julilili42/papers huggingface dataset:
Different inhibition of Gβγ-stimulated class IB phosphoinositide 3-kinase (PI3K) variants by a monoclonal antibody. Specific function of p101 as a Gβγ-dependent regulator of PI3Kγ enzymatic activity
2015-06-19

Class IB phosphoinositide 3-kinases γ (PI3Kγ) are second-messenger-generating enzymes downstream of signalling cascades triggered by G-protein-coupled receptors (GPCRs). PI3Kγ variants have one catalytic p110γ subunit that can form two different heterodimers by binding to one of a pair of non-catalytic subunits, p87 or p101. Growing experimental data argue for a different regulation of p87-p110γ and p101-p110γ allowing integration into distinct signalling pathways. Pharmacological tools enabling distinct modulation of the two variants are missing. The ability of an anti-p110γ monoclonal antibody [mAb(A)p110γ] to block PI3Kγ enzymatic activity attracted us to characterize this tool in detail using purified proteins. In order to get insight into the antibody-p110γ interface, hydrogen-deuterium exchange coupled to MS (HDX-MS) measurements were performed demonstrating binding of the monoclonal antibody to the C2 domain in p110γ, which was accompanied by conformational changes in the helical domain harbouring the Gβγ-binding site. We then studied the modulation of phospholipid vesicles association of PI3Kγ by the antibody. p87-p110γ showed a significantly reduced Gβγ-mediated phospholipid recruitment as compared with p101-p110γ. Concomitantly, in the presence of mAb(A)p110γ, Gβγ did not bind to p87-p110γ. These data correlated with the ability of the antibody to block Gβγ-stimulated lipid kinase activity of p87-p110γ 30-fold more potently than p101-p110γ. Our data argue for differential regulatory functions of the non-catalytic subunits and a specific Gβγ-dependent regulation of p101 in PI3Kγ activation. In this scenario, we consider the antibody as a valuable tool to dissect the distinct roles of the two PI3Kγ variants downstream of GPCRs.
Structure of the two-neutrino double-βdecay matrix elements within perturbation theory
2015-06-19

The two-neutrino double- Gamow-Teller and Fermi transitions are studied within an exactly solvable model, which allows a violation of both spin-isospin SU(4) and isospin SU(2) symmetries, and is expressed with generators of the SO(8) group. It is found that this model reproduces the main features of realistic calculation within the quasiparticle random-phase approximation with isospin symmetry restoration concerning the dependence of the two-neutrino double- decay matrix elements on isovector and isoscalar particle-particle interactions. By using perturbation theory an explicit dependence of the two-neutrino double- decay matrix elements on the like-nucleon pairing, particle-particle and , and particle-hole proton-neutron interactions is obtained. It is found that double- decay matrix elements do not depend on the mean field part of Hamiltonian and that they are governed by a weak violation of both SU(2) and SU(4) symmetries by the particle-particle interaction of Hamiltonian. It is pointed out that there is a dominance of two-neutrino double- decay transition through a single state of intermediate nucleus. The energy position of this state relative to energies of initial and final ground states is given by a combination of strengths of residual interactions. Further, energy-weighted Fermi and Gamow-Teller sum rules connecting nuclei are discussed. It is proposed that these sum rules can be used to study the residual interactions of the nuclear Hamiltonian, which are relevant for charge-changing nuclear transitions.
Nucleoside Diphosphate Kinase B–Activated Intermediate Conductance Potassium Channels Are Critical for Neointima Formation in Mouse Carotid Arteries
2015-06-19

