gebhart/patrepeval huggingface dataset:
Total Synthesis of Stipiamide and Designed Polyenes as New Agents for the Reversal of Multidrug Resistance (1997)

The synthesis of (−)-stipiamide (1) is reported together with the designed enynes 2 (6,7-dehydrostipiamide) and 3 that are now shown to reverse the multidrug resistance (MDR) of human breast cancer cells (MCF-7adrR). Stipiamide was assembled using a Stille coupling with (E)-vinyl iodide 17 and (Z)-stannyl amide 16 in 78% yield. (E)-Vinyl iodide 17 was made using a Takai reaction and a selective dihydroxylation of the terminal olefin of nonconjugated diene 7 using the Sharpless AD-mix reagent. The precursor to 16, (E,Z)-stannyl diene ester 13, was assembled with high selectivity in a single operation using a tandem syn-addition of tributyltin cuprate to acetylene followed by conjugate addition to ethyl propiolate. Structural variants 2 and 3 were assembled using palladium-catalyzed Sonogashira couplings with vinyl iodides 17 and 35 and acetylenes 22 and 26 in high yield at near 1:1 stoichiometry. Compound 2 was found to be far less toxic than stipiamide and performed much better as an MDR reversal agent. Compound 3 was better still due to even lower toxicity.
Time Resolved LADA Using a Modulated Pulsed Laser to Fault Isolate Bridging Defects and Framing High Accuracy Physical FA Plan in 14 nm FinFET Technologies (2017)

Abstract Dynamic Laser Stimulation using Continuous Wave (CW) Lasers has been a very important technique in fault isolating soft failures due to process defects and design speed paths in microprocessors. However, the rapid scaling down of the process technologies and the high density of logic laid out in silicon has made it difficult to precisely fault isolate using a conventional continuous wave laser which has a laser spot size of about ~300nm. Also, the remnant effects of a CW laser DLS like banding due to n-well interactions make it further difficult to achieve high resolution fault isolation. In this paper we discuss how by using a modulated pico-second pulsed laser, a DLS suspect is isolated to cell internal nets, which using a CW laser spanned across multiple cells. This is achieved by modulating the pulsed laser using an Electro-optical modulator and restricting the stimulation to only those parts of a test-pattern where the signal propagation occurs. Also, by synchronizing the pulsed laser with the clock of the test-program and changing the laser pulse delivery in time, high stimulation levels were achieved without being invasive. This revealed extra data points (DLS sites) that can help with making precisely accurate Physical FA plans that reduce turnaround time and also ensure high success rates. Specifically, in the case of a bridging defect between two nets wherein DLS sites were only seen on the victim net using conventional CW laser, the time resolved pulsed laser revealed DLS sites on the aggressor net as well. This confirmed the bridging between the two nets since the aggressor net was not electrically connected with the victim net. We discuss in detail how the DLS sites play their role in framing the perfect Physical FA plan. A detailed study of the resolution achieved using time resolved pulsed laser and its comparison with the same using a CW laser is shown on 14nm FinFET technology.
Spectroscopic studies of myoglobin at low pH: heme structure and ligation (1991)

We explore heme structure and ligation subsequent to a low-pH conformational transition in sperm whale myoglobin. Below pH 4.0, the iron-histidine bond breaks in metMb and deoxyMb. In MbCO, the majority of the iron-histidine bonds remain intact down to pH 2.6; however, the observation of a weak Fe-CO mode at 526 cm-1 indicates that a small fraction of the sample has the histidine replaced by a weak ligand, possibly water. The existence of a sterically hindered CO subpopulation in MbCO and the continued association of the four-coordinate heme with the protein in deoxyMb suggest that the heme pocket remains at least partially intact in the acid-induced conformation. The global pH-dependent conformational change described here is clearly distinguished from the local "closed" to "open" transition described previously in MbCO [Morikis et al. (1989) Biochemistry 28, 4791-4800]. Further observations of the four-coordinate heme state yield insights on the mechanism of heme photoreduction and the assignment of the 760-nm band in deoxyMb.
Characterization of the IE110 Gene of Herpes Simplex Virus Type 1 (1986)

