gebhart/patrepeval huggingface dataset:
The genome of Pelotomaculum thermopropionicum reveals niche-associated evolution in anaerobic microbiota (2008)

The anaerobic biodegradation of organic matter is accomplished by sequential syntrophic catabolism by microbes in different niches. Pelotomaculum thermopropionicum is a representative syntrophic bacterium that catalyzes the intermediate bottleneck step in the anaerobic-biodegradation process, whereby volatile fatty acids (VFAs) and alcohols produced by upstream fermenting bacteria are converted to acetate, hydrogen, and carbon dioxide (substrates for downstream methanogenic archaea). To reveal genomic features that contribute to our understanding of the ecological niche and evolution of P. thermopropionicum, we sequenced its 3,025,375-bp genome and performed comparative analyses with genomes of other community members available in the databases. In the genome, 2920 coding sequences (CDSs) were identified. These CDSs showed a distinct distribution pattern in the functional categories of the Clusters of Orthologous Groups database, which is considered to reflect the niche of this organism. P. thermopropionicum has simple catabolic pathways, in which the propionate-oxidizing methylmalonyl-CoA pathway constitutes the backbone and is linked to several peripheral pathways. Genes for most of the important catabolic enzymes are physically linked to those for PAS-domain-containing regulators, suggesting that the catabolic pathways are regulated in response to environmental conditions and/or global cellular situations rather than specific substrates. Comparative analyses of codon usages revealed close evolutionary relationships between P. thermopropionicum and other niche members, while it was distant from phylogenetically related sugar-fermenting bacteria. These analyses suggest that P. thermopropionicum has evolved as a syntrophy specialist by interacting with niche-associated microbes.
Use of glucose-insulin-potassium (GIK) in human septic shock (1985)

Fifteen patients with septic shock and perfusion failure received a 20-min infusion of glucose-insulin-potassium (GIK, glucose 50%, 1 g/kg body weight; insulin 1.5 U/kg, potassium, 10 mMol) after volume loading and vasoactive medication had failed to eliminate hypotension and lactacidemia. Hemodynamic and oxygen measurements were obtained before, immediately and 30 min after GIK infusion. GIK improved hemodynamic status, at least temporarily, in 14 of 15 patients. Cardiac index (CI) increased simultaneously with an increase in cardiac filling pressure. Systemic vascular resistance decreased, particularly in patients with an initially low CI (less than 4 L/min X m2). Mean arterial and pulmonary artery pressures did not change. After 30 min, cardiac filling pressure fell while CI was still elevated, but this decrease was only significant for those with an initially low CI. Although arterial oxygen content decreased after GIK, oxygen consumption did not fall. Serum lactate increased. Six patients died because of ongoing sepsis. Nine patients survived at least 48 h, showing further clinical improvement. Only four patients were hospital survivors. Because GIK increased cardiac output and possibly oxygen consumption, its administration may be considered in the treatment of septic shock when conventional therapy fails.
RAD 001 (everolimus) prevents mTOR and Akt late re‐activation in response to imatinib in chronic myeloid leukemia (2009)

The mammalian target of rapamycin (mTOR) is one target of BCR-ABL fusion gene of chronic myeloid leukemia (CML). Moreover, it drives a compensatory route to Imatinib mesylate (IM) possibly involved in the progression of leukemic progenitors towards a drug-resistant phenotype. Accordingly, mTOR inhibitors are proposed for combined therapeutic strategies in CML. The major caveat in the use of mTOR inhibitors for cancer therapy comes from the induction of an mTOR-phosphatidylinositol 3 kinase (PI3k) feedback loop driving the retrograde activation of Akt. Here we show that the rapamycin derivative RAD 001 (everolimus, Novartis Institutes for Biomedical Research) inhibits mTOR and, more importantly, revokes mTOR late re-activation in response to IM. RAD 001 interferes with the assembly of both mTOR complexes: mTORC1 and mTORC2. The inhibition of mTORC2 results in the de-phosphorylation of Akt at Ser(473) in the hydrophobic motif of C-terminal tail required for Akt full activation and precludes Akt re-phosphorylation in response to IM. Moreover, RAD 001-induced inhibition of Akt causes the de-phosphorylation of tuberous sclerosis tumor suppressor protein TSC2 at 14-3-3 binding sites, TSC2 release from 14-3-3 sigma (restoring its inhibitory function on mTORC1) and nuclear import (promoting the nuclear translocation of cyclin-dependent kinase [CDK] inhibitor p27(Kip1), the stabilization of p27(Kip1) ligand with CDK2, and the G(0)/G(1) arrest). RAD 001 cytotoxicity on cells not expressing the BCR-ABL fusion gene or its p210 protein tyrosine kinase (TK) activity suggests that the inhibition of normal hematopoiesis may represent a drug side effect.
Biochemical and Biological Characterization of a Dodecameric CD4-Ig Fusion Protein (2002)