Objective— Vascular smooth muscle cells (VSMC) proliferation is a hallmark of atherosclerosis and vascular restenosis. The intermediate conductance Ca 2+ -activated K + (SK4) channel is required for pathological VSMC proliferation. In T lymphocytes, nucleoside diphosphate kinase B (NDPKB) has been implicated in SK4 channel activation. We thus investigated the role of NDPKB in the regulation of SK4 currents (I SK4 ) in proliferating VSMC and neointima formation. Approach and Results— Function and expression of SK4 channels in VSMC from injured mouse carotid arteries were assessed by patch-clamping and real-time polymerase chain reaction. I SK4 was detectable in VSMC from injured but not from uninjured arteries correlating with the occurrence of the proliferative phenotype. Direct application of NDPKB to the membrane of inside-out patches increased I SK4 , whereas NDPKB did not alter currents in VSMC obtained from injured vessels of SK4-deficient mice. The NDPKB-induced increase in I SK4 was prevented by protein histidine phosphatase 1, but not an inactive protein histidine phosphatase 1 mutant indicating that I SK4 is regulated via histidine phosphorylation in proliferating VSMC; moreover, genetic NDPKB ablation reduced I SK4 by 50% suggesting a constitutive activation of I SK4 in proliferating VSMC. In line, neointima formation after wire injury of the carotid artery was substantially reduced in mice deficient in SK4 channels or NDPKB. Conclusions— NDPKB to SK4 signaling is required for neointima formation. Constitutive activation of SK4 by NDPKB in proliferating VSMC suggests that targeting this interaction via, for example, activation of protein histidine phosphatase 1 may provide clinically meaningful effects in vasculoproliferative diseases such as atherosclerosis and post angioplasty restenosis.
Decisions and Higher‐Order Knowledge
2015-06-20

A knowledge‐based decision theory faces what has been called the prodigality problem (Greco, 2013): given that many propositions are assigned probability 1, agents will be inclined to risk everything when betting on propositions which are known. In order to undo probability 1 assignments in high risk situations, the paper develops a theory which systematically connects higher level goods with higher‐order knowledge.
Survival of SLNB-positive melanoma patients with and without complete lymph node dissection: A multicenter, randomized DECOG trial.
2015-06-20

LBA9002 Background: Complete lymph node dissection (CLND) following positive sentinel node biopsy (SLNB) was evaluated in a randomized phase III trial. Methods: 1,258 patients with cutaneous melanoma of the trunk and extremities and with positive SLNB were evaluated. Of these, 483 (39%) agreed to randomization into the clinical trial. 241 patients underwent observation only, 242 received CLND. Both groups had a subsequent 3-years follow-up. Recurrence-free (RFS), distant metastases free (DMFS) and melanoma specific (MSS) survival were analyzed as endpoints. Results: Patient enrolment was performedfrom January 2006 to December 2014. In the intent to treat analysis, both groups did not differ significantly in distribution of age, gender, localization, ulceration, tumor thickness (median 2,4 mm in both groups), number of positive nodes, or tumor burden in the SN. The mean follow-up time was 34 months (SD ± 22.1). No significant treatment-related difference was seen in the 5-years RFS (P = 0.72), DMFS (P= 0 .76) and MSS (P = 0.86) in the overall study population. Conclusions: In this early analysis of trial results, no survival benefit was achieved by CLND in melanoma patients with positive SLNB. A subsequent analysis three years after inclusion of the last patient is planned.
First In Vivo Results of a Novel Pediatric Oxygenator with an Integrated Pulsatile Pump
2015-06-20

Extracorporeal membrane oxygenation (ECMO) is a pivotal bridge to recovery for cardiopulmonary failure in children. Besides its life-saving quality, it is often associated with severe system-related complications, such as hemolysis, inflammation, and thromboembolism. Novel oxygenator and pump systems may reduce such ECMO-related complications. The ExMeTrA oxygenator is a newly designed pediatric oxygenator with an integrated pulsatile pump minimizing the priming volume and reducing the surface area of blood contact. The aim of our study was to investigate the feasibility and safety of this new ExMeTrA (expansion mediated transport and accumulation) oxygenator in an animal model. During 6 h of extracorporeal circulation (ECC) in pigs, parameters of the hemostatic system including coagulation, platelets and complement activation, and flow rates were investigated. A nonsignificant trend in C3 consumption, thrombin-antithrombin-III (TAT) complex formation and a slight trend in hemolysis were detected. During the ECC, the blood flow was constantly at 500 ml/min using only flexible silicone tubes inside the oxygenator as pulsatile pump. Our data clearly indicate that the hemostatic markers were only slightly influenced by the ExMeTrA oxygenator. Additionally, the oxygenator showed a constant quality of blood flow. Therefore, this novel pediatric oxygenator shows the potential to be used in pediatric and neonatal support with ECMO.
Restoration of synaptic function in sight for degenerative retinal disease
2015-06-21

