gebhart/patrepeval huggingface dataset:
Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: Implications for drug design (2005)

Typanosoma cruzi, the causative agent of Chagas disease, has recently been shown to be sensitive to the action of the bisphosphonates currently used in bone resorption therapy. These compounds target the mevalonate pathway by inhibiting farnesyl diphosphate synthase (farnesyl pyrophosphate synthase, FPPS), the enzyme that condenses the diphosphates of C5 alcohols (isopentenyl and dimethylallyl) to form C10 and C15 diphosphates (geranyl and farnesyl). The structures of the T. cruzi FPPS (TcFPPS) alone and in two complexes with substrates and inhibitors reveal that following binding of the two substrates and three Mg2+ ions, the enzyme undergoes a conformational change consisting of a hinge-like closure of the binding site. In this conformation, it would be possible for the enzyme to bind a bisphosphonate inhibitor that spans the sites usually occupied by dimethylallyl diphosphate (DMAPP) and the homoallyl moiety of isopentenyl diphosphate. This observation may lead to the design of new, more potent anti-trypanosomal bisphosphonates, because existing FPPS inhibitors occupy only the DMAPP site. In addition, the structures provide an important mechanistic insight: after its formation, geranyl diphosphate can swing without leaving the enzyme, from the product site to the substrate site to participate in the synthesis of farnesyl diphosphate.
Hydrogen evolution on nano-particulate transition metal sulfides (2008)

The hydrogen evolution reaction (HER) on carbon supported MoS2 nanoparticles is investigated and compared to findings with previously published work on Au(111) supported MoS2. An investigation into MoS2 oxidation is presented and used to quantify the surface concentration of MoS2. Other metal sulfides with morphologies similar to MoS2 such as WS2, cobalt-promoted WS2, and cobalt-promoted MoS2 were also investigated in the search for improved HER activity. Experimental findings are compared to density functional theory (DFT) calculated values for the hydrogen binding energies (deltaGH) on each system.
Priming of Human Neutrophil Respiratory Burst by Granulocyte/Macrophage Colony-stimulating Factor (GM-CSF) Involves Partial Phosphorylation of p47 (1999)

Neutrophil superoxide production can be potentiated by prior exposure to "priming" agents such as granulocyte/macrophage colony stimulating factor (GM-CSF). Because the mechanism underlying GM-CSF-dependent priming is not understood, we investigated the effects of GM-CSF on the phosphorylation of the cytosolic NADPH oxidase components p47(phox) and p67(phox). Preincubation of neutrophils with GM-CSF alone increased the phosphorylation of p47(phox) but not that of p67(phox). Addition of formyl-methionyl-leucyl-phenylalanine (fMLP) to GM-CSF-pretreated neutrophils resulted in more intense phosphorylation of p47(phox) than with GM-CSF alone and fMLP alone. GM-CSF-induced p47(phox) phosphorylation was time- and concentration-dependent and ran parallel to the priming effect of GM-CSF on superoxide production. Two-dimensional tryptic peptide mapping of p47(phox) showed that GM-CSF induced phosphorylation of one major peptide. fMLP alone induced phosphorylation of several peptides, an effect enhanced by GM-CSF pretreatment. In contrast to fMLP and phorbol 12-myristate 13-acetate, GM-CSF-induced phosphorylation of p47(phox) was not inhibited by the protein kinase C inhibitor GF109203X. The protein-tyrosine kinase inhibitor genistein and the phosphatidylinositol 3-kinase inhibitor wortmannin inhibited the phosphorylation of p47(phox) induced by GM-CSF and by fMLP but not that induced by phorbol 12-myristate 13-acetate. GM-CSF alone did not induce p47(phox) or p67(phox) translocation to the membrane, but neutrophils treated consecutively with GM-CSF and fMLP showed an increase (compared with fMLP alone) in membrane translocation of p47(phox) and p67(phox). Taken together, these results show that the priming action of GM-CSF on the neutrophil respiratory burst involves partial phosphorylation of p47(phox) on specific serines and suggest the involvement of a priming pathway regulated by protein-tyrosine kinase and phosphatidylinositol 3-kinase.
A growth factor for cardiac myocytes is produced by cardiac nonmyocytes. (1991)

