gebhart/patrepeval huggingface dataset:
Synthesis and Biological Evaluation of Analogues of AKT (Protein Kinase B) Inhibitor-IV (2011)

Inhibitors of the PI3-kinase/AKT (protein kinase B) pathway are under investigation as anticancer and antiviral agents. The benzimidazole derivative AKT inhibitor-IV (ChemBridge 5233705) affects this pathway and exhibits potent anticancer and antiviral activity. To probe its biological activity, we synthesized AKT inhibitor-IV and 21 analogues using a novel six-step route based on ZrCl(4)-catalyzed cyclization of 1,2-arylenediamines with α,β-unsaturated aldehydes. We examined effects on viability of HeLa carcinoma cells, viability of normal human cells (NHBE), replication of recombinant parainfluenza virus 5 (PIV5) in HeLa cells, and replication of the intracellular bacterium Mycobacterium fortuitum in HeLa cells. Replacement of the benzimidazole N-ethyl substitutent of AKT inhibitor-IV with N-hexyl and N-dodecyl groups enhanced antiviral activity and cytotoxicity against the cancer cell line, but these compounds showed substantially lower toxicity (from 6-fold to >20-fold) against NHBE cells and no effect on M. fortuitum, suggesting inhibition of one or more host protein(s) required for proliferation of cancer cells and PIV5. The key structural elements identified here may facilitate identification of targets of this highly biologically active scaffold.
Rh-Catalyzed Cyclization of Diynes and Enynes Initiated by Carbonyl-Directed Activation of Aromatic and Vinylic C−H Bonds (2007)

The Rh-catalyzed hydroarylative and hydrovinylative cyclization of diynes with aryl ketones or enones gave monocyclic 1,3-dienes. Enynes also underwent the same reaction and chiral products were obtained with high ee using a chiral Rh catalyst. Carbonyl-directed activation of aromatic and vinylic C-H bonds is likely the initial step in the present transformation.
Akt1 governs breast cancer progression in vivo (2007)

The serine threonine kinase Akt1 has been implicated in the control of cellular metabolism, survival and growth. Here, disruption of the ubiquitously expressed member of the Akt family of genes, Akt1, in the mouse demonstrates a requirement for Akt1 in ErbB2-induced mammary tumorigenesis. Akt1 deficiency delayed tumor growth and reduced lung metastases, correlating with a reduction in phosphorylation of the Akt1 target, tuberous sclerosis 2 (TSC2) at Ser-939. Akt1-deficient mammary epithelial tumor cells (MEC) were reduced in size and proliferative capacity, with reduced cyclin D1 and p27(KIP1) abundance. Akt1 deficiency abrogated the oncogene-induced changes in polarization of MEC in three-dimensional culture and reverted oncogene-induced relocalization of the phosphorylated ezrin-radixin-moesin proteins. Akt1 increased MEC migration across an endothelial cell barrier, enhancing the persistence of migratory directionality. An unbiased proteomic analysis demonstrated Akt1 mediated MEC migration through paracrine signaling via induction of expression and secretion of CXCL16 and MIP1gamma. Akt1 governs MEC polarity, migratory directionality and breast cancer onset induced by ErbB2 in vivo.
DNA Vaccines: Progress and Challenges (2005)

In the years following the publication of the initial in vivo demonstration of the ability of plasmid DNA to generate protective immune responses, DNA vaccines have entered into a variety of human clinical trials for vaccines against various infectious diseases and for therapies against cancer, and are in development for therapies against autoimmune diseases and allergy. They also have become a widely used laboratory tool for a variety of applications ranging from proteomics to understanding Ag presentation and cross-priming. Despite their rapid and widespread development and the commonplace usage of the term "DNA vaccines," however, the disappointing potency of the DNA vaccines in humans underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the varied immunological mechanisms that play a role in their ability to generate immune responses.
High-Performance and Scalable MPI over InfiniBand with Reduced Memory Usage: An In-Depth performance Analysis (2006)