Drug toxicities associated with HAART lend urgency to the development of new anti-HIV therapies. Inhibition of viral replication at the entry stage of the viral life cycle is an attractive strategy because it prevents de novo infection. Soluble CD4 (sCD4), the first drug in this class, failed to suppress viral replication in vivo. At least three factors contributed to this failure: sCD4 demonstrated poor neutralizing activity against most primary isolates of HIV in vitro; it demonstrated an intrinsic capacity to enhance viral replication at low concentrations; and it exhibited a relatively short half-life in vivo. Many anti-gp120 monoclonal antibodies, including neutralizing monoclonal antibodies also enhance viral replication at suboptimal concentrations. Advances in our understanding of the events leading up to viral entry suggest strategies by which this activity can be diminished. We hypothesized that by constructing a sCD4-based molecule that is large, binds multiple gp120s simultaneously, and is highly avid toward gp120, we could remove its capacity to enhance viral entry. Here we describe the construction of a polymeric CD4-IgG1 fusion protein. The hydrodynamic radius of this molecule is approximately 12 nm. It can bind at least 10 gp120 subunits with binding kinetics that suggest a highly avid interaction toward virion-associated envelope. This protein does not enhance viral replication at suboptimal concentrations. These observations may aid in the design of new therapeutics and vaccines.
The Ultimate Display (1965)

&lt;p&gt;We live in a physical world whose properties we have come to know well through long familiarity. We sense an involvement with this physical world which gives us the ability to predict its properties well. For example, we can predict where objects will fall, how well-known shapes look from other angles, and how much force is required to push objects against friction. We lack corresponding familiarity with the forces on charged particles, forces in non-uniform fields, the effects of nonprojective geometric transformations, and high-inertia, low friction motion. A display connected to a digital computer gives us a chance to gain familiarity with concepts not realizable in the physical world. It is a looking glass into a mathematical wonderland. Computer displays today cover a variety of capabilities. Some have only the fundamental ability to plot dots. Displays being sold now generally have built in line-drawing capability. An ability to draw simple curves would be useful. Some available displays are able to plot very short line segments in arbitrary directions, to form characters or more complex curves. Each of these abilities has a history and a known utility. &lt;/p&gt;
Multifunctional Plasmonic Shell–Magnetic Core Nanoparticles for Targeted Diagnostics, Isolation, and Photothermal Destruction of Tumor Cells (2012)

Cancer is the greatest challenge in human healthcare today. Cancer causes 7.6 million deaths and economic losses of around 1 trillion dollars every year. Early diagnosis and effective treatment of cancer are crucial for saving lives. Driven by these needs, we report the development of a multifunctional plasmonic shell-magnetic core nanotechnology-driven approach for the targeted diagnosis, isolation, and photothermal destruction of cancer cells. Experimental data show that aptamer-conjugated plasmonic/magnetic nanoparticles can be used for targeted imaging and magnetic separation of a particular kind of cell from a mixture of different cancer cells. A targeted photothermal experiment using 670 nm light at 2.5 W/cm(2) for 10 min resulted selective irreparable cellular damage to most of the cancer cells. We also showed that the aptamer-conjugated magnetic/plasmonic nanoparticle-based photothermal destruction of cancer cells is highly selective. We discuss the possible mechanism and operating principle for the targeted imaging, separation, and photothermal destruction using magnetic/plasmonic nanotechnology.
Monolithic Two-Terminal III–V//Si Triple-Junction Solar Cells With 30.2% Efficiency Under 1-Sun AM1.5g (2016)

