gebhart/patrepeval huggingface dataset:
Secondary Amides of (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropionic Acid as Inhibitors of Pyruvate Dehydrogenase Kinase (1999)

N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.
Stereochemistry of α-halogeno-sulphoxides. Part 5. Absolute stereochemistry of α-chlorination of benzyl t-butyl sulphoxide (1977)

α-Halogenation of benzyl t-butyl sulphoxide (2) by electrophilic halogenating agents in pyridine affords a mixture of the diasteroisomeric α-halogenobenzyl t-butyl sulphoxides in the ratio 5:1. In the case of the (R)-sulphoxide (2), chlorination involves selective replacement of the pro-R-hydrogen atom and occurs both with inversion at sulphur and retention at carbon (major path) and with retention at both sulphur and carbon (minor path).
INITIATION OF DNA REPLICATION IN EUKARYOTIC CELLS (1997)

The recent identification of proteins that recognize origins of DNA replication and control the initiation of eukaryotic DNA replication has provided critical molecular tools to dissect this process. Dynamic changes in the assembly and disassembly of protein complexes at origins are important for the initiation of DNA replication and occur throughout the cell cycle. Herein, we review the key proteins required for the initiation of DNA replication, their involvement in the protein complex assembly at replication origins, and how the cell cycle machinery regulates this process.
Biophysical and Structural Characterization of a Robust Octameric β-Peptide Bundle (2007)

Proteins composed of alpha-amino acids are essential components of the machinery required for life. Stanley Miller's renowned electric discharge experiment provided evidence that an environment of methane, ammonia, water, and hydrogen was sufficient to produce alpha-amino acids. This reaction also generated other potential protein building blocks such as the beta-amino acid beta-glycine (also known as beta-alanine); however, the potential of these species to form complex ordered structures that support functional roles has not been widely investigated. In this report we apply a variety of biophysical techniques, including circular dichroism, differential scanning calorimetry, analytical ultracentrifugation, NMR and X-ray crystallography, to characterize the oligomerization of two 12-mer beta3-peptides, Acid-1Y and Acid-1Y*. Like the previously reported beta3-peptide Zwit-1F, Acid-1Y and Acid-1Y* fold spontaneously into discrete, octameric quaternary structures that we refer to as beta-peptide bundles. Surprisingly, the Acid-1Y octamer is more stable than the analogous Zwit-1F octamer, in terms of both its thermodynamics and kinetics of unfolding. The structure of Acid-1Y, reported here to 2.3 A resolution, provides intriguing hypotheses for the increase in stability. To summarize, in this work we provide additional evidence that nonnatural beta-peptide oligomers can assemble into cooperatively folded structures with potential application in enzyme design, and as medical tools and nanomaterials. Furthermore, these studies suggest that nature's selection of alpha-amino acid precursors was not based solely on their ability to assemble into stable oligomeric structures.
The application of flow microfluorimetry to biomedical research and diagnosis: a review. (1986)

The application of flow cytometric or microfluorimetric techniques to the biomedical sciences is a major growth area. Flow microfluorimetry is the science of analyzing and separating populations of cells (and their sub-cellular components) using fluorescent markers (usually fluorescent antibodies or fluorescent DNA-binding dyes). Each cell is analysed individually allowing assays to be performed on small samples (less than 10,000 cells). Interesting cells can be sorted out to a high degree of purity (up to 99%). Flow microfluorimetric analysis enjoys multidisciplinary use, ranging from cell biology, microbiology and immunology to cell cycle analysis and "flow karyotyping" of cells. Examples taken from both clinical and research settings are discussed.
Paper‐Based Electrical Respiration Sensor (2016)

Current methods of monitoring breathing require cumbersome, inconvenient, and often expensive devices; this requirement sets practical limitations on the frequency and duration of measurements. This article describes a paper-based moisture sensor that uses the hygroscopic character of paper (i.e. the ability of paper to adsorb water reversibly from the surrounding environment) to measure patterns and rate of respiration by converting the changes in humidity caused by cycles of inhalation and exhalation to electrical signals. The changing level of humidity that occurs in a cycle causes a corresponding change in the ionic conductivity of the sensor, which can be measured electrically. By combining the paper sensor with conventional electronics, data concerning respiration can be transmitted to a nearby smartphone or tablet computer for post-processing, and subsequently to a cloud server. This means of sensing provides a new, practical method of recording and analyzing patterns of breathing.
Prevalence, intensity and ocular manifestations of Onchocerca volvulus infection in Dimbelenge, Zaire. (1989)

