gebhart/patrepeval huggingface dataset:
Inhibition of c-Myc By Apto-253 As an Innovative Therapeutic Approach to Induce Cell Cycle Arrest and Apoptosis in Acute Myeloid Leukemia (2016)

Abstract The c-Myc multifunctional transcription factor protein, a product on the c-myc proto-oncogene, contributes to the pathogenesis of many types of human cancers through mechanisms of proliferation, apoptosis, cell cycle progression and cellular senescence. c-Myc is frequently overexpressed in acute myeloid leukemia, yet strategies to effectively modulate c-Myc function do not exist. We evaluated inhibition of c-myc gene expression by APTO-253, a small molecule anticancer agent that is being developed clinically for the treatment of acute myelogenous (myeloid) leukemia (AML) and high risk myelodysplastic syndromes (MDS). We first confirmed that c-Myc mRNA level were significantly higher in AML cell lines as compared to peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors. However, the c-Myc expression in AML cells was inhibited by APTO-253 in dose-dependent and time-dependent manners at both the mRNA and protein levels. Likewise, APTO-253 was found to induce AML cell apoptosis in dose-dependent and time-dependent manners as demonstrated by positive Annexin-V staining and increases in cleaved poly (ADP-ribose) polymerase (c-PARP). APTO-253 induced AML cells arrest at G1/G0 phase of cell cycle by increasing p21 expression and decreasing expression of cyclin D3 and cyclin-dependent kinases 4/6 (CDK4/6). For the p53 positive cell lines MV4-11 and EOL-1, p53 was also increased by APTO-253 at early time points (less than 6-hour treatment), suggesting that p53-dependent cell cycle arrest and apoptosis is mechanistically operative as a consequence of treatment with APTO-253. Importantly, we demonstrated that APTO-253 selectively targeted tumor cells but not normal healthy cells, with MV4-11 AML cells and normal PBMCs having IC50s of 0.25±0.03µM and more than 100µM, respectively. Our previous studies (56th ASH abstract #4813) showed that APTO-253 induces the Krüppel-like Factor 4 (KLF4) transcription factor and was effective and well tolerated as a single agent in multiple AML xenograft models without causing bone marrow suppression. Taken together, our results suggested that APTO-253 may serve as an effective and safe agent for AML chemotherapy, and that APTO-253 mechanistically inhibits c-Myc expression in AML cells and subsequently induces cell cycle arrest and apoptosis. Disclosures No relevant conflicts of interest to declare.
Sparsely-Connected Neural Networks: Towards Efficient VLSI Implementation of Deep Neural Networks (2016)

Recently deep neural networks have received considerable attention due to their ability to extract and represent high-level abstractions in data sets. Deep neural networks such as fully-connected and convolutional neural networks have shown excellent performance on a wide range of recognition and classification tasks. However, their hardware implementations currently suffer from large silicon area and high power consumption due to the their high degree of complexity. The power/energy consumption of neural networks is dominated by memory accesses, the majority of which occur in fully-connected networks. In fact, they contain most of the deep neural network parameters. In this paper, we propose sparsely-connected networks, by showing that the number of connections in fully-connected networks can be reduced by up to 90% while improving the accuracy performance on three popular datasets (MNIST, CIFAR10 and SVHN). We then propose an efficient hardware architecture based on linear-feedback shift registers to reduce the memory requirements of the proposed sparsely-connected networks. The proposed architecture can save up to 90% of memory compared to the conventional implementations of fully-connected neural networks. Moreover, implementation results show up to 84% reduction in the energy consumption of a single neuron of the proposed sparsely-connected networks compared to a single neuron of fully-connected neural networks.
A Study of the Proteins of the Wool Follicle (1966)

