julilili42/papers huggingface dataset:
Deleveraging, deflation and depreciation in the euro area
2015-12-01

During the post-crisis period, economic performance has been highly heterogenous across the euro area. While some economies rebounded quickly after the 2009 output collapse, others are undergoing a protracted further decline as part of an extensive deleveraging process. At the same time, inflation has been subdued throughout the whole of the euro area and intra-euro-area exchange rates have hardly moved. We interpret these facts through the lens of a two-country model of a currency union. We find that deleveraging in one country generates deflationary spillovers which cannot be contained by monetary policy, as it becomes constrained by the zero lower bound. As a result, the real exchange rate response becomes muted, and the output collapse---concentrated in the deleveraging economies.
Vision, Perception, and Attention through the Lens of Microsaccades: Mechanisms and Implications
2015-12-02

Microsaccades are small saccades. Neurophysiologically, microsaccades are generated using similar brainstem mechanisms as larger saccades. This suggests that peri-saccadic changes in vision that accompany large saccades might also be expected to accompany microsaccades. In this review, we highlight recent evidence demonstrating this. Microsaccades are not only associated with suppressed visual sensitivity and perception, as in the phenomenon of saccadic suppression, but they are also associated with distorted spatial representations, as in the phenomenon of saccadic compression, and pre-movement response gain enhancement, as in the phenomenon of pre-saccadic attention. Surprisingly, the impacts of peri-microsaccadic changes in vision are far reaching, both in time relative to movement onset as well as spatial extent relative to movement size. Periods of ~100 ms before and ~100 ms after microsaccades exhibit significant changes in neuronal activity and behavior, and this happens at eccentricities much larger than the eccentricities targeted by the microsaccades themselves. Because microsaccades occur during experiments enforcing fixation, these effects create a need to consider the impacts of microsaccades when interpreting a variety of experiments on vision, perception, and cognition using awake, behaving subjects. The clearest example of this idea to date has been on the links between microsaccades and covert visual attention. Recent results have demonstrated that peri-microsaccadic changes in vision play a significant role in both neuronal and behavioral signatures of covert visual attention, so much so that in at least some attentional cueing paradigms, there is very tight synchrony between microsaccades and the emergence of attentional effects. Just like large saccades, microsaccades are genuine motor outputs, and their impacts can be substantial even during perceptual and cognitive experiments not concerned with overt motor generation per se.
Remote Sensing for Characterisation and Kinematic Analysis of Large Slope Failures: Debre Sina Landslide, Main Ethiopian Rift Escarpment
2015-12-02

Frequently occurring landslides in Ethiopia endanger rapidly expanding settlements and infrastructure. We investigated a large landslide on the western escarpment of the Main Ethiopian Rift close to Debre Sina. To understand the extent and amplitude of the movements, we derived vectors of horizontal displacements by feature matching of very high resolution satellite images (VHR). The major movements occurred in two phases, after the rainy seasons in 2005 and 2006 reaching magnitudes of 48 ± 10.1 m and 114 ± 7.2 m, respectively. The results for the first phase were supported by amplitude tracking using two Envisat/ASAR scenes from the 31 July 2004 and the 29 October 2005. Surface changes in vertical direction were analyzed by subtraction of a pre-event digital elevation model (DEM) from aerial photographs and post-event DEM from ALOS/PRISM triplet data. Furthermore, we derived elevation changes using satellite laser altimetry measurement acquired by the ICESat satellite. These analyses allowed us to delineate the main landslide, which covers an area of 6.5 km2, shallow landslides surrounding the main landslide body that increased the area to 8.5 km2, and the stable area in the lower part of the slope. We assume that the main triggering factor for such a large landslide was precipitation cumulated over several months and we suspect that the slope failure will progress towards the foot of the slope.
Asteroseismology of rapidly rotating neutron stars: An alternative approach
2015-12-02