Cardiac nonmyocytes, primarily fibroblasts, surround cardiac myocytes in vivo. We examined whether nonmyocytes could modulate myocyte growth by production of one or more growth factors. Cardiac myocyte hypertrophic growth was stimulated in cultures with increasing numbers of cardiac nonmyocytes. This effect of nonmyocytes on myocyte size was reproduced by serum-free medium conditioned by the cardiac nonmyocytes. The majority of the nonmyocyte-derived myocyte growth-promoting activity bound to heparin-Sepharose and was eluted with 0.75 M NaCl. Several known polypeptide growth factors found recently in cardiac tissue, namely acidic fibroblast growth factor (aFGF), basic FGF (bFGF), platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF alpha), and transforming growth factor beta 1 (TGF beta 1), also caused hypertrophy of cardiac myocytes in a dose-dependent manner. However, the nonmyocyte-derived growth factor (tentatively named NMDGF) could be distinguished from these other growth factors by different heparin-Sepharose binding profiles (TNF alpha, aFGF, bFGF, and TGF beta 1) by neutralizing growth factor-specific antisera (PDGF, TNF alpha, aFGF, bFGF, and TGF beta 1), by the failure of NMDGF to stimulate phosphatidylinositol hydrolysis (PDGF and TGF beta 1), and, finally, by the apparent molecular weight of NMDGF (45-50 kDa). This nonmyocyte-derived heparin-binding growth factor may represent a novel paracrine growth mechanism in myocardium.
Smallpox and pregnancy: from eradicated disease to bioterrorist threat (2002)

Health care personnel must be prepared for the threat of bioterrorism. Our objective is to educate primary care providers, obstetricians in particular, in the prevention, diagnosis, and treatment of smallpox. Smallpox poses a particularly serious threat because of its high case-fatality rate in unvaccinated populations (no one younger than 25 years has been vaccinated, and older persons have little remaining residual immunity). Routine nonemergency smallpox vaccination is restricted to laboratory staff working with smallpox-related viruses. Under these circumstances, contraindications to vaccination are pregnancy, immunodeficiency, exfoliative skin conditions (eczema), and allergy to vaccine components. In case of an intentional release of the smallpox virus, those directly exposed and their close contacts must be vaccinated and isolated. Under such emergency circumstances, pregnant women exposed to the variola virus should be vaccinated because of the lethality of the disease during pregnancy. Currently, there is a limited supply of vaccine available.
Selective evidence was used to support link between immunisation and asthma (1999)

EDITOR—Blomfield says that there is accumulating evidence that immunisation causes asthma.1 But he presents only evidence supporting the hypothesis when there is also evidence against it.

He quotes a retrospective cohort study …
Intracranial circulation: preliminary clinical results with three-dimensional (volume) MR angiography. (1989)

The authors assessed the clinical utility of a magnetic resonance angiography technique in the evaluation of intracranial circulation. Eighteen patients with a low likelihood of cerebrovascular disease (control group) and 40 patients with suspected cerebrovascular disease were imaged with a FISP (fast imaging with steady precession) sequence (repetition time of 50 msec, echo time of 15 msec, velocity compensation in the read and section-select directions with acceleration compensation in the read direction, 15 degrees anisotropic volume, and a 1.25-mm partition thickness). Ninety-four percent of images in the control group and 72% of images in the group with cerebrovascular disease were considered useful for diagnosis. This technique can provide accurate images of intracranial circulation and can be performed in conjunction with two-dimensional spin-echo or gradient-echo imaging. It was most useful in the evaluation of patent intracranial aneurysms, vessel displacement, and large-vessel occlusive disease. Disadvantages included limited field of view, persistent signal voids, limited spatial resolution, and inadequate depiction of lesions with slow flow.
Neurons Generated in the Adult Brain Are Recruited into Functional Circuits (1984)

Adult canaries, Serinus canarius, received injections of 3H-labeled thymidine, a marker of DNA synthesis. Thirty days after the last injection, intracellular potentials were recorded from neurons in the nucleus hyperstriatum ventralis pars caudalis, a vocal control nucleus in the telencephalon; these same cells were then injected with horseradish peroxidase. Of the 74 neurons labeled with horseradish peroxidase that were recovered, the nuclei of seven were radioactively labeled. Four of these seven neurons had responded to auditory stimuli. These double-labeled neurons were apparently generated during or after the 3H-labeled thymidine treatment (during adulthood) and subsequently incorporated into functional neural circuits.
The effect of pressure on the crystal structure of hexagonalL-cystine (2005)