Stacking III-V p-n junctions on top of wafer-based silicon solar cells is a promising way to go beyond the silicon single-junction efficiency limit. In this study, triple-junction GaInP/Al <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">x</sub> Ga <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1-x</sub> As//Si solar cells were fabricated using surface-activated direct wafer bonding. Metal-organic-vapor-phase-epitaxy-grown GaInP/Al <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">x</sub> Ga <sub xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">1-x</sub> As top cells are bonded at low temperature to independently prepared wafer-based silicon cells. n-Si//n-GaAs interfaces were investigated and achieved bulk-like bond strength, high transparency, and conductivity homogeneously over 4-inch wafer area. We used transfer-matrix optical modeling to identify the best design options to reach current-matched two-terminal devices with different mid-cell bandgaps (1.42, 1.47, and 1.52 eV). Solar cells were fabricated accordingly and calibrated under AM1.5g 1-sun conditions. An improved Si back-side passivation process is presented, leading to a current density of 12.4 mA/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> (AM1.5g), measured for a flat Si cell below GaAs. The best 4 cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> GaInP/GaAs//Si triple-junction cell reaches 30.2% 1-sun efficiency.
Effects of combinations of azaserine and of 6-diazo-5-oxo-L-norleucine with purine analogs and other antimetabolites on the growth of two mouse mammary carcinomas. (1957)

1. Combined treatment of mice bearing the RC mammary carcinoma with azaserine or DON, on the one hand, and 6-mercaptopurine, 6-methyl-mercaptopurine, 6-chloropurine, and thioguanine, on the other, caused a significantly greater number of complete tumor regressions and produced a synergistically increased inhibitory effect on tumor growth.

2. More tumor regressions after combined therapy were observed when treatment started on the next day following implantation of the RC carcinoma than in the cases when treatment was initiated 4 days later.

3. No synergistic therapeutic response could be elicited with these combinations of chemicals in the mouse mammary carcinoma S-790.

4. Therapy of the RC carcinoma with combinations of azaserine or DON and A-methopterin, deoxypyridoxine, N-methylformamide, β-2-thienylalanine, or purine hydrochloride produced no synergistic therapeutic response.

5. Subcutaneous administration of cortisone to the mice bearing RC carcinoma subsequent to their treatment with 6-mercaptopurine, thioguanine, or 6-mercaptopurine and azaserine markedly decreased the number of complete tumor regressions, which observation indicated that some presumably immunogenetic factors may contribute to the causation of tumor regression in chemically treated mice.

6. Several purines, amino acids, and vitamins were tested for their ability to counteract the inhibition of growth of the RC carcinoma caused by DON. Only adenine was found to be partially effective in this respect.
Significant structural and functional change of an antigen-binding site by a distant amino acid substitution: proposal of a structural mechanism. (1989)

To study the molecular basis for antibody diversity and the structural basis for antigen binding, we have characterized the loss of phosphocholine (P-Cho) binding both experimentally and computationally in U10, a somatic mutant of the antibody S107. Nucleotide sequencing of U10 shows a single base change in JH1, substituting Asp-101 with Ala, over 9 A distant from the P-Cho-binding pocket. Probing with antiidiotypic antibodies suggests local, not global, conformational changes. Computational results support a specific structural mechanism for the loss of P-Cho binding. The U10 mutation eliminates the charged interaction between Asp-101 and Arg-94, which allows the Arg-94 side chain to disrupt P-Cho binding sterically and electrostatically by folding into the P-Cho-binding site. These results specifically show the importance of the Arg-94 to Asp-101 side chain salt bridge in the heavy-chain CDR3 conformation and suggest that residues distant from the binding site play an important role in antibody diversity and inducible complementarity.
Nucleotide sequence of the rodA gene, responsible for the rod shape of Escherichia coli: rodA and the pbpA gene, encoding penicillin-binding protein 2, constitute the rodA operon (1989)

