gebhart/patrepeval huggingface dataset:
Treatment Of Spinocerebellar Ataxia Type 2 (SCA2) with MOE Antisense Oligonucleotides (S47.006) (2014)

OBJECTIVE: Our study objective is to develop a molecular approach for lowering ATXN2 expression that could be utilized therapeutically for treating spinocerebellar ataxia type 2 (SCA2). BACKGROUND: SCA2 is an autosomal dominant inherited disorder caused by CAG repeat expansion in the ATXN2 gene. The ATXN2 gene protein product ataxin-2 is characterized by gains of function upon ATXN2 mutation, caused by expansion of the CAG-encoded polyglutamine tract in ataxin-2. We hypothesize that lowering ATXN2 expression using antisense oligonucleotides (ASOs) would be therapeutic for SCA2. This hypothesis is supported by the lack of neurodegeneration in ATXN2 knockout mice, and inducible reversibility of polyQ disease mouse phenotypes of HD and SCA1. DESIGN/METHODS: We screened 160 ASOs designed to lower ATXN2 expression in vitro in HepG2 cells. We evaluated the most efficacious ASOs for lowering ATXN2 expression in two mouse models of ATXN2. Expression of ATXN2 and the microgliosis marker Iba1 was evaluated by qPCR, Ataxin-2 expression was determined by immunoblotting, and ASO localization was evaluated by immunostaining. RESULTS: Eight ASOs were further evaluated in vivo. Of these ASO-1 consistently lowered both human ATXN2 and mouse Atxn2 expression in vitro. ASO-1 lowered expression maximally (80% reduction) after 7 days in ATXN2-Q172 transgenic mice, and performed similarly in BAC-ATXN2-Q72 and BAC-ATXN2-Q72 mice. ATXN2 expression was significantly reduced by a single bolus of ASO-1 after 7 weeks. Expression of Iba1 was not significantly elevated by ASO-1 treatment in vivo. Immunohistochemical staining of ASO-1 using anti-ASO antibody demonstrated ASO-1 penetrance into Purkinje cells and cells of the deep cerebellar nuclei. CONCLUSIONS: In order to model ASO therapy for SCA2 in mice, experimental ASOs need to target both exogenous human ATXN2 and endogenous mouse Atxn2. ASO-1 potently lowers both of these targets in mouse models of SCA2. We are continuing these studies to demonstrate ASO-1 efficacy on SCA2 mouse phenotypes. Support: This work was supported by National Institutes of Health grants R01NS033123, R21NS081182, and RC4NS073009.
Stimulation and inhibition of human mammary epithelial cell duct morphogenesis in vitro. (1996)

We previously determined that normal human mammary epithelial cells (HMECs) placed on the basement membrane-like substance Matrigel form structures, whereas malignant breast cells do not (1). In the present study, we determined that the structures formed by normal cells on Matrigel resembled breast ducts in vivo by electron microscopy, and the process of their formation recapitulated what is known of duct formation in vivo. We therefore used this model to study less well-understood aspects of breast morphogenesis. Two priming signals appeared necessary for initiation of morphogenesis: one provided by the Matrigel and one by the cells in an autocrine fashion. Evidence for this included diminished duct formation by cells plated low-concentration Matrigel or at low cell densities, and the reversal of the latter by conditioned medium from high-density cells on Matrigel. Antibodies to bFGF inhibited morphogenesis, suggesting a stimulatory autocrine role for this factor, and antibodies to TGF-beta 1 stimulated duct formation, suggesting an inhibitory autocrine role. Added TGF-beta 1 abolished morphogenesis and stimulated normal cells to wander through Matrigel as do malignant cells. Conditioned medium from normal cells did not stimulate malignant cells to form ducts, but conditioned medium from tumor cells diminished normal morphogenesis, suggesting that malignant cells secrete an inhibitor of morphogenesis.
Trace signal selection for visibility enhancement in post-silicon validation (2009)

Today's complex integrated circuit designs increasingly rely on post-silicon validation to eliminate bugs that escape from pre-silicon verification. One effective silicon debug technique is to monitor and trace the behaviors of the circuit during its normal operation. However, designers can only afford to trace a small number of signals in the design due to the associated overhead. Selecting which signals to trace is therefore a crucial issue for the effectiveness of this technique. This paper proposes an automated trace signal selection strategy that is able to dramatically enhance the visibility in post-silicon validation. Experimental results on benchmark circuits show that the proposed technique is more effective than existing solutions.
Chemical Sensors Based on Micromachined Transducers with Integrated Piezoresistive Readout (2006)