The crystal structure of hexagonal L-cystine has been determined at room temperature at pressures between 0.4 and 3.7 GPa; unit-cell dimensions were measured up to 6.4 GPa. The structure of this phase consists of molecules in their zwitterionic form, and crystallizes in the hexagonal space group P6(1)22. The structure consists of hydrogen-bonded layers which are strongly reminiscent of those seen in alpha-glycine, and consist of R_4;4(16) hydrogen-bonded ring motifs. These layers are connected on one side by the disulfide bridges within the cystine molecules, and on the other by NH...O hydrogen bonds to other glycine-like layers. The most compressible unit-cell dimension, and the direction of greatest strain in the structure, is along the c-axis, and application of pressure pushes the layers closer together. The compression occurs approximately equally in the regions of the interlayer hydrogen bonds and the disulfide bridges; in the latter, changes in the C-S-S-C torsion angles allow the cystine molecules to act like springs. The effects of pressure can be interpreted in terms of closing-up of voids in the structure, and this leads to (i) a lessening of the N-C-C-O and C-S-S-C torsional angles, (ii) shortening of the N-H...O hydrogen bonds by 0.10-0.60 A and (iii) a further shortening of an already short S...S contact from 3.444 (4) A to 3.264 (4) A.
Assessment of selected road funds in Africa : case study of Benin, Ethiopia, Ghana, Kenya, and Zambia (2000)

In response to the deteriorating condition of the road network and the high associated economic costs, various stakeholder consultations were held during the 1980s under the umbrella of the Road Management Initiative (RMI), which set the broad outline of a new policy framework for the road sector. The new policy framework advocates establishment of dedicated Road Funds (RFs), managed by autonomous road boards as commercial entities and made up of user representatives who both gain the benefits from the road facilities they provide and bear the cost of any increase in charges which they approve. The issue has been controversial because some see the road funds as a form of earmarking, hampering the optimal allocation of resources, and infringing on requirements of efficient cash and financial management. In contrast, others view road funds as offering a mechanism to insure stable financing of a low profile activity with particularly high rates of return. This paper examines road fund performance in five countries (Benin, Ethiopia, Ghana, Kenya, and Zambia) where reasonably extensive implementation experience exists. The country study is based on three guiding principles: (i) have they improved resource allocation? (ii) have they improved operational efficiency?, and (iii) have they improved road maintenance? Finding of this paper are based on an assessment of the structure and process of setting up and implementing the road funds as well as of an assessment of the objective achievements to date. The paper should be viewed as a work-in-progress, and the analysis would be updated periodically as the conditions and macroeconomic environment changes.
Transplantation as a tool to study progenitors within the vertebrate nervous system (1998)

In recent years, many studies have focused on the fate and potential of neural progenitors in vertebrates. While much progress has been made, many questions remain about the mechanisms which lead to neural diversity, in terms of both the regionalization of the nervous system and specification of cell fates within those regions. Studies aimed at addressing these questions have fallen into three main categories: in vivo lineage tracings, in vitro differentiation analyses, and in vivo cell transplantation studies. This body of work has pointed to the existence of both pluripotent and unipotent neural progenitors, and has suggested that both cell intrinsic and extrinsic cues play a role in the determination of neural cell fate. In addition, the existence of neural "stem cells" maintained into adulthood has been suggested. This review will focus on transplantation studies in mammals, and will emphasize how this method has been useful as a means of determining the changing potential of neural precursors and their environments within the developing nervous system.
Vortex pinning in Nb films patterned with nano-scale hole-arrays. (2002)

