gebhart/patrepeval huggingface dataset:
Glutamate dehydrogenase from the hyperthermophile Pyrococcus furiosus. Thermal denaturation and activation. (1992)

Pyrococcus furiosus is a marine hyperthermophile that grows optimally at 100 degrees C. Glutamate dehydrogenase (GDH) from P. furiosus is a hexamer of identical subunits and has an M(r) = 270,000 +/- 5500 at 25 degrees C. Electron micrographs showed that the subunit arrangement is similar to that of GDH from bovine liver (i.e. 3/2 symmetry in the form of a triangular antiprism). However, GDH from P. furiosus is inactive at temperatures below 40 degrees C and undergoes heat activation above 40 degrees C. Both NAD+ and NADP+ are utilized as cofactors. Apparently the inactive enzyme also binds cofactors, since the enzyme maintains the ability to bind to an affinity column (Cibacron blue F3GA) and is specifically eluted with NADP+. Conformational changes that accompany activation and thermal denaturation were detected by precision differential scanning microcalorimetry. Thermal denaturation starts at 110 degrees C and is completed at 118 degrees C. delta(cal) = 414 Kcal [mol GDH]-1. Tm = 113 degrees C. This increase in heat capacity indicates an extensive irreversible unfolding of the secondary structure as evidenced also by a sharp increase in absorbance at 280 nm and inactivation of the enzyme. The process of heat activation of GDH from 40 to 80 degrees C is accompanied by a much smaller increase in absorbance at 280 nm and a reversible increase in heat capacity with delta(cal) = 187 Kcal [mol GDH]-1 and Tm = 57 degrees C. This absorbance change as well as the moderate increase in heat capacity suggest that thermal activation leads to some exposure of hydrophobic groups to solvent water as the GDH structure is opened slightly. The increase in absorbance at 280 nm during activation is only 12% of that for denaturation. Overall, GDH appears to be well adapted to correspond with the growth response of P. furiosus to temperature.
Reconstructed human epidermis: absence of Langerhans cells and failure to stimulate allogeneic lymphocytes in vitro. (1988)

Whole human skin can be reconstructed in vitro, using dermal equivalents made of fibroblasts in a collagen matrix. We recently described a new method of epidermalization of dermal equivalents, based on the insertion of punch biopsies and the migration of epidermal cells (EC) on the reconstructed dermis. In the present study, we show that no MHC class II or T6 positive Langerhans cells (LC) can be detected in this new epidermis. Functional studies with EC of this reconstructed epidermis show that these EC completely fail to induce proliferation of allogeneic lymphocytes in mixed epidermal cell lymphocyte reactions and to raise an allogeneic T cell response. In contrast, fresh EC from the same donors induce a strong proliferative and cytotoxic response of the same effector cells. Moreover, the addition of fresh LC-containing EC autologous to effector lymphocytes does not restore an allogeneic proliferative and cytotoxic response directed against class I different EC of the new epidermis. Such a non-immunogenic whole skin model composed of two compartments, dermis and epidermis, completely devoid of class II-bearing antigen presenting cells, is thus a very promising technique for allogeneic skin grafting in the treatment of burns.
Simultaneous calibration of a robot and a hand-mounted camera (1995)

A popular configuration widely used in a variety of robotic applications is to mount a camera on the robot manipulator hand. Before performing a measurement task using such a system, both the camera and the robot need to be calibrated. In this paper, a procedure is developed for simultaneous calibration of a robot and a monocular camera. Unlike conventional approaches based on first calibrating the camera and then calibrating the robot, the algorithm solves for the kinematic parameters of the robot and camera in one stage, thus eliminating error propagation and improving noise sensitivity. Only two parameters are added to a robot calibration model to represent camera geometry. With this addition, different levels of calibration can be done under a unified framework. An error model relating-image measurement residuals to kinematic parameter deviations is derived. Simulation and experimental studies have been conducted to assess the effectiveness of the proposed procedure.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Thrombin Generation in Plasma: Its Assessment Via the Endogenous Thrombin Potential (1995)

