gebhart/patrepeval huggingface dataset:
The effect of ligand efficacy on the formation and stability of a GPCR-G protein complex (2009)

G protein-coupled receptors (GPCRs) mediate the majority of physiologic responses to hormones and neurotransmitters. However, many GPCRs exhibit varying degrees of agonist-independent G protein activation. This phenomenon is referred to as basal or constitutive activity. For many of these GPCRs, drugs classified as inverse agonists can suppress basal activity. There is a growing body of evidence that basal activity is physiologically relevant, and the ability of a drug to inhibit basal activity may influence its therapeutic properties. However, the molecular mechanism for basal activation and inhibition of basal activity by inverse agonists is poorly understood and difficult to study, because the basally active state is short-lived and represents a minor fraction of receptor conformations. Here, we investigate basal activation of the G protein Gs by the beta(2) adrenergic receptor (beta(2)AR) by using purified receptor reconstituted into recombinant HDL particles with a stoichiometric excess of Gs. The beta(2)AR is site-specifically labeled with a small, environmentally sensitive fluorophore enabling direct monitoring of agonist- and Gs-induced conformational changes. In the absence of an agonist, the beta(2)AR and Gs can be trapped in a complex by enzymatic depletion of guanine nucleotides. Formation of the complex is enhanced by the agonist isoproterenol, and it rapidly dissociates on exposure to concentrations of GTP and GDP found in the cytoplasm. The inverse agonist ICI prevents formation of the beta(2)AR-Gs complex, but has little effect on preformed complexes. These results provide insights into G protein-induced conformational changes in the beta(2)AR and the structural basis for ligand efficacy.
Aggregation of dispersed human cytotrophoblastic cells: Lessons relevant to the morphogenesis of the placenta (1990)

The syncytial trophoblast of the human placenta forms by the fusion of mononuclear cytotrophoblast cells. Cytotrophoblast cells only fuse with other trophoblastic cells, indicating a specificity to this interaction. To explore the cellular aggregation which precedes fusion, we examined the association of cytotrophoblast cells isolated from term placentae and JEG-3 choriocarcinoma cells, a cytotrophoblast-like cell line, in suspension culture. Cytotrophoblast cells were isolated by dispersion of chorionic villi in trypsin-DNase in Ca2+Mg2+-free medium. JEG-3 cells were released from culture flasks by trypsinization in Versene-EDTA buffer. In suspension culture, each cell type aggregated forming tissue-like masses over a 24-hr period. Transmission electron microscope analysis demonstrated the formation of numerous desmosomes between the aggregated cells. In outgrowth culture, the aggregates created in suspension were maintained as microvilli-covered multicellular structures with hollow cores. The extent of aggregation was dependent upon the concentration of cells in the incubations with greater aggregation occurring with higher cell densities. Aggregation of both cytotrophoblast cells and JEG-3 cells progressed rapidly during the initial 10 hr of incubation and then continued at a slower rate. Aggregation took place in serum-containing and serum-free medium, but was impeded in Ca2+Mg2+-free medium. Incubation of JEG-3 and cytotrophoblast cells in the presence of the protein synthesis inhibitor, cycloheximide, prevented aggregation, whereas the inhibitor of N-linked glycosylation, tunicamycin, did not. The inhibitor of RNA synthesis, actinomycin D, had no effect on the aggregation of the cells during the initial 6 hr of aggregation. These findings suggest that trypsin treatment in Ca2+Mg2+-poor medium removed a protein(s) from the trophoblast cell surface which must be resynthesized for cell-cell association to take place.
Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience. (1988)

Cyclobenzaprine hydrochloride became available for the treatment of acute skeletal muscle spasm ten years ago. The initial clinical trials conducted during the premarketing evaluation of this drug showed that it was significantly superior to placebo in relieving the signs and symptoms of acute skeletal muscle spasm. In addition, cyclobenzaprine was found to have a more rapid onset of action than diazepam. Data obtained both in controlled clinical investigations and in a postmarketing surveillance program indicated that cyclobenzaprine treatment was associated with few serious adverse experiences. Cyclobenzaprine represents a cost-effective approach to the management of acute muscle spasm, primarily because of the rapid symptomatic relief that it provides.
Quantitative motor assessment in amyotrophic lateral sclerosis (1986)

