gebhart/patrepeval huggingface dataset:
Novel heteroarotinoids: synthesis and biological activity (1991)

In this study, 13 heteroarotinoids were synthesized. The key step in each preparation was the condensation of the appropriate chroman-, thiochroman-, or benzothienyl-substituted phosphorus ylide, obtained from the independent synthesis of the corresponding phosphonium salts, with selected polyene-substituted aldehyde esters. Nine of these heterocycles contained a thiochroman group, two had a chroman group, and two others had a benzothienyl system. Screening of the compounds was with one of two assays. One assay measured the ability of a retinoid to inhibit the phorbol ester induced increase of mouse epidermal ornithine decarboxylase (ODC) activity. The other assay measured retinoid-induced differentiation of the human myoloid leukemia cell line HL-60. In the ODC assay, all thirteen compounds were screened. The most active heteroarotinoids were ester 10 [methyl (E)-4-[2-(2,2,4,4-tetramethylthiochroman-6-yl)-1- propenyl]benzoate] and acid 11 [(E)-4-[2-(2,2,4,4-tetramethyl-3,4- dihydro-2H-1- benzothiopyran-6-yl)-1-propenyl]benzoic acid]. Both of these retinoids had ID50 values (dose required for half-maximal inhibition of phorbol ester induced ODC activity) of about 0.3 nmol. In comparison, the ID50 value for trans-retinoic acid (1) was 0.12 nmol while the ID50 values for acids 7 and 9, namely (2Z,4E,6E)-3,7-dimethyl-7-(4,4-dimethyl-thiochroman -6-yl)-2,4,6-heptatrienoic acid and (2E,4E,6E)-3,7-dimethyl-7-(2,2,4,4-tetramethylthiochroman -6-yl)-2,4,6- heptatrienoic acid, respectively, were about 3.5 nmol. Heteroarotinoids 8 and 12-17 had ID50 values of 35 nmol or greater. With a thiochroman unit, the most active acids in decreasing order of activity in the ODC assay were 7 greater than 9 greater than 8. Thus, simple replacement of the terminal propenyl system [C(16,17,18)] in 7 with a cyclopropyl group produced acid 8 [(2E,4E,6E)-7-methyl-7-(4,4-dimethylthiochroman-6-yl)- 2,3-methylene-4,6-heptadienoic acid with markedly reduced activity. With a benzoic acid group as part of the structure attached to the thiochroman unit, the ODC activity was enhanced as shown in 10 and 11. The combination of the 2,2,4,4-tetramethylthiochroman group and the benzoic acid (or ester) terminal group seemed to enhance the biological action which resembles that found with (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)- 1-propenyl]benzoic acid (TTNPB, 6b), a well-known model system.(ABSTRACT TRUNCATED AT 400 WORDS)
Detection of anti-pertussis toxin IgG in oral fluids for use in diagnosis and surveillance of Bordetella pertussis infection in children and young adults (2006)

Bordetella pertussis infection is being increasingly recognized as a cause of prolonged, distressing cough (without whooping symptoms) in children and young adults. Diagnosis of infection in this population is important for treatment and surveillance purposes, and may also prove useful in reducing transmission to unvaccinated babies, for whom disease can be fatal. Serum IgG titres against pertussis toxin (PT) are routinely used as a marker of recent or persisting B. pertussis infection. However, collection of serum from young children is difficult, and compliance amongst these subjects to give samples is low. To circumvent these problems, an IgG-capture ELISA capable of detecting anti-PT IgG in oral fluid was devised. The assay was evaluated by comparison to a serum ELISA, using 187 matched serum and oral fluid samples from children (aged 5-16 years) with a history of prolonged coughing, whose serum anti-PT titre had already been determined (69 seropositive, 118 seronegative). The results showed that, using a cutoff of 70 arbitrary units (AU), the oral fluid assay detected seropositive subjects with a sensitivity of 79.7% [95% confidence interval (CI) 68.3-88.4] and a specificity of 96.6% (95% CI 91.5-99.1). Thus, oral fluid titres of >or=70 AU would possess a positive predictive value of 76.2-93.2% for pertussis amongst children with chronic coughs when used as a surrogate for the serum ELISA (assuming disease prevalence of 12-37%). This oral fluid ELISA will greatly assist in the convenience of B. pertussis disease diagnosis and surveillance.
A real time OCSVM Intrusion Detection module with low overhead for SCADA systems (2014)