Thrombin generation is a pivotal function of plasma in haemostasis and thrombosis. Its mechanism is essentially the classical cascade, the velocity of which is governed by the availability of factors Va and VIIIa and that is confined to the surface of the procoagulant membranes which appear at the site of injury. There is no routine test that quantitatively renders the thrombin forming capacity of a plasma sample. Clotting times (PT-prothrombin time, APTT-activated partial tromboplastin time) do not reflect the over all thrombin generation and are insensitive to hypercoagulative states. The endogenous thrombin potential (ETP), i.e. the area under the thrombin generation curve, better represents this function. We developed a method to assess the ETP in the routine laboratory. The first results suggest that it is a sensitive indicator for every form of anticoagulation. It is increased in hypercoagulable states thus far studied, both congenital and acquired and can be designed to indicate deficiencies in protein C and S and APC (activated protein C) resistance.
A user-centred approach to functions in Excel (2003)

We describe extensions to the Excel spreadsheet that integrate user-defined functions into the spreadsheet grid, rather than treating them as a "bolt-on". Our first objective was to bring the benefits of additional programming language features to a system that is often not recognised as a programming language. Second, in a project involving the evolution of a well-established language, compatibility with previous versions is a major issue, and maintaining this compatibility was our second objective. Third and most important, the commercial success of spreadsheets is largely due to the fact that many people find them more usable than programming languages for programming-like tasks. Thus, our third objective (with resulting constraints) was to maintain this usability advantage.Simply making Excel more like a conventional programming language would not meet these objectives and constraints. We have therefore taken an approach to our design work that emphasises the cognitive requirements of the user as a primary design criterion. The analytic approach that we demonstrate in this project is based on recent developments in the study of programming usability, including the Cognitive Dimensions of Notations and the Attention Investment model of abstraction use. We believe that this approach is also applicable to the design and extension of other programming languages and environments.
Biomimetic Chemical Sensors Using Nanoelectronic Readout of Olfactory Receptor Proteins (2011)

We have designed and implemented a practical nanoelectronic interface to G-protein coupled receptors (GPCRs), a large family of membrane proteins whose roles in the detection of molecules outside eukaryotic cells make them important pharmaceutical targets. Specifically, we have coupled olfactory receptor proteins (ORs) with carbon nanotube transistors. The resulting devices transduce signals associated with odorant binding to ORs in the gas phase under ambient conditions and show responses that are in excellent agreement with results from established assays for OR-ligand binding. The work represents significant progress on a path toward a bioelectronic nose that can be directly compared to biological olfactory systems as well as a general method for the study of GPCR function in multiple domains using electronic readout.
Chemical treatment of Escherichia coli: 1. Extraction of intracellular protein from uninduced cells (1997)

Extraction of intracellular protein from Escherichia coli is traditionally achieved by mechanical disruption. A chemical treatment that destroys the integrity of the bacterial cell wall and could provide an alternative technique is examined in this study. Treatment with a combination of the chelating agent ethylenediaminetet-raacetate (EDTA) (greater than 0.3 mM) and the chaotropic agent urea (6 M) is highly effective at releasing protein from uninduced E. coli. The 6 M urea in the presence of 3 mM EDTA can release cytoplasmic protein from both logarithmic-phase and stationary-phase E. coli cells at levels equivalent to mechanical disruption. The concentrations of the two chemical agents were the major variables affecting the maximum levels of protein release. Several minor variables and interactions were also identified. The kinetics of protein release is first order. For 2, 4, and 6 M urea with 3 mM EDTA, the time constant is approximately 2.5 min independent of urea concentration. Kinetics for 3 mM EDTA without urea is considerably slower, with a time constant of 12.3 min. © 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 53: 453–458, 1997.
The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members (2008)

Contrary to expectations, patients receiving perioperative ketamine had a lower prevalence of PTSD than soldiers receiving no ketamine during their surgeries despite having larger burns, higher injury severity score, undergoing more operations, and spending more time in the ICU.
Lens-ended fibers for medical applications: a new fabrication technique (1984)

Microlens-ended fibers may be of great usefulness in medical applications, in particular in endoscopic laser treatment and surgery. Previous fabrication techniques of integral microlenses have mainly faced the problems related to optical communications, where damage due to high-power lasers does not occur. We describe a novel method, the laser-microfurnace technique, which uses the laser energy delivered by the fiber itself to create a microfurnace in a suitable material that reirradiates energy in a different wavelength band and causes the fiber tip to melt. This easy and reliable method is applicable to all types of fiber, even those with pure-silica core and large core diameter. No special equipment or training of the operator is required, so fabrication of microlenses may be carried out even in the surgery room. Experimental process parameters are reported.
Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive (2003)