Reliable measurements are needed to document the natural history of ALS and to determine therapeutic efficacy. We have devised a standardized protocol that generates interval data sensitive to change-the Tufts Quantitative Neuromuscular Exam (TQNE). The TQNE consists of the following four major categories: pulmonary function, oropharyngeal function, timed functional activities, and isometric strength using an electronic strain gauge. The 29-item exam takes about 1 hour to administer and has excellent test-retest reliability.
A united-residue force field for off-lattice protein-structure simulations. II. Parameterization of short-range interactions and determination of weights of energy terms by Z-score optimization (1997)

Continuing our work on the determination of an off-lattice united-residue force field for protein-structure simulations, we determined and parameterized appropriate functional forms for the local-interaction terms, corresponding to the rotation about the virtual bonds (Utor), the bending of virtual-bond angles (Ub), and the energy of different rotameric states of side chains (Urot). These terms were determined by applying the Boltzmann principle to the distributions of virtual-bond torsional and virtual-bond angles and side-chain rotameric states, respectively, calculated from a data base of 195 high-resolution nonhomologous proteins. The complete energy function was constructed by combining the individual energy terms with appropriate weights. The weights were determined by optimizing the so-called Z-score value (which is the normalized difference between the energy of the native structure and the mean energy of non-native structures) of the histidine-containing phosphocarrier protein from Streptococcus faecalis (1PTF; an 88-residue α + β protein). To accomplish this, a database of Cα patterns was created using high-resolution nonhomologous protein structures from the Protein Data Bank, and the distributions of energy components of 1PTF were obtained by threading its sequence through ∼500 randomly chosen Cα-patterns from the X-ray structures in the PDB, followed by energy minimization, with the energy function incorporating initially guessed weights. The resulting minimized energies were used to optimize the Z-score value of 1PTF as a function of the weights of the various energy terms, and the new weights were used to generate new energy-component distributions. The process was iterated, until the weights used to generate the distributions and the optimized weights were self-consistent. The potential function with the weights of the various energy terms obtained by optimizing the Z-score value for 1PTF was found to locate the native structures of other test proteins (within an average RMS deviation of 3 Å): calcium-binding protein (4ICB), ubiquitin (1UBQ), α-spectrin (1SHG), major cold-shock protein (1MJC), and cytochrome b5 (3B5C) (which included α and β structures) as distinctively lowest in energy in similar threading experiments. © 1997 by John Wiley & Sons, Inc. J Comput Chem 18: 874–887, 1997
Sampling Theory for not Necessarily Band-Limited Functions: A Historical Overview (1992)

Shannon’s sampling theorem is one of the most powerful results in signal analysis. The aim of this overview is to show that one of its roots is a basic paper of de la Vallee Poussin of 1908. The historical development of sampling theory from 1908 to the present, especially the matter dealing with not necessarily band-limited functions (which includes the duration-limited case actually studied in 1908), is sketched. Emphasis is put on the study of error estimates, as well as on the delicate point-wise behavior of sampling sums at discontinuity points of the signal to be reconstructed.
Design of Alloy Electrocatalysts for  CO 2 Reduction: III . The Selective and Reversible Reduction of on Cu Alloy Electrodes (1991)

Many Cu alloys have been studied for electrocatalytic activity of reduction in aqueous solution. Anomalously low overpotentials with highly selective Cu alloy catalysts have been seen for the reduction of to, , or . Cu‐Ni alloys produce and selectively at reversible potentials and Cu‐Sn and Cu‐Pb produce and with an enhanced reaction rate at the reversible potentials of formation. Other alloy catalysts such as Cu‐Zn, Cu‐Cd, or Cu‐Ag also exhibit behaviors distinct from those of the elemental metals. The results reported here indicate further possibilities for the development of powerful new electrocatalysts for the reduction of .
Biological Differences between Vesicular Stomatitis Virus Indiana and New Jersey Serotype Glycoproteins: Identification of Amino Acid Residues Modulating pH-Dependent Infectivity (2005)

