gebhart/patrepeval huggingface dataset:
In vivo biocompatibility studies. I. The cage implant system and a biodegradable hydrogel (1983)

A cage implant system has been utilized to examine the in vivo biocompatibility of a biodegradable hydrogel, poly(2-hydroxy-ethyl-L-glutamine) (PHEG). This system permits the quantitative determination of the components of the inflammatory exudate which surrounds the implanted polymer within the cage system. This system permits the serial examination of exudate components without sacrificing the animal. In addition, this system allows the subsequent removal of the polymer for surface and mechanical studies. Following implantation of the biodegradable hydrogel, quantitative and differential white cell counts of the exudates were determined over a 21-day period. In addition, concomitant extracellular enzyme analyses for alkaline phosphatase, acid phosphatase, prostatic acid phosphatase, leucine amino-peptidase, and Cathepsin B1 were determined. Corresponding control samples from exudates of the cage implant without the polymer were also determined. The two-tailed Student's t-test for unpaired samples was used to statistically compare the control and implanted polymer values for these respective analyses at the various time periods. A comparison of the cellular response for the control system and the PHEG system did not show statistically significant differences during the first 7 days following implantation. The acute inflammatory response, polymorphonuclear leukocyte predominant, was followed by a mild chronic inflammatory response, macrophage and lymphocyte predominant, and during this time period, 8-14 days, macrophages were present in significantly larger numbers for the PHEG system when compared to the control values. Enzymic analysis of the exudates revealed statistically significant differences between control and PHEG values at time intervals where no differences were noted in cell density or population. These results are discussed in terms of cell-polymer interactions leading to cellular activation and enhanced enzyme exocytosis by the inflammatory cells. Stress-strain measurements on implanted PHEG samples showed that significant in vivo degradation had occurred during the acute inflammatory phase of the response, i.e., the first 7 days.
Human and rodent decay‐accelerating factors (CD55) are not species restricted in their complement‐inhibiting activities (2000)

Homologous complement activation is restricted on cells by the complement regulators, decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59. These proteins act in concert with other membrane structures to protect cells from homologous complement attack. In contrast, cells are usually sensitive to heterologous complement attack. It has been suggested that species-specific restriction of complement activation can be attributed to the inability of regulators to inhibit across species. We have investigated the capacities of human, rat and mouse analogues of DAF to regulate homologous and heterologous complement. Cells transfected with cDNA encoding these analogues were protected from heterologous complement attack. C3b-deposition experiments indicated that whilst cells were best protected by DAF from the same species, all three analogues inhibited human, rat and mouse complement. Comparable results were obtained in haemolysis assays using soluble, recombinant forms of the proteins. Inhibition of the classical pathway (CP) was best achieved with homologous DAF, although human DAF also inhibited rat complement, rat DAF also inhibited human complement and mouse DAF inhibited complement from all species. Human DAF was the best inhibitor of alternative pathway (AP)-mediated attack, inhibiting complement from all species. Mouse DAF inhibited mouse and rat AP, whilst rat DAF inhibited only rat AP. These data indicate that human and rodent analogues of DAF are not species restricted and highlights interesting differences in the capacity to regulate AP and CP. This has implications in broader fields of research, such as xenotransplantation, where cross-species regulation of complement is of paramount importance.
Reduction in thrombus formation by placement of endovascular stents at endarterectomy sites in baboon carotid arteries. (1991)

We postulate that endovascular stents reduce the thrombogenic effects of flap formation, tearing, dissection, and vasospasm in ECAs.
Successful Gene Therapy in Utero for Lethal Murine Hypophosphatasia (2011)