A study has been made of the incorporation at different levels in the developing fibre of 35S into the two main protein fractions of wool. The proteins have been studied as the S-carboxymethyl derivatives rather than as the oxidized derivatives previously investigated. The results obtained give further support for a mechanism of synthesis which involves two stages. However, the incorporation of some 35S into the low-sulphur fraction of the keratinized fibre only 24 hr after the injection of [35S]cystine is somewhat surprising and possible explanations for this have been considered. A detailed comparison has been made of the proteins extracted from the unkeratinized portions of wool roots by 8M urea with those which can be extracted from the keratinized residue with urea-thioglycollate. As might be expected the latter proteins were very similar to those isolated from wool itself. The group of urea-soluble, high-sulphur proteins was different in containing considerable amounts of protein lower in both molecular weight and sulphur content than the comparable fraction from the fully keratinized wool. The possibility is discussed that some of these urea-soluble, high-sulphur proteins may be precursors of those in the fully keratinized fibre, conversion taking place by a process of sulphur enrichment.
Three-dimensional microwave tomography. Theory and computer experiments in scalar approximation (2000)

The results of computer simulated experiments in three-dimensional microwave tomography in scalar approximation are presented. The gradient method is employed to solve three-dimensional high-contrast microwave tomographic problems. A computer model for full-scale three-dimensional imaging has been created. Three-dimensional tomographic images of mathematical models of the human torso were obtained. Significant differences between two-dimensional and three-dimensional cases are emphasized. Some illumination schemes which can be applied in the three-dimensional case are discussed. A dependence of image quality on the number of vertically placed transmitters has been demonstrated. The computer simulation showed that three-dimensional full-scale human torso dielectrical properties images can be produced with acceptable computational time.
The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization (2012)

Monoallelic point mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) and its mitochondrial homolog IDH2 can lead to elevated levels of 2-hydroxyglutarate (2HG) in multiple cancers. Here we report that cellular 2HG production from cytosolic IDH1 mutation is dependent on the activity of a retained wild-type IDH1 allele. In contrast, expression of mitochondrial IDH2 mutations led to robust 2HG production in a manner independent of wild-type mitochondrial IDH function. Among the recurrent IDH2 mutations at Arg-172 and Arg-140, IDH2 Arg-172 mutations consistently led to greater 2HG accumulation than IDH2 Arg-140 mutations, and the degree of 2HG accumulation correlated with the ability of these mutations to block cellular differentiation. Cytosolic IDH1 Arg-132 mutations, although structurally analogous to mutations at mitochondrial IDH2 Arg-172, were only able to elevate intracellular 2HG to comparable levels when an equivalent level of wild-type IDH1 was co-expressed. Consistent with 2HG production from cytosolic IDH1 being limited by substrate production from wild-type IDH1, we observed 2HG levels to increase in cancer cells harboring an endogenous monoallelic IDH1 mutation when mitochondrial IDH flux was diverted to the cytosol. Finally, expression of an IDH1 construct engineered to localize to the mitochondria rather than the cytosol resulted in greater 2HG accumulation. These data demonstrate that allelic and subcellular compartment differences can regulate the potential for IDH mutations to produce 2HG in cells. The consequences of 2HG elevation are dose-dependent, and the non-equivalent 2HG accumulation resulting from IDH1 and IDH2 mutations may underlie their differential prognosis and prevalence in various cancers.
Characterization of the microglial response in murine scrapie (1994)

The nature of the glial and inflammatory cell responses to infection in scrapie-affected brains was studied in terminally-affected mice of five scrapie models. There were marked astrocytic and microglial responses. Microglia showed increased staining of the surface antigens F4/80, leucocyte-common antigen, type 3 complement receptor, and elevated endocytotic and lysosomal activity. In all models, the astrocytic and microglial responses were largely restricted to anatomical regions of the brain showing vacuolation and/or plaque formation and pathological accumulations of PrP. Expression of MHC Class II was patchy and present on microglia in the neuropil of areas with the most intense microglial activation and on occasional perivascular macrophages. This microglial response may represent a modified form of inflammatory response.
Protein Inhibitor of Activated STAT-1 (Signal Transducer and Activator of Transcription-1) Is a Nuclear Receptor Coregulator Expressed in Human Testis (2000)

