Miracle-dz/UniFAR-FTUs huggingface dataset:
A Phase I Pharmacologic Study of Necitumumab (IMC-11F8), a Fully Human IgG1 Monoclonal Antibody

AB StR ACt Through unbiased metabolomics, we identified elevations of the metabolite 2-hydroxyglutarate (2HG) in renal cell carcinoma (RCC). 2HG can inhibit 2-oxoglutaratre (2-OG)–dependent dioxygenases that mediate epigenetic events, including DNA and histone demethylation. 2HG accumulation, specifically the d enantiomer, can result from gain-of-function mutations of isocitrate dehydrogenase (IDH1, IDH2) found in several different tumors. In contrast, kidney tumors demonstrate elevations of the l enantiomer of 2HG (l-2HG). High-2HG tumors demonstrate reduced DNA levels of 5-hydroxymethylcytosine (5hmC), consistent with 2HG-mediated inhibition of ten-eleven translocation (TET) enzymes, which convert 5-methylcytosine (5mC) to 5hmC. l-2HG elevation is mediated in part by reduced expression of l-2HG dehydrogenase (L2HGDH). L2HGDH reconstitution in RCC cells lowers l-2HG and promotes 5hmC accumulation. In addition, L2HGDH expression in RCC cells reduces histone methylation and suppresses in vitro tumor phenotypes. Our report identifies l-2HG as an epigenetic modifier and putative oncometabolite in kidney cancer. SIGNIFICANCE: Here, we report elevations of the putative oncometabolite l-2HG in the most common subtype of kidney cancer and describe a novel mechanism for the regulation of DNA 5hmC levels. Our findings provide new insight into the metabolic basis for the epigenetic landscape of renal cancer.
The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer.

BACKGROUND The aim of the study was to evaluate the efficacy of gefitinib and the epidermal growth factor receptor (EGFR) mutation to gefitinib response in a series of Chinese patients with pretreated advanced non-small-cell lung cancer (NSCLC). METHODS A total of 98 patients who had failed at least one platinum-based regimen received gefitinib 250 mg once daily. The mutation analysis of the EGFR kinase domain was performed for 30 patients using paraffin-embedded tumor tissue. RESULTS The response rate was 31.6% and the disease control rate was 67.3%. Objective response was correlated with adenocarcinoma, female gender and non-smokers. Median progress free survival (PFS) was 7.0 months, median overall survival (OS) was 12.0 months and 1-year survival was 53.1%. The median PFS and OS were improved among patients with adenocarcinoma, gefitinib responders and non-smokers. Active gene mutation was detected in 12 patients. Mutation rates were higher among gefitinib responders, non-smokers, patients with adenocarcinoma and female patients. OS was longer for patients with gene mutation than for patients without mutation. CONCLUSION Gefitinib demonstrated significant antitumor activity with a favorable toxicity profile for pretreated Chinese patients with advanced NSCLC. The active mutation of the EGFR kinase domain was strongly associated with response to gefitinib and prolonged overall survival.
Zeaxanthin Induces Apoptosis in Human Uveal Melanoma Cells through Bcl-2 Family Proteins and Intrinsic Apoptosis Pathway

The cytotoxic effects of zeaxanthin on two human uveal melanoma cell lines (SP6.5 and C918) and related signaling pathways were studied and compared to effects on normal ocular cells (uveal melanocytes, retinal pigment epithelial cells, and scleral fibroblasts). MTT assay revealed that zeaxanthin reduced the cell viability of melanoma cells in a dose-dependent manner (10, 30, and 100 μM), with IC50 at 40.8 and 28.7 μM in SP6.5 and C918 cell lines, respectively. Zeaxanthin did not affect the viability of normal ocular cells even at the highest levels tested (300 μM), suggesting that zeaxanthin has a selectively cytotoxic effect on melanoma cells. Zeaxanthin induced apoptosis in melanoma cells as indicated by annexin V and ethidium III flow cytometry. Western blot analysis demonstrated that zeaxanthin decreased the expression of antiapoptotic proteins (Bcl-2 and Bcl-xL) and increased the expression of proapoptotic proteins (Bak and Bax) in zeaxanthin-treated melanoma cells. Zeaxanthin increased mitochondrial permeability as determined by JC-1 fluorescein study. Zeaxanthin also increased the level of cytosol cytochrome c and caspase-9 and -3 activities, but not caspase-8, as measured by ELISA assay or colorimetric assay. All of these findings indicate that the intrinsic (mitochondrial) pathway is involved in zeaxanthin-induced apoptosis in uveal melanoma cells.
MEMBRANES OF SACCHAROMYCES CEREVISIAE the membranes of microsomes