Synaptic disorganization is a prominent feature of many neurological diseases of the CNS, including Parkinson's disease, intellectual development disorders, and autism. Although synaptic plasticity is critical for learning and memory, it is unclear whether this innate property helps restore synaptic function in disease once the primary cause of disease is abrogated. An answer to this question may come from a recent investigation in X-linked retinoschisis, a currently untreatable retinopathy. In this issue of the JCI, Ou, Vijayasarathy, and colleagues showed progressive disorganization of key functional elements of the synapse between photoreceptors and ON-bipolar cells in a retinoschisin-deficient mouse model. Moreover, they demonstrated that adeno-associated virus-mediated (AAV-mediated) delivery of the retinoschisin gene restores structure and function to the photoreceptor to ON-bipolar cell synapse in mouse models, even in adults at advanced stages of the disease. The results of this study hold promise that AAV-based supplemental gene therapy will benefit patients with X-linked retinoschisis in a forthcoming clinical trial.
Land use intensification alters ecosystem multifunctionality via loss of biodiversity and changes to functional composition
2015-06-22

Abstract Global change, especially land‐use intensification, affects human well‐being by impacting the delivery of multiple ecosystem services (multifunctionality). However, whether biodiversity loss is a major component of global change effects on multifunctionality in real‐world ecosystems, as in experimental ones, remains unclear. Therefore, we assessed biodiversity, functional composition and 14 ecosystem services on 150 agricultural grasslands differing in land‐use intensity. We also introduce five multifunctionality measures in which ecosystem services were weighted according to realistic land‐use objectives. We found that indirect land‐use effects, i.e. those mediated by biodiversity loss and by changes to functional composition, were as strong as direct effects on average. Their strength varied with land‐use objectives and regional context. Biodiversity loss explained indirect effects in a region of intermediate productivity and was most damaging when land‐use objectives favoured supporting and cultural services. In contrast, functional composition shifts, towards fast‐growing plant species, strongly increased provisioning services in more inherently unproductive grasslands.
Lateral Resolution and Image Formation in Scanning Ion Conductance Microscopy
2015-06-22

The scanning ion conductance microscope (SICM) is a powerful tool for imaging the topography of soft samples in an aqueous environment. Despite the rising popularity of the SICM, the image formation process and the fundamental limit of the lateral resolution are still a matter of debate. Using microfabricated samples, we investigated the imaging of small cylindrical particles, elongated objects, and topography steps and present the first direct comparison of numerical and experimental data. For the lateral resolution we considered two alternative definitions: the distance at which two small particles can clearly be resolved from each other in an image, and the apparent full width at half-maximum of small particles. For both definitions, we found a lateral resolution of about 3 times the inner opening radius of the pipet. We further validated this resolution limit in measurements on supported lipid bilayers and a polycarbonate sample using pipets with opening radii down to 8 nm.
Examining the Causes and Consequences of Short-Term Behavioral Change during the Middle Stone Age at Sibudu, South Africa
2015-06-22