We have determined the DNA sequence of the herpes simplex virus type 1 (HSV-1) gene encoding the immediate early protein IE110, which is involved in transcriptional activation of later virus genes. The locations of the 5' and 3' termini of IE110 mRNA together with the positions of two introns, were identified. Examination of the DNA sequence suggested that translation starts at the first ATG after the 5' terminus of the mRNA, and that both introns occur in protein-coding sequence. The predicted IE110 polypeptide contains 775 amino acids, and has a molecular weight of 78452. It contains a cysteine-rich region resembling regions found in several proteins which interact functionally with DNA. An antiserum was raised to the predicted C terminal amino acid sequence of the IE110 polypeptide and was shown to immunoprecipitate the native protein from HSV-1-infected cell extracts. The functional importance of regions of the protein was evaluated by construction of frameshift and deletion mutants of a plasmid-borne IE110 gene. The mutants were tested for IE110 function by short-term transfection assays, and the results were correlated with the DNA sequence and RNA mapping studies.
Amino Acid Residues Conferring Ligand Binding Properties of Prostaglandin I and Prostaglandin D Receptors (2000)

Using chimeras of the mouse prostaglandin (PG) I receptor (mIP) and the mouse PGD receptor (mDP), we previously revealed that the cyclopentane ring recognition by these receptors is specified by a region from the first to third transmembrane domain of each receptor; recognition by this region of mIP is broad, accommodating the D, E, and I types of cyclopentane rings, whereas that of mDP binds the D type of PGs alone (Kobayashi, T., Kiriyama, M., Hirata, T., Hirata, M., Ushikubi, F., and Narumiya, S. (1997) J. Biol. Chem. 272, 15154-15160). In the present study, we performed a more detailed chimera analysis, and narrowed the domain for the ring recognition to a region from the first transmembrane domain to the first extracellular loop. One chimera with the replacement of the second transmembrane domain and the first extracellular loop of mDP with that of mIP bound only iloprost. The amino acid substitutions in this chimera suggest that Ser(50) in the first transmembrane domain of mIP confers the broad ligand recognition of mIP and that Lys(75) and Leu(83) in the second transmembrane domain of mDP confer the high affinity to PGD(2) and the strict specificity of ligand binding of mDP, respectively.
Tumor‐infiltrating endothelial cells and endothelial precursor cells in inflammatory breast cancer (2002)

Inflammatory breast cancer (IBC) is a specific type of breast tumor that generally has a poor prognosis, in spite of recent advances in treatment. In the present study, semiquantitative reverse transcriptase polymerase chain reaction examination of resected specimens showed that angiogenic factors, not lymphangiogenic factors, are overexpressed in IBC tumors, compared with non-IBC tumors. Immunohistochemical analysis of the specimens revealed a significantly higher population of tumor-infiltrating (TI) endothelial cells (ECs) or endothelial precursor cells (EPCs) in tumor-associated stroma of IBC specimens than in non-IBC specimens. In a previous study, we examined the phenotype of host cells in response to transplanted IBC cells, using an established human IBC xenograft model (WIBC-9) (Shirakawa et al., Cancer Res 2001;61:445-51). The data obtained in that study are consistent with the findings of the present study. To explore the therapeutic potential of blocking vascular endothelial growth factor (VEGF) and angiopoietin (Ang) pathways in IBC, established vectors encoding soluble Flt-1 (sFlt-1) and soluble Tie2 (sTie2) were injected directly into WIBC-9. Both vectors produced growth inhibition ratios of WIBC-9 that were significantly higher than those of a non-IBC xenograft (MC-5). Also, both vectors suppressed WIBC-9 lung metastases. The efficacy correlated with the number of TI ECs/EPCs, which was determined by fluorescence-activated cell sorting. These ECs/EPCs incorporated acetylated lipoprotein and were integrated within a HUVEC monolayer in vitro culture on day 5.
Nonstoichiometric Interfaces andAl2O3Adhesion with Al and Ag (2000)

We have determined the relative stability of stoichiometric, oxygen-rich, and aluminum-rich Al/Al 2O (3) and Ag/Al 2O (3) interfaces from first principles. Stable structures vary significantly with oxygen chemical potentials. Computed works of adhesion agree reasonably well with sessile drop experimental values, including correlation with measured oxygen chemisorption effects on Ag. The ordering of predicted bond energies of the interfaces, ceramics, and metals seems consistent with monotonic and fatigue fracture experiments.
Achieving high utilization with software-driven WAN (2013)

We present SWAN, a system that boosts the utilization of inter-datacenter networks by centrally controlling when and how much traffic each service sends and frequently re-configuring the network's data plane to match current traffic demand. But done simplistically, these re-configurations can also cause severe, transient congestion because different switches may apply updates at different times. We develop a novel technique that leverages a small amount of scratch capacity on links to apply updates in a provably congestion-free manner, without making any assumptions about the order and timing of updates at individual switches. Further, to scale to large networks in the face of limited forwarding table capacity, SWAN greedily selects a small set of entries that can best satisfy current demand. It updates this set without disrupting traffic by leveraging a small amount of scratch capacity in forwarding tables. Experiments using a testbed prototype and data-driven simulations of two production networks show that SWAN carries 60% more traffic than the current practice.
Phosphorus sorption and chemical characteristics of lightweight aggregates (LWA)-potential filter media in treatment wetlands (1997)