InfiniBand is an emerging HPC interconnect being deployed in very large scale clusters, with even larger InfiniBand-based clusters expected to be deployed in the near future. The message passing interface (MPI) is the programming model of choice for scientific applications running on these large scale clusters. Thus, it is very critical for the MPI implementation used to be based on a scalable and high-performance design. We analyze the performance and scalability aspects of MVAPICH, a popular open-source MPI implementation on InfiniBand, from an application standpoint. We analyze the performance and memory requirements of the MPI library while executing several well-known applications and benchmarks, such as NAS, SuperLU, NAMD, and HPL on a 64-node InfiniBand cluster. Our analysis reveals that latest design of MVAPICH requires an order of magnitude less internal MPI memory (average per process) and yet delivers the best possible performance. Further, we observe that for these benchmarks and applications evaluated, the internal memory requirement of MVAPICH remains nearly constant at around 5-10 MB as the number of processes increase, indicating that the MVAPICH design is highly scalable
LEUKEMIA AFTER LIVER TRANSPLANT (2001)

Acute leukemia, although rare after liver transplantation, should be considered in the differential diagnosis of hematological complications.
Single-Drug Multiligand Conjugates:  Synthesis and Preliminary Cytotoxicity Evaluation of a Paclitaxel−Dipeptide “Scorpion” Molecule (2006)

To improve the targeting properties of receptor-directed drug-peptide conjugates, a multiligand approach was proposed and a model "scorpion" conjugate (6, Figure 1), consisting of two peptide "claws" and a paclitaxel (PTX) "tail", was synthesized. The cell surface receptor-directed peptide used in this single-drug multiligand (SDML) model was a segment of the amphibian peptide bombesin (BBN) which had the Y6Q7W8A9V10G11H12L13M14-NH2 sequence, designated here as BBN[6-14] (2, Figure 2). Due to the lipophilic nature of both PTX and BBN[6-14], compound 6 had a low water solubility. To enhance the solubility, PEG derivatives of this conjugate were prepared with the polymer inserted either in the claws or in the tail regions. In a preliminary random screening, conjugate 6 showed superior cytotoxic activity in several GRPR-positive human cancer cell lines as compared to free PTX and two single-drug single-ligand (SDSL) conjugates. In a receptor blocking experiment, addition of excess unconjugated BBN[6-14] ligand reduced the cytotoxicity of conjugate 6, indicating the receptor-mediated mechanism of drug delivery. The PEG-derived conjugates showed activities which were intermediate between SDSL and the SDML congeners. Also, an increase in the number of the PEG segments lowered cytotoxicity, possibly due to steric hindrance against ligand-receptor binding. Taken together, these results demonstrate the potential of the multiligand approach in the design of receptor-targeting conjugates for tumor-specific drug delivery.
Solution structure and backbone dynamics of an antigen‐free heavy chain variable domain (VHH) from Llama (2002)

Camelids, (dromedaries, camels, and llamas) produce heavy-chains antibodies, with their antigen recognition sites composed of a single VH-like domain, referred to as VHH. The solution structure of one of these VHHs domains (VHH-H14), raised against the α subunit of the human chorionic gonadotropin hormone (hCG), has been determined by 15N heteronuclear three-dimensional NMR spectroscopy. The framework is well resolved within the set of 20 best-calculated NMR structures and is close to that of classical VH domains from vertebrate antibodies, consisting of two antiparallel β-sheets organized in a β-barrel. Loops display a lower precision, especially the Complementarity Determining Regions (CDRs), involved in antigen recognition. Comparison of the three-dimensional VHH-H14 solution structure with its previously solved crystal structure (Spinelli et al., Nature Struct. Biol. 1996;3:752–757) reveals a high similarity to the framework, whereas significant conformational differences occur on CDRs, leading to the assumption that the antigen recognition site is a more mobile part. In order to deepen our insights into the dynamics of VHH-H14 in solution, 15N relaxation was measured with longitudinal R1 and transverse R2 self-relaxation rates, and 15N steady-state heteronuclear nuclear Overhauser enhancements (NOE), making it possible to probe picosecond-to-millisecond internal motions. Determination of dynamic parameters (S2, τe, and Rex) through the Lipari-Szabo Model-free approach enables the identification of several regions with enhanced dynamics. Especially, the mobility measurements from NMR confirm that the antigen recognition site is the most mobile part of the VHH-H14 domain on picosecond-to-nanosecond fast time scales. Several residues belonging to the three CDRs are submitted to chemical exchange processes occurring on slow microsecond-to-millisecond time scales, suggesting that the formation of the VHH/antigen complex should be accompanied by structural changes. Proteins 2002;47:546–555. © 2002 Wiley-Liss, Inc.
Molecular Tripods Showing Fluorescence Enhancement upon Binding to Streptavidin (2004)