In the present paper we examine gravitational wave asteroseismology relations\\nfor f-modes of rapidly rotating neutron stars. An approach different to the\\nprevious studies is employed - first, the moment of inertia is used instead of\\nthe stellar radius, and second, the normalization of the oscillation\\nfrequencies and damping times is different. It was shown that in the\\nnon-rotating case this can lead to a much stronger equation of state\\nindependence and our goal is to generalize the static relations to the rapidly\\nrotating case and values of the spherical mode number . We employ\\nrealistic equations of state that cover a very large range of stiffness in\\norder to check better the universality of the relations. At the end we explore\\nthe inverse problem, i.e. obtain the neutron star parameters from the observed\\ngravitational frequencies and damping times. It turns out that with this new\\nset of relations we can solve the inverse problem with a very good accuracy\\nusing three frequencies that was not possible in the previous studies where one\\nneeds also the damping times. The asteroseismology relations are also\\nparticularly good for the massive rapidly rotating models that are subject to\\nsecular instabilities.\\n
Novel AKT phosphorylation sites identified in the pluripotency factors OCT4, SOX2 and KLF4
2015-12-02

The four OSKM factors OCT4, SOX2, KLF4 and c-MYC are key transcription factors modulating pluripotency, self-renewal and tumorigenesis in stem cells. However, although their transcriptional targets have been extensively studied, little is known about how these factors are regulated at the posttranslational level. In this study, we established an <i>in vitro</i> system to identify phosphorylation patterns of the OSKM factors by AKT kinase. OCT4, SOX2, KLF4 and c-MYC were expressed in Sf9 insect cells employing the baculoviral expression system. OCT4, SOX2 and KLF4 were localized in the nucleus of insect cells, allowing their easy purification to near homogeneity upon nuclear fractionation. All transcription factors were isolated as biologically active DNA-binding proteins. Using <i>in vitro</i> phosphorylation and mass spectrometry-based phosphoproteome analyses several novel and known AKT phosphorylation sites could be identified in OCT4, SOX2 and KLF4.
Corrigendum to “Gene networks and transcription factor motifs defining the differentiation of human stem cells into hepatocyte-like cells” [J Hepatol 2015;63:934–942]
2015-12-02

Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cellsJournal of HepatologyVol. 63Issue 4PreviewPrimary human hepatocytes represent a well-established tool in pharmacology and toxicology [1] and have been applied for transplantation in metabolic liver diseases [2]. However, a major limitation is availability, since primary hepatocytes have to be isolated from surgically resected liver tissue [1]. Recently, protocols have been established and optimized to generate hepatocyte-like cells (HLC) from human embryonic stem cells (ESC) or human-induced pluripotent stem cells (hiPSC) [3–7], and human-induced pluripotent stem cells (hiPSC) [8,9]. Full-Text PDF Open Access An error was introduced in Fig. 4 of the original manuscript. Please find the corrected figure below. The authors apologize for any inconvenience.
Foam Stabilized by Fly Ash Nanoparticles for Enhancing Oil Recovery
2015-12-03

Foam has been employed as an improved or enhanced oil recovery method to overcome gravity override and the channeling and fingering of the injected gas, which arises because of the low density and viscosity of the injected fluid combined with the rock heterogeneity. A major challenge, however, is the stability of the generated foam when it contacts the oil. In this study we investigate the feasibility of using inexpensive nanoparticles made of coal fly ash, an abundantly available waste product of coal power plants, as a foam booster. We investigate the viability of reducing the size of fly ash particles to 100–200 nm using high-frequency ultrasonic grinding. We also study the foaminess (foamability), strength, and stability of the foams made with minor concentrations of fly ash nanoparticles and surfactant, both in bulk and porous media. The effect of monovalent and divalent ion concentration on the foaminess of the nanoash suspension combined with very low concentrations of a commercial alpha olefin sulfonate (AOS) surfactant, in the presence and absence of oil, is studied. We observe that bulk foam that contains very small amounts of nanoash particles shows a higher stability in the presence of model oils. Furthermore, experiments in porous media exhibit remarkably stronger foam with mixtures of nanoash and surfactant, such that the amount of produced liquids from the cores significantly increases. For the first time we show that nanoash can be used to stabilize nitrogen foam in the presence of crude oil at high temperature and pressure. In the presence of oil, the nanoash–AOS foam shows a higher stability, although crude oil tends to form stable emulsions in water in the presence of nanoash.
Induction of NK Cell Reactivity Against Myeloid Leukemia By a Novel Fc-Optimized CD133 Antibody
2015-12-03