Five light-weight aggregates (LWAs), suitable for filter media in subsurface flow constructed wetlands, were tested for potential removal of phosphorus (P). P-sorption variation is dependent on the chemical characteristics of the LWA. All LWAs exhibited high pH and high total metal content; however, P-sorption capacity varied by two orders of magnitude. Of the LWAs' chemical characteristics (total metal content, cation exchange capacity, and oxalate soluble Fe and Al), total metal content has the closest relationship with the P-sorption capacity. Among the four major metal ions (Mg, Ca, Fe and Al), Ca has the strongest correlation with the P-sorption capacity.
Structural Characterization of a Soluble Amyloid β-Peptide Oligomer (2009)

Alzheimer's disease (AD) is a neurodegenerative disorder that is linked to the presence of amyloid beta-peptides that can form insoluble fibrils or soluble oligomeric assemblies. Soluble forms are present in the brains and tissues of Alzheimer's patients, and their presence correlates with disease progression. Long-lived soluble forms can be generated in vitro by using small amounts of aliphatic hydrocarbon chains of detergents or fatty acids in preparations of amyloid beta-peptides. Using NMR, we have characterized soluble oligomers of Abeta preglobulomer and globulomer that are stable and alter synaptic activity. The NMR data indicate that these soluble forms have a mixed parallel and antiparallel beta-sheet structure that is different from fibrils which contain only parallel beta-sheets. Using the structural data, we engineered a disulfide bond into the soluble Abeta globulomer to give a "new" soluble antigen that is stable, homogeneous, and binds with the same affinity to selective antibodies as the parent wt globulomer.
Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML (2014)

Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.
Isolation, crystallization in the macrogravitation field, preliminary X-ray investigation of uridine phosphorylase from Escherichia coli K-12. (1992)

Uridine phosphorylase (UPH) from Escherichia coli K-12 has been purified to near homogeneity from a strain harbouring the udp gene, encoding UPH, on a multicopy plasmid. UPH was purified to electrophoretic homogeneity with the specific activity 230 units/mg with a recovery of 80%, yielding 120 mg of enzyme from 3g cells. Crystals of enzyme suitable for X-ray diffraction analysis were obtained in a preparative ultracentrifuge. The packing of the molecules in the crystals may be described by the space group P2(1)2(1)2(1) with the unit cell constants a = 90.4; b = 128.8; c = 136.8 A. There is one molecule per asymmetric unit, Vm = 2.4. These crystals diffract to at least 2.5-2.7 A resolution. The hexameric structure of UPH was directly demonstrated by electron microscopy study and image processing.
Scientific Review of Phase I Protocols With Novel Dose-Escalation Designs: How Much Information Is Needed? (2015)

Article Tools STATISTICS IN ONCOLOGY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2014.59.8466 Journal of Clinical Oncology - published online before print May 4, 2015 PMID: 25940721 Scientific Review of Phase I Protocols With Novel Dose-Escalation Designs: How Much Information Is Needed? Alexia IasonosxAlexia IasonosSearch for articles by this author , Mithat GönenxMithat GönenSearch for articles by this author , George J. BoslxGeorge J. BoslSearch for articles by this author Show More All authors: Memorial Sloan Kettering Cancer Center, New York, NY. https://doi.org/10.1200/JCO.2014.59.8466 First Page Full Text PDF Figures and Tables © 2015 by American Society of Clinical Oncology
Sequence of galR gene indicates a common evolutionary origin of lac and gal repressor in Escherichia coli. (1982)

The nucleotide sequence of the galR gene of Escherichia coli, which codes for galactose repressor, has been determined. The subunits of gal repressor are predicted to consist of 343 residues, including the NH2-terminal methionine. Twenty-six of the predicted NH2-terminal 55 residues of gal repressor are identical to the NH2-terminal residues of lac repressor. Additional homologies appear between residues 165 and 200, between residues 235 and 255, and around residue 325.
Pathogenesis of Systemic Sclerosis (2015)

Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.
Making transgenic livestock: Genetic engineering on a large scale (1992)

