gebhart/patrepeval huggingface dataset:
Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. (2001)

Curcumin (diferuloylmethane), a yellow substance from the root of the plant Curcuma longa Linn., has been demonstrated to inhibit carcinogenesis of murine skin, stomach, intestine and liver. However, the toxicology, pharmacokinetics and biologically effective dose of curcumin in humans have not been reported. This prospective phase-I study evaluated these issues of curcumin in patients with one of the following five high-risk conditions: 1) recently resected urinary bladder cancer; 2) arsenic Bowen's disease of the skin; 3) uterine cervical intraepithelial neoplasm (CIN); 4) oral leucoplakia; and 5) intestinal metaplasia of the stomach. Curcumin was taken orally for 3 months. Biopsy of the lesion sites was done immediately before and 3 months after starting curcumin treament. The starting dose was 500 mg/day. If no toxicity > or = grade II was noted in at least 3 successive patients, the dose was then escalated to another level in the order of 1,000, 2,000, 4,000, 8,000, and 12,000 mg/day. The concentration of curcumin in serum and urine was determined by high pressure liquid chromatography (HPLC). A total of 25 patients were enrolled in this study. There was no treatment-related toxicity up to 8,000 mg/day. Beyond 8,000 mg/day, the bulky volume of the drug was unacceptable to the patients. The serum concentration of curcumin usually peaked at 1 to 2 hours after oral intake of crucumin and gradually declined within 12 hours. The average peak serum concentrations after taking 4,000 mg, 6,000 mg and 8,000 mg of curcumin were 0.51 +/- 0.11 microM, 0.63 +/- 0.06 microM and 1.77 +/- 1.87 microM, respectively. Urinary excretion of curcumin was undetectable. One of 4 patients with CIN and 1 of 7 patients with oral leucoplakia proceeded to develop frank malignancies in spite of curcumin treatment. In contrast, histologic improvement of precancerous lesions was seen in 1 out of 2 patients with recently resected bladder cancer, 2 out of 7 patients of oral leucoplakia, 1 out of 6 patients of intestinal metaplasia of the stomach, I out of 4 patients with CIN and 2 out of 6 patients with Bowen's disease. In conclusion, this study demonstrated that curcumin is not toxic to humans up to 8,000 mg/day when taken by mouth for 3 months. Our results also suggest a biologic effect of curcumin in the chemoprevention of cancer.
Clearance of HIV — Lessons from Newborns (1995)

AIDS is probably the most intensively studied infectious disease in history, yet enormous gaps remain in our knowledge of its pathogenesis. Clinicians have long been intrigued by the question “Is human immunodeficiency virus type 1 [HIV-1] infection permanent and always (with time) fatal, or do some people recover?” The paper by Bryson and her colleagues1 in this issue of the Journal solves a small but important piece of the puzzle and raises intriguing questions about perinatally transmitted HIV infection.A child whose mother had HIV infection had negative HIV cultures of blood at birth, but then had two positive blood . . .
Vicious Cycle Involving Na+Channels, Glutamate Release, and NMDA Receptors Mediates Delayed Neurodegeneration through Nitric Oxide Formation (1996)

The mechanisms by which neurons die after cerebral ischemia and related conditions in vivo are unclear, but they are thought to involve voltage-dependent Na+ channels, glutamate receptors, and nitric oxide (NO) formation because selective inhibition of each provides neuroprotection. It is not known precisely what their roles are, nor whether they interact within a single cascade or in parallel pathways. These questions were investigated using an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief (5 min) challenge with the glutamate receptor agonist NMDA. Unexpectedly, NO was generated continuously by the cultures for up to 16 hr after the NMDA exposure. Neuronal death followed the same general time course except that its start was delayed by approximately 4 hr. Application of the NO synthase inhibitor nitroarginine after, but not during, the NMDA exposure inhibited NO formation and protected against delayed neuronal death. Blockade of NMDA receptors or of voltage-sensitive Na+ channels [with tetrodotoxin (TTX)] during the postexposure period also inhibited both NO formation and cell death. The NMDA exposure resulted in a selective accumulation of glutamate in the culture medium during the period preceding cell death. This glutamate release could be inhibited by NMDA antagonism or by TTX, but not by nitroarginine. These data suggest that Na+ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegeneration. At the core of the mechanism is a vicious cycle in which NMDA receptor stimulation causes activation of TTX-sensitive Na+ channels, leading to glutamate release and further NMDA receptor stimulation. The output of the cycle is an enduring production of NO from neuronal sources, and this is responsible for delayed neuronal death. The same neurons, however, could be induced to undergo more rapid NMDA receptor-dependent death that required neither TTX-sensitive Na+ channels nor NO.
Cell-Free Production of Integral Membrane Proteins on a Preparative Scale (2007)