Sibudu in KwaZulu-Natal (South Africa) with its rich and high-resolution archaeological sequence provides an ideal case study to examine the causes and consequences of short-term variation in the behavior of modern humans during the Middle Stone Age (MSA). We present the results from a technological analysis of 11 stratified lithic assemblages which overlie the Howiesons Poort deposits and all date to ~58 ka. Based on technological and typological attributes, we conducted inter-assemblage comparisons to characterize the nature and tempo of cultural change in successive occupations. This work identified considerable short-term variation with clear temporal trends throughout the sequence, demonstrating that knappers at Sibudu varied their technology over short time spans. The lithic assemblages can be grouped into three cohesive units which differ from each other in the procurement of raw materials, the frequency in the methods of core reduction, the kind of blanks produced, and in the nature of tools the inhabitants of Sibudu made and used. These groups of assemblages represent different strategies of lithic technology, which build upon each other in a gradual, cumulative manner. We also identify a clear pattern of development toward what we have previously defined as the Sibudan cultural taxonomic unit. Contextualizing these results on larger geographical scales shows that the later phase of the MSA during MIS 3 in KwaZulu-Natal and southern Africa is one of dynamic cultural change rather than of stasis or stagnation as has at times been claimed. In combination with environmental, subsistence and contextual information, our high-resolution data on lithic technology suggest that short-term behavioral variability at Sibudu can be best explained by changes in technological organization and socio-economic dynamics instead of environmental forcing.
Critical role of the NKG2D receptor for NK cell‐mediated control and immune escape of B‐cell lymphoma
2015-06-22

Little is known on the control of lymphomas by NK cells. Here, we study the role of the NK group 2D (NKG2D) receptor for the immunosurveillance of lymphoma. By using transplantable tumors as well as a λ‐myc‐transgenic model of endogenously arising lymphoma and NKG2D‐deficient mice, we show that NK cells eliminate tumor cells in vivo after receiving two signals. One step involved the activation of NK cells giving rise to IFN‐γ expression, which was effected by MHCI low tumor cells or DCs. However, this was necessary but not sufficient to mediate cytotoxicity. Triggering cytotoxicity additionally required a second step, which could be mediated by engagement of the NKG2D receptor. Thus, NKG2D‐deficient NK cells could become activated in vivo, but they were not able to reject transplanted lymphomas or to degranulate in animals bearing autochthonous lymphomas. Tumor growth in NKG2D‐deficient λ‐myc‐transgenic mice was significantly accelerated compared to NKG2D‐competent animals. Whereas the latter developed tumors that lost expression of NKG2D ligands (NKG2D‐L) in late disease stages, this did not occur in NKG2D‐deficient mice. This indicates that NK cells and the NKG2D receptor play a role for control of lymphomas and that selection for NKG2D‐L loss mutants provides a mechanism of tumor escape.
17O relaxation times in the rat brain at 16.4 tesla
2015-06-22

Relaxation times of brain H2 (17) O were measured for the first time in vivo in different types of tissues with high spatial resolution. Because the relaxation times of H2 (17) O are expected to be independent of field strength, our results should help in optimizing the acquisition parameters for experiments also at other MRI field strengths.
Uniqueness of the static spacetimes with a photon sphere in Einstein-scalar field theory
2015-06-22

In the present paper we prove a uniqueness theorem for the static and asymptotically flat solutions to the Einstein-scalar field equations which possess a photon sphere. We show that such solutions are uniquely specified by their mass and scalar charge and that they are isometric to the Janis-Newman-Winicour solution with the same mass and scalar charge subject to the inequality .
A Novel Point Mutation Promotes Growth Phase-Dependent Daptomycin Tolerance in Staphylococcus aureus
2015-06-23

