julilili42/papers huggingface dataset:
Translational approaches targeting the p53 pathway for anti‐cancer therapy
2011-06-30

The p53 tumour suppressor blocks cancer development by triggering apoptosis or cellular senescence in response to oncogenic stress or DNA damage. Consequently, the p53 signalling pathway is virtually always inactivated in human cancer cells. This unifying feature has commenced tremendous efforts to develop p53‐based anti‐cancer therapies. Different strategies exist that are adapted to the mechanisms of p53 inactivation. In p53‐mutated tumours, delivery of wild‐type p53 by adenovirus‐based gene therapy is now practised in China. Also, remarkable progress has been made in the development of p53‐binding drugs that can rescue and reactivate the function of mutant or misfolded p53. Other biologic approaches include the development of oncolytic viruses that are designed to specifically replicate in and kill p53‐defective cells. Inactivation of wt‐p53 frequently results from dysregulation of MDM2, an E3 ligase that regulates p53 levels. Small‐molecule drugs that inhibit the interaction of MDM2 and p53 and block p53 degradation are currently tested in clinical trials. This survey highlights the recent developments that attempt to modulate the function of p53 and outlines strategies that are being investigated for pharmacological intervention in the p53 pathway.
Multi-isotope degeneracy of neutrinoless double-βdecay mechanisms in the quasiparticle random-phase approximation
2011-06-30

We calculate nuclear matrix elements (NME) of neutrinoless double beta decay\\nin four different candidate nuclei (Ge-76, Se-82, Mo-100, Te-130) within the\\nquasiparticle random phase approximation (QRPA) and its uncertainties. We\\nassume (up to) four coexisting mechanisms for neutrinoless double beta decay,\\nmediated by light Majorana neutrino exchange, heavy Majorana neutrino exchange,\\nR-parity breaking supersymmetry, and squark-neutrino, interfering either\\nconstructively or destructively with each other. We find that, unfortunately,\\ncurrent NME uncertainties appear to prevent a robust determination of the\\nrelative contribution of each mechanism to the decay amplitude, even assuming\\naccurate measurements of decay lifetimes. The near-degeneracy of the decay\\nmechanisms is analyzed with simple algebraic techniques, which do not involve\\nassumptions about the statistical distribution of errors. We discuss\\nimplications of such degeneracy on prospective searches for absolute neutrino\\nmasses.\\n
The pulsations of PG 1351+489
2011-06-30

PG 1351+489 is one of the 20 DBVs - pulsating helium-atmosphere white dwarf stars - known and has the simplest power spectrum for this class of star, making it a good candidate to study cooling rates. We report accurate period determinations for the main peak at 489.33448s and two other normal modes using data from the Whole Earth Telescope (WET) observations of 1995 and 2009. In 2009, we detected a new pulsation mode and the main pulsation mode exhibited substantial change in its amplitude compared to all previous observations. We were able to estimate the star's rotation period, of 8.9h, and discuss a possible determination of the rate of period change of (2.0 ± 0.9) × 10-13ss -1, the first such estimate for a DBV.
The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers
2011-07-01

Background The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program. Methods The program is open for laboratories using commercially available kits for Aβ, T‐tau, or P‐tau. CSF samples (aliquots of pooled CSF) are sent for analysis several times a year from the Clinical Neurochemistry Laboratory at the Mölndal campus of the University of Gothenburg, Sweden. Each round consists of three quality control samples. Results Forty laboratories participated. Twenty‐six used INNOTEST enzyme‐linked immunosorbent assay kits, 14 used Luminex xMAP with the INNO‐BIA AlzBio3 kit (both measure Aβ‐(1‐42), P‐tau(181P), and T‐tau), and 5 used Meso Scale Discovery with the Aβ triplex (AβN‐42, AβN‐40, and AβN‐38) or T‐tau kits. The total coefficients of variation between the laboratories were 13% to 36%. Five laboratories analyzed the samples six times on different occasions. Within‐laboratory precisions differed considerably between biomarkers within individual laboratories. Conclusions Measurements of CSF AD biomarkers show large between‐laboratory variability, likely caused by factors related to analytical procedures and the analytical kits. Standardization of laboratory procedures and efforts by kit vendors to increase kit performance might lower variability, and will likely increase the usefulness of CSF AD biomarkers.
Effects of Peyton's Four-Step Approach on Objective Performance Measures in Technical Skills Training: A Controlled Trial
2011-07-01