In this paper we present a intrusion detection module capable of detecting malicious network traffic in a SCADA (Supervisory Control and Data Acquisition) system. Malicious data in a SCADA system disrupt its correct functioning and tamper with its normal operation. OCSVM (One-Class Support Vector Machine) is an intrusion detection mechanism that does not need any labeled data for training or any information about the kind of anomaly is expecting for the detection process. This feature makes it ideal for processing SCADA environment data and automate SCADA performance monitoring. The OCSVM module developed is trained by network traces off line and detect anomalies in the system real time. In order to decrease the overhead induced by communicated alarms we propose a new detection mechanism that is based on the combination of OCSVM with a recursive k-means clustering procedure. The proposed intrusion detection module K??OCSVMis capable to distinguish severe alarms from possible attacks regardless of the values of parameters and , making it ideal for real-time intrusion detection mechanisms for SCADA systems. The most severe alarms are then communicated with the use of IDMEF files to an IDSIDS (Intrusion Detection System) system that is developed under CockpitCI project. Alarm messages carry information about the source of the incident, the time of the intrusion and a classification of the alarm.
Direct Molar Mass Determination of Self-Assembled Amphiphilic Block Copolymer Nanoobjects Using Electrospray-Charge Detection Mass Spectrometry (2012)

Charge detection mass spectrometry (CD-MS) combined with electrospray ionization was used to determine, in a direct way and for the first time, the molar mass of self-assembled amphiphilic block copolymer nanoobjects prepared via living radical emulsion polymerization. CD-MS supplies enough data for calculating statistically significant measurements of the mass of particles in the megadalton to gigadalton range and their resulting mass distribution.
1-N-Iminosugars:  Potent and Selective Inhibitors of β-Glycosidases (1998)

A series of 1-N-iminosugars were synthesized to supply the need for glycosidase inhibitors that are both highly potent and selective for β-glycosidases. Designed on the basis of the transition-state model of the β-glucosidase reaction, these iminosugar inhibitors differ from the currently available inhibitors in possessing a nitrogen atom at the anomeric position of the pyranose ring, thereby generating a positive charge on the anomeric position rather than on the ring oxygen of the sugar. Their syntheses, starting with a readily available carbohydrate derivative, involve (i) introduction of an amino functionality as an azido group, (ii) formation of a 1-N-iminopyranose ring with reductive amination, and (iii) stereoselective introduction of a hydroxymethyl or methyl group and were accomplished in a highly stereoselective and efficient manner. The inhibitory potencies of the 1-N-iminosugars were evaluated against several α- and β-glycosidases, and they were found to be extremely potent and highly specific against the corresponding β-glycosidases, with Ki values in the nanomolar range.
Anti-mitochondrial effects of bisethyl polyamines in mammalian cells. (1994)

The effects of three bisethyl polyamine analogs on mitochondrial structure and function were examined in human HeLa and L1210 murine leukemia cells. N, N' Bis-[3(ethylamino)-propyl]1-7- heptane diamine (BEPH), and its octane (BEPO), and butane (BESPM) derivative, were shown by electron microscopy and/or Rhodamine 123 uptake studies to alter the structural integrity of mitochondria when both cell lines were treated at the approximate IC50 dose of each drug. At this dose, BEPH had no marked effects on levels of the naturally occurring polyamines, putrescine, spermidine or spermine, in either cell line whereas BEPO and BESPM treatment did result in pool depletion. Southern blot analysis demonstrated a time and dose-dependent loss of mitochondrial DNA from BEPH-treated L1210 cultures suggesting that loss of mitochondrial integrity extended to the DNA level. Treatment of L1210 cells with all three analogs revealed marked reductions in the activity of two mitochondrial enzymes citrate synthase and cytochrome C oxidase. HeLa cells treated with all three analogs exhibited markedly reduced levels of ATP, complete loss of cytidine triphosphate (CTP) and near total depletion of uridine triphosphate (CTP) and near total depletion of uridine triphosphate (UTP). There was also a loss of colony forming ability in HeLa cells which could be nearly completely reversed by the addition of either uridine or cytidine suggesting that NTP reduction may be the primary antiproliferative determinant in these cells. Growth inhibition by BEPH in L1210 cells was markedly potentiated by the glycolysis inhibitor, 2-deoxyglucose, which had no such effect in otherwise untreated cells. This suggests that BEPH treatment of L1210 cells results in impairment of mitochondrial ATP synthesis and activation of the glycolytic pathway for energy production. 2-deoxyglucose treatment also completely prevented the increase of ATP by BEPH treatment of L1210 cells. It is concluded that all three bisethyl polyamines alter HeLa and L1210 mitochondria both structurally and functionally and that these alterations may play a primary role in the antiproliferative activity of these agents in HeLa cells. In L1210, the different spectra of cellular biochemical changes following bisethyl polyamine treatment suggests that additional mechanisms may be in effect.
Expedient Parallel Synthesis of 2-Amino-4-heteroarylpyrimidines (2005)