We introduce a new approach to biotin-streptavidin assays based on a molecular tripod which consists of biotin, a fluorophore, and a quencher. The interaction between streptavidin and molecular tripods perturbs the ground-state quencher-fluorophore dimeric conformation in the absence of streptavidin and diminishes the intrinsic self-quenching of a quencher-fluorophore pair. The emission intensity of the molecular tripods plus streptavidin is 3.5-5.2 times that of molecular tripods in the absence of streptavidin.
Detection of tumor cells in bone marrow of patients with primary breast cancer: a prognostic factor for distant metastasis. (1992)

This study suggests that tumor-cell detection in bone marrow of patients with primary breast carcinoma is a good predictor for all distant relapses (P < .0005, Cox multiple regression analysis) and provides additional information in regard to other prognostic factors. The highest predicting value for distant metastasis results from the combination of nodal status, negative PR, and tumor-cell presence in bone marrow.
Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib (2006)

EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations.
Cytokines in chronic inflammatory arthritis. I. Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony-stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. (1988)

Because previous studies showed low levels of IFN-gamma in rheumatoid arthritis (RA) synovial fluid (SF) and synovial tissue (ST) explant supernatants, we assayed RA SF and ST for IL-2 and IL-3-like activity. Using an IL-2 dependent murine CTLL line, 6 of 14 RA SF caused increased thymidine uptake (greater than three times control). The activity was distinct from IL-2 because it was not blocked by antibody to IL-2-R. In addition, IL-2 was not detected (less than 50 pg/ml) in 16 joint samples using an ELISA. Multi-colony-stimulating factor (CSF) activity was measured using two assays that can detect murine IL-3 (mast cell proliferation, and bone marrow CSF). In the mast cell assay, [3H]TdR uptake was 493 +/- 67 cpm for medium, 2,910 +/- 329 cpm in the presence of RA SF (p less than 0.001), 1,246 +/- 156 cpm in the presence of SF from patients with seronegative spondyloarthropathies (p less than 0.001), and 736 +/- 100 cpm in the presence of osteoarthritis SF (p greater than 0.1). In the CSF assay, four of five RA SF and five of five RA ST induced colony formation from bone marrow nonadherent cells. Macrophage colonies were most common, although mixed colonies and granulocytes were occasionally observed. The multi-CSF activity in RA is not due to IL-3 since human rIL-3 was not active in either murine assay, and IL-3 mRNA was not detected in RA synovium. Sephadex column chromatography of RA SF revealed that the mast cell growth factor (approximately 6 x 10(3) mol wt) and the CSF (approximately 40 and 100 x 10(3) mol wt) are distinct. The colony-stimulating aspect of the "IL-3-like" activity in RA SF is likely due to CSF-1 because it is the appropriate mol wt and because the activity was neutralized by specific anti-CSF-1 antibody. Finally, an RIA detected 1.6-25 ng/ml of CSF-1 in RA SF and ST and CSF-1 mRNA was detected in four of five RA synovial tissue samples tested.
Operative Management of Neuromatous Knee Pain: Patient Selection and Outcome (2001)