Nb films containing extended arrays of holes with 45-nm diameter and 100-nm spacing have been fabricated using anodized aluminum oxide (AAO) as substrate. Pronounced matching effects in the magnetization are seen in fields up to 9 kOe. Flux pinning in the patterned samples is enhanced by two orders of magnitude as compared to unpatterned reference samples in applied fields exceeding 5 kOe. The matching effects are a dominant contribution to vortex pinning at temperatures as low as 4.2 K due to the nano-scale spacing of the holes.
Type IX Ehlers-Danlos syndrome and Menkes syndrome: the decrease in lysyl oxidase activity is associated with a corresponding deficiency in the enzyme protein. (1985)

Type IX of the Ehlers-Danlos syndrome (E-D IX) and the Menkes syndrome are X-linked recessively inherited disorders characterized by abnormalities in copper metabolism. These abnormalities are associated with a severe reduction in the activity of lysyl oxidase, the extracellular copper enzyme that initiates crosslinking of collagens and elastin. No increase in this deficient enzyme activity was obtained when culture media from fibroblasts of patients with E-D IX or the Menkes syndrome were incubated with copper under various conditions in vitro. A distinct, although small, increase in lysyl oxidase activity was obtained, however, when copper-supplemented media were used during culturing of the fibroblasts, although even under these conditions, the enzyme activity in the media from the affected cells remained markedly below that of the controls. Immunoprecipitation, dot-blotting, and immunoperoxidase staining experiments with antisera to human lysyl oxidase indicated that fibroblasts from patients with E-D IX or the Menkes syndrome do not secrete into their medium, or contain inside the cell, any significant amounts of a copper-deficient, catalytically inactive lysyl oxidase protein. These findings appear to be consistent with the hypothesis that synthesis of the lysyl oxidase protein itself is impaired. The possibility is not excluded, however, that a copper-deficient enzyme protein may be synthesized in normal amounts but become degraded very rapidly inside the cell. The failure to obtain any large increase in the deficient lysyl oxidase activity upon various forms of copper administration suggests that it may not be possible to obtain any significant improvement in the connective tissue manifestations of these disorders by copper therapy.
Thermal analysis of laser drilling processes (1972)

A model has been developed that uses a continuous, distributed, and moving heat source to describe the temperature profile and thermal stress propagation for laser drilled holes in high-purity fired-alumina ceramic substrate material. The temperature profile and the tangential stress distribution of the laser-formed hole are calculated to indicate the magnitude of those factors that can influence the potential fracture of the alumina material. These factors are of interest in order to help establish optimum laser-drilling parameters. Experimental data are obtained from the ruby and CO <inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf> lasers operated in the pulsed mode. The experimental results are found to be in excellent agreement with the theoretical analysis.
Case Report: Efficacy and Tolerability of Ketamine in Opioid-Refractory Cancer Pain (2014)

A 36-year-old female with metastatic breast cancer involving bones, liver, lung, and pleura/chest wall with worsening back pain received weight-based intravenous (IV) ketamine and was transitioned to oral ketamine for cancer-related neuropathic pain. She had responded poorly to outpatient pain regimen of oxycodone sustained and immediate release, hydromorphone, gabapentin, and duloxetine (approximate 480 mg total oral morphine equivalents [OME]), reporting an initial pain score of 10/10. She was started on hydromorphone parenteral patient-controlled analgesia (PCA) bolus dose in addition to her outpatient regimen. Despite escalating doses of opioids and the addition of a lidocaine 5% patch, the patient's pain remained uncontrolled 6 days after admission. On hospital day 7, utilizing a hospital weight-based ketamine protocol, the patient was started on subanesthetic doses of ketamine at 0.2 mg/kg/h (288 mg/24 h) and titrated over 2 days to 0.4 mg/kg/h (576 mg/24 h). Then, a 3-day rotation from intravenous to oral ketamine was initiated, and the patient was discharged on ketamine oral solution, 75 mg every 8 hours. When the patient's dose was increased to 0.4 mg/kg/h, adequate pain relief was charted by the nurse within 120 minutes, "patient pain free and resting comfortably." Her pain continued to be well managed, with an average pain score of 5/10 with the ketamine continuous infusion and sustained with conversion to oral ketamine without any report of side effects. This was a 37% reduction in pain scores. With the patient's stabilized dose of ketamine, opioid requirements decreased by 61.4% (1017.5 mg reduction in total OME). The use of weight-based dosing of IV continuous infusion and transition to oral ketamine was effective and tolerable in the management of opioid-refractory, neuropathic cancer pain. It is hoped that this case report promotes a discussion regarding ketamine dosing in refractory neuropathic cancer pain.
Isolation and biochemical characterization of the soluble and membrane forms of folate binding protein expressed in the ovarian carcinoma cell line IGROV1 (1993)

