gebhart/patrepeval huggingface dataset:
Clinical Implications of the p53 Tumor-Suppressor Gene (1993)

The crucial differences between normal cells and cancer cells stem from discrete changes in specific genes controlling proliferation and tissue homeostasis. Over 100 such cancer-related genes have been discovered, several of which are implicated in the natural history of human cancer because they are consistently found to be mutated in tumors. The p53 tumor-suppressor gene is the most striking example because it is mutated in about half of almost all types of cancer arising from a wide spectrum of tissues. Other tumor-suppressor genes important in human cancers, such as adenomatous polyposis coli, Wilms' tumor type 1, and neurofibromatosis type 1, . . .
Headache and botulinum toxin (2005)

The authors discuss clinical and international experience about botulinum toxins (BTX types A and B) in headache treatment. Data from literature suggest good results for the treatment of tension-type headache, migraine and chronic tension-type headache. In the present paper mechanisms of action and injection sites will also be discussed.
Low Plasma Ghrelin Is Associated With Insulin Resistance, Hypertension, and the Prevalence of Type 2 Diabetes (2003)

Experimental studies have suggested that ghrelin plays a role in glucose homeostasis and in the regulation of blood pressure (BP). We therefore assessed the hypothesis that a low ghrelin concentration may be a risk factor for type 2 diabetes and hypertension. We also characterized the effect of the ghrelin Arg51Gln and Leu72Met mutations on ghrelin concentrations in the population-based hypertensive (n = 519) and control (n = 526) cohorts of our OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. The fasting plasma ghrelin concentrations of 1,040 subjects were analyzed using the radioimmunoassay method. Insulin sensitivity was assessed using the quantitative insulin sensitivity check index (QUICKI). Ghrelin concentrations were negatively associated with fasting insulin (P < 0.001), systolic (P = 0.026) and diastolic BP (P = 0.018), and the prevalence of type 2 diabetes (P = 0.015) and insulin resistance (P < 0.001) in the multivariate models. In the control cohort, low ghrelin was associated with hypertension (BP >140/90 mmHg) (P = 0.031). The subjects with the ghrelin 51Gln allele had lower ghrelin concentrations than the Arg51Arg homozygotes (P = 0.001). We conclude that low ghrelin is independently associated with type 2 diabetes, insulin concentration, insulin resistance, and elevated BP. Therefore, it might have some role in the etiology of type 2 diabetes and the regulation of BP. The ghrelin Arg51Gln mutation is associated with low plasma ghrelin concentrations.
Immunology of multiple sclerosis. (1994)

Multiple sclerosis (MS), a putative autoimmune disease of unknown etiology, is characterized by CNS perivascular inflammation, foci of demyelination, and elevated intrathecal production of oligoclonal IgG's. T and B cells, macrophages, and microglia are all implicated in contributing to the initiation and perpetuation of the disease. In this brief review we discuss the possible role of T cells, B cells, macrophages, and microglia in contributing to the initiation and perpetuation of inflammation and demyelination in MS. Data from the rodent model of MS, experimental allergic encephalomyelitis (EAE) supporting a immunological basis for the pathology of MS is noted. This paper discusses recent data suggesting an interaction of the above-mentioned cells, as well as serum and CSF proteins including complement and anti-myelin/oligodendrocyte antibodies, in the pathogenesis of MS and EAE. Additionally, this review describes each cell type including the clinical and experimental evidence for their contribution to the immunologically mediated pathology of MS. Following the description of the role of individual cells, there is consideration of: the possible interaction of cells with the blood brain barrier (BBB) under normal and pathologic inflammatory conditions; the traffic of cells into the CNS in inflammation; and the role of antigen presentation within the CNS in the initiation, and perpetuation, of the CNS immune response. Finally, the review suggests a role for T cells in the initiation, amplification, and possibly the termination of CNS inflammatory events with particular attention paid to the pattern of T cell activation and T cell cytokine production.
Construction of Linker-Scanning Mutations Using the Polymerase Chain Reaction (2003)

In the previous chapter we described linker scanning mutagenesis by oligonucleotide ligation. In this chapter we describe a more recent and versatile procedure that makes use of amplification by the polymerase chain reaction (PCR). For a description of the traditional method of generating linker scanning mutants by combination of deletion fragments, see ref. .
Dendritic Cells Can Turn CD4+ T Lymphocytes into Vascular Endothelial Growth Factor-Carrying Cells by Intercellular Neuropilin-1 Transfer (2006)