Hypophosphatasia (HPP), caused by mutations in the gene ALPL encoding tissue-nonspecific alkaline phosphatase (TNALP), is an inherited systemic skeletal disease characterized by mineralization defects of bones and teeth. The clinical severity of HPP varies widely, from a lethal perinatal form to mild odontohypophosphatasia showing only dental manifestations. HPP model mice (Akp2−/−) phenotypically mimic the severe infantile form of human HPP; they appear normal at birth but die by 2 weeks of age because of growth failure, hypomineralization, and epileptic seizures. In the present study, we investigated the feasibility of fetal gene therapy using the lethal HPP model mice. On day 15 of gestation, the fetuses of HPP model mice underwent transuterine intraperitoneal injection of adeno-associated virus serotype 9 (AAV9) expressing bone-targeted TNALP. Treated and delivered mice showed normal weight gain and seizure-free survival for at least 8 weeks. Vector sequence was detected in systemic organs including bone at 14 days of age. ALP activities in plasma and bone were consistently high. Enhanced mineralization was demonstrated on X-ray images of the chest and forepaw. Our data clearly demonstrate that systemic injection of AAV9 in utero is an effective strategy for the treatment of lethal HPP mice. Fetal gene therapy may be an important choice after prenatal diagnosis of life-threatening HPP. Sugano and colleagues investigate the feasibility of fetal gene therapy for hypophosphatasia (HPP), which is caused by mutations in tissue-nonspecific alkaline phosphatase (TNALP). Mice that phenotypically mimic the severe infantile form of human HPP underwent transuterine intraperitoneal injection of adeno-associated viral vector type 9 (AAV9) expressing bone-targeted TNALP. Treated mice showed normal weight gain and seizure-free survival for at least 8 weeks after birth, with consistently high levels of ALP activity in plasma and bone.
The Hydrophobic Residues Phenylalanine 184 and Leucine 187 in the Type-1 Parathyroid Hormone (PTH) Receptor Functionally Interact with the Amino-terminal Portion of PTH-(1–34) (1999)

Recent mutagenesis and cross-linking studies suggest that three regions of the PTH-1 receptor play important roles in ligand interaction: (i) the extreme NH(2)-terminal region, (ii) the juxtamembrane base of the amino-terminal extracellular domain, and (iii) the third extracellular loop. In this report, we analyzed the second of these segments in the rat PTH-1 receptor (residues 182-190) and its role in functional interaction with short PTH fragment analogs. Twenty-eight singly substituted PTH-1 receptors were transiently transfected into COS-7 cells and shown to be fully expressed by surface antibody binding analysis. Alanine-scanning analysis identified Phe(184), Arg(186), Leu(187), and Ile(190) as important determinants of maximum binding of (125)I-labeled bovine PTH-(1-34) and (125)I-labeled bovine PTH-(3-34) and determinants of responsiveness to the NH(2)-terminal analog, PTH-(1-14) in cAMP stimulation assays. Alanine mutations at these four sites augmented the ability of the COOH-terminal peptide [Glu(22), Trp(23)]PTHrP-(15-36) to inhibit the cAMP response induced by PTH-(1-34). At Phe(184) and Leu(187), hydrophobic substitutions (e.g. Ile, Met, or Leu) preserved PTH-(1-34)-mediated cAMP signaling potency, whereas hydrophilic substitutions (e.g. Asp, Glu, Lys, or Arg) weakened this response by 20-fold or more, as compared with the unsubstituted receptor's response. The results suggest that hydrophobicity at positions occupied by Phe(184) and Leu(187) in the PTH-1 receptor plays an important role in determining functional interaction with the 3-14 portion of PTH.
Knowledge Sources for Word-Level Translation Models (2001)

We present various methods to train word-level translation models for statistical machine translation systems that use widely different knowledge sources ranging from parallel corpora and a bilingual lexicon to only monolingual corpora in two languages. Some novel methods are presented and previously published methods are reviewed. Also, a common evaluation metric enables the first quantitative comparison of these approaches.
Gene Expression Profiles in Pancreatic Intraepithelial Neoplasia Reflect the Effects of Hedgehog Signaling on Pancreatic Ductal Epithelial Cells (2005)