In the zone of Dimbelenge (West Kasai region), Zaire we studied the prevalence, intensity and ocular manifestations of Onchocerca volvulus infection. We used the cluster sampling method to draw a sample of 327 people from a total population of 17,870. The prevalence of microfilaria in skin snips was 82.1% in people 20 years of age and older. The Community Microfilarial Load was 3.5. Blindness in 12 of 13 adults (92.3%) was caused by onchocerciasis. The rate of onchocercal blindness in the adult population was 5.1%. Twenty-four percent of adults had retinal changes as a result of onchocercal infection.
Debcl, a Proapoptotic Bcl-2 Homologue, Is a Component of the Drosophila melanogaster Cell Death Machinery (2000)

Bcl-2 family of proteins are key regulators of apoptosis. Both proapoptotic and antiapoptotic members of this family are found in mammalian cells, but no such proteins have been described in insects. Here, we report the identification and characterization of Debcl, the first Bcl-2 homologue in Drosophila melanogaster. Structurally, Debcl is similar to Bax-like proapoptotic Bcl-2 family members. Ectopic expression of Debcl in cultured cells and in transgenic flies causes apoptosis, which is inhibited by coexpression of the baculovirus caspase inhibitor P35, indicating that Debcl is a proapoptotic protein that functions in a caspase-dependent manner. debcl expression correlates with developmental cell death in specific Drosophila tissues. We also show that debcl genetically interacts with diap1 and dark, and that debcl-mediated apoptosis is not affected by gene dosage of rpr, hid, and grim. Biochemically, Debcl can interact with several mammalian and viral prosurvival Bcl-2 family members, but not with the proapoptotic members, suggesting that it may regulate apoptosis by antagonizing prosurvival Bcl-2 proteins. RNA interference studies indicate that Debcl is required for developmental apoptosis in Drosophila embryos. These results suggest that the main components of the mammalian apoptosis machinery are conserved in insects.
Substrate specificity of isopenicillin N synthase (1992)

Highly purified isopenicillin N synthase (IPNS) from two sources (naturally occurring in Penicillium chrysogenum and that expressed in Escherichia coli via a cloned gene derived from Cephalosporium acremonium) have been isolated and utilized in vitro to test synthetic modifications of the natural substrate, (L-alpha-amino-delta-adipyl)-L-cysteinyl-D-valine (ACV). A very sensitive procedure utilizing the ability of beta-lactams to induce the synthesis of beta-lactamase was employed to determine whether an ACV analogue could serve as a substrate for IPNS. A wide variety of amino and carboxyl terminal tripeptide substitutions were examined and found to elicit positive beta-lactamase induction profiles. However, none of these modifications were found to function as efficiently as a substrate as ACV. One of the beta-lactam products which was formed from the reaction of IPNS and the tripeptide analogue was independently synthesized and evaluated for antibacterial activity. Modification of the L-cysteine residue in the second position of ACV resulted in tripeptides that were unable to serve as substrates. Conversion of the D-valine residue in the third position of ACV to an aromatic amino acid or to a highly electronegative residue such as trifluorovaline resulted in elimination of substrate activity and creation of an inhibitor of the enzyme.
Gene transfer from bacteria to mammalian cells. (1995)

Transfer of genetic information between phylogenetically remote bacterial genera [1], from bacteria to yeast [2] and from bacteria to plants [3] by plasmid conjugation has been described. However, direct DNA transfer from prokaryotes to mammalian cells has not yet been demonstrated. Certain bacterial species have evolved the ability to enter mammalian cells by inducing their own internalization [4]. We show that invasive strains of Shigella flexneri and Escherichia coli, that undergo lysis upon entry into mammalian cells because of impaired cell wall synthesis, can act as stable DNA delivery systems to their host. This direct gene transfer is efficient, of broad host cell range and the replicative or integrative vectors so delivered are stably inherited and expressed by the cell progeny. DNA delivery by abortive invasion of eukaryotic cells by bacteria is of potential interest for stimulation of mucosal immunity and for in vivo or ex vivo gene therapy of human diseases.
A novel electromagnetic bandgap (EBG) structure for mixed-signal system applications (2005)

A novel electromagnetic bandgap (EBG) structure called alternating impedance EBG (AI-EBG) for isolation in mixed-signal systems is proposed. Currently, split planes are usually used for isolation in mixed-signal systems. However, split planes show a poor isolation at high frequencies due to electromagnetic coupling through a gap. This novel EBG structure shows excellent isolation by suppressing almost all possible electromagnetic modes in stopband frequencies. The S-parameter measurements show that this novel EBG structure could suppress noise coupling between RF/analog circuits and digital circuits, especially where a single common power supply is used. Mixed-signal system simulations with and without this novel EBG structure were performed to see improvement of isolation due to this novel EBG structure.
Home treatment with recombinant activated factor VII: results from one centre. (1998)