We demonstrate an approach for the development of chemical sensors utilizing silicon micromachined physical transducers with integrated piezoresistive readout. Originally, these transducers were developed and optimized as sensitive accelerometers for automotive applications. However, by applying a chemically responsive layer onto the transducer, we convert these transducers into chemical sensors. These transducers are attractive for chemical sensing applications for several key reasons. First, the required sensitivity of the chemical sensor can be achieved by choosing the right spring constant of the transducer. Second, the integrated piezoresistive readout of the transducer is already optimized and is very straightforward, providing a desired reproducibility in measurements, while not requiring bulky equipment. Third, chemically responsive film deposition is simple due to the ease of access to the transducer's surface. Fourth, such transducers are already available for another (automotive) application, making these sensors very cost-effective. The applicability of this approach is illustrated by the fabrication of highly sensitive CO2 sensors. To study hysteresis effects, we selected high CO2 concentrations (10−100% CO2) to provide the worst-case scenario for the sensor operation. These sensors demonstrate a hysteresis-free performance over the concentration range from 10 to 100% vol CO2, have detection limits of 160−370 ppm of CO2, and exhibit a relatively rapid response time, T90 = 45 s. Importantly, we demonstrate a simple method for cancellation of vibration effects when these physical transducers, initially developed as accelerometers, are applied as chemical sensors.
The Ligand for Osteoprotegerin (OPGL) Directly Activates Mature Osteoclasts (1999)

Osteoprotegerin (OPG) and OPG-ligand (OPGL) potently inhibit and stimulate, respectively, osteoclast differentiation (Simonet, W.S., D.L. Lacey, C.R. Dunstan, M. Kelley, M.-S. Chang, R. Luethy, H.Q. Nguyen, S. Wooden, L. Bennett, T. Boone, et al. 1997. Cell. 89:309-319; Lacey, D.L., E. Timms, H.-L. Tan, M.J. Kelley, C.R. Dunstan, T. Burgess, R. Elliott, A. Colombero, G. Elliott, S. Scully, et al. 1998. Cell. 93: 165-176), but their effects on mature osteoclasts are not well understood. Using primary cultures of rat osteoclasts on bone slices, we find that OPGL causes approximately sevenfold increase in total bone surface erosion. By scanning electron microscopy, OPGL-treated osteoclasts generate more clusters of lacunae on bone suggesting that multiple, spatially associated cycles of resorption have occurred. However, the size of individual resorption events are unchanged by OPGL treatment. Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption. Furthermore, we show that antibodies raised against the OPGL receptor, RANK, also induce actin ring formation. OPGL-treated mice exhibit increases in blood ionized Ca++ within 1 h after injections, consistent with immediate OC activation in vivo. Finally, we find that OPG blocks OPGL's effects on both actin ring formation and bone resorption. Together, these findings indicate that, in addition to their effects on OC precursors, OPGL and OPG have profound and direct effects on mature OCs and indicate that the OC receptor, RANK, mediates OPGL's effects.
Comparative Effects of an Insect Growth Regulator, S-31183, Against the Formosan Subterranean Termite and Eastern Subterranean Termite (Isoptera: Rhinotermitidae) (1989)

In a no-choice experiment, the insect growth regulator 2-[I-methyl-2(4-phenoxyphenoxy) ethoxy] pyridine (S-31183) induced presoldier formation more effectively in the eastern subterranean termite, Reticulitermes flavipes (Kollar) than in the Formosan subterranean termite, Coptotermes formosanus Shiraki. When given a choice of treated or untreated wood cubes, C. formosanus avoided feeding on cubes treated with concentrations of 1,500 and 7,500 ppm. A S-31183 concentration of 300 ppm (AI) did not deter feeding or increase presoldier formation in C. formosanus. Feeding of R. flavipes groups exposed to cubes containing 30 or 150 ppm S-31183 was not deterred, but these concentrations caused approximately 80% worker mortality by the end of the 12-wk test. The results indicate that S-31183 might control R. flavipes colonies if 30-150 ppm were applied to a bait.
Fault detection and localization in distributed systems using invariant relationships (2013)