A crude small particle pellet, obtained from postmitochondrial supernatant fractions of Saccharomyces cerevisiae, contains about half the ergosterol and phospholipid of crude cell homogenates. Most of the phospholipid of this pellet is in a "heavy" fraction which, with the aid of electron microscopy, shows membranous elements in addition to discrete particles. The "heavy" fraction, upon treatment with deoxycholate, can be freed of membranes, or, with ribonuclease treatment, ribosomes can be removed, leaving relatively clean membranes. The "heavy" fraction resembles the microsomes of animal cells, but contains considerably less lipids, including phospholipids, thus suggesting a less well-developed intracellular membrane system.
Dyna-Style Planning with Linear Function Approximation and Prioritized Sweeping

We consider the problem of efficiently learning optimal control policies and value functions over large state spaces in an online setting in which estimates must be available after each interaction with the world. This paper develops an explicitly model-based approach extending the Dyna architecture to linear function approximation. Dyna-style planning proceeds by generating imaginary experience from the world model and then applying model-free reinforcement learning algorithms to the imagined state transitions. Our main results are to prove that linear Dyna-style planning converges to a unique solution independent of the generating distribution, under natural conditions. In the policy evaluation setting, we prove that the limit point is the least-squares (LSTD) solution. An implication of our results is that prioritized-sweeping can be soundly extended to the linear approximation case, backing up to preceding features rather than to preceding states. We introduce two versions of prioritized sweeping with linear Dyna and briefly illustrate their performance empirically on the Mountain Car and Boyan Chain problems.
Nuclear DNA microsatellites reveal genetic variation but a lack of phylogeographical structure in an endangered species, Fraxinus mandshurica, across North-east China.

BACKGROUND AND AIMS The widely accepted paradigm that the modern genetic structure of plant species in the northern hemisphere has been largely determined by recolonization from refugia after the last glacial maximum fails to explain the presence of cold-tolerant species at intermediate latitudes. Another generally accepted paradigm is that mountain ridges act as important barriers causing genetic isolation of species, but this too has been challenged in recent studies. The aims of the work reported here were to determine the genetic diversity and distribution patterns of extant natural populations of an endangered cool temperate species, Faxinus mandshurica, and to examine whether these two paradigms are appropriate when applied to this species over a wide geographical scale. METHODS 1435 adult individuals were sampled from 30 natural populations across the main and central range of the species, covering major mountain ranges across North-east China (NEC). Genetic variation was estimated based on nine polymorphic nuclear microsatellite loci. Phylogeographical analyses were employed using various approaches, including Bayesian clustering, spatial analysis of molecular variance, Monmonier's algorithm, neighbor-joining trees, principal co-ordinate analysis and isolation by distance. KEY RESULTS Genetic diversity within populations was relatively high, and no significant recent bottlenecks were detected in any of the populations. A significant negative correlation between intra-population genetic diversity and latitude was identified. In contrast, genetic differentiation among all the populations examined was extremely low and no clear geographic genetic structure was identified, with the exception of one distinct population. CONCLUSIONS The modern genetic structure in this species can be explained by extensive gene flow, an absence of mountains acting as barriers, and the presence of a wide refuge across NEC rather than multiple small refugia. Intra-population genetic variation along latitudes is probably associated with the systematically northward shifts of forest biomes in eastern China during the mid-Holocene. To determine important genetic patterns and identify resources for conservation, however, it will be necessary to examine differentially inherited genetic markers exposed to selection pressures (e.g. chloroplast DNA) and to investigate different generations.
How to Evolve Autonomous Robots: Different Approaches in Evolutionary Robotics

A methodology for evolving the control systems of autonomous robots has not yet been well established. In this paper we will show different examples of applications of evolutionary robotics to real robots by describing three different approaches to develop neural controllers for mobile robots. In all the experiments described real robots are involved and are indeed the ultimate means of evaluating the success and the results of the procedures employed. Each approach will be compared with the others and the relative advantages and drawbacks will be discussed. Last, but not least, we will try to tackle a few important issues related to the design of the hardware and of the evolutionary conditions in which the control system of the autonomous agent should evolve.
Expression of vascular endothelial growth factor and its receptors in the porcine corpus luteum during the estrous cycle and early pregnancy