The management of intractable knee pain secondary to neuromata continues to be optimized. Forty-three patients with intractable knee pain were studied prospectively. Consideration for this procedure requires pain of at least a 1-year duration, failure of conservative management, pain localization at a Tinel's point, and at least a 5-point reduction of pain on a visual analog scale after nerve blockade with 1% lidocaine. Thirty patients met the criteria for the procedure and 25 patients underwent the procedure. Mean patient age was 50.3 years and mean duration of pain was 6.6 years. Pain etiology included total knee replacement in 10 patients and trauma in 15 patients. Mean number of prior operations on the knee was 5.1. Sixty-two nerves were excised in the 25 patients, including the infrapatellar branch of the saphenous nerve (N = 24), the tibiofibular branch of the peroneal nerve (N = 5), the medial retinacular nerve (N = 12), the lateral retinacular nerve (N = 8), the medial cutaneous nerve (N = 6), the anterior cutaneous nerve (N = 3), and the lateral femoral cutaneous nerve (N = 4). Complete pain relief was obtained in 11 patients (44%). Partial pain relief was reported in 10 patients (40%). No pain relief was reported in 4 patients (16%). Follow-up ranged from 1 to 4 years. Selective denervation for neuromatous knee pain is beneficial in select patients. Patient satisfaction was 84% (21 of 25 patients) after the procedure. No patient was made worse.
Endoplasmic Reticulum Stress Links Dyslipidemia to Inhibition of Proteasome Activity and Glucose Transport by HIV Protease Inhibitors (2005)

The lipid and metabolic disturbances associated with human immunodeficiency virus (HIV) protease inhibitor therapy in AIDS have stimulated interest in developing new agents that minimize these side effects in the clinic. The underlying explanation of mechanism remains enigmatic, but a recently described link between endoplasmic reticulum (ER) stress and dysregulation of lipid metabolism suggests a provocative integration of existing and emerging data. We provide new evidence from in vitro models indicating that proteasome inhibition and differential glucose transport blockade by protease inhibitors are proximal events eliciting an ER stress transcriptional response that can regulate lipogenic pathways in hepatocytes or adipocytes. Proteasome activity was inhibited in vitro by several protease inhibitors at clinically relevant (micromolar) levels. In the intact cells, protease inhibitors rapidly elicited a pattern of gene expression diagnostic of intracellular proteasome inhibition and activation of an ER stress response. This included induction of transcription factors GADD153, ATF4, and ATF3; amino acid metabolic enzymes; proteasome components; and certain ER chaperones. In hepatocyte lines, the ER stress response was closely linked to moderate increases in lipogenic and cholesterogenic gene expression. However, in adipocytes where GLUT4 was directly inhibited by some protease inhibitors, time-dependent suppression of lipogenic genes and triglyceride synthesis was observed in coordination with the ER stress response. These results further link ER stress to dyslipidemia and contribute to a unifying mechanism for the pathophysiology of protease inhibitor-associated lipodystrophy, helping explain differences in clinical metabolic profiles among protease inhibitors.
Effects of Cigarette Smoke in Mice with Different Levels of α1-Proteinase Inhibitor and Sensitivity to Oxidants (2001)

The role of strain difference in the response to cigarette smoke was investigated in mice. Mice of the strains DBA/2 and C57BL/6J responded to acute cigarette smoke with a decrease of the antioxidant defenses of their bronchoalveolar lavage (BAL) fluids. On the other hand, under these conditions ICR mice increased their BAL antioxidant defenses. Mice of these three strains were then exposed to cigarette smoke (three cigarettes/d, 5 d/wk) for 7 mo. Lung elastin content was significantly decreased in C57BL/6J and DBA/2 but not in ICR mice. Also, emphysema, assessed morphometrically using three methods, was present in C57BL/6J and DBA/2 but not in ICR mice. In an additional study pallid mice, with a severe serum alpha(1)-proteinase inhibitor (alpha(1)-PI) deficiency and that develop spontaneous emphysema, were exposed to cigarette smoke for 4 mo. This resulted in an acceleration of the development of the spontaneous emphysema assessed with morphometrical and biochemical (lung elastin content) methods. All these results indicate that sensitivity to the effects of cigarette smoke is strain-dependent and cigarette smoke accelerates the effects of alpha(1)-PI deficiency.
The methylmercury‐l‐cysteine conjugate is a substrate for the L‐type large neutral amino acid transporter (2008)