The feasibility of introducing foreign genes into the genomes of cattle, goats, pigs, and sheep has only recently been demonstrated. Studies have thus far focused on improving growth efficiency or directing expression of pharmaceutical proteins to the mammary glands of these species. The general strategy for producing transgenic livestock and mice is similar. In addition to the obvious difference in scale between mice and livestock experiments, there are noteworthy obstacles that significantly reduce the efficiency of producing transgenic livestock. Low embryo viability, low transgene integration rates, and high animal costs contribute to project costs that can easily exceed hundreds of thousands of dollars. A better understanding of the mechanisms that govern transgene integration should lead to improved efficiencies. But, the full potential of the transgenic livestock system will not be fully realized until: 1) gene constructs can be designed that function in a reproducible, predictable manner; and 2) the genetic control of physiological processes are more clearly elucidated. Newly emerging approaches may resolve at least some of these issues within the next decade.
Data compression with finite windows (1989)

Several methods are presented for adaptive, invertible data compression in the style of Lempel's and Ziv's first textual substitution proposal. For the first two methods, the article describes modifications of McCreight's suffix tree data structure that support cyclic maintenance of a window on the most recent source characters. A percolating update is used to keep node positions within the window, and the updating process is shown to have constant amortized cost. Other methods explore the tradeoffs between compression time, expansion time, data structure size, and amount of compression achieved. The article includes a graph-theoretic analysis of the compression penalty incurred by our codeword selection policy in comparison with an optimal policy, and it includes empirical studies of the performance of various adaptive compressors from the literature.
Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. (1993)

Thirty children presenting to the dental clinic of a pediatric hospital who required brief but urgent dental care, and who could not be satisfactorily examined or treated, were administered one of three medications--ketamine (Ketalar), 3 mg/kg; midazolam (Versed), 0.4 mg/kg; or sufentanil (Sufenta), 1.5 or 1.0 micrograms/kg--intranasally in a randomized, double-blinded protocol. The patients were brought to the day surgery area following appropriate fasting and administered one of the medications diluted in a dose of 0.1 mL/kg normal saline while sitting in a nurse's arms. Cardiorespiratory monitors were applied when tolerated, and the child was placed on the operating room table. Each child was injected locally with up to one dental cartridge of 2% lidocaine with 1:100,000 epinephrine before dental extractions. A sedation score was recorded using a scale where 1 = hysterical/untreatable, 5 = ideal sedation, and 10 = obtunded and desaturated, requiring airway management assistance. Midazolam administration resulted in acceptable sedation (mean score: 4) with no desaturations below 90% as measured by pulse oximetry and a mean recovery room observation time of only 3 +/- 2 min (+/- SD). Ketamine also had a mean sedation score of 4 and a short recovery period (7 +/- 7 min); however, two children experienced brief desaturations. Sufentanil at 1.5 micrograms/kg was noted to produce much more heavily sedated children (mean score 7), with a high incidence of significant oximetry desaturation (80%) and prolonged recovery room duration (58 +/- 40 min). Use of 1.0 microgram/kg sufentanil resulted in no desaturations, less sedation (mean score 4), and a brief recovery time (7 +/- 13 min).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypothermia-induced cardioprotection using extended ischemia and early reperfusion cooling (2006)

Optimal timing of therapeutic hypothermia for cardiac ischemia is unknown. Our prior work suggests that ischemia with rapid reperfusion (I/R) in cardiomyocytes can be more damaging than prolonged ischemia alone. Also, these cardiomyocytes demonstrate protein kinase C (PKC) activation and nitric oxide (NO) signaling that confer protection against I/R injury. Thus we hypothesized that hypothermia will protect most using extended ischemia and early reperfusion cooling and is mediated via PKC and NO synthase (NOS). Chick cardiomyocytes were exposed to an established model of 1-h ischemia/3-h reperfusion, and the same field of initially contracting cells was monitored for viability and NO generation. Normothermic I/R resulted in 49.7 +/- 3.4% cell death. Hypothermia induction to 25 degrees C was most protective (14.3 +/- 0.6% death, P < 0.001 vs. I/R control) when instituted during extended ischemia and early reperfusion, compared with induction after reperfusion (22.4 +/- 2.9% death). Protection was completely lost if onset of cooling was delayed by 15 min of reperfusion (45.0 +/- 8.2% death). Extended ischemia/early reperfusion cooling was associated with increased and sustained NO generation at reperfusion and decreased caspase-3 activation. The NOS inhibitor N(omega)-nitro-L-arginine methyl ester (200 microM) reversed these changes and abrogated hypothermia protection. In addition, the PKCepsilon inhibitor myr-PKCepsilon v1-2 (5 microM) also reversed NO production and hypothermia protection. In conclusion, therapeutic hypothermia initiated during extended ischemia/early reperfusion optimally protects cardiomyocytes from I/R injury. Such protection appears to be mediated by increased NO generation via activation of protein kinase Cepsilon; nitric oxide synthase.