gebhart/patrepeval huggingface dataset:
Thrombin Cleavage-Independent Deposition of Fibrinogen in Extracellular Matrices (1997)

Lung epithelial cells (A549) synthesize and secrete fibrinogen (FBG) in vitro when stimulated with interleukin-6 and dexamethasone. This FBG secretion is polarized in the basolateral direction, suggesting that FBG is a component of the extracellular matrix (ECM). Immunofluorescent staining of A549 cells showed a fibrillar pattern of FBG, similar to the staining detected using antibodies against the matrix constituents, collagen type IV and fibronectin (FN). The same pattern of staining was detected using antibodies against fibrinopeptides A and B, as well as with the T2G1 monoclonal antibody against the fibrin-specific epitope, beta15-21. Matrix staining was unaltered in the presence of the thrombin inhibitor, hirudin, or the plasmin inhibitor, aprotinin, consistent with the interpretation that matrix deposition of FBG does not require such enzymatic action. Metabolic labeling studies confirmed that FBG secreted from A549 cells or deposited into the ECM showed no evidence of thrombin or plasmin proteolytic processing or of transglutaminase-mediated covalent cross-linking (gamma-gamma dimers or alpha-polymers). Incubation of either A549 cell-derived or purified plasma FBG with cultures of human foreskin fibroblasts resulted in FBG deposition in the ECM that colocalized with matrix fibrils containing endogenously produced FN and laminin (LN). Binding of FBG to this exogenously produced matrix was unaltered by inhibition of thrombin and plasmin action, yet also exhibited exposure of the fibrin-specific epitope, beta15-21. The majority (approximately 70%) of newly synthesized and secreted FBG is bound to the cell surface as determined by its trypsin-sensitivity. Cell surface-bound FBG is initially deoxycholate-soluble, which, over time, becomes incorporated in the deoxycholate-insoluble ECM in a similar fashion to FN. These data suggest that matrix incorporation requires the binding of secreted FBG to cell-associated matrix assembly sites. However, unlike FN, FBG in the ECM is composed of the dimeric protamer (A alpha/B beta/gamma gamma) and not high molecular weight polymers indicative of fibrin. This study provides evidence that deposition of FBG in both endogenous and exogenously produced matrices results in conformational changes that occur independently of thrombin cleavage. This matrix-bound FBG, on which unique cell-reactive domains are likely exposed, could augment cellular response mechanisms evoked during injury and inflammation.
Knock-Down of Gene Expression in Hematopoietic Cells (2009)

RNA interference (RNAi) is an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism triggered by double-stranded RNA (dsRNA) that results either in degradation of homologues mRNAs or inhibition of mRNA translation. The effector molecules which activate the RNAi pathway are small regulatory RNAs including small interfering RNAs (siRNAs) which are processed from longer dsRNAs by the RNAse III enzyme Dicer, and microRNAs (miRNAs) generated in a regulated multistep process from endogenous primary transcripts (pri-miRNA). Since, in principle, any gene can be silenced, RNAi provides a powerful tool to investigate gene function, and it is therefore a widely used gene silencing method in functional genomics. This chapter provides a collection of protocols for specific gene knock-down in hematopoietic cells by the application of short-hairpin RNAs (shRNAs) transcribed by RNA polymerase III (pol III) promoters or artificial-miRNAs (art-miRNAs) expressed from RNA pol II promoters using lentiviral vectors, respectively.
Magnetic flux compression Generators (2004)

Magnetic flux compression generators offer the largest pulsed power output per unit size or weight when compared with other more conventional systems. They have found widespread use as pulsed power sources for hydrodynamics programs and high magnetic field research at national laboratories or in commercial applications, including exploration for oil and minerals and mine detection. Also, due to their nature as a true one-time-use device with superior energy density, a large portion of applications is defense related. A variety of basic magnetic flux compression generator designs have been developed and tested during the past four decades. All of them rely on the explosive-driven deformation of a system of conductors having an initial, preferably large, inductance. The most successful basic design is the helical flux compression generator, which is capable of producing a high-energy output into large impedance loads, just as it is needed for a practical pulsed power source. This paper will review the advances and state of the art of primarily helical magnetic flux compression generators mainly developed as pulsed power sources and will offer new insights gained as a result of a recently completed five-year AFOSR/DoD Multidisciplinary University Research Initiative program that studied the basic physics and engineering aspects of helical flux compression generators.
Tumor-targeted induction of oxystress for cancer therapy (2007)

