry on full tissue routine slides, consisting of 442 glioblastomas, 303 astrocytomas, 41 oligodendrogliomas and 43 oligoastrocytomas. In addition public WT1 gene expression data of 351 gliomas were analysed. Results Our data show that WT1 expression in diffuse astrocytic tumours increases with WHO tumour grade and is associated with older age, absence of IDH1 mutation but not related to O(6)- methyl guanine methyl transferase (MGMT) promoter methylation status. Univariable, but not multivariable survival analysis indicates that WT1 expression is associated with worse outcome in patients with diffuse astrocytoma but not glioblastoma. Conclusions The significant WT1 expression differences between diffuse astrocytomas, oligoastrocytomas and oligodendrogliomas, which are also present in the Repository for Molecular Brain Neoplasia Data, National Cancer Institute (REMBRANDT, 2005, http://rembrandt.nci.nih.gov) gene database set, provide a rationale for use of WT1 as part of a routine immunohistochemistry panel.
Characterization of the physiology and cell-mineral interactions of the marine anoxygenic phototrophic Fe(II) oxidizerRhodovulum iodosum- implications for Precambrian Fe(II) oxidation
2014-03-09

Anoxygenic phototrophic Fe(II)-oxidizing bacteria (photoferrotrophs) are suggested to have contributed to the deposition of banded iron formations (BIFs) from oxygen-poor seawater. However, most studies evaluating the contribution of photoferrotrophs to Precambrian Fe(II) oxidation have used freshwater and not marine strains. Therefore, we investigated the physiology and mineral products of Fe(II) oxidation by the marine photoferrotroph Rhodovulum iodosum. Poorly crystalline Fe(III) minerals formed initially and transformed to more crystalline goethite over time. During Fe(II) oxidation, cell surfaces were largely free of minerals. Instead, the minerals were co-localized with EPS suggesting that EPS plays a critical role in preventing cell encrustation, likely by binding Fe(III) and directing precipitation away from cell surfaces. Fe(II) oxidation rates increased with increasing initial Fe(II) concentration (0.43-4.07 mM) under a light intensity of 12 μmol quanta m(-2) s(-1). Rates also increased as light intensity increased (from 3 to 20 μmol quanta m(-2) s(-1)), while the addition of Si did not significantly change Fe(II) oxidation rates. These results elaborate on how the physical and chemical conditions present in the Precambrian ocean controlled the activity of marine photoferrotrophs and confirm the possibility that such microorganisms could have oxidized Fe(II), generating the primary Fe(III) minerals that were then deposited to some Precambrian BIFs.