Peyton's Four-Step Approach is superior to standard instruction with respect to professionalism and accompanying doctor-patient communication and leads to faster performance when trainees perform the learned skill for the first time.
Cancer therapy trials employing level-of-evidence-1 disease forecast cancer biomarkers uPA and its inhibitor PAI-1
2011-07-01

Clinical research on cancer biomarkers is essential in understanding recent discoveries in cancer biology and heterogeneity of the cancer disease. However, there are only a few examples of clinically useful studies that have identified cancer biomarkers with clinical benefit. Urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) are two of the few tumor tissue-associated cancer biomarkers that have been evaluated successfully and extensively in many preclinical and clinical studies for their clinical utility. Most of the studies have been conducted in early breast cancer to demonstrate the prognostic and predictive value for this malignancy. As a result of these investigations, uPA and PAI-1 have reached the highest level of clinical evidence, level of evidence 1. This article sheds light on the current status of major clinical Phase II and III breast cancer therapy trials (Chemo-N0, NNBC-3 and Plan B), and introduces ongoing clinical trials targeting uPA in advanced cancers of the breast and pancreas, employing synthetic small-size drugs to counteract uPA activity (WX-UK1, Mesupron(®)). The therapeutic effect of a uPA-derived small-size synthetic peptide (Å6) is tested in advanced ovarian cancer patients.
Prevalence of follicular lymphoma in situ in consecutively analysed reactive lymph nodes
2011-07-01

We found a prevalence of 2.3% for FL in situ lesions in an unselected series of lymph nodes, as a surrogate for the normal population. Taking into account the incidence of manifest FL, the risk of progression of this lesion is probably limited. It can be speculated that some FL in situ lesions do indeed represent an early step in lymphomagenesis, whereas others persist without further progression to overt FL. The underlying mechanisms, however, remain to be elucidated.
Relevance of local compound‐specific transverse dispersion for conservative and reactive mixing in heterogeneous porous media
2011-07-01

Different measures of dilution have been proposed to describe solute mixing in heterogeneous porous media. Most of these approaches lead to the definition of effective dispersion coefficients. In order to quantify mixing, these up‐scaled parameters should account for both local‐scale dispersion and effects of flow variability in heterogeneous formations (e.g., flow focusing in high‐conductivity and defocusing in low‐conductivity inclusions). The correct quantification of mixing is particularly important for transport of compounds undergoing reactions. Recent results of multitracer laboratory experiments showed a dependency of local transverse dispersion on molecular diffusion over a wide range of flow velocities, implying compound‐specific transverse mixing even at intermediate and high Péclet numbers. The goal of this study is to assess the relevance of a compound‐specific local‐scale transverse dispersion on conservative and reactive mixing in heterogeneous domains at the field scale. We restrict our analysis to steady state two‐dimensional flow and transport with continuous injection from a line source. We present numerical simulations in heterogeneous domains with different characteristics of variability in the conductivity field, and apply as measures of solute mixing: (1) the effective transverse dispersion coefficient derived from second central spatial moments, (2) a dispersion coefficient derived from flux‐related second central spatial moments, (3) the scalar dissipation rate, and (4) a dispersion coefficient derived from the flux‐related dilution index. The results indicate compound‐specific transverse mixing behavior also at the field scale which is particularly significant in case of low to moderately heterogeneous porous media. Moreover, we show that measures of dilution calculated in a flux‐related framework result in an improved quantification of mixing processes and allow to define up‐scaled parameters (i.e., effective transverse dispersion coefficients) affected by a low degree of uncertainty. For mixing‐controlled reactive transport we illustrate the importance of compound‐dependent local effects on the length of reactive solute plumes.
Shape‐free inference of hyporheic traveltime distributions from synthetic conservative and “smart” tracer tests in streams
2011-07-01