Abstract NK cells largely contribute to the success of monoclonal antibody (mAb) application in cancer due to their ability to mediate antibody-dependent cellular cytotoxicity (ADCC), a feature considered critical for therapeutic success. Up to now, no immunotherapeutic antibodies are available for the treatment of myeloid leukemias. Recently, we reported on the development of mAb targeting CD133, which is expressed on a wide variety of tumor cells (Koerner et al., Blood 2014 124:2309). Here we extend our analyses and provide further data on the preclinical characterization of an Fc-engineered CD133 mAb for the treatment of myeloid leukemia. Compared to two other anti-human CD133 mAb (clones AC133 and W6B3), which both bound to primary AML and CML cells in 15/25 and 7/10 cases, respectively, clone 293C3 recognized the leukemic cells in 22/25 AML cases and 7/10 CML cases. Based on these results, clone 293C3 was chosen to generate chimeric mAb with either a wildtype Fc part (293C3-WT) or a variant containing amino acid exchanges (S239D/I332E) to enhance affinity to the activating Fc receptor CD16 on NK cells (293C3-SDIE). Treatment with 293C3-SDIE resulted in significantly enhanced activation, degranulation and lysis of primary CD133-positive AML cells by NK cells in allogeneic and autologous experimental ex vivo settings as compared to its wildtype counterpart. Considering the expression of CD133 on healthy hematopoietic progenitor cells, we further performed colony forming unit assays with healthy bone marrow (BM) cells. In line with the observed lower expression levels of CD133 on healthy compared to malignant hematopoietic cells no relevant toxicity of 293C3-SDIE at the level of committed hematopoietic progenitor cells was observed. Moreover, 293C3-SDIE did not induce lysis of of healthy BM cells by allogeneic or autologous NK cells. In a NOD.Cg-Prkdcscid IL2rgtmWjl/Sz (NSG) xenotransplantation model, induction of ADCC by treatment with 293C3-SDIE resulted in the elimination of patient AML cells by NK cells from a matched human donor. Thus, 293C3-SDIE constitutes an attractive immunotherapeutic compound, in particular for the elimination of minimal residual disease in CD133 bearing leukemia in the context of allogenic SCT. Disclosures No relevant conflicts of interest to declare.
Belimumab, a Neutralizing BAFF (B Cell Activating Factor) Antibody, Enhances the Susceptibility of Chronic Lymphoid Leukemia (CLL) Cells to Abt-199 Treatment
2015-12-03

Abstract Abt-199 is a small molecule BCL-2 inhibitor which has recently been approved for treatment of CLL and mediates its effects by induction of apoptosis in the leukemic cells. The TNF family member B cell activating factor (BAFF) contributes to disease pathophysiology in mature B cell malignancies including CLL by sustaining survival and preventing apoptosis of the malignant B cells. BAFF also plays a prominent role in autoimmune diseases, and accordingly a BAFF-neutralizing antibody termed Belimumab (Benlysta®) has been developed and is approved for treatment of systemic lupus erythematosus. Notably, elevated levels of BAFF have also been detected in sera of B cell lymphoma patients. We demonstrated recently that BAFF protects CLL cells from NK cell cytotoxicity including Rituximab-induced antibody-dependent cellular cytotoxicity (ADCC), the major mechanism by which this CD20-antibody mediates its therapeutic effects. In turn, susceptibility of CLL cells to both direct and Rituximab-induced NK cell killing could be restored by BAFF neutralization with Belimumab (Wild et al, Leukemia 2015). Here we studied whether Belimumab could also serve to increase the susceptibility of CLL cells to Abt-199 treatment. As no information on Abt-199 plasma peak levels in CLL patients is available, we first exposed primary CLL cells of leukemia patients to varying concentrations of Abt-199 and identified 5 nMas in vitro LC50 concentration in analyses of leukemia cell metabolic activity. Next we studied how BAFF influenced the therapeutic efficacy of Abt-199. Analyses of CLL cell metabolic activity and apoptosis/cell death revealed that BAFF concentration-dependently protected primary CLL cells from the therapeutic effects of Abt-199. Notably, CLL cell susceptibility to Abt-199 could be restored by neutralization of BAFF by Belimumab. Together, our findings demonstrate that BAFF contributes to CLL cell resistance to Abt-199 treatment. BAFF neutralization by Belimumab may in turn constitute a promising strategy to increase/restore the therapeutic efficacy of Abt-199, which warrants future clinical studies of combinatorial approaches to improve CLL treatment. Disclosures No relevant conflicts of interest to declare.
Inhibition of the NAMPT-Triggered Deacetylation of HCLS1 Protein: A New Therapeutic Option in Chronic Myeloid Leukemia
2015-12-03