The aim of this study was to evaluate the roles of IL-18 and IL-12 in potentiating the encephalitogenic activity of T cell lines specific for myelin oligodendrocyte glycoprotein (MOG(35-55)). MOG-specific T cells stimulated with anti-CD3 and anti-CD28 in the presence of IL-12 or IL-18 alone transferred only mild experimental autoimmune encephalomyelitis (EAE) into a low percentage of recipients. However, T cells cocultured with both cytokines transferred aggressive clinical and histological EAE into all recipients. Coculture of T cells with IL-12 enhanced the secretion of IFN-gamma, but not TNF-alpha, whereas coculture with IL-18 enhanced the secretion of TNF-alpha, but not INF-gamma. However, coculture with both IL-18 and IL-12 induced high levels of both TNF-alpha and IFN-gamma. Additionally, IL-12 selectively enhanced mRNA expression of CCR5, whereas IL-18 selectively enhanced the expression of CCR4 and CCR7, and CCR4 and CCR5 were coexpressed on the surface of T cells cocultured with IL-12 and IL-18. Finally, estrogen treatment, previously found to inhibit both TNF-alpha and IFN-gamma production, completely abrogated all signs of passive EAE. These data demonstrate that optimal potentiation of encephalitogenic activity can be achieved by conditioning MOG-specific T cells with the combination of IL-12 and IL-18, which, respectively, induce the secretion of IFN-gamma/CCR5 and TNF-alpha/CCR4/CCR7, and that estrogen treatment, which is known to inhibit both proinflammatory cytokines, can completely ablate this aggressive form of passive EAE.
Design of potent and selective human cathepsin K inhibitors that span the active site (1997)

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.
Immobilization of Arthrobacter simplex in Thermally Reversible Hydrogels: Effect of Gel Hydrophobicity on Steroid Conversion (1991)

Arthrobacter simplex cells have been immobilized in a series of thermally reversible hydrogels having different gel hydrophobicities. Steroid conversion from hydrocortisone to prednisolone via the delta 1-dehydrogenase system was greatly affected by the relative hydrophobicities of the gel matrices, which were prepared by copolymerizing varying ratios of N-isopropylacrylamide to acrylamide. The characteristics of the immobilized cells, such as optimal temperatures, Km values, and the effects of an added artificial electron acceptor, were largely influenced by the gel matrices and their different lower critical solution temperatures (LCST). The data indicate that the microenvironment of the dehydrogenation system is quite different within the different hydrophilic/hydrophobic gel matrices. The high partitioning of water-insoluble steroids into the hydrophobic regions and the reduced possibility of product inhibition within the more hydrophobic gel matrices may cause the observed higher steroid conversion in these gels. A possible model for immobilized A. simplex cells in such different gel matrices is proposed.
A Vision System for Real Time Road and Object Recognition for Vehicle Guidance (1987)

One crucial component of a control system for autonomous vehicle guidance is real time image analysis. This system part is burdened by the maximum flow of information. To overcome the high demands in computation power a combination of knowledge based scene analysis and special hardware has been developed. The use of knowledge based image analysis supports real time processing not by schematically evaluating all parts of the image, but only evaluating those which contain relevant information. This is due to the fact that in many practical problems the relevant information is very unevenly distributed over the image. Preknowledge of the problem or the aim of the mission and expectations or predictions about the scene sustantially reduce the amount of information to be processed. The operations during such an analysis may be divided into two classes - simple processes, e.g. filters, correlation, contour processing and simple search strategies - complex search and control strategy This classification supplied the concept for a special hardware. The complex tasks are performed by a universal processor 80286 while the remaining tasks are executed by a special coprocessor (including image memory). This combination permits the use of filter masks with a arbitrary geometry together with a powerful search strategy. A number of these basic modules may be configured into a multiprocessor system. The universal processor is programmed in a high level language. To support the coprocessor a set of software tools has been built. They permit interactive graphical manipulation of filtermasks, generation of simple search strategies and non real time simulation. Also the real data structures that control the function of the coprocessor are generated by this software package. The system is used within our autonomous vehicle project. One set of algorithms tracks the border lines of the road even if they are broken or disturbed by dirt. Also shadows of bridges crossing the road are tolerated. Another algorithm tracks prominent points on other objects (e.g. vehicles) to collect possible candidates of obstacles during the real time run. A complete image analysis for the relevant features is performed in one video cycle (16.6 ms).
Information Needed to Conduct First-in-Human Oncology Trials in the United States: A View from a Former FDA Medical Reviewer (2010)