Neuropilin-1 (NRP1) is a transmembrane protein expressed on neuronal and endothelial cells where it plays a crucial role in guiding axons and regulating angiogenesis. We have recently shown that NRP1 also is expressed on dendritic cells (DC) in the human immune system and have proposed a role for NRP1 in the first stages of the immune response. In these studies, we show that NRP1 can be transferred with a high efficiency from human DC to T lymphocytes by trogocytosis. The NRP1 transfer can occur independently of T lymphocyte activation; the amount of NRP1 transferred depends on the NRP1 expression level on APC and is enhanced when T cells are activated through the TCR. Moreover, the NRP1 transfer occurs between specific donor and recipient cells, because no NRP1 transfer is observed between endothelial cells and T lymphocytes or between APCs and CD34(+) hemopoietic cells. Finally, we show that a major NRP1 ligand, vascular endothelial growth factor (VEGF)(165), is secreted by mature human DCs and binds to NRP1 captured by T lymphocytes. These results show that NRP1 transfer to T lymphocytes during the immune synapse can convert T lymphocytes into VEGF(165)-carrying cells. Together with the enhanced signaling of VEGF-R2 on endothelial cells in the presence, in trans, of the NRP1-VEGF(165) complex, our results suggest that the intercellular transfer of NRP1 might participate in the Ag-independent remodelling of the endothelial vessels in secondary lymphoid organs during inflammation.
A Mammalian Helix-Loop-Helix Factor Structurally Related to the Product of Drosophila Proneural Gene atonal Is a Positive Transcriptional Regulator Expressed in the Developing Nervous System (1995)

We report the molecular characterization of a mouse basic helix-loop-helix factor, designated MATH-1, structurally related to the product of the Drosophila proneural gene atonal. MATH-1 mRNA is first detected in the cranial ganglions and the dorsal part of the central nervous system on embryonic day 9.5 (E9.5). From E10.5 onward, prominent expression of MATH-1 continues in the dorsal part of the central nervous system but becomes restricted to the external granular layer of the cerebellum by E18 and is undetectable in the adult nervous system. MATH-1 activates E box-dependent transcription in collaboration with E47, but the activity is completely antagonized by the negative regulator of neurogenesis HES-1. These results suggest that MATH-1 may be a target of HES-1 and play a role in the differentiation of subsets of neural cells by activating E box-dependent transcription.
Reversible Passivation of Silicon Dangling Bonds with the Stable Radical TEMPO (2003)

TEMPO, 2,2,6,6-tetramethylpiperidinyloxy, was used to passivate dangling bonds on hydrogen-terminated Si(100) and Si(111) surfaces. TEMPO reacts with the dangling bond through a radical coupling reaction of the oxygen and silicon atoms. STM images reveal that the TEMPO-passivated Si is stable under typical imaging conditions and also protects the surface from reaction with styrene. TEMPO may also be desorbed from the surface by scanning at elevated voltages (greater than −3.5 V) and provides the ability to selectively remove TEMPO to prepare single dangling bonds on an otherwise passivated surface.
ENHANCING THE LONGEVITY AND IN VIVO POTENCY OF THERAPEUTIC PROTEINS: THE POWER OF CTP (2015)