An androgen receptor (AR) interacting protein was isolated from a HeLa cell cDNA library by two-hybrid screening in yeast using the AR DNA+ligand binding domains as bait. The protein has sequence identity with human protein inhibitor of activated signal transducer and activator of transcription (PIAS1) and human Gu RNA helicase II binding protein (GBP). Binding of PIAS1 to human AR DNA+ligand binding domains was androgen dependent in the yeast liquidβ -galactosidase assay. Activation of binding by dihydrotestosterone was greater than testosterone > estradiol > progesterone. PIAS1 binding to full-length human AR in a reversed yeast two hybrid system was also androgen dependent.[ 35S] PIAS1 bound a glutathione S-transferase-AR-DNA binding domain (amino acids 544–634) fusion protein in affinity matrix assays. In transient cotransfection assays using CV1 cells with full-length human AR and a mouse mammary tumor virus luciferase reporter vector, there was an androgen-dependent 3- to 5-fold greater increase in luciferase activity with PIAS1 over that obtained with an equal amount of control antisense cDNA or mutant PIAS1. Constitutive transcriptional activity of the AR N-terminal+DNA binding domain was increased 6-fold by PIAS1. PIAS1 also enhanced glucocorticoid receptor transactivation in response to dexamethasone but inhibited progesterone-induced progesterone receptor transactivation in the same assay system. mRNA for PIAS1 was highly expressed in testis of human, monkey, rat, and mouse. In rat testis the onset of PIAS1 mRNA expression coincided with the initiation of spermatogenesis between 25–30 days of age. Immunostaining of human and mouse testis with PIAS1-specific antiserum demonstrated coexpression of PIAS1 with AR in Sertoli cells and Leydig cells. In addition, PIAS1 was expressed in spermatogenic cells. The results suggest that PIAS1 functions in testis as a nuclear receptor transcriptional coregulator and may have a role in AR initiation and maintenance of spermatogenesis.
Direct Extraction of Double-Stranded DNA Into Ionic Liquid 1-Butyl-3-methylimidazolium Hexafluorophosphate and Its Quantification (2007)

Ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate (BmimPF6), as a green solvent, was successfully used for the direct extraction of dsDNA. The extraction efficiency and the distribution coefficient values indicated that trace amounts of DNA at the levels of <5 ng microL-1 facilitate quantitative fast extraction, while proteins and metal species do not interfere. A total of 30% of the DNA in ionic liquid at approximately 20 ng microL-1 was back extracted into aqueous phase in phosphate-citrate buffer with a single-stage extraction. The extraction is demonstrated to be endothermic with an enthalpy of 34.3 kJ moL-1. The extraction mechanisms were proposed and verified by 31P NMR and FT-IR spectra. Interactions between cationic 1-butyl-3-methylimidazolium (Bmim+) and P-O bonds of phosphate groups in the DNA strands take place both in the dissolved BmimPF6 in aqueous phase and at the interface of the two phases. This interaction consequently led to the transformation of DNA conformations, along with a reduction of ethidium resonance light scattering at 510 nm, and a procedure for DNA quantification in ionic liquid was developed based on this observation.
Canine spontaneous glioma: A translational model system for convection-enhanced delivery (2010)

Canine spontaneous intracranial tumors bear striking similarities to their human tumor counterparts and have the potential to provide a large animal model system for more realistic validation of novel therapies typically developed in small rodent models. We used spontaneously occurring canine gliomas to investigate the use of convection-enhanced delivery (CED) of liposomal nanoparticles, containing topoisomerase inhibitor CPT-11. To facilitate visualization of intratumoral infusions by real-time magnetic resonance imaging (MRI), we included identically formulated liposomes loaded with Gadoteridol. Real-time MRI defined distribution of infusate within both tumor and normal brain tissues. The most important limiting factor for volume of distribution within tumor tissue was the leakage of infusate into ventricular or subarachnoid spaces. Decreased tumor volume, tumor necrosis, and modulation of tumor phenotype correlated with volume of distribution of infusate (Vd), infusion location, and leakage as determined by real-time MRI and histopathology. This study demonstrates the potential for canine spontaneous gliomas as a model system for the validation and development of novel therapeutic strategies for human brain tumors. Data obtained from infusions monitored in real time in a large, spontaneous tumor may provide information, allowing more accurate prediction and optimization of infusion parameters. Variability in Vd between tumors strongly suggests that real-time imaging should be an essential component of CED therapeutic trials to allow minimization of inappropriate infusions and accurate assessment of clinical outcomes.
A comparison between propofol and thiopentone as induction agents in obstetric anaesthesia (1989)