Recent advances in sensing and communication technologies enable us to collect round-the-clock monitoring data from a wide-array of distributed systems including data centers, manufacturing plants, transportation networks, automobiles, etc. Often this data is in the form of time series collected from multiple sensors (hardware as well as software based). Previously, we developed a time-invariant relationships based approach that uses Auto-Regressive models with eXogenous input (ARX) to model this data. A tool based on our approach has been effective for fault detection and capacity planning in distributed systems. In this paper, we first describe our experience in applying this tool in real-world settings. We also discuss the challenges in fault localization that we face when using our tool, and present two approaches - a spatial approach based on invariant graphs and a temporal approach based on expected broken invariant patterns - that we developed to address this problem.
Tocilizumab for the treatment of large‐vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica (2012)

TCZ therapy led to clinical and serologic improvement in patients with refractory/relapsing GCA, TA, or PMR. The demonstration of persistent large-vessel vasculitis at autopsy of 1 patient who had shown a substantial response requires close scrutiny in larger studies.
Colony formation of clone-sorted human hematopoietic progenitors (1990)

To characterize human hematopoietic progenitors, we performed methylcellulose cultures of single cells isolated from a population of CD34+ cells by fluorescence-activated cell-sorting (FACS) clone-sorting system. CD34+ cells were detected in bone marrow (BM) and peripheral blood (PB) cells at incidences of 1.0% and 0.01% of total mononuclear cells, respectively. Single cell cultures revealed that approximately 37% of BM CD34+ cells formed colonies in the presence of phytohemagglutinin-leukocyte conditioned medium and erythropoietin. Erythroid bursts-, granulocyte-macrophage (GM) colony-, and pure macrophage (Mac) colony-forming cells were 10% each in CD34+ cells. Approximately 15% of PB CD34+ cells formed colonies in which erythroid bursts were predominant. CD34+ cells were heterogeneous and fractionated by several antibodies in FACS multicolor analysis. In these fractionated cells, CD34+, CD33+ cells formed GM and Mac colonies 7 to 10 times as often as CD34+, CD33- cells. Most of the erythroid bursts and colonies were observed in the fraction of CD34+, CD13- cells or CD34+, CD33- cells. The expression of HLA-DR on CD34+ cells was not related to the incidence, size, or type of colonies. There was no difference in the phenotypical heterogeneity of CD34+ cells between BM and PB. About 10% of CD34+ cells were able to form G colonies in response to granulocyte colony-stimulating factor (G-CSF) and to form Mac colonies in GM-CSF or interleukin-3 (IL-3). Progenitors capable of generating colonies by stimulation of G-CSF were more enriched in CD34+, CD33+ fraction than in CD34+, CD33- fraction. Thus, single cell cultures using the FACS clone-sorting system provide an accurate estimation of hematopoietic progenitors and an assay system for direct action of colony-stimulating factors.
.alpha.-Melanotropin: the minimal active sequence in the frog skin bioassay (1987)

The minimal sequence required for biological activity of alpha-MSH (alpha-melanotropin, alpha-melanocyte stimulating hormone) was determined in the frog (Rana pipiens) skin bioassay. The sequence required to elicit measurable biological activity was the central tetrapeptide sequence, Ac-His-Phe-Arg-Trp-NH2 (Ac-alpha-MSH6-9-NH2), which was about 6 orders of magnitude less potent than the native tridecapeptide. Smaller fragments of this sequence (Ac-His-Phe-NH2, Ac-Phe-Arg-NH2, Ac-His-Phe-Arg-NH2) were devoid of melanotropic activity at concentrations as high as 10(-4) M. We were unable to demonstrate biological activity for the tetrapeptide, Ac-Phe-Arg-Trp-Gly-NH2 (Ac-alpha-MSH7-10-NH2), and for several carboxy terminal analogues including Ac-Lys-Pro-Val-NH2 (Ac-alpha-MSH11-13-NH2). We prepared a series of fragment analogues of alpha-MSH in an attempt to determine the contribution of each individual amino acid to the biological activity of the native hormone. The minimal potency of Ac-alpha-MSH6-9-NH2 could be enhanced about a factor of 16 by the addition of glycine to the C-terminus, yielding Ac-alpha-MSH6-10-NH2 (Ac-His-Phe-Arg-Trp-Gly-NH2). Addition of glutamic acid to the N-terminus provided the peptide, Ac-alpha-MSH5-10-NH2, which was only slightly more potent than Ac-alpha-MSH6-10-NH2, indicating that position 5 contributes little to the biological potency of alpha-MSH in this assay. Addition of methionine to the N-terminus of Ac-alpha-MSH5-10-NH2 resulted in the heptapeptide, Ac-alpha-MSH4-10-NH2, which was only about 4-fold more potent than Ac-alpha-MSH5-10-NH2. Addition of lysine and proline to the C-terminal of the Ac-alpha-MSH4-10-NH2 sequence yielded the peptide, Ac-alpha-MSH4-12-NH2 with a 360-fold increase in potency relative to Ac-alpha-MSH4-10-NH2. This peptide was only about 6-fold less potent than alpha-MSH. A series of Nle-4-substituted analogues also were prepared. Ac-[Nle4]-alpha-MSH4-10-NH2 was about 4 times more potent than Ac-alpha-MSH4-10-NH2. Ac-[Nle4]-alpha-MSH4-11-NH2 also was about 4 times more potent than Ac-alpha-MSH4-10-NH2, demonstrating that lysine-11 contributes somewhat to the biological activity of alpha-MSH on the frog skin melanocyte receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Synthesis of Neisseria meningitidis Serogroup W135 Capsular Oligosaccharides for Immunogenicity Comparison and Vaccine Development (2013)

