gebhart/patrepeval huggingface dataset:
Stereochemical Studies on the Nucleophilic Substitution in the Reaction of Allylic Phosphates with Organoaluminum Reagents (1980)

Abstract The reaction of cis- or trans-5-isopropenyl-2-methyl-2-cyclohexenyl diethyl phosphate (1) with Me2AlX (X=OPh, SPh, NHPh) in hexane results in substitution of the –O–PO(OEt)2 group with X under predominant inversion. In contrast, treatment of cis- or trans-1 with trialkylaluminum produces predominantly the allyl-nonallyl couplingproducts of the same (thermodynamically more stable) configuration. Similar alkylation of endo- and exo-2-acetoxynorcarane gave endo-2-methylnorcarane, exclusively.
Effects of S1 Cleavage on the Structure, Surface Export, and Signaling Activity of Human Notch1 and Notch2 (2009)

S1 cleavage has distinct effects on the surface expression of Notch1 and Notch2, but is not generally required for physiologic or pathophysiologic activation of Notch proteins. These findings are consistent with models for receptor activation in which ligand-binding or T-ALL-associated mutations lead to conformational changes of the NRR that permit metalloprotease cleavage.
The Ras-Raf-MEK-ERK Pathway in the Treatment of Cancer (2002)

The mitogen activated protein kinases (MAPKs) are conserved proteins that regulate cell growth, division and death. Although activated in the cytosol, the MAPKs translocate to the nucleus upon activation and phosphorylate a large number of nuclear proteins. Investigating how Ras transmits extracellular growth signals, the MAPK pathway has emerged as the crucial route between membrane-bound Ras and the nucleus. The MAPK pathway represents a cascade of phosphorylation events including three pivotal kinases, namely Raf, MEK (MAP kinase kinase), and ERK (MAP kinase). These kinases present new opportunities for the development of novel anti-cancer drugs designed to be target-specific and probably less toxic than conventional chemotherapeutic agents. A number of drugs inhibiting Ras, Raf or MEK are currently under clinical investigation. This review addresses the rationale for targeting the MAP kinase pathway and the current status of various pharmacological approaches.
Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: The additive and subtractive effect of the three dopaminergic genes—DRD2, DβH, and DAT1 (1996)

Polymorphisms of three different dopaminergic genes, dopamine D2 receptor (DRD2), dopamine beta-hydroxylase (D beta H), and dopamine transporter (DAT1), were examined in Tourette syndrome (TS) probands, their relatives, and controls. Each gene individually showed a significant correlation with various behavioral variables in these subjects. The additive and substractive effects of the three genes were examined by genotyping all three genes in the same set of subjects. For 9 of 20 TS associated comorbid behaviors there was a significant linear association between the degree of loading for markers of three genes and the mean behavior scores. The behavior variables showing the significant associations were, in order attention deficit hyperactivity disorder (ADHD), stuttering oppositional defiant, tics, conduct, obsessive-compulsive, mania, alcohol abuse and general anxiety-behaviors that constitute the most overt clinical aspects of TS. For 16 of the 20 behavior scores there was a linear progressive decrease in the mean score with progressively lesser loading for the three gene markers. These results suggest that TS, ADHD, stuttering oppositional defiant and conduct disorder, and other behaviors associated with TS, are polygenic, due in part to these three dopaminergic genes, and that the genetics of other polygenic psychiatric disorders may be deciphered using this technique.
Recombinant Human DNA (Cytosine-5) Methyltransferase (1999)