Methylmercury (MeHg) is a potent neurotoxin. The mechanism(s) that governs MeHg transport across the blood-brain barrier and other biological membranes remains unclear. This study addressed the role of the L-type large neutral amino acid transporter, LAT1, in MeHg transport. Studies were carried out in CHO-k1 cells. Over-expression of LAT1 in these cells was associated with enhanced uptake of [(14)C]-MeHg when treated with L-cysteine, but not with the D-cysteine conjugate. In the presence of excess L-methionine, a substrate for LAT1, L-cysteine-conjugated [(14)C]-MeHg uptake was significantly attenuated. Treatment of LAT-1 over-expressing CHO-k1 cells with L-cysteine-conjugated MeHg was also associated with increased leakage of lactate dehydrogenase into the media as well as reduced cell viability measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. In contrast, knock-down of LAT1 decreased the uptake of l-cysteine-conjugated MeHg and attenuated the effects of MeHg on lactate dehydrogenase leakage and CHO-k1 cell viability. These results indicate that the MeHg-L-cysteine conjugate is a substrate for the neutral amino acid transporter, LAT1, which actively transports MeHg across membranes.
Miniature all-silica optical fiber pressure sensor with an ultrathin uniform diaphragm (2010)

This paper presents an all-silica miniature optical fiber pressure/acoustic sensor based on the Fabry-Perot (FP) interferometric principle. The endface of the etched optical fiber tip and silica thin diaphragm on it form the FP structure. The uniform and thin silica diaphragm was fabricated by etching away the silicon substrate from a commercial silicon wafer that has a thermal oxide layer. The thin film was directly thermally bonded to the endface of the optical fiber thus creating the Fabry-Perot cavity. Thin films with a thickness from 1microm to 3microm have been bonded successfully. The sensor shows good linearity and hysteresis during measurement. A sensor with 0.75 microm-thick diaphragm thinned by post silica etching was demonstrated to have a sensitivity of 11 nm/kPa. The new sensor has great potential to be used as a non-intrusive pressure sensor in a variety of sensing applications.
Monolithic integration of GaAs/AlGaAs double-heterostructure LED's and Si MOSFET's (1986)

Fully monolithic integration of interconnected GaAs/Al-GaAs double-heterostructure LED's and Si MOSFET's is demonstrated for the first time. The Si MOSFET's, with a gate length of 5 µm and gate width of 1.6 mm, have almost the same characteristics as those of control devices fabricated on a separate Si wafer. The LED output collected by a microscope lens with a numerical aperture of 0.65 is about 6.5 µW at 100- mA dc current. LED modulation rates up to 27 Mbit/s have been achieved by applying a stream of voltage pulses to the MOSFET gate. The modulation rate is limited by the speed of the MOSFET.
The Action of Acids on Nitronic Esters and Nitroparaffin Salts. Concerning the Mechanisms of the Nef and the Hydroxamic Acid Forming Reactions of Nitroparaffins1,2 (1965)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe Action of Acids on Nitronic Esters and Nitroparaffin Salts. Concerning the Mechanisms of the Nef and the Hydroxamic Acid Forming Reactions of Nitroparaffins1,2Nathan Kornblum and R. Alan BrownCite this: J. Am. Chem. Soc. 1965, 87, 8, 1742–1747Publication Date (Print):April 1, 1965Publication History Published online1 May 2002Published inissue 1 April 1965https://pubs.acs.org/doi/10.1021/ja01086a023https://doi.org/10.1021/ja01086a023research-articleACS PublicationsRequest reuse permissionsArticle Views308Altmetric-Citations54LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Structural basis for microRNA targeting (2014)

MicroRNAs (miRNAs) control expression of thousands of genes in plants and animals. miRNAs function by guiding Argonaute proteins to complementary sites in messenger RNAs (mRNAs) targeted for repression. We determined crystal structures of human Argonaute-2 (Ago2) bound to a defined guide RNA with and without target RNAs representing miRNA recognition sites. These structures suggest a stepwise mechanism, in which Ago2 primarily exposes guide nucleotides (nt) 2 to 5 for initial target pairing. Pairing to nt 2 to 5 promotes conformational changes that expose nt 2 to 8 and 13 to 16 for further target recognition. Interactions with the guide-target minor groove allow Ago2 to interrogate target RNAs in a sequence-independent manner, whereas an adenosine binding-pocket opposite guide nt 1 further facilitates target recognition. Spurious slicing of miRNA targets is avoided through an inhibitory coordination of one catalytic magnesium ion. These results explain the conserved nucleotide-pairing patterns in animal miRNA target sites first observed over two decades ago.