The human ovarian carcinoma cell line, IGROV1, produces two forms of folate binding protein (FBP), the membrane form that is anchored to the cell surface by a glycosylphosphatidylinositol tail and the soluble form that is shed into the tissue culture medium. Both forms are recognized by the monoclonal antibodies MOv18 and MOv19. Here we describe their purification and biochemical characterization. The purified soluble protein appeared as a single band with an apparent Mr of 36 kDa after SDS-PAGE, whereas the membrane form appeared as a single band with an apparent Mr of 38 kDa. The size difference between the two forms of FBP was confirmed by gel filtration of both the native and the N-glycanase-treated proteins. Both purified proteins had equal capacity to bind folic acid. The immunological cross-reactivity and the folic acid binding capability of the FBPs extracted from IGROV1 gave more evidence of the possible existence of a precursor-product relationship between them.
Autoregulation of pituitary corticotroph SOCS-3 expression: Characterization of the murine SOCS-3 promoter (1999)

Pituitary corticotroph SOCS-3 is a novel intracellular regulator of leukemia inhibitory factor (LIF)-mediated proopiomelanocortin gene expression and adrenocorticotropic hormone (ACTH) secretion, inhibiting LIF-activated Janus kinase-signal transducers and activators of transcription (STAT) signaling in a negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants, respectively. We characterized ≈3.8-kb genomic 5′ sequence of murine SOCS-3, including ≈2.9-kb sequence upstream of the transcription start site (+1), which was determined by 5′ rapid amplification of cDNA ends and RNase protection assay. Different 5′ constructs were cloned into the pGL3Basic vector, and luciferase activity was assayed in transiently transfected ACTH-secreting corticotroph AtT-20 cells. A STAT-1/STAT-3 binding element, located at nucleotides −72 to −64, was essential for LIF stimulation of SOCS-3 promoter activity. LIF induced 10-fold increased luciferase activity in a wild-type construct spanning −2757 to +929 bases. However, deletion or point mutation of the STAT-1/STAT-3 binding element abrogated LIF action (2- to 3-fold). Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT-1 and STAT-3 to this region. These results characterize the genomic 5′ region of murine SOCS-3 and identify an important STAT-1/STAT-3 binding element therein. Thus, LIF-stimulated SOCS-3 gene expression is at least in part mediated by STAT-3 and STAT-1. The cytokine inhibitor SOCS-3 acts in a negative loop to autoregulate its own gene expression, thus limiting its accumulation in the corticotroph cell. These results demonstrate a mechanism for corticotroph plasticity with rapid “on” and “off” ACTH induction in response to neuro-immuno-endocrine stimuli, such as LIF.
Effect of extracellular ATP on the growth of hormone‐refractory prostate cancer in vivo (2008)

Our results show, for the first time, that ATP effectively reduces the growth of advanced HRPC tumours in vivo. This may represent a step in establishing ATP as an effective agent for HRPC treatment.
Primary and secondary glioblastomas: From concept to clinicaldiagnosis (1999)

Glioblastomas may develop de novo (primary glioblastomas) or through progression from low-grade or anaplastic astrocytomas, (secondary glioblastomas). These subtypes of glioblastoma constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients and typically show EGFR overexpression, PTEN (MMAC1) mutations, CDKN2A (p16) deletions, and less frequently, MDM2 amplification. Secondary glioblastomas develop in younger patients and often contain TP53 mutations as the earliest detectable alteration. These characteristics are derived largely from patients selected on the basis of clinical history and sequential biopsies. Currently available data are insufficient for a substitution of histologic classification and grading of astrocytic tumors by genetic typing alone. More subtypes of glioblastomas may exist with intermediate clinical and genetic profiles, a factor exemplified by the giant-cell glioblastoma that clinically and genetically occupies a hybrid position between primary (de novo) and secondary glioblastomas. Future research should aim at the identification of criteria for a combined clinical, histologic, and genetic classification of astrocytic tumors.