The hyporheic zone has been identified as important for river ecology, natural biogeochemical turnover, filtration of particles, degradation of dissolved pollutants—and thus for the self‐cleaning capacity of streams, and for groundwater quality. Good estimation of the traveltime distribution in the hyporheic zone is required to achieve a better understanding of transport in the river system. The transient‐storage model has been accepted as an appropriate tool for reach‐scale transport in rivers undergoing hyporheic exchange, but the choice of the best parametric function for the hyporheic traveltime distribution has remained unclear. We present an approach to obtaining hyporheic traveltime distributions from synchronous conservative and “smart” tracer experiments that does not rely on a particular functional form of the hyporheic traveltime distribution, but treats the latter as a continuous function. Nonnegativity of the hyporheic traveltime distribution is enforced by the application of Lagrange multipliers. A smoothness parameter, needed for regularization, and uncertainty bounds are obtained by the expectation‐maximization method relying on conditional realizations. The shape‐free inference provides the opportunity for capturing unconventional shapes, e.g., multiple peaks, in the estimation. We test the approach by applying it to a virtual test case with a bimodal hyporheic traveltime distribution, which is recaptured in the inversion of noisy data.
Cranial anatomy and phylogenetic placement of the enigmatic turtleCompsemys victaLeidy, 1856
2011-07-01

The skull of the enigmatic turtle Compsemys victa Leidy, 1856 is described. A number of unique characteristics are apparent, including the extremely thick nature of all cranial bones, the presence of rod-like epipterygoids, placement of the foramen posterius canalis carotici interni halfway along the contact between the pterygoid and basisphenoid, lack of cheek emarginations, and the reduction of the size of the cavum tympani relative to the orbit. Two differing global turtle analyses and one paracryptodiran analysis were performed to determine the phylogenetic placement of C. victa. Both global analyses converged by placing C. victa within Paracryptodira, herein defined as the most inclusive clade that includes Pleurosternon bullockii and Baena arenosa , but no species of living turtle, whereas the paracryptodiran analysis places C. victa outside of Baenoidea, herein defined as the least inclusive clade that contains P. bullockii and B. arenosa. Although a number of similarities are apparent between C. victa and the uncommon, extant testudinoid Platysternon megacephalum , the available data indicate that these similarities are convergent, likely due to their carnivorous diet. Taphonomic evidence reveals that basal paracryptodires, including C. victa , preferred slow moving or ponded water environments. The riverine habitat preference of baenodds must therefore be derived.
Iron Silylamide-Grafted Periodic Mesoporous Silica
2011-07-01

The surface chemistry of a series of well-defined metalorganic ferrous and ferric iron complexes on periodic mesoporous silica (PMS) was investigated. In addition to literature known Fe(II)[N(SiMe(3))(2)](2)(THF), Fe(II)[N(SiPh(2)Me(2))(2)](2), and Fe(III)[N(SiMe(3))(2)](2)Cl(THF), the new complexes [Fe(II){N(SiHMe(2))(2)}(2)](2) and Fe(III)[N(SiHMe(2))(2)](3)(μ-Cl)Li(THF)(3) were employed as grafting precursors. Selection criteria for the molecular precursors were the molecular size (monoiron versus diiron species), the oxidation state of the iron center (II versus III), and the functionality of the silylamido ligand (e.g., built-in spectroscopic probes). Hexagonal channel-like MCM-41 and cubic cage-like SBA-1 were chosen as two distinct PMS materials. The highest iron load (12.8 wt %) was obtained for hybrid material [Fe(II){N(SiHMe(2))(2)}(2)](2)@MCM-41 upon stirring the reaction mixture iron silylamide/PMS/n-hexane for 18 h at ambient temperature. Size-selective grafting and concomitantly extensive surface silylation were found to be prominent for cage-like SBA-1. Here, the surface metalation is governed by the type of iron precursor, the pore size, the reaction time, and the solvent. The formation of surface-attached iron-ligand species is discussed on the basis of diffuse reflectance infrared Fourier transform (DRIFT) and electron paramagnetic resonance (EPR) spectroscopy, nitrogen physisorption, and elemental analysis.
Very-high-energy gamma-ray emission from the direction of the Galactic globular cluster Terzan 5
2011-07-01