The rodA gene, which is responsible for the rod shape of Escherichia coli, was located 5 nucleotides downstream of another rod-shape-determining gene, pbpA, encoding penicillin-binding protein 2. The coding region for the RodA protein was 1,110 base pairs in length. Two plasmids, carrying a rodA-lacZ gene fusion with and without the pbpA promoter upstream of the gene fusion, were constructed. On the basis of the difference between the expression levels of the beta-galactosidase activity dependent on and independent of the pbpA promoter, we concluded that the pbpA and rodA genes constitute a single transcriptional unit called the rodA operon.
Detection of Hepatitis G Virus Replication Sites by Using Highly Strand-Specific Tth-Based Reverse Transcriptase PCR (1998)

The replication sites of the recently discovered hepatitis G virus (HGV) remain unknown. Using highly strand-specific Tth-based reverse transcriptase PCR, we searched for the presence of viral RNA negative strand in multiple autopsy tissues from four patients with AIDS and in peripheral blood mononuclear cells from six other human immunodeficiency virus-positive patients. Negative-strand HGV RNA was detected in three of four bone marrow samples, in two of two spleen samples, and in one of four liver tissue samples. However, the specific cellular site of replication within the positive tissues was not determined. This study does not support HGV as a primary hepatotropic virus.
Successful short term treatment of severe undifferentiated spondyloarthropathy with the anti-tumor necrosis factor-alpha monoclonal antibody infliximab. (2002)

These observations suggest that anti-TNF-alpha therapy has significant short term efficacy in patients with severe uSpA.
The VIVID System Approach to Technology Independence: the Master Technology File System (1985)

Technology independence has been given to a complete range of design tools in the VIVID System with the master technology file (MTF) System. The MTF System manages a set of technology specification files in which a user specifies technology-dependent aspects of the target fabrication process. This information includes facts about process layers, circuit primitives, graphical representation, design rules, and physical and electrical constants. The specifications are written partly in the C programming language and partly in the MTF System's own language. The master technology files are compiled, yielding a binary representation that is compact and quickly manipulated at run time by design tools using the MTF System procedural interface.
Fluorine-enhanced oxidation of polycrystalline silicon and application to thin-film transistor fabrication (1992)

The kinetics of the fluorinated oxidation of polycrystalline silicon thin films has been investigated and compared to the (100) single-crystal silicon case. The growth of silicon dioxide was performed at oxidation temperatures down to 650 °C in dry ambients, which was made possible by fluorine-induced oxidation enhancement; growth rates in the presence of fluorine additions approach those of wet oxidation. Silicon dioxide films grown on polycrystalline silicon were found to be thicker by about 10%–20% compared to films grown on (100) single-crystal silicon oxidized under the same conditions. The application of fluorinated gate oxides in the fabrication of n-channel polycrystalline silicon thin-film transistors was found to improve the effective electron mobility.
Peptide transport in yeast: utilization of leucine- and lysine-containing peptides by Saccharomyces cerevisiae (1977)

A variety of leucine-containing di- and tripeptides and two lysine-containing dipeptides supported the growth of strain Z1-2D, a leucine, lysine auxotroph of Saccharomyces cerevisiae. However, (Lys)2, (Lys)3, (Lys)4, and (Lys)5 as well as Gly-Leu-Gly, three tetra- and one pentapeptide containing leucine were not utilized by the mutant. Cellular peptidases released leucine or lysine from all of these non-growth-supporting peptides, suggesting that the failure of strain Z1-2D to utilize these compounds reflects their failure to enter the yeast. Competition studies employing phenylalanine or non-leucine-containing peptides showed that the uptake of peptides into S. cerevisiae Z1-2D is distinct from that of amino acids and that di- and oligopeptides may share a common transport system. The failure of strain Z1-2D to utilize any peptide larger than (Leu)3 may indicate a transport size limit. Such a size limit would influence the construction of models that explain the action of yeast mating factors.
Low-density lipoprotein modification and arterial wall accumulation in a rabbit model of atherosclerosis (1993)