A method is described to express and purify human DNA (cytosine-5) methyltransferase (human DNMT1) using a protein splicing (intein) fusion partner in a baculovirus expression vector. The system produces approximately 1 mg of intact recombinant enzyme >95% pure per 1.5 x 10(9) insect cells. The protein lacks any affinity tag and is identical to the native enzyme except for the two C-terminal amino acids, proline and glycine, that were substituted for lysine and aspartic acid for optimal cleavage from the intein affinity tag. Human DNMT1 was used for steady-state kinetic analysis with poly(dI-dC).poly(dI-dC) and unmethylated and hemimethylated 36- and 75-mer oligonucleotides. The turnover number (k(cat)) was 131-237 h(-1) on poly(dI-dC).poly(dI-dC), 1.2-2.3 h(-1) on unmethylated DNA, and 8.3-49 h(-1) on hemimethylated DNA. The Michaelis constants for DNA (K(m)(CG)) and S-adenosyl-L-methionine (AdoMet) (K(m)(AdoMet)) ranged from 0.33-1.32 and 2.6-7.2 microM, respectively, whereas the ratio of k(cat)/K(m)(CG) ranged from 3.9 to 44 (237-336 for poly(dI-dC).poly(dI-dC)) x 10(6) M(-1) h(-1). The preference of the enzyme for hemimethylated, over unmethylated, DNA was 7-21-fold. The values of k(cat) on hemimethylated DNAs showed a 2-3-fold difference, depending upon which strand was pre-methylated. Furthermore, human DNMT1 formed covalent complexes with substrates containing 5-fluoro-CNG, indicating that substrate specificity extended beyond the canonical CG dinucleotide. These results show that, in addition to maintenance methylation, human DNMT1 may also carry out de novo and non-CG methyltransferase activities in vivo.
Expression of Girdin in primary hepatocellular carcinoma and its effect on cell proliferation and invasion. (2015)

Girdin has been proven to play a vital role in the process of proliferation, apoptosis, and invasion in various cancer cells, yet the underlying molecular mechanism in primary hepatocellular carcinoma (HCC) has not yet been clarified. Thereafter, we performed immunohistochemistry to detect the expression of Girdin in 40 primary HCC tissues and 30 matched adjacent tissues using hepatic carcinoma tissue microarray. Our data showed that the positive expression rate of Girdin in hepatocellular carcinoma tissues was 67.5%, higher than that found in adjacent tissues of 16.7% (P < 0.05). It closely correlates to tumor size, T stage, TNM stage and Edmondson-Steiner stage (P < 0.05) of HCC patients. After specific small interfering RNA of Girdin was transfected into HepG2 and Huh7.5.1 cells, the proliferation and invasion ability of tumor cells were significantly inhibited. In summary, we suggest that the oncogenic role of Girdin could provide new molecular target for the treatment of HCC.
Session traces: an enhancement to network simulator (1999)

This paper discusses a methodology for lifting a sessions trace from a packet trace. The session trace is created from a packet trace by removing many of the physical and network layer control mechanisms from the packet trace. The session trace embodies the true client/server transaction induced on the network link. We show that the session trace is superior to a packet trace for network simulation workloads in Network Simulator.
Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles (2005)

Measles remains a major worldwide problem partly because of difficulties with vaccination of young infants. New vaccine strategies need to be safe and to provide sustained protective immunity. We have developed Sindbis virus replicon particles that express the measles virus (MV) hemagglutinin (SIN-H) or fusion (SIN-F) proteins. In mice, SIN-H induced high-titered, dose-dependent, MV-neutralizing antibody after a single vaccination. SIN-F, or SIN-H and SIN-F combined, induced somewhat lower responses. To assess protective efficacy, juvenile macaques were vaccinated with a single dose of 10(6) or 10(8) SIN-H particles and infant macaques with two doses of 10(8) particles. A dose of 10(8) particles induced sustained levels of high-titered, MV-neutralizing antibody and IFN-gamma-producing memory T cells, and most monkeys were protected from rash when challenged with wild-type MV 18 months later. After challenge, there was a biphasic appearance of H- and F-specific IFN-gamma-secreting CD4+ and CD8+ T cells in vaccinated monkeys, with peaks approximately 1 and 3-4 months after challenge. Viremia was cleared within 14 days, but MV RNA was detectable for 4-5 months. These studies suggest that complete clearance of MV after infection is a prolonged, phased, and complex process influenced by prior vaccination.
The earliest pathologic alterations in dysferlinopathy (2001)

Dysferlin is likely required for maintaining the structural integrity of the muscle fiber plasma membrane, and plasma membrane injury is an early event in the pathogenesis of dysferlinopathy. MAC activation can participate in but is not an initial or primary event causing muscle fiber injury.
[Intravenous catheters. Use and complications at an infective disease unit]. (2003)