Sweetening the deal: N. meningitidis serogroup W135 capsular oligosaccharides were synthesized in lengths from disaccharides to decasaccharides. Sera from mice immunized with these oligosaccharide–protein conjugates were examined by a glycan microarray (see picture) and bactericidal assay for antibody specificity and the ability to kill bacteria. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Erythrosine is a potential photosensitizer for the photodynamic therapy of oral plaque biofilms (2006)

PDT using erythrosine as photosensitizer shows excellent potential as a treatment for oral plaque biofilms.
Anti-DKK1 mAb (BHQ880) as a Potential Therapeutic for Multiple Myeloma. (2007)

Abstract Decreased activity of osteoblasts (OB) contributes to osteolytic lesions in multiple myeloma (MM). Dickkopf-1 (DKK1) is a soluble Wnt inhibitor produced by MM cells that inhibits osteoblastogenesis in the bone marrow (BM) microenvironment. DKK1, also present in MM patient plasma, has been shown to inhibit the differentiation of osteoblast precursor cells in vitro, and its plasma level correlates with focal bone lesions in MM. Therefore, we have evaluated DKK1 as a target in MM in the context of the BM microenvironment. We first analyzed the effects of a DKK1 neutralizing antibody (BHQ880) on OB differentiation. Anti-DKK1 Ab was able to increase differentiation of mesenchymal stem cells (MSCs) to OB and reduce IL-6 levels following MSC differentiation to OB. While OB activity in MSCs cultured with osteoblast differentiation media was reduced in the presence of INA-6 MM cells, treatment with DKK1 neutralizing antibody was able to restore OB activity in a dose-dependent manner, overcoming the negative effect of MM cells. We did not observe a direct effect of this Ab on growth or survival of human MM cell lines. However, when a panel of MM cell lines was cultured with BM stromal cells (BMSC), the Ab induced significant growth inhibitory effects on MM cells, associated with downregulation of IL-6 produced by MSCs. To evaluate the in vivo bone and antitumor effects of anti-DKK1 Ab treatment on MM cells in the human microenvironment, we used a SCID-hu murine model, using INA-6 MM cells. In this model we observed a direct correlation between the level of soluble human DKK1 in murine blood and the tumor growth. Following treatment with BHQ880, by bone histology analysis, we observed increased trabecular bone and numbers of OBs in the retrieved bone chip from BHQ880 treated mice compared to control mice, one month after initial dose. We also found an increase in human osteocalcin in the serum of BHQ880-treated mice compared to the controls, suggesting an increase in OB activity. Interestingly, we observed suppression of myeloma growth, measured by changes in serum level of soluble huIL6sR, 4 weeks following BHQ880 treatment of the mice. These results support DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of this molecule in MM to improve bone disease and to inhibit MM growth.
Computed Medical Imaging (1980)

Nobel Lecture, December 8, 1979 From the Medical Systems Department of Central Research Laboratories, EMI. Schoenberg House. Trevor Road. Hayes. Middlesex UB3 1HH. England.
Breast Augmentation: A Risk Factor for Breast Cancer? (1992)