The present study was undertaken to determine the expression of vascular endothelial growth factor (VEGF) and its receptors, fms‐like tyrosine kinase (Flt‐1) and fetal liver kinase‐1/kinase insert domain‐containing receptor (Flk‐1/KDR), in the porcine corpus luteum (CL) during the estrous cycle and early pregnancy. Immunohistochemical studies localized proteins of VEGF ligand‐receptor system in the cytoplasm of luteal cells and in some blood vessels. Western blot analysis revealed significantly higher levels of VEGF protein during early and mid‐luteal phase (vs. late luteal phase; P < 0.001 and P < 0.01, respectively). Quantification of VEGF mRNA in the CL showed increased mRNA levels during entire luteal phase (vs. Days 16–17; P < 0.05). Expression of Flt‐1 protein remained high during luteal phase (P < 0.001), but the mRNA levels tended to increase from the early to the late luteal phase. Elevated protein expression of Flk‐1/KDR was found in the mid‐luteal phase (vs. Days 16–17; P < 0.05). However, induction of Flk‐1/KDR mRNA expression occurred earlier, in early luteal phase. The lowest VEGF, Flt‐1 and Flk‐1/KDR mRNA and protein levels were observed in regressed CL (P < 0.001). During pregnancy, VEGF, Flt‐1 and Flk‐1/KDR mRNA and protein expression was comparable to the mid‐luteal phase. In conclusion, the present study has demonstrated dynamic expression of VEGF and its receptors in the porcine CL during the estrous cycle and early pregnancy. These data suggest that the VEGF ligand‐receptor system may play an important role in the development and maintenance of the CL in pigs. Mol. Reprod. Dev. 74: 730–739, 2007. © 2006 Wiley‐Liss, Inc.
T cell anergy.

T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naïve T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.
Mechanism of apoptosis induced by S100A8/A9 in colon cancer cell lines: the role of ROS and the effect of metal ions

The protein complex S100A8/A9, abundant in the cytosol of neutrophils, is secreted from the cells upon cellular activation and induces apoptosis in tumor cell lines and normal fibroblasts in a zinc‐reversible manner. In the present study, we present evidence that the S100A8/A9 also exerts its apoptotic effect by a zinc‐independent mechanism. Treatment of the colon carcinoma cells with different concentrations of human S100A8/A9 or the metal ion chelator diethylenetriaminepentacetic acid (DTPA) resulted in a significant increase of cell death. Annexin V/phosphatidylinositol and Hoechst 33258 staining revealed that cell death was mainly of the apoptotic type. A significant increase in the activity of caspase‐3 and ‐9 was observed in both cell lines after treatment. Caspase‐8 activation was negligible in both cell lines. The cytotoxicity/apoptotic effect of human S100A8/A9 and DTPA was inhibited significantly (P<0.05) by Zn+2 and Cu+2, more effectively than by Ca2+ and Mg2+. The antioxidant N‐acetyl‐L‐cysteine inhibited the cytotoxicity/apoptotic effect of S100A8/A9 and DTPA. However, as a result of the different time‐courses of both agents and that the S100A8/A9‐induced apoptosis was not completely reversed, we conclude that S100A8/A9 exerts its apoptotic effect on two colon carcinoma cell lines through a dual mechanism: one via zinc exclusion from the target cells and the other through a yet‐undefined mechanism, probably relaying on the cell‐surface receptor(s).
HOT ROLLED ASPHALT: EFFECT OF BINDER PROPERTIES ON RESISTANCE TO DEFORMATION

Serious deformation has occurred in recent years on certain heavily-trafficked roads with rolled asphalt surfacing. The performance of this material is dependent on many compositional factors with the rheological properties of the binder being among the most important. The report considers those properties of binders that most affect the resistance to deformation of rolled asphalt. Thirteen binders were studied and mixtures containing them were subjected to design tests from BS 594: 1973 and the wheel-tracking test. These laboratory mechanical tests show that, within the range of binders tested, significant improvements in resistance to deformation can be achieved over a range of high road temperatures by increasing the softening point of the binder, irrespective of its penetration at 25 degrees C. A suggested specification for a "heavy duty" bitumen is based on a softening point (r & b) to BS 4692 of 63 + or - 5 degrees C and a penetration at 25 degrees C to BS 4691, of 40 + or = 10. (Author/TRRL)
Risk and Liquidity in a System Context