Two comparable series of 21 patients who had elective Caesarean section had general anaesthesia induced by thiopentone sodium 4.53 (SD 0.65) mg/kg or propofol 2.15 (SD 0.26) mg/kg. Maintenance was similar for both groups. Blood pressure was lower in the propofol group during the induction-delivery interval. Umbilical/maternal vein ratios for thiopentone and propofol were 8.5 and 7.2 respectively. Infant wellbeing as judged by Apgar score and cord blood analysis showed little difference between the two induction agents. Factors associated with uterine relaxation and bleeding were similar in the two groups.
[Synthesis of receptor reagent--estradiol-polyethyleneglycol-fluorescein isothiocyanate]. (1991)

Estradiol conjugate has been used as a tracer to detect estrogen receptor of human mammary cancer cells. In order to look for more stable carrier of fluorescent estradiol conjugate, we substituted polyethyleneglycol (PEG) for bovine serum albumin (BSA) and synthsized 17 beta-estradiol-6-carboxymethyl-oxime-PEG-fluorescein isothiocyanate. The structure of the title compound was confirmed by IR and UV. In this paper, we also describe another procedure to convert the terminal hydroxyl groups of PEG to the more reactive primary amino PEG by tosylation, azide group substitution and catalytic hydrogenation. The ratio of conversion is about 87%.
Beyond document similarity (2000)

In the face of small, one or two word queries, high volumes of diverse documents on the Web are overwhelming search and ranking technologies that are based on document similarity measures. The increase of multimedia data within documents sharply exacerbates the shortcomings of these approaches. Recently, research prototypes and commercial experiments have added techniques that augment similarity-based search and ranking. These techniques rely on judgments about the 'value' of documents. Judgments are obtained directly from users, are derived by conjecture based on observations of user behavior, or are surmised from analyses of documents and collections. All these systems have been pursued independently, and no common understanding of the underlying processes has been presented. We survey existing value-based approaches, develop a reference architecture that helps compare the approaches, and categorize the constituent algorithms. We explain the options for collecting value metadata, and for using that metadata to improve search, ranking of results, and the enhancement of information browsing. Based on our survey and analysis, we then point to several open problems.
Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation (2007)

The phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway has attracted much recent interest due to its central role in modulating diverse downstream signalling pathways associated with cell survival, proliferation, differentiation, morphology and apoptosis. An increasing amount of information has demonstrated that many viruses activate the PI3K/Akt pathway to augment their efficient replication. In this study, the effect of the PI3K/Akt signalling pathway on influenza virus propagation was investigated. It was found that Akt phosphorylation was elevated in the late phase of influenza A/PR/8/34 infection in human lung carcinoma cells (A549). The PI3K-specific inhibitor LY294002 could suppress Akt phosphorylation, suggesting that influenza A virus-induced Akt phosphorylation is PI3K-dependent. UV-irradiated influenza virus failed to induce Akt phosphorylation, indicating that viral attachment and entry were not sufficient to trigger PI3K/Akt pathway activation. Blockage of PI3K/Akt activation by LY294002 and overexpression of the general receptor for phosphoinositides-1 PH domain (Grp1-PH) led to a reduction in virus yield. Moreover, in the presence of LY294002, viral RNA synthesis and viral protein expression were suppressed and, possibly as a consequence of low NP and M1 protein level, viral RNP nuclear export was also suppressed. These data suggest that the PI3K/Akt signalling pathway plays a role in influenza virus propagation.
Biosynthesis of Ganglioside Mimics in Campylobacter jejuni OH4384 (2000)