The relatively short serum half-life of polypeptides poses a challenge in the design of protein therapeutics. Extending the half-life and bioavailability while maintaining safety and efficacy has been attempted using various techniques such as sustained-release preparations and long-acting conjugations. A novel, alternative approach involves the fusion of a natural polypeptide, the C-terminal peptide (CTP) of human chorionic gonadotropin (hCG), to the target protein. The fertility drug FSH-CTP (Elonva®) was the first CTP-containing protein to receive marketing approval. This versatile platform has been utilized to improve the pharmacokinetic (PK) and pharmacodynamic (PD) properties of additional target proteins from different families. This includes CTP fused to erythropoietin (EPO), interferon beta (IFNβ) and coagulation factors VII and IX, as well as thyroid-stimulating hormone (TSH), oxyntomodulin, and growth hormone (GH). Two long-acting, CTP-containing chimeras are currently in clinical development by OPKO Biologics. Long-acting FVIIa-CTP (MOD-5014) is being developed for the treatment of hemophilia with an expected dosing regimen of 2-3 times a week. MOD-5014 exhibited improved in vivo PK/PD, coagulation, and safety parameters in comparison to rFVIIa. This supports the upcoming clinical evaluation of MOD-5014 in hemophilic patients. Long-acting CTP-modified hGH (MOD-4023), currently in advanced clinical development by OPKO, may replace current GH therapy in patients suffering from GH deficiency (GHD) by requiring fewer injections. Animal studies showed that once-weekly administration of MOD-4023 resulted in favorable weight gain response in comparison to daily hGH and established an excellent safety profile. A Phase 1 study in healthy volunteers and Phase 2 trial in GHD patients confirmed the safety and tolerability of MOD-4023 in adults; a pivotal Phase 3 study in GHD adults in ongoing. A recently completed Phase 2 study in GHD children demonstrated an improved PK/PD profile and efficacy for once-weekly MOD-4023 in comparison to daily hGH, supporting OPKO's upcoming Phase 3 trial in pediatric GHD patients. Based on recent pre-clinical and clinical experience, CTP technology was proven a valid, flexible platform for the generation of safe and effective long-acting protein therapeutics, with the potential to offer an improved treatment for patients and better quality of life.
Domain motions in phosphoglycerate kinase: determination of interdomain distance distributions by site-specific labeling and time-resolved fluorescence energy transfer. (1992)

3-Phosphoglycerate kinase is composed of two globular domains separated by a wide cleft. The substrate binding sites are situated on the inner surfaces of the two domains. By analogy to other kinases, it has been postulated that the catalytic mechanism of phosphoglycerate kinase involves a hinge bending domain motion that brings the substrates together to allow phosphoryl transfer. To characterize this large-scale conformational change, as well as the dynamics of the unliganded enzyme in solution, we have applied site-directed mutagenesis and time-resolved nonradiative energy transfer techniques. Two genetically engineered cysteines (Cys-135 and Cys-290), one in each of the two domains, were covalently labeled with a donor and acceptor pair of fluorescent probes. Analysis of subnanosecond fluorescence decay curves yielded the equilibrium distribution of interdomain distances. In the absence of substrates, the distribution of distances between the two labeled sites was very broad, with a full width at half maximum estimated as 20 A or broader, indicative of a large number of conformational substates in solution. The mean distance, 31.5 +/- 1 A, was 8 A smaller than in the crystal structure. Upon addition of ATP alone or of ATP and 3-phosphoglycerate, the average distance increased to 38 +/- 1 A and the width of the distribution decreased. Addition of 3-phosphoglycerate alone induced a similar but smaller change. The rate of conformational state fluctuations (interconversion between states) was found to be slow on the nanosecond time scale, as expected for a protein with a relatively large interdomain contact area.
Expression and function of CD40 on Hodgkin and Reed-Sternberg cells and the possible relevance for Hodgkin's disease (1994)

CD40 was originally described as a B-cell-restricted antigen and was subsequently found to be a member of the tumor necrosis factor (TNF) receptor superfamily. CD40 is also expressed on dendritic cells, thymic epithelium, monocytes, and some carcinoma cell lines, and plays a critical role in cell contact-dependent activation. Primary and cultured Hodgkin and Reed-Sternberg (H-RS) cells, the presumed malignant cells of Hodgkin's disease (HD); were found to express high levels of cell surface CD40. We found that recombinant CD40 ligand (CD40L) induced interleukin-8 (IL-8) secretion and enhanced IL-6, TNF, and lymphotoxin-alpha (LT-alpha/TNF-beta) release from cultured H-RS cells. These cytokines play a significant role in the clinical presentation and pathology of HD, a tumor of cytokine-producing cells. CD40L had no mitogenic activity for HD-derived cell lines. In contrast, CD40L enhanced expression of costimulatory molecules intracellular adhesion molecule-T and B7–1 on cultured H-RS cells, both of which are overexpressed on primary H-RS cells. In addition, CD40L induced a 40% to 60% reduction of the expression of the HD-associated CD30 antigen, another member of the TNF receptor superfamily. Primary and cultured H- RS cells express not only CD30, but also CD40. CD40L has pleiotropic biologic activities on H-RS cells, and the CD40-CD40L interaction might be a critical element in the deregulated cytokine network and cell contact-dependent activation cascade typical for HD.
Education in a declining economy : the case of Zambia, 1975-1985 (1991)