[reaction: see text] An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.
Reflexes to sacral parasympathetic neurones concerned with micturition in the cat (1969)

1. Reflexes to sacral parasympathetic neurones were studied by electrophysiological techniques in decerebrate, in chloralose-anaesthetized, and in chronic spinal cats.2. Excitatory reflexes from pelvic nerve and sacral somatic afferent nerve fibres were present before and after chronic transection of the spinal cord, but the latencies differed markedly. It was concluded that the long-latency reflexes observed when the spinal cord was intact involved long-loop reflexes to the brain-stem. The weak, short-latency reflexes in the chronic spinal cat were never observed when the spinal cord was intact and could be due to reorganized spinal connexions. The short-latency reflexes are probably unimportant in normal micturition.3. Stimulation of afferent fibres in the pelvic or sacral somatic nerves produced short-latency inhibitory post-synaptic potentials (IPSPs) and inhibition of discharges in parasympathetic neurones. This inhibition was due to a spinal reflex.4. A local reflex was demonstrated in the pelvic plexus. This was probably a cholinergic axon reflex, but the remote possibility that it was a local cholinergic reflex involving sensory neurones in the bladder wall has not been excluded.
Systemic radionuclide therapy using indium-111-DTPA-D-Phe1-octreotide in midgut carcinoid syndrome. (1996)

A 55-yr-old woman with a midgut carcinoid syndrome due to metastatic spread of an ileal tumor to the liver, paraortic and mediastinal lymph nodes and to the skeleton was given systemic radionuclide therapy with 111In-DTPA-D-Phe1-octreotide. Before therapy, dosimetric calculations were performed on whole-body scintigraphs and 111In retention was shown to be long-lasting. Excretion was mainly seen during the first 24 hr after injection; thereafter whole-body retention remained stationary at 30%. Indium-111 activity in tumor biopsies and blood was measured using a gamma counter. Very high tumor-to-blood ratios were obtained: 150 for the primary tumor and 400-650 for liver metastases, which further justified radiation therapy. Indium-111-DTPA-D-Phe1-octreotide treatment was given on three separate occasions (3.0, 3.5 and 3.1 GBq) 8 and 4 wk apart. After each therapy, the patient experienced facial flush and pain over the skeletal lesions followed by symptomatic relief, even though no objective tumor regression was found radiologically after 5 mo. After initiation of octreotide treatment, there was a 14% reduction of the main tumor marker, urinary 5-HIAA. After three subsequent radionuclide therapies, there was a further 31% reduction of 5-HIAA levels. No adverse reactions, other than a slight decrease in leukocyte counts, were seen. The mean absorbed radiation dose after the three treatments was estimated to be about 10-12 Gy in liver metastases and 3-6 Gy in other tumors, depending on the size and location of the metastases. Assuming internalization of 111In into tumor cells and a radiobiological effect from short range Auger and conversion electrons, there might be a therapeutic effect on the tumor.
A Robust Method for Estimating Respiratory Flow Using Tracheal Sounds Entropy (2006)

The relationship between respiratory sounds and flow is of great interest for researchers and physicians due to its diagnostic potentials. Due to difficulties and inaccuracy of most of the flow measurement techniques, several researchers have attempted to estimate flow from respiratory sounds. However, all of the proposed methods heavily depend on the availability of different rates of flow for calibrating the model, which makes their use limited by a large degree. In this paper, a robust and novel method for estimating flow using entropy of the band pass filtered tracheal sounds is proposed. The proposed method is novel in terms of being independent of the flow rate chosen for calibration; it requires only one breath for calibration and can estimate any flow rate even out of the range of calibration flow. After removing the effects of heart sounds (which distort the low-frequency components of tracheal sounds) on the calculated entropy of the tracheal sounds, the performance of the method at different frequency ranges were investigated. Also, the performance of the proposed method was tested using 6 different segment sizes for entropy calculation and the best segment sizes during inspiration and expiration were found. The method was tested on data of 10 healthy subjects at five different flow rates. The overall estimation error was found to be 8.3 +/- 2.8% and 9.6 +/- 2.8% for inspiration and expiration phases, respectively.
Superior cytotoxicity with ganciclovir compared with acyclovir and 1-beta-D-arabinofuranosylthymine in herpes simplex virus-thymidine kinase-expressing cells: a novel paradigm for cell killing. (1998)