ABSTRACT Recalcitrance of genetically susceptible bacteria to antibiotic killing is a hallmark of bacterial drug tolerance. This phenomenon is prevalent in biofilms, persisters, and also planktonic cells and is associated with chronic or relapsing infections with pathogens such as Staphylococcus aureus . Here we report the in vitro evolution of an S. aureus strain that exhibits a high degree of nonsusceptibility to daptomycin as a result of cyclic challenges with bactericidal concentrations of the drug. This phenotype was attributed to stationary growth phase-dependent drug tolerance and was clearly distinguished from resistance. The underlying genetic basis was revealed to be an adaptive point mutation in the putative inorganic phosphate (P i ) transporter gene pitA . Drug tolerance caused by this allele, termed pitA6 , was abrogated when the upstream gene pitR was inactivated. Enhanced tolerance toward daptomycin, as well as the acyldepsipeptide antibiotic ADEP4 and various combinations of other drugs, was accompanied by elevated intracellular concentrations of P i and polyphosphate, which may reversibly interfere with critical cellular functions. The evolved strain displayed increased rates of survival within human endothelial cells, demonstrating the correlation of intracellular persistence and drug tolerance. These findings will be useful for further investigations of S. aureus drug tolerance, toward the development of additional antipersister compounds and strategies.
Genetic variants in VEGF pathway genes in neoadjuvant breast cancer patients receiving bevacizumab: Results from the randomized phase III GeparQuinto study
2015-06-23

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.
Impact of non-idealities in gas-tracer tests on the estimation of reaeration, respiration, and photosynthesis rates in streams
2015-06-23

Estimating respiration and photosynthesis rates in streams usually requires good knowledge of reaeration at the given locations. For this purpose, gas-tracer tests can be conducted, and reaeration rate coefficients are determined from the decrease in gas concentration along the river stretch. The typical procedure for analysis of such tests is based on simplifying assumptions, as it neglects dispersion altogether and does not consider possible fluctuations and trends in the input signal. We mathematically derive the influence of these non-idealities on estimated reaeration rates and how they are propagated onto the evaluation of aerobic respiration and photosynthesis rates from oxygen monitoring. We apply the approach to field data obtained from a gas-tracer test using propane in a second-order stream in Southwest Germany. We calculate the reaeration rate coefficients accounting for dispersion as well as trends and uncertainty in the input signals and compare them to the standard approach. We show that neglecting dispersion significantly underestimates reaeration, and results between sections cannot be compared if trends in the input signal of the gas tracer are disregarded. Using time series of dissolved oxygen and the various estimates of reaeration, we infer respiration and photosynthesis rates for the same stream section, demonstrating that the bias and uncertainty of reaeration using the different approaches significantly affects the calculation of metabolic rates.
Genome surveillance in pluripotent stem cells: Low apoptosis threshold and efficient antioxidant defense
2015-06-23

Pluripotent stem cells must be endowed with efficient genome surveillance. Here we describe the multiple mechanisms that ensure their genome integrity, including high susceptibility to apoptosis and efficient prevention of DNA lesions. In induced pluripotent stem cells, apoptosis hypersensitivity is mediated by increased expression of proapoptotic BCL-2 protein, whereas DNA damage is prevented by the upregulation of several antioxidant enzymes. Antioxidants might be therefore employed for safer stem cell therapies.
Increased Umbilical Artery Pulsatility Index in Third-Trimester Fetuses with Trisomy 21
2015-06-23

&lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; To examine the umbilical arterial Doppler flow patterns in late third-trimester fetuses with trisomy 21. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This is a retrospective study on fetuses with trisomy 21 that were evaluated after 33 weeks' gestation at the Department of Obstetrics and Gynaecology of the University of Tuebingen, Germany. The umbilical and the middle cerebral artery (UA and ACM) pulsatility index (PI) measurements and the abdominal circumference were transformed into z-values. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Forty-two fetuses met the study criteria.&lt;b&gt; &lt;/b&gt;The mean gestational age at the time of the first and the second visit was 35.0 and 36.6 weeks, respectively. The mean UA PI was 1.31 and 1.38, which corresponds to z-values of 2.20 and 2.70. In 24 (57.1%) cases, both PI measurements were above the 95th centile. A linear regression analysis demonstrated that the mean of both UA PI was not dependent on the abdominal circumference or on any other examined maternal and pregnancy characteristics. The mean ACM PI at the first and the second visit was 1.62 and 1.48, respectively, corresponding to mean z-values of -0.59 and -0.75, and in none of the cases was it below the 5th centile. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; In half of the third-trimester fetuses with trisomy 21, the resistance in the UA is increased - even in the absence of placental insufficiency.