The purpose of this project is to learn what are the characteristics of using Intravenous Catheters, the complications related to their use, and to evaluate the effectiveness of a treatment protocol for nurses in an infectious illness ward according to a prospective and observational study on 187 cases involving intravenous catheters. Samples were carried out according to protocol. We note the low frequency of infectious complications which we believe is due to the scarce use of central catheters and parenteral nutritional methods as well as the use of a nursing treatment protocol which contributed to this reduction. The cases of non-infectious phlebitis was associated with peripheral catheters and with canalizations which occurred outside our ward. These results were published as a poster at the XXIII Congress of the Andalucian Society of Internal Medicine.
Prefetching the means for document transfer: a new approach for reducing Web latency (2002)

User-perceived latency is recognized as the central performance problem in the Web. We systematically measure factors contributing to this latency, across several locations. Our study reveals that DNS query times, TCP connection establishment, and start-of-session delays at HTTP servers, more so than transmission time, are major causes of long waits. Wait due to these factors also afflicts high-bandwidth users and has detrimental effect on perceived performance. We propose simple techniques that address these factors: (i) pre-resolving host-names (pre-performing DNS lookup); (ii) pre-connecting (prefetching TCP connections prior to issuance of HTTP request); and (iii) pre-warming (sending a "dummy" HTTP HEAD request to Web servers). Trace-based simulations demonstrate a potential to reduce perceived latency dramatically. Our techniques surpass document prefetching in performance improvement per bandwidth used and can be used with non-prefetchable URL. Deployment of these techniques at Web browsers or proxies does not require protocol modifications or the cooperation of other entities. Applicable servers can be identified, for example, by analyzing hyperlinks. Bandwidth overhead is minimal, and so is processing overhead at the user's browser. We propose scalable deployment solutions to control the potential overhead to proxies and particularly to Web servers.
Design of a Multifunctional Anthropomorphic Prosthetic Hand With Extrinsic Actuation (2009)

This paper presents an anthropomorphic prototype hand prosthesis that is intended for use with a multiple-channel myoelectric interface. The hand contains 16 joints, which are differentially driven by a set of five independent actuators. The hand prototype was designed with the minimum number of independent actuators required to provide a set of eight canonical hand postures. This paper describes the design of the prosthesis prototype, demonstrates the hand in the desired eight canonical postures, and experimentally characterizes the force and speed capability of the device. A video is included in the supplementary material that also illustrates the functionality and performance of the hand.
Benzodiazepine pharmacology and central nervous system-mediated effects. (2013)

For any patient taking a BZD, the prescribing physician must carefully evaluate the risks and benefits, and higher-risk patients require careful considerations. Clinically appropriate use of BZDs requires prudence and the understanding of pharmacology.
Interaction of Salmonella typhi strains with cultured human monocyte-derived macrophages (1997)

Human monocyte-derived macrophages (MDM) provided this laboratory with a tool to develop a primary-cell assay for evaluating the relative virulence of newly constructed Salmonella typhi carrier strains. In this study, the interaction with and survival within MDM were compared for delta aroA143-attenuated strains, wild-type virulent strains, and the current oral-vaccine strain, Ty21a.
Latency in Human Immunodeficiency Virus Type 1 Infection: No Easy Answers (2003)

In summary, HIV-1 latency represents a formidable therapeutic challenge for which there are no easy answers. As a result of viral tropism for activated CD4+ T cells and the reversion of some of these cells to a profoundly quiescent and long-lived memory state, the virus can persist through the same mechanisms responsible for the most fundamental characteristic of the immune system, immunologic memory. The dependence of viral gene expression on host factors that are inactive in resting T cells means that viral gene expression can be largely or completely extinguished in latently infected cells. In the absence of virus gene expression, latently infected cells will differ from their uninfected counterparts by only the presence of 10 kb of viral DNA integrated into a host cell chromosome. In this case, the virus is persisting as genetic information in a stably integrated form in rare memory cells that cannot be distinguished from their uninfected counterparts. It is difficult to envision any targeting mechanism that will allow specific elimination of this reservoir. Optimism stems from the fact that antiretroviral drugs come very close to stopping the active replication of the virus, with its attendant damage to the immune system. In some patients on HAART, the evolution of drug-resistant viruses, which is the principal cause of treatment failure, is largely halted. The development of nontoxic, convenient, and affordable combinations of antiretroviral drugs may allow infected individuals to live a normal life despite the indefinite persistence of latent HIV-1 in resting memory CD4+ T cells.
Variable Deficiencies in the Interferon Response Enhance Susceptibility to Vesicular Stomatitis Virus Oncolytic Actions in Glioblastoma Cells but Not in Normal Human Glial Cells (2006)