The H.E.S.S. very-high-energy (VHE, E &gt; 0.1 TeV) gamma-ray telescope system\\nhas discovered a new source, HESS J1747-248. The measured integral flux is (1.2\\n+/- 0.3) \\\\times 10^-12 cm-2 s-1 above 440 GeV for a power-law photon spectral\\nindex of 2.5 +/- 0.3 stat +/- 0.2 sys. The VHE gamma-ray source is located in\\nthe close vicinity of the Galactic globular cluster Terzan 5 and extends beyond\\nthe H.E.S.S. point spread function (0.07 degree). The probability of a chance\\ncoincidence with Terzan 5 and an unrelated VHE source is quite low (~ 10^-4).\\nWith the largest population of identified millisecond pulsars (msPSRs), a very\\nhigh core stellar density and the brightest GeV range flux as measured by\\nFermi-LAT, Terzan 5 stands out among Galactic globular clusters. The properties\\nof the VHE source are briefly discussed in the context of potential emission\\nmechanisms, notably in relation to msPSRs. Interpretation of the available data\\naccommodates several possible origins for this VHE gamma-ray source, although\\nnone of them offers a satisfying explanation of its peculiar morphology.\\n
Boremys(Testudines, Baenidae) from the latest Cretaceous and early Paleocene of North Dakota: an 11-million-year range extension and an additional K/T survivor
2011-07-01

ABSTRACT For over a century, the baenid turtle Boremys has been recognized as being restricted to the Campanian of North America. Herein we describe new material of Boremys sp. from the Hell Creek Formation (Maastrichtian) and Fort Union Formation (Puercan) of southwestern North Dakota and eastern Montana, increasing the stratigraphic range of this taxon by 11 million years. The material was recovered from the base of the Hell Creek Formation to 14 m above the pollen-calibrated K/T boundary in the basal Fort Union Formation. Most of the specimens consist of isolated shell elements, which are easily misidentified as belonging to a kinosternid or chelydrid turtle, but complete shells are present as well. The presence of Boremys sp. in the Hell Creek formation increases the baenid taxonomic diversity of this particular rock unit to nine and the overall turtle diversity to 20 taxa, and the presence of Boremys sp. in the Fort Union Formation increases the number of baenid lineages that survive the K/T extinction event to eight.
Encoding of Smooth-Pursuit Eye Movement Initiation by a Population of Vermal Purkinje Cells
2011-07-01

Lesion studies suggest that the oculomotor vermis (OMV) is critical for the initiation of smooth-pursuit eye movements (SPEMs); yet, its specific role has remained elusive. In this study, we tested the hypothesis that vermal Purkinje cells (PCs) may be needed to fine-tune the kinematic description of SPEM initiation. Recording from identified PCs from the monkey OMV, we observed that SPEM-related PCs were characterized by a formidable diversity of response profiles with typically only modest reflection of eye movement kinematics. In contrast, the PC population discharge could be perfectly predicted based on a linear combination of eye acceleration, velocity, and position. This finding is in full accord with a role of the OMV in shaping eye movement kinematics. It, moreover, supports the notion that this shaping action is based on a population code, whose anatomic basis is the convergence of PCs on target neurons in the cerebellar nuclei.
Population Genetics Models with Skewed Fertilities: A Forward and Backward Analysis
2011-07-01

Discrete population genetics models with unequal (skewed) fertilities are considered, with an emphasis on skewed versions of Cannings models, conditional branching process models in the spirit of Karlin and McGregor, and compound Poisson models. Three particular classes of models with skewed fertilities are investigated, the Wright–Fisher model, the Dirichlet model, and the Kimura model. For each class the asymptotic behavior as the total population size N tends to infinity is investigated for power law fertilities and for geometric fertilities. This class of models can exhibit a rich variety of sub-linear or even constant effective population sizes. Therefore, the models are not necessarily in the domain of attraction of the Kingman coalescent. For a substantial range of the parameters, discrete-time coalescent processes with simultaneous multiple collisions arise in the limit.
The activation of the Arabidopsis P-ATPase 1 by the brassinosteroid receptor BRI1 is independent of threonine 948 phosphorylation
2011-07-01