Reactive oxygen species (ROS), such as superoxide anion radicals (O.-2) and hydrogen peroxide (H2O2) are potentially harmful by-products of normal cellular metabolism that directly affect cellular functions. ROS is generated by all aerobic organisms and it seems to be indispensable for signal transduction pathways that regulate cell growth and reduction-oxidation (redox) status. However, overproduction of these highly reactive oxygen metabolites can initiate lethal chain reactions, which involve oxidation and damage to structures that are crucial for cellular integrity and survival. In fact, many antitumor agents, such as vinblastine, cisplatin, mitomycin C, doxorubicin, camptothecin, inostamycin, neocarzinostatin and many others exhibit antitumor activity via ROS-dependent activation of apoptotic cell death, suggesting potential use of ROS as an antitumor principle. Thus, a unique anticancer strategy named "oxidation therapy" has been developed by inducing cytotoxic oxystress for cancer treatment. This goal could be achieved mainly by two methods, namely, (i) inducing the generation of ROS directly to solid tumors and (ii) inhibiting the antioxidative enzyme (defense) system of tumor cells. Since 1950s, many strategies have been employed based on the first method, namely, administration of ROS per se (e.g. H2O2) or ROS generating enzyme to tumor bearing animals. However no successful and practical results were obtained probably because of the lack of tumor selective ROS delivery and hence resulting in subsequent induction of severe side effects. To overcome these obstacles, we developed polyethylene glycol (PEG) conjugated O.-2 or H2O2-generating enzymes, xanthine oxidase (XO) and D-amino acid oxidase (DAO) (PEG-DAO) respectively. More recently, a pegylated (PEG) zinc protoporphyrin (PEG-ZnPP) and a highly water soluble micellar formulation of ZnPP based on amphiphilic styrene maleic acid (SMA) copolymer, SMA-ZnPP, are prepared, which are potent inhibitors of heme oxygenase-1 (HO-1). HO-1 is a major antioxidative enzyme of tumors, that is different in mechanism of catalase or superoxide dismutase (SOD). Consequently, both PEG-enzymes and PEG-ZnPP exhibited superior in vivo pharmacokinetics than their parental molecules, particularly in tumor delivery by taking advantage of the EPR effect of macromolecular nature, and thus showed remarkable antitumor effects suggesting the potentials of this anticancer therapeutic for clinical application. Furthermore, it has been well known that many antioxidative enzymes such as catalase, SOD are down-regulated in most solid tumors in vivo. On the contrary, HO-1 is highly upregulated and it plays a very important role of antioxidation, because HO-1 generates biliverdin, which being converted to bilirubin exhibits a very potent antioxidative effect, and hence antiapoptosis in tumors. Thus this oxidation therapy, by inhibiting this HO-1 dependent antioxidant (bilirubin) formation by ZnPP, and by enhancing ROS generation, is expected to offer a powerful therapeutic modality for future anticancer therapy.
Multi-Material Processing By Lens (2018)

During the past few years, solid freeform fabrication has evolved into direct fabrication of&#13;\nmetallic components using computer aided design (CAD) solid models. [1-4] Laser Engineered&#13;\nNet Shaping (LENS™) is one such technique [5-7] being developed at Sandia to fabricate high&#13;\nstrength, near net shape metallic components. In the past two years a variety of components have&#13;\nbeen fabricated using LENS™ for applications ranging from prototype parts to injection mold&#13;\ntooling. [8]&#13;\nTo advance direct fabrication capabilities, a process must be able to accommodate a wide&#13;\nrange ofmaterials, including alloys and composites. This is important for tailoring certain&#13;\nphysical properties critical to component performance. Examples include graded deposition for&#13;\nmatching coefficient ofthermal expansion between dissimilar materials, layered fabrication for&#13;\nnovel mechanical properties, and new alloy design where elemental constituents and/or alloys are&#13;\nblended to create new materials. In this paper, we will discuss the development ofprecise&#13;\npowder feeding capabilities for the LENSTM process to fabricate graded or layered material parts.&#13;\nWe also present preliminary results from chemical and microstructural analysis.
The genetic code of the fungal CTG clade (2011)