Abstract G-CSFR-triggered phosphorylation and activation of the hematopoietic-specific lyn-substrate 1 (HCLS1) protein is important for the granulocytic differentiation of hematopoietic stem cells (HSCs) (Skokowa J. et al., Nat Med 2012). G-CSF also activates protein deacetylation via Nicotinamide phosphoribosyltransferase (NAMPT)/NAD+/sirtuin 1 (SIRT1) pathway (Skokowa J. et al., Nat Med 2009). SIRT1 is NAD+-dependent protein deacetylase playing an important role in the regulation of gene transcription. Interestingly, having strong pro-differentiation effects on myeloid progenitors, both HCLS1 and NAMPT are markedly hyper-activated in myeloid leukemias, inducing proliferation and survival of undifferentiated blasts. Knowing this, we investigated whether HCLS1 could be activated by NAMPT/NAD+/SIRT1 pathway via deacetylation in HSCs. Indeed, we found that HCLS1 is deacetylated in HSCs by NAMPT/SIRT1 and that G-CSF treatment of these cells induced deacetylation and phosphorylation of HCLS1 via NAMPT/SIRT1. Moreover, we found that deacetylation of HCLS1 is important for myeloid differentiation and proliferation of HSCs. We further demonstrated that HCLS1 protein was activated by deacetylation in blasts of chronic myeloid leukemia (CML) patients, as compared to HSCs of healthy individuals. This was in line with elevated mRNA and protein levels of NAMPT and HCLS1. We further investigated, whether inhibition of NAMPT-triggered deacetylation of HCLS1 has any effect on the survivial and differentiation of CML blasts in vitro. We found that treatment of CML blasts with the specific NAMPT inhibitor FK866 resulted in increased acetylation of HCLS1. In addition, treatment of CML blasts with the FK866 in a dose of 10nM resulted in marked inhibition of proliferation and elevated cell death, which was consistent between different patients and was comparable to the effects of Imatinib treatment. In CFU assay in the presence of FK866 (10nM) no CFU colonies were grown. Even at a dose of 3nM FK866 drastically suppressed total colony counts. This inhibitory effect was further amplified by combination of FK866 with Imatinib. Addition of 10nM of FK866 to CFU culture medium was not toxic for CD34+ cells of healthy donors. Taken together, we demonstrated that NAMPT and HCLS1 have dose-dependent effects on hematopoietic cells and that NAMPT activates HCLS1 functions by SIRT1-triggered deacetylation. Inhibition of NAMPT in CML blasts markedly reduced their survival, proliferation and differentiation. In conclusion, we suggest a possible therapeutic application of NAMPT inhibition in the treatment of CML patients via deactivation of HCLS1 function by acetylation. This therapy could be applied in combination with Imatinib, or in Imatinib-resistant CML patients. Disclosures No relevant conflicts of interest to declare.
Induction of NK and T Cell Immune Responses Against Leukemia Cells By Bispecific NKG2D-CD16 and -CD3 Fusion Proteins
2015-12-03