The plasma membrane-spanning receptor brassinosteroid insenstive 1 (BRI1) rapidly induces plant cell wall expansion in response to brassinosteroids such as brassinolide (BL). Wall expansion is accompanied by a rapid hyperpolarisation of the plasma membrane which is recordable by measuring the fluorescence lifetime (FLT) of the green fluorescent protein (GFP) fused to BRI1. For the BL induction of hyperpolarisation and wall expansion, the activation of the plasma membrane P-type H+-ATPase is necessary. Furthermore, the activation of the P-ATPase requires BRI1 kinase activity and appears to be mediated by a BL-modulated association of BRI1 with the proton pump. Here, we show that BRI1 also associates with a mutant version of the Arabidopsis P-ATPase 1 (AHA1) characterized by an exchange of a well-known regulatory threonine for a non-phosphorylatable residue in the auto-inhibitory C-terminal domain. Even more important, BRI1 is still able to activate this AHA1 mutant in response to BL. This suggests a novel mechanism for the enzymatic activation of the P-ATPase by BRI1 in the plasma membrane. Furthermore, we demonstrate that the FLT of BRI1-GFP can be used as a non-invasive probe to analyse long-distance BL signaling in Arabidopsis seedlings.
ATG7contributes to plant basal immunity towards fungal infection
2011-07-01

Autophagy has an important function in cellular homeostasis. In recent years autophagy has been implicated in plant basal immunity and assigned negative (“anti-death”) and positive (“pro-death”) regulatory functions in controlling cell death programs that establish sufficient immunity to microbial infection. We recently showed that Arabidopsis mutants lacking the autophagy-associated (ATG) genes ATG5, ATG10 and ATG18a are compromised in their resistance towards infection with necrotrophic fungal pathogens but display an enhanced resistance towards biotrophic bacterial invaders. Thus, the function of autophagy as either being pro-death or anti-death depends critically on the lifestyle and infection strategy of invading microbes. Here we show that ATG7 contributes to resistance to fungal pathogens. Genetic inactivation of ATG7 results in elevated susceptibility towards the necrotrophic fungal pathogen, Alternaria brassicicola, with atg7 mutants developing spreading necrosis accompanied by production of reactive oxygen intermediates. Likewise, treatment with the fungal toxin fumonisin B1 causes spreading lesion formation in the atg7 mutant. We conclude that ATG7-dependent autophagy constitutes an “anti-death” (“pro-survival”) plant mechanism to control the containment of cell death and immunity to necrophic fungal infection.
Stata Tip 97: Getting at ρ's and σ's
2011-07-01

There are several models in Stata that estimate coefficients other than regular “regression-like” coefficients. Often these have an interpretation as a standard deviation or a correlation of either error terms or random coefficients. Examples are xtmixed or heckman (see [XT] xtmixed or [R] heckman). Sometimes, we want access to these coefficients to perform a test or to impose a constraint. However, getting access to these parameters is not always straightforward. The problem is that Stata programs often do not estimate these coefficients directly, but instead estimate a transformed version of those parameters. In this Stata tip, I will illustrate how to recover these parameters, test hypotheses, and impose constraints.
Democracy, Regional Security Institutions, and Rivalry Mitigation: Evidence From Europe, South America, and Asia
2011-07-01

The fact that democracies maintain peaceful relations with each other is regarded as one of the few law-like correlations in international relations, but the causes of this empirical phenomenon remain contested. This paper tries to fill this theoretical gap by attributing the remarkable stability between democracies to inter-democratic institutions. At the same time, it contributes to the debate on the need to differentiate among international organizations in order to assess their peace-building effects. We identify transnational and trans-governmental linkages as crucial features that distinguish inter-democratic from traditional institutions with non-democratic or mixed membership. In order to explain these institutions’ peace-building effect, we analyze the impact of international institutions on rivalry mitigation with a view to five pairs of states: France-Germany, Greece-Turkey, Argentina-Brazil, Indonesia-Malaysia, and Japan-South Korea. Those dyads all look back at a history of rivalry, conflict, and mutual threat perceptions, and they are located in highly institutionalized regional settings but vary with regard to their political regime type. The controlled comparison of cases demonstrates that the embeddedness of international institutions in transnational and trans-governmental linkages corresponds to each member's regime type and that these institutional differences are responsible for the varying extent of rivalry mitigation.