Enzyme-prodrug therapy using ganciclovir and herpes simplex virus-thymidine kinase (HSV-TK) has demonstrated excellent antitumor activity in many different types of malignant cells. Previously, we noted that ganciclovir was substantially more cytotoxic than other HSV-TK substrates. Therefore, we embarked on a study to determine the basis for the superior cytotoxicity of ganciclovir. In U251tk human glioblastoma cells that stably express HSV-TK, ganciclovir elicited a >4 log cell kill instead of the < or =1.5 log cell kill mediated by two other HSV-TK substrates, 1-beta-D-arabinofuranosylthymine (araT) and acyclovir. Study of the metabolism of these drugs demonstrated that acyclovir was poorly phosphorylated to its active triphosphate with DNA incorporation below the limit of detection, which may explain the < 1 log cell kill in these cells. Lower levels of ganciclovir triphosphate accumulated compared with araT triphosphate (araTTP) under conditions that induced < or =1 log cell kill (67 versus 1235 pmol/10(7) cells, respectively), and the half-life for the triphosphate of ganciclovir was shorter than that of araT (terminal half-lives of 15 and 41 h, respectively). Incorporation of ganciclovir monophosphate into DNA was less than that of araT monophosphate, and both analogues were retained in DNA for > or =48 h. Thus, the superior cytotoxicity of ganciclovir was not due to enhanced metabolism to active forms. Highly cytotoxic concentrations of ganciclovir produced only weak inhibition of DNA synthesis. This allowed cells to proceed through S and G2-M phases during and after drug exposure, resulting in a doubling of cell number by 48 h after drug washout. As they attempted to progress through the cell cycle a second time, ganciclovir-treated cells accumulated in early S-phase and remained there until cell death, suggesting that ganciclovir incorporation in the DNA template was important for cytotoxicity. In contrast, strong inhibition of DNA synthesis by araTTP prevented cells from traversing the cell cycle for at least 12 h after drug washout, when the active metabolite was largely degraded araT-treated cells were unable to divide for at least 72 h after drug exposure, at which point the surviving cells displayed a normal cell cycle distribution pattern. Based on the results presented here, we propose a novel paradigm in which the ability of ganciclovir to incorporate into DNA without inhibiting progression through S-phase, combined with high cytotoxicity for incorporated ganciclovir monophosphate, produces multilog cytotoxicity.
Mutations in the Nijmegen Breakage Syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). (2001)

The Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder associated with immune deficiency, chromosome fragility, and increased susceptibility to lymphoid malignancies. The aim of the present study was to elucidate the potential role of the gene mutated in NBS (NBS1) in the pathogenesis and disease progression of childhood acute lymphoblastic leukemia (ALL). Samples from 47 children with first relapse of ALL were analyzed for mutations in all 16 exons of the NBS1 gene, and in 7 of them (14.9%), four novel amino acid substitutions were identified. Mutations S93L, D95N, and I171V occur in the two known domains of nibrin that are probably involved in protein-protein interactions. Germ-line origin of the I171V mutation was confirmed in three patients, whereas the D95N exchange was present only in leukemic cells. The R215W mutation was observed in one ALL but also in a population-based study and probably represents a rare sequence variant. No additional mutations were found on the second allele in any of these seven patients. The observed NBS1 gene mutations in ALL patients points to its possible involvement in the pathogenesis of this disease.
Synthesis and biological properties of N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid dipeptides. A novel group of antimicrobial agents (1987)