Abstract Monoclonal antibodies (mAbs) have by now become an established tool in therapy of many malignancies. The interaction of a mAb's Fc portion with Fcγ receptors (FcγR) on immune effector cells is important for its efficacy, but often insufficient to potently induce antitumor immunity e.g. due to FcγR polymorphisms. Moreover, Fc parts of mAbs may bind to FcγRs expressed on non-cytotoxic cells (e.g., platelets and B cells) and interact with FcγRs that do not trigger cytotoxicity (e.g. CD16b on granulocytes). These shortcomings can be overcome by novel antibody formats like bispecific antibodies allowing for improved activation of a specific pool of effector cells. Here we report on the development and preclinical characterization of two bispecific fusion proteins that target ligands of the immunoreceptor NKG2D (NKG2DL) which are widely expressed on malignant cells but generally absent on healthy tissue. Our fusion proteins consist of the extracellular domain of NKG2D as targeting moiety for tumor-expressed NKG2DL fused to Fab-fragments of either an agonistic CD3 or CD16 antibody. Specific binding of these NKG2D-CD3 and NKG2D-CD16 constructs was confirmed using NKG2DL-transfectants with regard to their target arm and either NK cells or T cells with regard to their different effector parts. Dose titration assays revealed an increased affinity of NKG2D-CD16 to the FcγR on NK cells as compared to our previously described (e.g., Steinbacher et al, 2014) Fc-optimized NKG2D-IgG1 fusion protein, which was mirrored by a potently increased ability to induce lysis of NKG2DL-tranfectants and NKG2DL-positive primary acute myeloid leukemia (AML) cells by allogeneic NK cells. The novel NKG2D-CD3 construct in turn was found to potently activate allogeneic and autologous CD4+ and CD8+ T cells. Next we comparatively analyzed the efficacy of T cells and NK cells to lyse autologous leukemia cells upon treatment with NKG2D-CD3 and NKG2D-CD16, respectively, by using PBMC of AML patients (blast counts 30-70%) directly ex vivo in long term cytotoxicity assays. NKG2D-CD16 potently induced AML cell lysis, and this was, in line with their proliferative and higher effector potential, by far exceeded upon stimulation of T cells with NKG2D-CD3. Taken together, we here introduce novel "antibody-like" bispecific constructs that take advantage of the highly tumor-restricted expression of NKG2DL and potently activate the reactivity of NK or T cells for immunotherapy of leukemia. Disclosures No relevant conflicts of interest to declare.
Leukemia Related Co-Stimulation / Co-Inhibition Predict T-Cell Attack of Acute Lymphoblastic Leukemia Mediated By Blinatumomab
2015-12-03

Abstract Refractory B-precursor acute lymphoblastic leukemia (ALL) remains an unsolved therapeutic challenge. Various T-cell immunotherapies are promising options in relapsed/refractory B-ALL, like the CD19/CD3-bispecific T-cell engaging antibody Blinatumomab. Until now it has not been possible to determine critical factors for T-cell attack against leukemia that decide on in vivo response or non-response to treatment. Immune-checkpoint molecules regulate immune escape of malignant cells and antibody blockade of these inhibitory pathways enhances antitumor immune responses. Therefore, we investigated the role of co-stimulatory and co-inhibitory molecules for effector-target cell interactions and influence on T-cell attack against leukemia. CD19+ lymphoblast lines, primary pediatric B-ALL bone marrow blasts (n=10) and physiologic CD19+ CD10+ pre-B bone marrow precursors from healthy bone marrow were screened for surface expression of 20 different co-signaling molecules. Surface expression of PD-L1, PD-1, LAG3, CD40, CD86, CD27, CD70 and HVEM revealed differences in stimulatory and inhibitory profiles of pediatric ALL blasts as compared to physiologic cells. Pediatric ALL patients refractory to Blinatumomab-treatment (n=4) as well as patients with relapsed leukemia (n=7) showed increased expression of PD-L1 on blasts. Expression of exhaustion markers PD-1 and TIM-3 was significantly higher on patients' T cells as compared to healthy donors and is induced by T-cell attack against blasts. Blinatumomab-mediated T-cell function was examined in healthy donors as compared to pediatric patients with ALL through analysis of proliferation and effector function. Significant differences in Blinatumomab-induced T-cell function were found to be target-cell dependent and correlated to expression of co-signaling molecules on target cells. Blockade of inhibitory PD-1-PD-L and CTLA-4-CD80/CD86 interactions could further enhance effector T-cell function of healthy donors and patients whereas blockade of co-stimulatory CD28-CD80/86 interactions resulted in reduced T-cell effector and proliferation potential. Combined treatment with Blinatumomab and PD-1 blocking antibody Pembrolizumab was feasible and induced an anti-leukemic immune response in a 12 year old patient with refractory ALL. In conclusion, we show that regulation of T-cell activation and inhibition by co-signaling molecules guides the efficacy of T-cell attack against ALL. Inhibitory interactions between leukemia-induced checkpoint molecules on T cells and their counterparts on ALL regulate in vivo resistance to T-cell immunotherapy and will guide future therapeutic interventions. Disclosures Off Label Use: Pembrolizumab.