Genetic code alterations discovered over the last 40 years in bacteria and eukaryotes invalidate the hypothesis that the code is universal and frozen. Mitochondria of various yeast species translate the UGA stop codon as tryptophan (Trp) and leucine (Leu) CUN codons (N = any nucleotide) as threonine (Thr) and fungal CTG clade species reassigned Leu CUG codons to serine and translate them ambiguously in their cytoplasms. This unique sense-to-sense genetic code alteration is mediated by a Ser-tRNA containing a Leu 5'-CAG-3'anticodon (ser-tRNA(CAG)), which is recognized and charged with Ser (~97%) by the seryl-tRNA synthetase (SerRS) and with Leu (~3%) by the leucyl-tRNA synthetase (LeuRS). This unusual tRNA appeared 272 ± 25 million years ago and had a profound impact on the evolution of the CTG clade species. Here, we review the most recent results and concepts arising from the study of this codon reassignment and we highlight how its study is changing our views of the evolution of the genetic code.
The Venus Fly Trap Domain of the Extracellular Ca2+-sensing Receptor Is Required for l-Amino Acid Sensing (2004)

We previously demonstrated that the human calcium-sensing receptor (CaR) is allosterically activated by L-amino acids (Conigrave, A. D., Quinn, S. J., and Brown, E. M. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 4814-4819). However, the domain-based location of amino acid binding has been uncertain. We now show that the Venus Fly Trap (VFT) domain of CaR, but none of its other major domains, is required for amino acid sensing. Several constructs were informative when expressed in HEK293 cells. First, the wild-type CaR exhibited allosteric activation by L-amino acids as previously observed. Second, two CaR-mGlu chimeric receptor constructs that retained the VFT domain of CaR, one containing the extracellular Cys-rich region of CaR and the other containing the Cys-rich region of the rat metabotropic glutamate type-1 (mGlu-1) receptor, together with the rat mGlu-1 transmembrane region and C-terminal tail, retained amino acid sensing. Third, a CaR lacking residues 1-599 of the N-terminal extracellular head but retaining an intact CaR transmembrane region and a functional but truncated C terminus (headless-T903 CaR) failed to respond to L-amino acids but retained responsiveness to the type-II calcimimetic NPS R-467. Finally, a T903 CaR control that retained an intact N terminus also retained L-amino acid sensing. Taken together, the data indicate that the VFT domain of CaR is necessary for L-amino acid sensing and are consistent with the hypothesis that the VFT domain is the site of L-amino acid binding. The findings support the concept that the mGlu-1 amino acid binding site for L-glutamate is conserved as an L-amino acid binding site in its homolog, the CaR.
Increased Delivery of Tumor-specific Monoclonal Antibodies to Brain after Osmotic Blood-Brain Barrier Modification in Patients with Melanoma Metastatic to the Central Nervous System (1987)

We evaluated the delivery of melanoma-specific radiolabeled monoclonal antibody (MAb) Fab fragments in a pilot study of three patients with melanoma metastatic to the central nervous system. Tumor samples demonstrated excellent immunohistochemical reactivity with Fab 96.5, specific for a 97,000-molecular-weight melanoma antigen (p97), or Fab 48.7, specific for a melanoma-associated proteoglycan antigen. All three patients received 131I-labeled tumor-specific Fab (5 to 7 mg, 1 mCi/mg) intravenously. On a separate occasion, two patients received 131I-labeled nonspecific Fab (5 to 7 mg, 1 mCi/mg). There was no uptake of either antibody into the region of the tumor (as documented by gamma camera brain images). However, there was increased uptake in the blood-brain barrier (BBB)-modified areas in all three patients when radiolabeled tumor-specific MAb was administered intravenously in conjunction with osmotic BBB opening. In one patient, the estimated cerebrovascular permeability X capillary surface area (PA) for the tumor-bearing hemisphere 3 hours after disruption was 1.16 X 10(-6) sec-1 compared to the PA of 0.395 X 10(-6) sec-1 in the nondisrupted hemisphere. Serial brain scans showed that greater than 90% of the radiolabeled antibody cleared from the brain by 72 hours. The highest radiation doses (rads) calculated per 7 mCi injection were: left brain (barrier-modified hemisphere), 5.46; right brain (non-barrier modified hemisphere), 1.68; thyroid, 98; stomach, 9.1; kidney, 39.9; and total body, 1.33. There seemed to be increased uptake of antibody in the tumor region after barrier modification in one patient, but antibody clearance from that region occurred at the same rate as from surrounding and apparently tumor-free brain. In one patient who had carcinomatous meningitis, we demonstrated antibody bound to only a fraction of the antigen binding sites on tumor cells in the cerebrospinal fluid after BBB modification. We have not shown distinct, persistent localization of antibody in brain tumor; studies investigating MAb dose and other parameters as the basis for this problem are under way.
Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia (2001)