A series of dipeptides with N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), the irreversible inhibitor of glucosamine-6-phosphate synthetase from bacteria and fungi, have been synthesized and their antibacterial and antifungal properties in vitro evaluated. The results demonstrate that these peptides inhibit the growth of a number of the tested microorganisms, especially pathogenic fungus Candida albicans. The results of competitive antagonism studies indicate specific peptide transport of the peptides via peptide permeases as drug delivery system and gives evidence for the high selectivity of the action upon the cells, as a result of the inhibition of generation of glucosamine.
Modeling and Fabrication of Hollow Optical Waveguide for Photonic Integrated Circuits (2002)

We present the design and fabrication of hollow optical waveguides with highly reflective mirrors on the guiding walls of waveguides. We demonstrate the possibility of polarization-insensitive and low-loss slab waveguides by loading properly designed dielectric multilayer mirrors. We also propose a novel three-dimensional (3D) hollow waveguide with an etched groove structure for confining light in a lateral direction. We also predict that the propagation constant is independent of the ambient temperature, resulting in temperature-insensitive photonic waveguide devices such as optical filters and grating optical demultiplexers. We fabricate slab and 3D hollow optical waveguides with Au coating and present their propagation characteristics. The propagation loss of a slab waveguide was 1–2 dB/cm and 3–4 dB/cm for transverse electric (TE) and transverse magnetic (TM) modes, respectively. We also suggest the possibility of low-loss 3D hollow waveguides.
Maternal and fetal amino acid concentrations and fetal outcomes during pre-eclampsia (2003)

The pathophysiology of pre-eclampsia is contested, but one hypothesis indicates that it is a heterogeneous condition in which only a subset of affected women bear small-for-gestational age (SGA) babies. In intrauterine growth-restricted (IUGR) infants, placental transport of amino acids is diminished and the resulting decrease in cord-blood amino acid concentrations is thought to contribute to their stunted growth. In contrast, the metabolic syndrome (dyslipidaemia, hyperinsulinaemia, hyperglycaemia, hypertension and obesity) which is associated with high amino acid concentrations is more prevalent in women with pre-eclampsia. The focus of this study was to compare maternal and fetal serum amino acid concentrations during normal pregnancy and pre-eclampsia and to evaluate the associations between the amino acid concentrations and fetal growth. The results indicate that maternal and cord-blood amino acid concentrations were significantly higher in women with pre-eclampsia compared with normal pregnant women and the concentrations were inversely associated with measures of infant growth. Maternal and cord-blood amino acid concentrations were also significantly higher in pre-eclamptic mothers with SGA infants compared with pre-eclamptic mothers whose babies were not SGA. These data indicate that, in contrast to IUGR, pre-eclampsia is associated with enhanced placental amino acid transport or reduced fetal amino acid utilization. Furthermore, the data are consistent with the hypothesis that pre-eclampsia is a heterogeneous disease associated with the metabolic syndrome.
Increased Expression of Mcl-1 Is Required for Protection against Serum Starvation in Phosphatase and Tensin Homologue on Chromosome 10 Null Mouse Embryonic Fibroblasts, but Repression of Bim Is Favored in Human Glioblastomas (2005)

Inactivating mutations in the tumor suppressor gene phosphatase and tensin homologue on chromosome 10 (PTEN) result in elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, activation of protein kinase B (PKB), and protection against apoptotic insults such as withdrawal of survival factors. Protection may arise through the inhibition of the pro-apoptotic protein Bim, which is normally repressed by a PKB-dependent mechanism. Here we show that PTEN-/- immortalized mouse embryonic fibroblasts (MEFs) exhibit elevated PKB phosphorylation and are resistant to serum withdrawal-induced death, but exhibit normal Bim expression following withdrawal of serum. In contrast, expression of Mcl-1, a prosurvival member of the Bcl-2 family, was elevated in PTEN-/- MEFs. Transient or stable overexpression of Mcl-1 in PTEN+/- MEFs conferred resistance to serum withdrawal, whereas ablating expression of Mcl-1 in PTEN-/- MEFs, using RNA interference, abolished their resistance to serum withdrawal-induced apoptosis. To determine if Mcl-1 is selected for overexpression in human tumors we examined human glioblastoma cell lines but found that loss of PTEN had no effect on Mcl-1 expression. In contrast, two of three PTEN-/- glioblastoma cell lines exhibited low expression of Bim, which was refractory to serum withdrawal. These results indicate that the resistance of PTEN-/- MEFs to serum withdrawal is largely due to the up-regulation of Mcl-1 but that loss of PTEN in tumor cell lines is more complex and may favor de-regulation of different apoptotic regulators such as Bim.