During the past twelve years, Zambia has experienced increasingly grave financial problems. The decline in the economy has affected all sectors, including education. The deterioration occurred at a time when the population was growing at a rapid rate. Hence the education sector has been subject to two opposing pressures : a fiscal pressure to curtail financial commitments and a demographic pressure to increase the provision of education. To set educational provision in its historical context, the study provides an overview of the development of education before 1975. Several issues have a relatively long history, such as concern about the system's coverage, about the quality of education being provided, and its suitability in preparing young people to face a world where the number of formal sector job opportunities is severely limited. In general, the study found evidence of serious structural imbalances in education financing that became more marked during the years of economic difficulty. In conclusion, the study reflected on how the more vulnerable areas - primary schools, teacher education, school leavers, and literacy - experienced economic constraints more severely; whereas improvements that occurred were enjoyed by universities and the secondary system.
Detection of Pediococcus spp. in brewing yeast by a rapid immunoassay (1992)

A membrane immunofluorescent-antibody test was developed to detect diacetyl-producing Pediococcus contaminants in brewery pitching yeast (yeast [Saccharomyces cerevisiae] slurry collected for reinoculation). Centrifugations at 11 and 5,100 x g separate yeast cells from bacteria and concentrate the bacteria, respectively. Pelleted bacteria resuspended and trapped on a black membrane filter are reacted with monoclonal antibodies specific for cell surface antigens and then with fluorescein-conjugated indicator antibodies. Whether pitching yeast is contaminated with pediococci at 0.001% is determined in less than 4 h. The sensitivity of the assay is 2 orders of magnitude below the Pediococcus detection limit of direct microscopy.
TnT - A Statistical Part-of-Speech Tagger (2000)

Trigrams'n'Tags (TnT) is an efficient statistical part-of-speech tagger. Contrary to claims found elsewhere in the literature, we argue that a tagger based on Markov models performs at least as well as other current approaches, including the Maximum Entropy framework. A recent comparison has even shown that TnT performs significantly better for the tested corpora. We describe the basic model of TnT, the techniques used for smoothing and for handling unknown words. Furthermore, we present evaluations on two corpora.
The relationship between catecholamine levels in the hypothalamus and amygdala under influence of glucose overloading in hungry and sated rats. (1979)

The effect of intragastric glucose infusion (1.5 g per rat) to sated rats on the catecholamine content in the medial basal and lateral hypothalamic regions and in the nuclei of the amygdaloid body was investigated. The effect of glucose overloading on the noradrenaline (NA) and dopamine (DA) content in the ventromedial (VMH) and arcuate hypothalamic nuclei was also studied in rats deprived of food for 48 hr. Glucose administration to rats fed ad lib. resulted in an increase in NA in the VMH and a decrease in DA in the central nucleus of the amygdaloid body. In fasted animals glucose overloading partially reversed the changes of NA concentration in the arcuate nucleus produced by starvation, whereas in the VMH glucose was not effective in producing any changes of catecholamine content. Possible interrelations between the amygdala and hypothalamus in respect to the role of catecholamines in the regulation of food intake are discussed.
First-in-Human Imaging with 89Zr-Df-IAB2M Anti-PSMA Minibody in Patients with Metastatic Prostate Cancer: Pharmacokinetics, Biodistribution, Dosimetry, and Lesion Uptake (2016)

<sup>89</sup>Zr-IAB2M is safe and demonstrates favorable biodistribution and kinetics for targeting metastatic prostate cancer. Imaging with 10 mg of minibody mass provides optimal biodistribution, and imaging at 48 h after injection provides good lesion visualization. Assessment of lesion targeting is being studied in detail in an expansion cohort.
PHF‐tau from Alzheimer's brain comprises four species on SDS‐PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase‐3β (1994)

Extensive in vitro phosphorylation of a purified preparation of control human brain tau consistently produces four rather than, as previously believed, three tau species on SDS-PAGE. The species thus generated are shifted on SDS-PAGE to positions that match those of PHF-tau isolated from Alzheimer's disease brain. A mixture of recombinant human tau isoforms phosphorylated by GSK-3 beta gave similar results to those obtained with control human brain tau. In vitro phosphorylation of the individual recombinant isoforms by GSK-3 beta showed that the four bands of PHF-tau are likely to consist of isoforms 3R,0 alone; 4R,0 with 3R,29; 4R,29 with 3R,58 and 4R,58 alone.
BRIEF: Computing a Local Binary Descriptor Very Fast (2011)