The clinical benefit of intravenous immunoglobulin (IVIG) preparations in the treatment of immune thrombocytopenic purpura (ITP) is supposed to be mediated by blockade of Fc gamma receptor--bearing phagocytes. In 2 experimental models for ITP, it is shown that the therapeutic efficacy of IVIG preparations is related to the IgG dimer content present in these preparations. A rat monoclonal antibody (mAb; MWReg30) directed to the murine platelet-specific integrin alpha(IIb)beta(3) (gpIIb/IIIa) was administered intraperitoneally either as bolus injection or continuous infusion. With bolus injection, the circulating platelet count dropped to almost zero within 3 hours. Pretreatment with cobra venom factor did not affect platelet depletion, whereas pretreatment with anti-Fc gamma RII/III mAb 2.4G2 or IVIG greatly reduced platelet clearance. With continuous infusion, platelet numbers reached a steady state after 4 days, at approximately 25% of control. This reduction in platelets was, however, not observed in mice deficient for the FcR gamma-chain, lacking Fc gamma RI, Fc gamma RIII, and Fc gamma RIII(-/-) mice. Infusion of a single dose of IVIG with a high IgG dimer content on the 4th day--ie, mimicking therapeutic administration--resulted in a platelet increase for several days. IVIG predominantly consisting of monomeric IgG had no effect on platelet numbers. In conclusion, continuous infusion of MWReg30 induces thrombocytopenia in mice by enhancing Fc gamma receptor--mediated clearance of platelets. In this model, it is shown that IgG dimers present in IVIG preparations are responsible for the increase in platelet counts. (Blood. 2001;98:1095-1099)
Downregulation of miR‐138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines (2008)

Alterations of several microRNA (miRNA) have been linked to cancer development and its biology. To search for unique miRNA that might play a role in the development of anaplastic thyroid carcinoma (ATC), we examined the expression of multiple miRNA and their functional effects on target genes in human thyroid carcinoma cell lines. We quantitatively evaluated the expression of multiple miRNA in 10 ATC and five papillary thyroid carcinoma (PTC) cell lines, as well as primary tumors from 11 thyroid carcinoma patients (three ATC and eight PTC), using the stem-loop-mediated reverse transcription real-time polymerase chain reaction method. We also examined the target gene specificity of unique miRNA that showed differences in expression between ATC and PTC cell lines. One miRNA, miR-138, was significantly downregulated in ATC cell lines in comparison with PTC (P < 0.01). Eleven miRNA (including miR-138) potentially targeting the human telomerase reverse transcriptase (hTERT) gene were totally downregulated in both ATC and PTC cell lines in comparison with normal thyroid tissues. A tendency for an inverse correlation between miR-138 and hTERT protein expression was observed in the thyroid cancer cell lines, although this failed to reach significance (r = -0.392, P = 0.148). We demonstrated that overexpression of miR-138 induced a reduction in hTERT protein expression, and confirmed target specificity between miR-138 and the hTERT 3'-untranslated region by luciferase reporter assay. These results suggest that loss of miR-138 expression may partially contribute to the gain of hTERT protein expression in ATC, and that further multiple miRNA targeting hTERT mRNA might be involved in the development of thyroid carcinoma.
Anti-Angiogenic Peptides for Cancer Therapeutics (2011)