With little improvement in the poor prognosis for humans with high-grade glioma brain tumors, alternative therapeutic strategies are needed. As such, selective replication-competent oncolytic viruses may be useful as a potential treatment modality. Here we test the hypothesis that defects in the interferon (IFN) pathway could be exploited to enhance the selective oncolytic profile of vesicular stomatitis virus (VSV) in glioblastoma cells. Two green fluorescent protein-expressing VSV strains, recombinant VSV and the glioma-adapted recombinant VSV-rp30a, were used to study infection of a variety of human glioblastoma cell lines compared to a panel of control cells, including normal human astrocytes, oligodendrocyte precursor cells, and primary explant cultures from human brain tissue. Infection rate, cell viability, viral replication, and IFN-alpha/beta-related gene expression were compared in the absence and presence of IFN-alpha or polyriboinosinic polyribocytidylic acid [poly(I:C)], a synthetic inducer of the IFN-alpha/beta pathway. Both VSV strains caused rapid and total infection and death of all tumor cell lines tested. To a lesser degree, normal cells were also subject to VSV infection. In contrast, IFN-alpha or poly(I:C) completely attenuated the infection of all primary control brain cells, whereas most glioblastoma cell lines treated with IFN-alpha or poly(I:C) showed little or no sign of protection and were killed by VSV. Together, our results demonstrate that activation of the interferon pathway protects normal human brain cells from VSV infection while maintaining the vulnerability of human glioblastoma cells to viral destruction.
Intestinal Macrophages Lack CD14 and CD89 and Consequently Are Down-Regulated for LPS- and IgA-Mediated Activities (2001)

The intestinal mucosa normally displays minimal inflammation despite the close proximity between mucosal macrophages and lumenal bacteria. Macrophages interact with bacteria and their products through CD14, a surface receptor involved in the response to LPS, and CD89, the receptor for IgA (FcalphaR). Here we show that resident macrophages isolated from normal human intestine lack CD14 and CD89. The absence of CD14 and CD89 was not due to the isolation procedure or mucosal cell products, but was evident at the transcriptional level, as the macrophages expressed neither CD14- nor CD89-specific mRNAs, but did express Toll-like receptor 2 and 4 transcripts. Consistent with their CD14(-) phenotype, lamina propria macrophages displayed markedly reduced LPS-induced cytokine production and LPS-enhanced phagocytosis. In addition, IgA-enhanced phagocytosis was sharply reduced in lamina propria macrophages. Thus, the absence of CD14 and CD89 on resident intestinal macrophages, due to down-regulated gene transcription, causes down-modulated LPS- and IgA-mediated functions and probably contributes to the low level of inflammation in normal human intestinal mucosa.
On Combination Therapy of Diabetes With Metformin and Dipeptidyl Peptidase IV Inhibitors (2002)

Recently, data were presented showing that metformin increased plasma active glucagon-like peptide (GLP)-1[7–36NH2] concentrations in obese nondiabetic male patients (1), and it was suggested that metformin was a direct dipeptidyl peptidase (DP) IV inhibitor. Contradiction of this hypothesis is simply found by examining the modes of action of metformin and of the DP IV inhibitors. Although the specific molecular target of metformin is still unknown, biguanides generally act to sensitize peripheral tissues to insulin action (particularly, skeletal muscle) and inhibit hepatic gluconeogenesis and glycogenolysis (2,3,4). In contrast, DP IV inhibitors act to enhance the insulin response to a meal, via preservation of …
OBSERVATIONS ON THE EFFECT OF MASSIVE DOSES OF IRON GIVEN INTRAVENOUSLY TO PATIENTS WITH HYPOCHROMIC ANEMIA (1946)