Any drug product not previously authorized for marketing in the United States requires the submission of an Investigational New Drug application (IND). Although the IND submission is regulated by law (21CFR 312), there are several issues that are not covered in the law or U.S. Food and Drug Administration (FDA) guidances that are important for a successful IND submission. For oncology products, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance (still in draft) is the most relevant. The most difficult issues to solve in an IND are chemistry, manufacturing and control information, and pharmacology and toxicology. In the United States, pivotal toxicological studies are done in two species: one rodent (i.e., rats) and one nonrodent (i.e., dogs). The safe starting dose is based on toxicological findings observed in the most sensitive species. Most first-in-humans studies in oncology include patients with advanced and/or metastatic disease, as serious to severe side effects of anticancer therapies are often less threatening to advanced cancer patients than their disease, and acceptable levels of toxicity are higher. For other indications (adjuvant therapy, chemoprevention, or healthy volunteers), first-in-human studies need to follow ICH M3 guidelines as the risk to benefit ratio in those subjects and/or patients without evidence of tumor is different. The division welcomes submissions before the IND, also known as pre-INDs, particularly for products with "atypical issues."
Characterization of the Pseudomonas aeruginosa pilus adhesin: confirmation that the pilin structural protein subunit contains a human epithelial cell-binding domain (1989)

Previous studies have suggested that the Pseudomonas aeruginosa PAK pilus adhesin moiety resides in an epithelial cell-binding domain located in the C-terminal region of the PAK pilin structural protein. Synthetic peptides Ac17red (a synthetic peptide with a sequence identical to that of PAK pilin residues 128 to 144, with the Cys-129 and Cys-142 residues being in the reduced state) and Ac17ox (a synthetic peptide with a sequence identical to that of PAK pilin residues 128 to 144, with a formed disulfide bridge between the amino acid residues Cys-129 and Cys-142), which should contain the epithelial cell-binding domain, were synthesized. Ac17red and Ac17ox both bound to buccal epithelial cells (BECs) and to ciliated tracheal epithelial cells (TECs). Ac17ox had a Km of 6.40 microM for binding to BECs, while Ac17red had a Km of 9.87 microM. Ac17red bound to the same receptor sites that purified pili did and competitively inhibited the binding of purified PAK pili to BECs. BEC glycoproteins with molecular masses of 82, 55 to 51, and 40 kilodaltons immobilized on nitrocellulose exhibited periodate-sensitive receptor activity for Ac17red; similar activity has been found for PAK pili. Ac17red, Ac17ox, and PAK pili bound to the cilia and luminal portions of the cytoplasmic membrane of human TECs, the same regions to which P. aeruginosa whole cells bind. PAK pilin has an epithelial cell-binding domain that resides in the C-terminal region of the protein.
Impact of theagrQuorum‐Sensing System on Adherence to Polystyrene inStaphylococcus aureus (2000)

Biofilm formation by Staphylococcus aureus is a serious problem in nosocomial infections. There are great differences in the capacity of S. aureus to express biofilms, but the reasons are unknown. In all, 105 S. aureus strains were tested for a correlation between the agr quorum-sensing system phenotype and the ability of S. aureus to adhere to polystyrene. Some 78% of agr-negative, but only 6% of agr-positive, strains formed a biofilm, demonstrating a profound impact of agr on biofilm formation. This result was confirmed with defined agr mutants and by inhibition of agr with quorum-sensing blockers. The observed effect was not due to differential expression of the autolysin Atl or of the exopolysaccharide polysaccharide intercellular adhesin but seemed to be caused, at least in part, by the surfactant properties of delta-toxin. The detected biofilm-enhancing effect of S. aureus quorum-sensing blockers call into question the proposed therapeutic use of such substances.
Targeting Indoleamine 2,3-dioxygenase (IDO) to Counteract Tumour- Induced ImmuneDysfunction: From Biochemistry to Clinical Development (2009)

The enzyme indoleamine 2,3-dioxygenase (IDO) regulates immune responses through the capacity to degrade the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favour the differentiation of regulatory T cells. Considerable experimental evidence indicates that IDO can be expressed by dendritic cells, by tumour cells or by surrounding stromal cells, either within proximity of the tumour or at distal sites. Recent advances in the biochemistry of IDO and in our understanding of the biological relevance of IDO-mediated tryptophan consumption to the establishment of dominant immune tolerance to cancer will be summarised and discussed. Within the wider context of cancer immunotherapy, this Review also delineates how IDO could be exploited as a molecular target for therapeutic intervention in order to boost anti-cancer immunity.