This paper explores the pricing of debt in a financial system where the assets that borrowers hold to meet their obligations include claims against other borrowers. Assessing financial claims in a system context captures features that are missing in a partial equilibrium setting. It is possible for spreads to fall as debts rise, as debt-fuelled increases in asset prices and stronger balance sheets reinforce each other. Conversely, it is possible that de-leveraging leads to increases in spreads, as is often observed during crises.
A distributed approach for a multiple sequence alignment algorithm using a parallel virtual machine

Multiple sequence alignment is a central topic of extensive research in computational biology. Basically, two or more protein sequences are compared so as to evaluate their similarity. This work reports a methodology for parallel processing of a multiple sequence alignment algorithm (ClustalW) in an environment of networked computers. A detailed description of the modules that compose the distributed system is provided, giving special attention to the way a dynamic programming algorithm can be executed in parallel. Extensive experiments were done to evaluate performance and scalability of the method. Results show that the proposed method is efficient and offers a real advantage for large-scale multiple protein sequence alignment
Convective and absolute electrokinetic instability with conductivity gradients

Electrokinetic flow instabilities occur under high electric fields in the presence of electrical conductivity gradients. Such instabilities are a key factor limiting the robust performance of complex electrokinetic bio-analytical systems, but can also be exploited for rapid mixing and flow control for microscale devices. This paper reports a representative flow instability phenomenon studied using a microfluidic T-junction with a cross-section of 11 $\umu$m by 155 $\umu$m. In this system, aqueous electrolytes of 10:1 conductivity ratio were electrokinetically driven into a common mixing channel by a steady electric field. Convectively unstable waves were observed with a nominal threshold field of $0.5\,\hbox{kV}\,\hbox{cm}^{-1}$, and upstream propagating waves were observed at $1.5\,\hbox{kV}\,\hbox{cm}^{-1}$. A physical model has been developed for this instability which captures the coupling between electric and flow fields. A linear stability analysis was performed on the governing equations in the thin-layer limit, and Briggs–Bers criteria were applied to select physically unstable modes and determine the nature of instability. The model predicts both qualitative trends and quantitative features that agree very well with experimental data, and shows that conductivity gradients and their associated bulk charge accumulation are crucial for such instabilities. Comparison between theory and experiments suggests the convective role of electro-osmotic flow. Scaling analysis and numerical results show that the instability is governed by two key controlling parameters: the ratio of dynamic to dissipative forces which governs the onset of instability, and the ratio of electroviscous to electro-osmotic velocities which governs the convective versus absolute nature of instability.
Rational tree relations

We investigate forests and relations on trees generated by grammars in which the non-terminals represent relations. This introduces some synchronization between productions. We show that these sets are also solutions of systems of equations, that they are described by rational expressions involving union, substitution and iterated substitution, and that they are preserved by residuals. We show that they are the images of k-copying descending transducers. Finally, we isolate a subset of these relations which is preserved by composition.
Resting-State Functional Connectivity and Cognitive Impairment in Children with Perinatal Stroke

Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6–17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (p < 0.05) were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. Our findings demonstrate impairment in cognitive functions and neural network profile in hemiparetic children with AIS compared to children with PVI and controls. Changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.
Microbotryum silenes-saxifragae sp. nov. sporulating in the anthers of Silene saxifraga in southern European mountains

Currently, the monophyletic lineage of anther smuts on Caryophyllaceae includes 22 species classified in the genus Microbotryum. They are model organisms studied in many disciplines of fungal biology. A molecular phylogenetic approach was used to resolve species boundaries within the caryophyllaceous anther smuts, as species delimitation based solely on phenotypic characters was problematic. Several cryptic species were found amongst the anther smuts on Caryophyllaceae, although some morphologically distinct species were discernible, and most species were characterized by high host-specificity. In this study, anther smut specimens infecting Silene saxifraga were analysed using rDNA sequences (ITS and LSU) and morphology to resolve their specific status and to discuss their phylogenetic position within the lineage of caryophyllaceous anther smuts. The molecular phylogeny revealed that all specimens form a monophyletic lineage that is supported by the morphological trait of reticulate spores with tuberculate interspaces (observed in certain spores). This lineage cannot be attributed to any of the previously described species, and the anther smut on Silene saxifraga is described and illustrated here as a new species, Microbotryum silenes-saxifragae. This species clusters in a clade that includes Microbotryum species, which infect both closely and distantly related host plants growing in diverse ecological habitats. It appears possible that host shifts combined with changes to ecological host niches drove the evolution of Microbotryum species within this clade.