The chapter will focus on the high level cell-free production of integral membrane proteins having multiple transmembrane segments by using an individual coupled transcription/translation system based on an Escherichia coli S30-extract. We describe in detail the setup and optimization of the cell-free expression technique to obtain the maximum yield of recombinant proteins. The protocol can be used for the expression of soluble membrane proteins as well as for their production as a precipitate. In addition, we will provide protocols for the efficient solubilization and reconstitution of membrane proteins directly from the cell-free produced precipitates.
Secrets of optical flow estimation and their principles (2010)

The accuracy of optical flow estimation algorithms has been improving steadily as evidenced by results on the Middlebury optical flow benchmark. The typical formulation, however, has changed little since the work of Horn and Schunck. We attempt to uncover what has made recent advances possible through a thorough analysis of how the objective function, the optimization method, and modern implementation practices influence accuracy. We discover that “classical” flow formulations perform surprisingly well when combined with modern optimization and implementation techniques. Moreover, we find that while median filtering of intermediate flow fields during optimization is a key to recent performance gains, it leads to higher energy solutions. To understand the principles behind this phenomenon, we derive a new objective that formalizes the median filtering heuristic. This objective includes a nonlocal term that robustly integrates flow estimates over large spatial neighborhoods. By modifying this new term to include information about flow and image boundaries we develop a method that ranks at the top of the Middlebury benchmark.
Aptamer-Mediated Nanoparticle-Based Protein Labeling Platform for Intracellular Imaging and Tracking Endocytosis Dynamics (2012)

Although nanoparticles have been widely used as optical contrasts for cell imaging, the complicated prefunctionalized steps and low labeling efficiency of nanoprobes greatly inhibit their applications in cellular protein imaging. In this study, we developed a novel and general strategy that employs an aptamer not only as a recognizer for protein recognition but also as a linker for nanoreporter targeting to specifically label membrane proteins of interest and track their endocytic pathway. With this strategy, three kinds of nanoparticles, including gold nanoparticles, silver nanoparticles, and quantum dots (QDs), have been successfully targeted to the membrane proteins of interest, such as nucleolin or prion protein (PrP(C)). The following investigations on the subcellular distribution with fluorescent immunocolocalization assay indicated that PrP(C)-aptamer-QD complexes most likely internalized into cytoplasm through a classical clathrin-dependent/receptor-mediated pathway. Further single-particle tracking and trajectory analysis demonstrated that PrP(C)-aptamer-QD complexes exhibited a complex dynamic process, which involved three types of movements, including membrane diffusion, vesicle transportation, and confined diffusion, and all types of these movements were associated with distinct phases of PrP(C) endocytosis. Compared with traditional multilayer methods, our proposed aptamer-mediated strategy is simple in procedure, avoiding any complicated probe premodification and purification. In particular, the new double-color labeling strategy is unique and significant due to its superior advantages of targeting two signal reporters simultaneously in a single protein using only one aptamer. What is more important, we have constructed a general and versatile aptamer-mediated protein labeling nanoplatform that has shown great promise for future biomedical labeling and intracellular protein dynamic analysis.
Interleukin-6 impairs endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of pregnant rats (2004)

IL-6 is elevated in plasma of preeclamptic women, and twofold elevation of plasma IL-6 increases vascular resistance and arterial pressure in pregnant rats, suggesting a role of the cytokine in hypertension of pregnancy. However, whether the hemodynamic effects of IL-6 reflect direct effects of the cytokine on the mechanisms of vascular contraction/relaxation is unclear. The purpose of this study was to test the hypothesis that IL-6 directly impairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. Active stress was measured in aortic strips isolated from virgin and late pregnant Sprague-Dawley rats and then nontreated or treated for 1 h with IL-6 (10 pg/ml to 10 ng/ml). In endothelium-intact vascular strips, phenylephrine (Phe, 10(-5) M) caused an increase in active stress that was smaller in pregnant (4.2 +/- 0.3) than virgin rats (5.1 +/- 0.3 x 10(4) N/m(2)). IL-6 (1,000 pg/ml) caused enhancement of Phe contraction that was greater in pregnant (10.6 +/- 0.7) than virgin rats (7.5 +/- 0.4 x 10(4) N/m(2)). ACh and bradykinin caused relaxation of Phe contraction and increases in vascular nitrite production that were greater in pregnant than virgin rats. IL-6 caused reductions in ACh- and bradykinin-induced vascular relaxation and nitrite production that were more prominent in pregnant than virgin rats. Incubation of endothelium-intact strips in the presence of N(omega)-nitro-L-arginine methyl ester (10(-4) M) to inhibit nitric oxide (NO) synthase, or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 10(-5) M) to inhibit cGMP production in smooth muscle, inhibited ACh-induced relaxation and enhanced Phe-induced stress in nontreated but to a lesser extent in IL-6-treated vessels, particularly those of pregnant rats. Removal of the endothelium enhanced Phe-induced stress in nontreated but not IL-6-treated vessels, particularly those of pregnant rats. In endothelium-denuded strips, relaxation of Phe contraction with sodium nitroprusside, an exogenous NO donor, was not different between nontreated and IL-6-treated vessels of virgin or pregnant rats. Thus IL-6 inhibits endothelium-dependent NO-cGMP-mediated relaxation and enhances contraction in systemic vessels of virgin and pregnant rats. The greater IL-6-induced inhibition of vascular relaxation and enhancement of contraction in systemic vessels of pregnant rats supports a direct role for IL-6 as one possible mediator of the increased vascular resistance associated with hypertension of pregnancy.
Studies of synthetic peptide analogs of the amphipathic helix. Effect of charged amino acid residue topography on lipid affinity. (1980)