Haemophilia patients developing an inhibitor against factor VIII (FVIII) or FIX require alternative treatment for the management of their bleeding, rather than standard procedures. In patients with low titre inhibitors, increased doses of FVIII or FIX may improve haemostasis. If a higher titre is present, a porcine FVIII concentrate may be efficacious in selected cases. 'Bypassing' agents, such as low purity FIX concentrates, or activated or unactivated concentrates of prothrombin complex may also be useful in inhibitor patients. An activated factor VII molecule (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark), has been produced by recombinant DNA cell technology. In June 1994, we established a home treatment programme with rFVIIa for five inhibitor patients to study its efficacy in the early intervention of bleeding episodes; our results from the first 3 years are presented. Self-treatment in the home took place in 50 instances of acute minor bleeding. A mean of 2.02 doses of rFVIIa (each dose of about 90 microg/kg bodyweight) was required to arrest bleeding (range 1-4 doses). Four bleeding episodes required in-hospital management either because the acute condition was caused by severe trauma, or because treatment had not been instituted in the early phase of bleeding. Here, the range of rFVIIa doses was 4-37. For comparison, we also report 36 minor bleeding episodes managed in-hospital in three of these five patients who participated in the Compassionate Use Study where home treatment was not permitted. These bleeding episodes required considerably more administrations of rFVIIa with a mean consumption of 8 doses in joint bleeds and 9.5 doses in muscle and soft tissue bleeds. In conclusion, we feel that our home treatment results strongly suggest that early intervention by home treatment with rFVIIa in acute minor bleeding is efficacious and cost effective.
Voice over IP Fundamentals (2000)

A systematic approach to understanding the basics of Voice over IP Understand the basics of PSTN services and IP signaling protocols, including SS7 Learn how VoIP can run the same applications as the existing telephony system, but in a more cost-efficient and scalable manner Delve into such VoIP topics as jitter, latency, packet loss, codecs, quality of service tools, and mean opinion scores Learn about the functional components involved in using Cisco gateways to deploy VoIP networksVoice over IP (VoIP), which integrates voice and data transmission, is quickly becoming an important factor in network communications. It promises lower operational costs, greater flexibility, and a variety of enhanced applications. Voice over IP Fundamentals provides a thorough introduction to this new technology to help experts in both the data and telephone industries plan for the new networks.You will learn how the telephony infrastructure was built and how it works today, the major concepts concerning voice and data networking, transmission of voice over data, and IP signaling protocols used to interwork with current telephony systems. The authors cover various benefits and applications of VoIP and how to ensure good voice quality in your network.This book is part of the Networking Technology Series from Cisco Press, which offers networking professionals valuable information for constructing efficient networks, understanding new technologies, and building successful careers.
First Successful Multi-Organ Gene Therapy (2002)

Dogs with the genetic disease mucopolysaccharidosis VII and a diagram of the retroviral vector used in intravenous neonatal gene therapy.The untreated 5 month-old dog on the right is unable to stand.The 17 month-old dog on the left, treated at 3 days of age, can stand and run and has not developed most signs of the disease.
Characterizing non-intermittent faults (1992)

A faulty component that behaves consistently over time is said to behave non-intermittently. For any given set of inputs, such a component will always generate the same output. Assuming that components fail non-intermittently is a common simplifying strategy used by diagnosticians, because (1) many real-world devices often fail this way, (2) this strategy removes the need to repeat experiments, and (3) this strategy allows information from independent examples of system behavior to be combined in relatively simple ways.

This paper extends the formal framework for diagnosis developed in [7, 12] to allow nonintermittency assumptions. In addition we show how the definitions can be easily integrated into ATMS-based diagnosis engines. Within our formulation, components can be individually assumed to be intermittent or nonintermittent.
ras and human tumors. (1992)

Mutational activation of ras oncogenes is frequently encountered in human tumors. For unexplained reasons, K-ras mutations are predominantly found in pancreatic cancer, colorectal cancer and adeno-carcinoma of the lung, N-ras is predominantly found in a subset of acute leukemias and in myelodysplastic syndromes, while H-ras mutations are rare. In most tumors, ras mutations are not clearly associated with specific clinical or biological features, but in lung cancer, childhood lymphoblastic leukemia and possibly in myelodysplastic syndromes ras mutations may predict a poor prognosis. Accumulating evidence suggests that exposure to chemical carcinogens is responsible for many ras mutations in humans.
Dense Stereo Matching with Robust Cost Functions and Confidence-based Surface Prior (2014)