Abstract Massive doses of iron (from 0.608 to 1.32 Gm. as colloidal terric hydroxide or colloidal ferric oxide) were given intravenously in single infusions to 8 different patients with hypochromic microcytic anemia. One patient was given a second injection after an interval of four months, so that nine administrations were made. The following observations were made: 1. The reticulocyte response was higher in each instance than would be expected in oral therapy. In 3 additional patients in whom injection had to be discontinued after 0.070, 0.180, and 0.123 Gm. of elemental iron had respectively been given, the reticulocyte rises were higher than were the average responses reported by Heath18 after optimal oral therapy. This at least suggests that "optimal" oral therapy does not provide a maximal stimulus to outpouring of reticulocytes from the bone marrow. Comparable doses of iron given to 3 control subjects with normal hemoglobin levels did not cause a reticulocytosis. 2. The average rate of hemoglobin regeneration per 100 cc. of blood per day was 0.224 Gm.; the lowest value was 0.16 Gm. and the highest 0.27 Gm. These figures were calculated for the rise that occurred from the day of iron administration to the time at which the rate of hemoglobin increase was obviously becoming slower. Since correction was not made for blood loss in 3 of the patients during the period of regeneration, the figures for the rate of hemoglobin formation are lower than they otherwise would have been. Even so they are distinctly greater than those usually obtained following oral therapy (table 2), but no greater than is found in an occasional patient given iron by mouth. The data suggest that the fastest rate of hemoglobin regeneration that can be stimulated by iron in subjects with hypochromic anemia approximates 0.3 Gm. per 100 cc. per day. 3. Calculations indicated that from 71.8 to 99.7 per cent of the injected iron was apparently used for the synthesis of hemoglobin. These figures are likewise lower than they would have been if several of the patients had not lost blood during the recovery period. The observation of other workers that parenterally administered iron is almost completely retained by the body and converted into hemoglobin was therefore confirmed. 4. Toxic reactions to the injected iron are described in detail. They were severe in all but two instances, and in 3 patients were so alarming that injection of iron had to be discontinued. There can be no doubt that the reactions to iron parenterally administered in large doses are great enough to contra-indicate use of this measure as a therapeutic procedure.
Follistatin Binds to both Activin and Inhibin through the Common Beta-Subunit (1991)

Inhibin, activin, and follistatin are three families of polypeptides originally isolated and characterized from ovarian follicular fluid based on their modulation of FSH release from pituitary cell culture. In addition to their effects on FSH synthesis and secretion, inhibin and activin have other biological functions. By contrast, the physiological significance of follistatin was obscure, until it was discovered that follistatin is a binding protein to activin. Since activin binds to follistatin, it is imperative to determine the nature of the activin/follistatin binding complex. Moreover, because inhibin contains a beta-subunit derived from activin, it is important to determine whether inhibin will also bind follistatin. Using a double-ligand blotting technique, we have determined that activin-A has two binding sites for follistatin, whereas inhibin-A has only one binding site for follistatin. Therefore, these results suggest that follistatin binds to both activin and inhibin through the common beta-subunit.
PALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function (2012)

PALB2/FANCN is mutated in breast and pancreatic cancers and Fanconi anemia (FA). It controls the intranuclear localization, stability, and DNA repair function of BRCA2 and links BRCA1 and BRCA2 in DNA homologous recombination repair and breast cancer suppression. Here, we show that PALB2 directly interacts with KEAP1, an oxidative stress sensor that binds and represses the master antioxidant transcription factor NRF2. PALB2 shares with NRF2 a highly conserved ETGE-type KEAP1 binding motif and can effectively compete with NRF2 for KEAP1 binding. PALB2 promotes NRF2 accumulation and function in the nucleus and lowers the cellular reactive oxygen species (ROS) level. In addition, PALB2 also regulates the rate of NRF2 export from the nucleus following induction. Our findings identify PALB2 as a regulator of cellular redox homeostasis and provide a new link between oxidative stress and the development of cancer and FA.