The amphipathic helix hypothesis for plasma lipoproteins was investigated using synthetic peptides. The lipid-associating properties of two potentially amphipathic model peptides and two analogs were studied by incubating synthetic peptides with small unilamellar vesicles and protein-lipid association examined by equilibrium density centrifugation, leakage of liposome-entrapped fluorescence compounds, intrinsic tryptophan fluorescence, and circular dichroism spectroscopy. The analog peptides were designed to determine the significance of the number and specific location of the charged residues in amphipathic domains of plasma lipoproteins to protein-lipid association. Based on the four procedures used to examine protein-lipid interactions, the two model peptides (18Aa, 18As) were found to associate strongly with liposomes; the two analog peptides (18As1, 18Asr), differing only with respect to the number and/or position of their charged residues, failed to demonstrate similar lipid binding properties. These findings support the earlier suggestions of the importance of the charged residues, but do not define the precise mechanisms involved. Such amino acids may help initiate the lipid-protein association by electrostatic interactions, contribute to the hydrophobicity of the nonpolar face of the helix by the acyl portion of lysine and arginine, and/or complement the charge distribution in the polar head regions of the phospholipid molecules.
Single Molecule Electronics and Tunneling in Molecules (2002)

Covalent tethering of single molecules between a gold surface and a gold nano-contact permits reliable measurement of the electronic properties of single molecules. Understanding of molecular electronics at the single molecule level should pave the way for understanding of more complex, multi-molecule devices. A single molecule study of n-alkanes shows that the electron decay rate, βN, is strongly affected by the nature of the connections to the molecule, βN being small and decreasing with applied bias. Mechanical (non-bonded) contacts result in βN increasing with bias, an outcome completely inconsistent with tunneling theory. The degree to which theory and experiment diverge even for such simple molecular electronic components is illustrated by the observation of contact charging in alkanethiol monolayers. We speculate that standard tunneling theory does not provide a full description of charge transport in even these simple molecules.
Effects of preventing O-glycosylation on the secretion of human chorionic gonadotropin in Chinese hamster ovary cells. (1987)

Human chorionic gonadotropin (hCG) is a member of a family of heterodimeric glycoprotein hormones that have a common alpha subunit but differ in their hormone-specific beta subunits. The beta subunit of hCG (hCG beta) is unique among the beta subunits in that it contains four mucin-like O-linked oligosaccharides attached to a carboxyl-terminal extension. To study the effects of O-glycosylation on the secretion and assembly of hCG, expression vectors containing either the hCG beta gene alone or together with the hCG alpha gene were transfected into a mutant Chinese hamster ovary cell line, IdID, which exhibits a reversible defect in O-glycosylation. Our results reveal that hCG beta can be secreted normally in the absence of its O-linked oligosaccharides. hCG beta devoid of O-linked carbohydrate can also combine efficiently with hCG alpha and be secreted as an intact dimer. We conclude that in Chinese hamster ovary cells, the hCG beta O-linked chains play no role in the assembly and secretion of hCG. The normal and O-linked oligosaccharide-deficient forms of hCG secreted by these cells should prove useful in examining the role of O-linked chains on the biological function of hCG.
Retrovirally transduced antisense sequences stably suppress P210BCR-ABL expression and inhibit the proliferation of BCR/ABL-containing cell lines (1993)