Binary descriptors are becoming increasingly popular as a means to compare feature points very fast while requiring comparatively small amounts of memory. The typical approach to creating them is to first compute floating-point ones, using an algorithm such as SIFT, and then to binarize them. In this paper, we show that we can directly compute a binary descriptor, which we call BRIEF, on the basis of simple intensity difference tests. As a result, BRIEF is very fast both to build and to match. We compare it against SURF and SIFT on standard benchmarks and show that it yields comparable recognition accuracy, while running in an almost vanishing fraction of the time required by either.
Assembly Dynamics and Stoichiometry of the Apoptosis Signal-regulating Kinase (ASK) Signalosome in Response to Electrophile Stress (2016)

Apoptosis signal-regulating kinase 1 (ASK1) is a key sensor kinase in the mitogen-activated protein kinase pathway that transduces cellular responses to oxidants and electrophiles. ASK1 is regulated by a large, dynamic multiprotein signalosome complex, potentially including over 90 reported ASK1-interacting proteins. We employed both shotgun and targeted mass spectrometry assays to catalogue the ASK1 protein-protein interactions in HEK-293 cells treated with the prototypical lipid electrophile 4-hydroxy-2-nonenal (HNE). Using both epitope-tagged overexpression and endogenous expression cell systems, we verified most of the previously reported ASK1 protein-protein interactions and identified 14 proteins that exhibited dynamic shifts in association with ASK1 in response to HNE stress. We used precise stable isotope dilution assays to quantify protein stoichiometry in the ASK signalosome complex and identified ASK2 at a 1:1 stoichiometric ratio with ASK1 and 14-3-3 proteins (YWHAQ, YWHAB, YWHAH, and YWHAE) collectively at a 0.5:1 ratio with ASK1 as the main components. Several other proteins, including ASK3, PARK7, PRDX1, and USP9X were detected with stoichiometries of 0.1:1 or less. These data support an ASK signalosome comprising a multimeric core complex of ASK1, ASK2, and 14-3-3 proteins, which dynamically engages other binding partners needed to mediate diverse stress-response signaling events. This study further demonstrates the value of combining global and targeted MS approaches to interrogate multiprotein complex composition and dynamics.
Enhancing Thermal Conductivity of Fluids With Nanoparticles (1995)

Abstract Low thermal conductivity is a primary limitation in the development of energy-efficient heat transfer fluids that are required in many industrial applications. In this paper we propose that an innovative new class of heat transfer fluids can be engineered by suspending metallic nanoparticles in conventional heat transfer fluids. The resulting “nanofluids” are expected to exhibit high thermal conductivities compared to those of currently used heat transfer fluids, and they represent the best hope for enhancement of heat transfer. The results of a theoretical study of the thermal conductivity of nanofluids with copper nanophase materials are presented, the potential benefits of the fluids are estimated, and it is shown that one of the benefits of nanofluids will be dramatic reductions in heat exchanger pumping power.
New Fluorescence Techniques for High-Throughput Drug Discovery (2003)

The rapid increase of compound libraries as well as new targets emerging from the Human Genome Project require constant progress in pharmaceutical research. An important tool is High-Throughput Screening (HTS), which has evolved as an indispensable instrument in the pre-clinical target-to-IND (Investigational New Drug) discovery process. HTS requires machinery, which is able to test more than 100,000 potential drug candidates per day with respect to a specific biological activity. This calls for certain experimental demands especially with respect to sensitivity, speed, and statistical accuracy, which are fulfilled by using fluorescence technology instrumentation. In particular the recently developed family of fluorescence techniques, FIDA (Fluorescence Intensity Distribution Analysis), which is based on confocal single-molecule detection, has opened up a new field of HTS applications. This report describes the application of these new techniques as well as of common fluorescence techniques--such as confocal fluorescence lifetime and anisotropy--to HTS. It gives experimental examples and presents advantages and disadvantages of each method. In addition the most common artifacts (auto-fluorescence or quenching by the drug candidates) emerging from the fluorescence detection techniques are highlighted and correction methods for confocal fluorescence read-outs are presented, which are able to circumvent this deficiency.