Peptides have emerged as important therapeutics that are being rigorously tested in angiogenesis-dependent diseases due to their low toxicity and high specificity. Since the discovery of endogenous proteins and protein fragments that inhibit microvessel formation (thrombospondin, endostatin) several peptides have shown promise in pre-clinical and clinical studies for cancer. Peptides have been derived from thrombospondin, collagens, chemokines, coagulation cascade proteins, growth factors, and other classes of proteins and target different receptors. Here we survey recent developments for anti-angiogenic peptides with length not exceeding 50 amino acid residues that have shown activity in pre-clinical models of cancer or have been tested in clinical trials; some of the peptides have been modified and optimized, e.g., through L-to-D and non-natural amino acid substitutions. We highlight technological advances in peptide discovery and optimization including computational and bioinformatics tools and novel experimental techniques.
THE EFFECTS OF EXOGENOUS MELATONIN ON ENDOCRINE FUNCTION IN MAN (1986)

At two different times of year (spring and autumn) an oral preparation of the pineal neurohormone melatonin, or placebo, was administered to 12 healthy volunteers (10 men and two women in spring: the same group minus one man in autumn) daily at 1700 h for 1 month (spring), or 3 weeks (autumn) using a double-blind cross-over protocol. The daily dose was 2 mg melatonin in 5 ml corn-oil, and placebo consisted of the vehicle only. In spring the anterior pituitary hormones LH, PRL, GH together with T4, cortisol, testosterone and melatonin were measured at 1- to 6-h intervals for 24 h in plasma on the day following the last dose. In autumn PRL, cortisol and melatonin levels were measured on the last day of treatment. Subjective fatigue, mood and sleep records were kept throughout the studies. Melatonin increased early evening fatigue and actual sleep, but had no effect on mood: these results are reported in full elsewhere. Melatonin administration had no effect on the levels or 24-h rhythm of LH, GH, T4, testosterone or cortisol. An earlier fall in the nocturnal PRL was observed on both occasions. Overall PRL levels were higher in spring than in autumn. In five of the subjects, the secretion of endogenous melatonin was advanced by 1-3 h in the presence of exogenous melatonin. These observations suggest that the potential therapeutic use of melatonin as a hypnotic or in the treatment of jet lag is unlikely to be complicated by undesirable endocrine effects.
A Novel Aerosol-Mediated Drug Delivery System for Inner Ear Therapy: Intratympanic Aerosol Methylprednisolone Can Attenuate Acoustic Trauma (2013)

We developed a novel aerosol-mediated drug delivery system for inner ear therapy by using a silicon-based multiple-Fourier horn nozzle. Intratympanic aerosol (ITA) methylprednisolone (MP) delivery can protect hearing after acoustic trauma. The highest concentration of MP (38.9 ± 5.47 ppm) appeared at 2 h and declined rapidly within 10 h. The concentrations of MP remained at a relatively low level for more than 10 h. Compared to the baseline, the auditory brainstem response (ABR) thresholds shifted markedly at 1 h after noise exposure in all groups (p < 0.05). From the cochleograms, it can be noted that the main lesions encompassed the 2-20 kHz frequency range. Significant differences ( ) were observed for the range between 5 and 8 kHz in the cell loss of outer hair cells (OHCs). The losses for IHCs were lower than for OHCs. The MP movement in the middle ear was simulated by a convection diffusion equation with a relaxation time. The relaxation time was 0.5 h, and the concentration threshold of MP on the round window membrane (RWM) in the middle ear (C T) was 8900 ppm. Using the unit hydrograph (UH) method, we obtained a proper boundary concentration on the RWM at the cochlea, which resulted in a well-fit concentration. Finally, a linking mechanism between the middle ear and the cochlea was established by the RWM. The adjustable permeability and concentration threshold provide the flexibility to match the peak times and peak values of the concentration on the RWM in the middle ear and the cochlea.
Determination of phase difference of backscatter signals from coherent-on-receive microwave marine radar for wave measurement (2013)

In present study, a X-band marine radar was installed at the northwestern coast of Taiwan. The IF signal from the super-heterodyne receiver of the marine radar was retrieved, amplified, band-pass filtered and digitized to be the raw dataset, from which the phase of transmitted and echo radar EM wave could be determined. Based on Doppler theory, the time rate change of the phases between succeeding pulses could be used for estimating the water particle velocity of wave orbital motion. Due to the fact that the magnetron in the marine radar produces random frequency jump, and leading to mis-estimate of the phase differences. We adopted the Ensemble Empirical Mode Decomposition method as a filter to exclude the effects of frequency jump. The results demonstrated the improved capability of coherent-on-receive marine radar for surface wave measurement.