Invasive pancreatic cancer is thought to develop through a series of noninvasive duct lesions known as pancreatic intraepithelial neoplasia (PanIN). We used cDNA microarrays interrogating 15,000 transcripts to identify 49 genes that were differentially expressed in microdissected early PanIN lesions (PanIN-1B/2) compared with microdissected normal duct epithelium. In this analysis, a cluster of extrapancreatic foregut markers, including pepsinogen C, MUC6, KLF4, and TFF1, was found to be up-regulated in PanIN. Up-regulation of these genes was further validated using combinations of real-time reverse transcription-PCR, in situ hybridization, and immunohistochemistry in a total of 150 early PanIN lesions from 81 patients. Identification of these gastrointestinal transcripts in human PanIN prompted assessment of other foregut markers by both semiquantitative and real-time reverse transcription-PCR, revealing similar up-regulation of Sox-2, Gastrin, HoxA5, GATA4/5/6, Villin and Forkhead 6 (Foxl1). In contrast to frequent expression of multiple gastric epithelial markers, the intestinal markers intestinal fatty acid binding protein, CDX1 and CDX2 were rarely expressed either in PanIN lesions or in invasive pancreatic cancer. Hedgehog pathway activation induced by transfection of immortalized human pancreatic ductal epithelial cells with Gli1 resulted in up-regulation of the majority of foregut markers seen in early PanIN lesions. These data show frequent up-regulation of foregut markers in early PanIN lesions and suggest that PanIN development may involve Hedgehog-mediated conversion to a gastric epithelial differentiation program.
Defeating script injection attacks with browser-enforced embedded policies (2007)

Web sites that accept and display content such as wiki articles or comments typically filter the content to prevent injected script code from running in browsers that view the site. The diversity of browser rendering algorithms and the desire to allow rich content make filtering quite difficult, however, and attacks such as the Samy and Yamanner worms have exploited filtering weaknesses. This paper proposes a simple alternative mechanism for preventing script injection called Browser-Enforced Embedded Policies (BEEP). The idea is that a web site can embed a policy in its pages that specifies which scripts are allowed to run. The browser, which knows exactly when it will run a script, can enforce this policy perfectly. We have added BEEP support to several browsers, and built tools to simplify adding policies to web applications. We found that supporting BEEP in browsers requires only small and localized modifications, modifying web applications requires minimal effort, and enforcing policies is generally lightweight.
[Role of Exosomal miRNA in Multiple Myeloma Progression and Its Possible Mechanism -Review]. (2017)

Multiple myeloma (MM)is a kind of plasma tumor originated from B cell line. Its incidence ranks in second place of hematopoietic malignancies. Although continued progress was made in treatment of MM,the survival rate and prognosis of MM patients are still not satisfactory. Further understanding of the pathogenesis of MM may provide information to develop new treatment strategies, so as to improve survival rate and ameliorate its prognosis. Many researches have demonstrated that bone marrow microenvironment plays an important role in MM pathogenesis, which regulates the biological properties of MM cells, including migration and proliferation, through miRNA, mRNA and protein contained in the exosomes released from the cells in the tumor microenvironment. Recently, as the tumor suppressor genes and oncogenes, exosomal microRNA become a hot spot in research. Compared with those of the normal ones, exosomes in MM have less miR-15a and/or more miR-135b and miR-21. These differences will accelerate the progression of MM via PI3K/Akt/eNOS/VEGF pathway, FIH-HIF pathway, MAPK/ERK/Ras pathway and so on, that are expected to become the new targets for the treatment of MM. This review summarizes the role and the possible mechanism of exosomes in the progression of MM.
Quantum Confined Atoms of Doped ZnO Nanocrystals (2002)

The luminescent properties of ZnO nanocrystals doped with divalent manganese and europium ions show efficient broad-band emission at room temperature. These ZnO based quantum confined atoms potentially offer efficient nanophosphors that can be excited in the near UV range for applications in the solid state lighting, displays and optically pumped lasers.
An open-label, dose-escalation phase 1b study of subcutaneous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO). (2016)