Women who undergo breast augmentation with silicone implants have a lower risk of breast cancer than the general population. This finding suggests that these women are drawn from a population already at low risk and that the implants do not substantially increase the risk.
Conservation of genomic sequences among isolates of Mycobacterium leprae (1989)

Restriction fragment length polymorphism analysis has been used to assess relatedness among the genomes of four isolates of Mycobacterium leprae, the causative agent of leprosy. The M. leprae isolates were from human patients from India, a Mangabey monkey from West Africa, and an armadillo from Louisiana. A total of 16 probes were used; these were insert fragments of M. leprae DNA from plasmid recombinant libraries, 5 of which had genes with identifiable functions and 11 of which were randomly chosen recombinant molecules. In spite of the widely diverse origins of the isolates, restriction fragment length polymorphism analysis demonstrated that less than 0.3% of the nucleotides differ among the genomes.
The intracisternal A-particle upstream element interacts with transcription factor YY1 to activate transcription: pleiotropic effects of YY1 on distinct DNA promoter elements. (1993)

Murine intracisternal A-particle long terminal repeats contain an intracisternal A-particle upstream enhancer (IUE) element that binds to a 65-kDa IUE binding protein (IUEB) present in both undifferentiated F9 embryonal carcinoma cells and differentiated parietal endoderm-like PYS-2 cells. This IUE element confers a CpG methylation-sensitive IUEB binding and enhancer activity. Using gel retardation, methylation interference, CpG methylation sensitivity binding, and cotransfection assays, we have now identified the 65-kDa IUEB as YY1 (also called NF-E1, delta, or UCRBP), a zinc finger protein related to the Krüppel family. YY1 binds to a number of similar but distinct DNA motifs, and cotransfection assays indicate that these motifs have different enhancer potentials in PYS-2 cells. The relative strengths of these elements are as follows: IUE &gt; kappa E3' from the human immunoglobulin kappa light-chain 3' enhancer &gt; upstream conserved region from the Moloney murine leukemia virus promoter. Results of DNA binding assays suggest that the differences in enhancer potentials are due to the different binding affinities of YY1 to the various motifs and the binding of two other transcription factors to the IUE sequence.
Neural Responding Machine for Short-Text Conversation (2015)

We propose Neural Responding Machine (NRM), a neural network-based response generator for Short-Text Conversation. NRM takes the general encoder-decoder framework: it formalizes the generation of response as a decoding process based on the latent representation of the input text, while both encoding and decoding are realized with recurrent neural networks (RNN). The NRM is trained with a large amount of one-round conversation data collected from a microblogging service. Empirical study shows that NRM can generate grammatically correct and content-wise appropriate responses to over 75% of the input text, outperforming state-of-the-arts in the same setting, including retrieval-based and SMT-based models.
A Soluble Secretory Reporter System in Trypanosoma brucei (1996)

A homolog of the endoplasmic reticulum (ER) hsp70 protein, binding protein (BiP), from the parasitic protozoan Trypanosoma brucei (Bangs, J. D., Uyetake, L., Brickman, M. J., Balber, A. E., and Boothroyd, J. C.(1993) J. Cell Sci. 105, 1101-1113) is further characterized. In co-precipitation experiments, BiP transiently associates with newly synthesized secretory proteins, including variant surface glycoprotein (VSG), confirming its role as a molecular chaperone. To study the molecular signals targeting BiP to the ER, we have developed soluble secretory reporters for expression in transformed procyclic trypanosomes. Deletion of the BiP C-terminal tetrapeptide (MDDL) and the glycosylphosphatidylinositol-anchor addition sequence of VSG converts these proteins to secreted forms. Attachment of MDDL to VSG results in intracellular retention confirming that MDDL is a trypanosomal ER localization signal. Secretion of both reporters is inefficient, but further truncation of the BiP C-terminal peptide-binding domain allows quantitative export ( t1/2 approximately 1 h) of the N-terminal ATPase domain (BiPN), consistent with the conserved domain structure of hsp70 proteins. This is the first demonstration of soluble protein secretion in African trypanosomes. Using the BiPN reporter, the sequence specificity of C-terminal tetrapeptide retention signals in trypanosomes is analyzed and found to be similar to higher eukaryotes. These results indicate that the basic signals mediating protein targeting to the ER lumen are conserved throughout the wide range of eukaryotic evolution.