There is now strong evidence that the BCR-ABL gene product of the Philadelphia chromosome (P210) plays a crucial role in the pathogenesis of chronic myeloid leukemia (CML). We have previously shown that introduction of antisense oligonucleotides into K562 cells could transiently block the expression of P210 and specifically inhibit cellular growth in culture. In this report, we describe the use of a retroviral vector to introduce selected antisense and sense sequences, first into murine B10 cells, previously rendered interleukin-3 (IL-3) independent by transfection of BCR-ABL sequences, and second into K562 cells. The antisense transcripts generated under the control of MoMLV promoter specifically killed B10 cells in the absence of IL-3 and inhibited P210 expression almost completely. In K562 cells, the antisense sequences led to a dramatic reduction of P210 expression and increased their doubling time by more than twofold. This effect was not reversed by the addition of exogenous IL-3 to the culture medium. Control HeLa or HL60 cells infected with the same constructs did not show any change in proliferation rate, despite abrogation of the normal BCR gene products. Rather unexpectedly, P210 suppression was not lethal in K562 cells, showing that such a cell line does not rely entirely on the expression of P210 for surviving, but depends on it as far as growth properties are concerned. We conclude that this approach can successfully achieve stable suppression of the oncogenic protein P210 and may be used to study further the mechanisms by which P210 is transforming cells. The effect on fresh CML cells in bone marrow cultures remains to be assessed before we can tell whether this technique may be used for selective suppression of leukemic hematopoiesis in vitro.
Delayed gastric emptying in Parkinson's disease (2013)

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l-dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD.
Interactive global illumination using fast ray tracing (2002)

Rasterization hardware provides interactive frame rates for rendering dynamic scenes, but lacks the ability of ray tracing required for efficient global illumination simulation. Existing ray tracing based methods yield high quality renderings but are far too slow for interactive use. We present a new parallel global illumination algorithm that perfectly scales, has minimal preprocessing and communication overhead, applies highly efficient sampling techniques based on randomized quasi-Monte Carlo integration, and benefits from a fast parallel ray tracing implementation by shooting coherent groups of rays. Thus a performance is achieved that allows for applying arbitrary changes to the scene, while simulating global illumination including shadows from area light sources, indirect illumination, specular effects, and caustics at interactive frame rates. Ceasing interaction rapidly provides high quality renderings.
Regenerable Biosensor Platform:  A Total Internal Reflection Fluorescence Cell with Electrochemical Control (1998)

A new biosensor platform that provides simultaneous fluorescence detection and electrochemical control of biospecific binding has been developed and investigated using antibody-antigen and streptavidin-biotin interactions. Specifically, biotin was covalently bound to a transparent indium-tin oxide (ITO) working electrode, which also served as an integral part of a total internal reflection fluorescence (TIRF) flow cell. TIRF was used to monitor biospecific interactions, while electrochemical polarization was employed to control interactions between biotin and streptavidin or between biotin and anti-biotin antibodies. Both streptavidin and polyclonal anti-biotin antibodies bound kinetically irreversibly to the biotinylated surface. In the absence of electrochemical control, the assay exhibited an extremely slow release of the bound analytes, causing poor regeneration ability of the biosensor surface. However, electrochemical polarization was found to stimulate dissociation of kinetically irreversibly bound biotin-streptavidin and antibody-antigen complexes. A "square wave" polarization function stimulated dissociation more effectively than a "saw tooth" function over the same voltage range. Application of the square wave polarization resulted in regeneration of an active biotinylated surface. Electrochemical polarization also modified affinity and kinetics of protein adsorption, which could likely be used to promote biospecific interactions and/or to suppress nonspecific adsorption.
A Functional Fibroblast Growth Factor-1 Immunoglobulin Fusion Protein (1998)

Proteins of the fibroblast growth factor (FGF) family play diverse roles in embryonic development, angiogenesis, and wound healing. The most well studied targets of FGF activity typically are cells of mesodermal and neuroectodermal origin; in addition, expression of FGF-1 (acidic FGF) is increased at several sites of chronic immunologic injury, and recent studies show that FGF-1 also may interact with cells of the immune system. In some human T cells, FGF-1 can induce signals necessary for production of interleukin-2, a key cytokine required for T cell proliferation. To better characterize the interaction of FGF-1 with FGF receptors on T cells, a fusion protein was constructed containing a portion of the constant region of human IgG1 (Fc) at the amino terminus of FGF-1. The Fc-FGF-1 fusion protein retained FGF function as determined by stimulation of tyrosine phosphorylation and DNA synthesis in NIH 3T3 cells. Binding of the intact fusion protein to FGF receptor 1 (FGFR1) on T cells was demonstrated by immunoprecipitation of the receptor bound to Fc-FGF-1 and by flow cytometry showing binding of fusion protein to T cells expressing FGFR1. This functional Fc-FGF-1 protein should prove useful in identifying FGFR-expressing cells.