The goal of dense stereo matching is to estimate the distance, or depth to an imaged object in every pixel of an input image; this is achieved by finding pixel orrespondences between the source image and one or more matching images. Applications that make dense stereopsis active come from areas such as photogrammetry, remote sensing, mobile robotics, and intelligent vehicles. For instance, many remote sensing applications require depth maps to generate digital elevation models from airborne and satellite imagery. There are hundreds, if not housands, of approaches seeking to solve stereopsis. A number of factors that make computational stereopsis quite challenging become apparent once one begins to use it in real-world applications; non-Lambertian refectance, complex scene and radiometric changes, among other factors, are usually present in real-world data. Dense stereo algorithms can be categorized into two methodologies based on the way the problem is solved: Local and global. Local algorithms aim to solve the problem via a local analysis at each input-image pixel, whereas global algorithms formulate the stereopsis problem as one of finding an optimal solution to a global energy, or probability function. Developing a global stereo method considers three main factors: calculation reliable observation to measure matching similarity, formulation of energy, or probability, function using additional priors, and optimization of the global function to find the global extremum. In this dissertation two methodical novelties are contributed - the merging strategy of match costs and the confidence-based surface prior incorporating a semiglobal optimization framework. All dense stereo matching algorithms use match cost functions to measure the similarity between two pixels. In a real-world scenario, good radiometric conditions are often disrupted by complicated and dynamic lighting sources, inappropriate camera configuration, and non-Lambertian reflectance of objects. We investigate the interdependencies among matching erformance, cost functions, and observation conditions using both close-range and remote-sensing data. Our cost-merging strategy combines the advantages of different match cost functions and gives consideration to imagery configurations. In addition, a novel probabilistic surface prior is introduced incorporating a new energy optimization method, called iSGM3. Our approach builds a probabilistic surface prior over the disparity space using confidences on a set of reliably matched correspondences. Unlike many region based methods, our method defines an energy formulation over pixels, instead of regions in a segmentation; this results in a decreased sensitivity to the quality of the initial segmentation. This dissertation suggests the way to developing robust stereo methods is on the level of obtaining costs and suitable energy formulation, and not only the energy optimization. Both costs merging and the surface prior are generally applicable for almost all extended stereo methods.
Measuring proliferation in breast cancer: practicalities and applications (2006)

Various methods are available for the measurement of proliferation rates in tumours, including mitotic counts, estimation of the fraction of cells in S-phase of the cell cycle and immunohistochemistry of proliferation-associated antigens. The evidence, advantages and disadvantages for each of these methods along with other novel approaches is reviewed in relation to breast cancer. The potential clinical applications of proliferative indices are discussed, including their use as prognostic indicators and predictors of response to systemic therapy.
A Spiroisoxazolinoproline-Based Amino Acid Scaffold for Solid Phase and One-Bead−One-Compound Library Synthesis (2006)

An efficient, multigram synthesis of a spiroisoxazolinoproline-based amino acid, 7, requiring minimal purification, delivering good cis:trans diastereoselectivity (approximately 1:4), and providing good yields is reported. Surface-bound studies of the reduction of an arylnitro group in the presence of an isoxazoline ring with tin(II) dichloride dihydrate were undertaken to confirm the stability of the isoxazoline ring. Full derivitization of this spiroisoxazolinoproline-based amino acid scaffold was performed during the synthesis of a sample library with high yields and high purity that validated the efficiency of the chemistry that was employed in resin-bound library synthesis. A 129,600 member one-bead-one-compound (OBOC) library based on the scaffold 7 was synthesized utilizing a dual amino acid encoding method and bifunctionalization of TentaGel resin.
Unusual Benefits of Macromolecular Shielding by Polyethylene Glycol for Reactions at the Diffusional Limit:  The Case of Factor VIIai and Tissue Factor (2002)

Protein modification with poly(ethylene glycol) (PEG) can prolong circulatory lifetime and lower protein antigenicity in an animal. These benefits may arise from the proposed mechanism of PEG action, molecular shielding of the protein surface, and lowered interaction with other macromolecules. Proteins that depend on macromolecule association for their function would not seem good targets for PEG modification as the benefits may be mitigated by loss of function. Indeed, high loss of function applied to PEG-modified factor VIIa and to active site-blocked blood clotting factors Xa or IXa was studied. A surprising finding was that PEG-modified, active site-blocked factor VIIa (PEG-VIIai, PEG-40 000) retained 40% of its function despite an 18-fold increase in circulatory lifetime. The discrepancy between functional loss and increased circulatory lifetime was consistent with a process that was limited by the diffusion step of assembly rather than the chemical binding step. The impact of PEG-40 000 on diffusion of VIIai is small (about 3-fold) relative to its potential impact on molecular shielding during the chemical binding step of association. These properties extended to a mutant of VIIai (P10Q/K32E, QE-VIIai) that has 25-fold higher function than wild-type factor VIIai. Overall, properties of PEG-modified proteins can suggest features of the kinetic mechanism and may provide enhanced proteins for anticoagulation therapy.