Chemically or enzymatically modified low-density lipoproteins (LDL), with and without changes in surface charge, were studied in vivo in the healing, balloon catheter-deendothelialized rabbit aorta to determine the effect of LDL modification on its accumulation in arterial lesions. In this model, in which healing (reendothelialization) proceeds radially outward from individual aortic branch arteries, it was previously shown by autoradiography that two kinetically distinct compartments accumulated 125I-labeled LDL. In aortic regions which were still deendothelialized, accumulation was diffuse and labile. In contrast, at the edges of the islands of regenerating endothelium, LDL accumulation was intensely focal, as it is in human atherosclerotic lesions, and persisted for at least 40 h after injection in spite of falling levels of radiolabeled LDL in plasma [Chang, M. Y., et al. (1992) Arterioscler. Thromb. 12, 1088-1098]. In the present study, modified LDLs with gradations in charge change were prepared to clarify the role of changes in surface charge on focal aortic LDL accumulation. Oxidized LDL (weakly anionized), desialated LDL (weakly cationized), and reductively methylated LDL (no change in net charge) all accumulated focally. Focal accumulation of native LDL also occurred in ballooned rabbits fed probucol to inhibit LDL oxidation. Strongly anionized succinylated and diazobenzenearsonylated LDL and strongly cationized dimethylpropanediamine LDL did not accumulate focally. The results support the concept that focal sequestration of LDL in arterial lesions is mediated by specific, oxidation-independent patterns of charge and polarity on LDL which are disrupted by major changes in LDL surface charge.
The Mla (Powdery Mildew) Resistance Cluster Is Associated With Three NBS-LRR Gene Families and Suppressed Recombination Within a 240-kb DNA Interval on Chromosome 5S (1HS) of Barley (1999)

Powdery mildew of barley, caused by Erysiphe graminis f. sp. hordei, is a model system for investigating the mechanism of gene-for-gene interaction between large-genome cereals and obligate-fungal pathogens. A large number of loci that confer resistance to this disease are located on the short arm of chromosome 5(1H). The Mla resistance-gene cluster is positioned near the telomeric end of this chromosome arm. AFLP-, RAPD-, and RFLP-derived markers were used to saturate the Mla region in a high-resolution recombinant population segregating for the (Mla6 + Mla14) and (Mla13 + Ml-Ru3) resistance specificities. These tightly linked genetic markers were used to identify and develop a physical contig of YAC and BAC clones spanning the Mla cluster. Three distinct NBS-LRR resistance-gene homologue (RGH) families were revealed via computational analysis of low-pass and BAC-end sequence data derived from Mla-spanning clones. Genetic and physical mapping delimited the Mla-associated, NBS-LRR gene families to a 240-kb interval. Recombination within the RGH families was at least 10-fold less frequent than between markers directly adjacent to the Mla cluster.
Isolation of a cDNA clone coding for a putative second potassium channel indicates the existence of a gene family (1989)

A putative second potassium channel expressed in rat brain is identified by cloning and characterization of cDNA clones. Two cDNA clones, isolated from rat brain libraries, encode a 499-residue protein that is 80% identical with a previously described rat brain potassium channel and 68% identical with a Drosophila potassium channel. This new potassium channel is called BK2 to distinguish it from the previously described potassium channel (BK1). The BK2 gene, unlike the Drosophila potassium channel gene complex, appears to produce a single, large (approximately 9.5-kilobase) RNA transcript. Southern analysis of rat genomic DNA indicates that the BK1 and BK2 transcripts are the products of independent genes. Analysis of the distribution of BK2 transcripts in rat brain by in situ hybridization histochemistry suggests that the BK2 gene is ubiquitously expressed by central nervous system neurons. Identification of this putative second mammalian potassium channel cDNA indicates the existence of a potassium channel gene family, confirming electrophysiological data on the diversity of potassium channels expressed in rat brain.
Chapter 1. Drugs and their Structural Motifs (2010)

The major focus of the research-based pharmaceutical industry is the discovery of safe, efficacious, new chemical entities (NCEs) for therapeutic targets. The pharmaceutical industry can look back at a history of successful innovations, indicated by the fact that there are currently just over 1,400 unique drugs on the market. This chapter starts with an introduction on the pharmaceutical industry in general, past achievements as well as current challenges, particularly focusing on recent developments in terms of productivity which affect the introduction of new drugs to market. The relationships of those drugs with their biological targets will be reviewed, particularly focusing on biological target space and chemical space, as well as the molecular properties of drugs. Furthermore, examples of chemical substructures which have been associated with a preference for certain biological target classes will be discussed. In addition, examples of marketed drugs bound to their target receptors will be highlighted in the context of binding site shape and properties. The chapter will finish with an outlook on future challenges for drug discovery.