TPS8071 Background: Daratumumab (DARA), a human CD38 IgG1 monoclonal antibody, is approved in the US for patients with relapsed/refractory multiple myeloma (RR MM; ≥ 3 lines including a PI and IMiD or PI/IMiD double refractory). DARA has promising efficacy and a favorable safety profile as a monotherapy and in combination. The recommended DARA dose and schedule is 16 mg/kg intravenous (IV) weekly (QW) for 8 weeks, every 2 weeks (Q2W) for 16 weeks, and every 4 weeks (Q4W) thereafter. Subcutaneous (SC) formulations of therapeutic antibodies with recombinant human hyaluronidase (rHuPh20) have been approved in Europe. Here, SC DARA delivery combined with rHuPh20 is being evaluated. Methods: This is an ongoing phase 1b open-label, dose-escalation study of DARA given SC or IV in patients with symptomatic RR MM who have received ≥ 2 prior therapies. In Part 1, approximately 8 patients will enroll in each sequential cohort treated with doses of DARA-rHuPh20 SC (1200 mg-30,000 U; 1800 mg-45,000 U; subsequent doses to be determined) given QW in Cycles 1-2 (28 days/cycle), Q2W in Cycles 3-6, and Q4W thereafter. In the absence of dose limiting toxicity in > 2 patients in Cycle 1, patients will be assigned to the next dose cohort; up to 5 additional dose cohorts may be evaluated. A Study Evaluation Team will review pharmacokinetics (PK) and safety data to determine dose escalation and the recommended part 2 dose (RP2D). Part 2 will evaluate PK, safety, and efficacy of SC DARA. Approximately 80 patients will be randomized 1:1 to receive DARA-rHuPh20 SC at RP2D or DARA IV (1200 mg). The primary endpoints are serum trough concentrations of DARA just prior to Cycle 3 Day 1 and clinical safety. All patients will be observed for ≥ 72 hours and ≥ 24 hours, respectively, after the first SC infusion and, if necessary, after subsequent doses. To prevent/manage infusion-related reactions, pre- and post-infusion medications (steroids, paracetamol, montelukast, and antihistamines) similar to those administered with IV DARA will be given. Approximately 128 patients will be enrolled at 12 sites in 6 countries. The first patient was enrolled in October 2015. Clinical trial information: NCT02519452.
MESH-BASED PARAMETRIZED L-SYSTEMS AND GENERALIZED SUBDIVISION FOR GENERATING COMPLEX GEOMETRY (2002)

We propose two mechanisms that can be used to generate complex geometry: generalized subdivision and mesh-based parametrized L-Systems. Instead of using standard subdivision, which uses the same subdivision rule at each level of the subdivision process, in order to converge to a limit surface, we employ a generalized approach, that allows different subdivision rules at each level. By limiting the variations at each level, it is possible to ensure convergence. Mesh-based parametrized L-Systems represent an extension to L-systems which associates symbols to the faces in a mesh. Thereby complex geometry can be introduced into an existing mesh by using procedural substitution rules. Combining both these mechanisms, a wide variety of complex models can be easily generated from very compact representations.
Validation of Serum Markers for Blood-Brain Barrier Disruption in Traumatic Brain Injury (2009)

The blood-brain barrier (BBB), which prevents the entry into the central nervous system (CNS) of most water-soluble molecules over 500 Da, is often disrupted after trauma. Post-traumatic BBB disruption may have important implications for prognosis and therapy. Assessment of BBB status is not routine in clinical practice because available techniques are invasive. The gold-standard measure, the cerebrospinal fluide (CSF)-serum albumin quotient (Q(A)), requires the measurement of albumin in CSF and serum collected contemporaneously. Accurate, less invasive techniques are necessary. The objective of this study was to evaluate the relationship between Q(A) and serum concentrations of monomeric transthyretin (TTR) or S100B. Nine subjects with severe traumatic brain injury (TBI; Glasgow Coma Scale [GCS] score < or =8) and 11 subjects with non-traumatic headache who had CSF collected by ventriculostomy or lumbar puncture (LP) were enrolled. Serum and CSF were collected at the time of LP for headache subjects and at 12, 24, and 48 h after ventriculostomy for TBI subjects. The Q(A) was calculated for all time points at which paired CSF and serum samples were available. Serum S100B and TTR levels were also measured. Pearson's correlation coefficient and area under the receiver operating characteristic (ROC) curve were used to determine the relationship between the serum proteins and QA. Seven TBI subjects had abnormal Q(A)'s indicating BBB dysfunction. The remaining TBI and control subjects had normal BBB function. No significant relationship between TTR and QA was found. A statistically significant linear correlation between serum S100B and Q(A) was present (r = 0.432, p = 0.02). ROC analysis demonstrated a significant relationship between Q(A) and serum S100B concentrations at 12 h after TBI (AUC = 0.800; SE 0.147, 95% CI 0.511-1.089). Using an S100B concentration cutoff of 0.027 ng=ml, specificity for abnormal Q(A) was 90% or higher at each time point. We conclude that serum S100B concentrations accurately indicate BBB dysfunction at 12 h after TBI.
Sequence characteristics of functional siRNAs (2005)