We have applied two strategies for the cloning of four genes responsible for the biosynthesis of the GT1a ganglioside mimic in the lipooligosaccharide (LOS) of a bacterial pathogen, Campylobacter jejuni OH4384, which has been associated with Guillain-Barré syndrome. We first cloned a gene encoding an alpha-2, 3-sialyltransferase (cst-I) using an activity screening strategy. We then used nucleotide sequence information from the recently completed sequence from C. jejuni NCTC 11168 to amplify a region involved in LOS biosynthesis from C. jejuni OH4384. The LOS biosynthesis locus from C. jejuni OH4384 is 11.47 kilobase pairs and encodes 13 partial or complete open reading frames, while the corresponding locus in C. jejuni NCTC 11168 spans 13.49 kilobase pairs and contains 15 open reading frames, indicating a different organization between these two strains. Potential glycosyltransferase genes were cloned individually, expressed in Escherichia coli, and assayed using synthetic fluorescent oligosaccharides as acceptors. We identified genes encoding a beta-1, 4-N-acetylgalactosaminyl-transferase (cgtA), a beta-1, 3-galactosyltransferase (cgtB), and a bifunctional sialyltransferase (cst-II), which transfers sialic acid to O-3 of galactose and to O-8 of a sialic acid that is linked alpha-2,3- to a galactose. The linkage specificity of each identified glycosyltransferase was confirmed by NMR analysis at 600 MHz on nanomole amounts of model compounds synthesized in vitro. Using a gradient inverse broadband nano-NMR probe, sequence information could be obtained by detection of (3)J(C,H) correlations across the glycosidic bond. The role of cgtA and cst-II in the synthesis of the GT1a mimic in C. jejuni OH4384 were confirmed by comparing their sequence and activity with corresponding homologues in two related C. jejuni strains that express shorter ganglioside mimics in their LOS.
Robotic lower limb exoskeletons using proportional myoelectric control (2009)

Robotic lower limb exoskeletons have been built for augmenting human performance, assisting with disabilities, studying human physiology, and re-training motor deficiencies. At the University of Michigan Human Neuromechanics Laboratory, we have built pneumatically-powered lower limb exoskeletons for the last two purposes. Most of our prior research has focused on ankle joint exoskeletons because of the large contribution from plantar flexors to the mechanical work performed during gait. One way we control the exoskeletons is with proportional myoelectric control, effectively increasing the strength of the wearer with a physiological mode of control. Healthy human subjects quickly adapt to walking with the robotic ankle exoskeletons, reducing their overall energy expenditure. Individuals with incomplete spinal cord injury have demonstrated rapid modification of muscle recruitment patterns with practice walking with the ankle exoskeletons. Evidence suggests that proportional myoelectric control may have distinct advantages over other types of control for robotic exoskeletons in basic science and rehabilitation.
TREATMENT WITH RAPAMYCIN AND MYCOPHENOLIC ACID REDUCES ARTERIAL INTIMAL THICKENING PRODUCED BY MECHANICAL INJURY AND ALLOWS ENDOTHELIAL REPLACEMENT (1995)

Rapamycin (RPM) and mycophenolic acid (MPA) inhibit immune responses by antagonizing IL-stimulated lymphocyte activation. These 2 drugs, used alone or preferably in combination, also significantly reduced the response of vascular cells to balloon-catheter arterial injury in rats. When rats were treated for 2 weeks with both drugs starting the day of injury, intimal thickening was significantly reduced (P < 0.001) 14 days after injury; however, by 44 days after injury, intimal thickening had progressed to the extent measured in arteries of untreated control rats. When RPM and MPA were administered for 3 days before and 13 days after injury, arterial intimal thickening was significantly (P = 0.024) reduced and endothelium had regrown in vessels analyzed 44 days after injury. Compared with initiation of treatment on the day of injury, starting the administration of RPM plus MPA before injury appears to limit the activation of cells or actions of factors responsible for the progression of intimal thickening that occurred after the administration of the drugs was terminated. RPM and MPA prevented the development of arterial intimal thickening in a model not dependent upon a rejection response. This direct antiproliferative action on smooth muscle cells by RPM and MPA, in vivo, may prevent the development of arterial intimal thickening associated with chronic rejection.