RNA interference in mammalian cells is actively used to conduct genetic screens, to identify and to validate targets, and to elucidate regulators and modifiers of cellular pathways. To ensure the specificity and efficacy of the active 21mer siRNA molecules, it is pertinent to develop a strategy for their rational design. Here we show that most functional siRNAs have characteristic sequence features. We tested 601 siRNAs targeting one exogenous and three endogenous genes. The efficacy of the siRNAs was determined at the protein level. Using a decision tree algorithm in combination with information analysis, our analyses revealed four sets of rules with a mean knockdown efficacy ranging from 60% to 73%. (To distinguish between percentages used to describe the quality of an siRNA and the percentages used to describe parts of data sets we underlined the former throughout this paper.) The best rule comprises an A/U at positions 10 and 19, a G/C at position 1, and more than three A/Us between positions 13 and 19, in the sense strand of the siRNA sequence. Using these rules, there is a 99.9% chance of designing an effective siRNA in a set of three with more than 50% knockdown efficiency in a biological readout.
Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1 (2010)

Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion within the 3'-untranslated region of the DMPK gene. The predominant mechanism of pathogenesis is a toxic gain of function of CUG repeat containing RNA transcribed from the expanded allele. The molecular mechanisms by which the RNA containing expanded repeats produce pathogenic effects include: sequestration of muscleblind-like 1 (MBNL1) protein and up-regulation of CUG binding protein 1 (CUGBP1). MBNL1 and CUGBP1 are RNA binding proteins that regulate alternative splicing transitions during development. Altered functions of these proteins in DM1 lead to misregulated splicing of their target genes, resulting in several features of the disease. The role of MBNL1 depletion in DM1 is well established through a mouse knock-out model that reproduces many disease features. Here we directly test the hypothesis that CUGBP1 up-regulation also contributes to manifestations of DM1. Using tetracycline-inducible CUGBP1 and heart-specific reverse tetracycline trans-activator transgenes, we expressed human CUGBP1 in adult mouse heart. Our results demonstrate that up-regulation of CUGBP1 is sufficient to reproduce molecular, histopathological and functional changes observed in a previously described DM1 mouse model that expresses expanded CUG RNA repeats as well as in individuals with DM1. These results strongly support a role for CUGBP1 up-regulation in DM1 pathogenesis.
Autophagy in neurodegeneration and development (2008)

Efficient protein turnover is essential for the maintenance of cellular health. Here we review how autophagy has fundamental functions in cellular homeostasis and possible uses as a therapeutic strategy for neurodegenerative diseases associated with intracytosolic aggregate formation, like Huntington's disease (HD). Drugs like rapamycin, that induce autophagy, increase the clearance of mutant huntingtin fragments and ameliorate the pathology in cell and animal models of HD and related conditions. In Drosophila, the beneficial effects of rapamycin in diseases related to HD are autophagy-dependent. We will also discuss the importance of autophagy in early stages of development and its possible contribution as a secondary disease mechanism in forms of fronto-temporal dementias, motor neuron disease, and lysosomal storage disorders.
Testing C-elements is not elementary (2002)

We examine stuck-at faults in several gate circuits realizing the C-element. We exhibit circuits with the following phenomena: (a) 50% of single faults do not cause the circuit to halt. (b) Some faults are not detectable by logic tests. (c) A test of length seven is required to detect all detectable single faults. (d) A fault may result in an oscillation. (e) A fault may destroy the speed-independence of a circuit. We also analyze static and dynamic CMOS implementations of the C-element.