We previously generated recombinant vesicular stomatitis viruses (VSV) based on the Indiana serotype genome which contained either the homologous glycoprotein gene from the Indiana serotype (VSIV-GI) or the heterologous glycoprotein gene from the New Jersey serotype (VSIV-GNJ). The virus expressing the GNJ gene was more pathogenic than the parental VSIV-GI virus in swine, a natural host (26). For the present study, we investigated the biological differences between the GI and GNJ proteins that may be related to the differences in pathogenesis between VSIV-GI and VSIV-GNJ. We show that the capacities of viruses with either the GNJ or GI glycoprotein to infect cultured cells differ depending on the pH. VSIV-GNJ could infect cells at acidic pHs, while the infectivity of VSIV-GI was severely reduced. VSIV-GNJ infection was also more sensitive to inhibition by ammonium chloride, indicating that the GNJ protein had a lower pH threshold for membrane fusion. We applied selective pressure to VSIV-GI by growing it at successively lower pH values and isolated variant viruses in which we identified amino acid changes that conferred low-pH-resistant infectivity. Repeated passage in cell culture at pH 6.8 resulted in the selection of a VSIV-GI variant (VSIV-6.8) that was similar to VSIV-GNJ regarding its pH- and ammonium chloride-dependent infectivity. Sequence analysis of VSIV-6.8 revealed that it had a single amino acid substitution in the amino-terminal region of the glycoprotein (F18L). This alteration was shown to be responsible for the observed phenotype by site-directed mutagenesis of a VSIV-GI full-length cDNA and analysis of the recovered engineered virus. A further adaptation of VSIV-6.8 to pHs 6.6 and 6.4 resulted in additional amino acid substitutions in areas of the glycoprotein that were not previously implicated in attachment or fusion.
Natural killer cells trigger differentiation of monocytes into dendritic cells (2007)

Circulating monocytes can differentiate into dendritic cells (moDCs), which are potent inducers of adaptive immune responses. Previous reports show that granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-4 induce monocyte differentiation into moDCs in vitro, but little is known about the physiological requirements that initiate moDC differentiation in vivo. Here we show that a unique natural killer (NK) cell subset (CD3(-)CD56(bright)) that accumulates in lymph nodes and chronically inflamed tissues triggers CD14(+) monocytes to differentiate into potent T-helper-1 (T(H)1) promoting DC. This process requires direct contact of monocytes with NK cells and is mediated by GM-CSF and CD154 derived from NK cells. It is noteworthy that synovial fluid (SF) from patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but not osteoarthritis (OA), induces monocytes to differentiate into DC. However, this process occurs only in the presence of NK cells. We propose that NK cells play a role in the maintenance of T(H)1-mediated inflammatory diseases such as RA by providing a local milieu for monocytes to differentiate into DC.
DEOXYRIBONUCLEIC ACID CYTOPHOTOMETRY OF STAINED HUMAN LEUKOCYTES II. THE MECHANICAL SCANNER OF CYDAC, THE THEORY OF SCANNING PHOTOMETRY AND THE MAGNITUDE OF RESIDUAL ERRORS (1970)

The mechanical scanner of CYDAC is a dual beam cytophotometer with a Nipkow scanning disc, analogue photometric circuits, digital conversion and accumulation of the photometric values and digital control of the scanning procedure. A measuring sequence involves object and clear field scans, and the final readout is virtually independent of fluctuations and heterogeneities in illumination and of variations in the size of the scanning apertures. Optical sources of error are analyzed both theoretically and experimentally as they apply to scanning cytophotometers. The effects of conical and polychromatic illumination, stray light and heterogeneous distribution of chromophore lead to negative averaging errors that are a function of optical density. The role of scan aperture size and optical resolution on distributional error is discussed and calculated in terms of three possible models. Non-absorptive phenomena, such as scattering and diffraction, lead to positive errors that are complementary, in a qualitative sense, to distributional error. In attempting to isolate these different errors experimentally, we show that measurements of the relative deoxyribonucleic acid stain content of human leukocytes are independent, within wide limits, of condenser and objective numerical aperture and of changes in absorptivity secondary to changes in wavelength. Where an adequate theory exists, these experimental results agree well with the theoretical predictions and, in any case, they indicate that for stained leukocytes the net effect of all optical errors must be less than 2%. Random measuring errors include both photon shot noise and errors associated with the geometry of the scanning disc. These errors contribute to an error of 1.2% among replicate measurements of leukocytes made under standard conditions. The previously reported differences in stain content among leukocyte types and among individual cells within types cannot be ascribed to either optical or instrumentation errors. Thus, the measured differences must reflect actual differences either in the amount or in the absorptivity of the stain.
Combined oncolytic and vaccination activities of parvovirus H-1 in a metastatic tumor model (2007)

Oncolytic viruses have emerged as a novel class of potent anticancer agents offering an improvement on chemo- and radiotherapy in terms of tumor targeting and reduction of side-effects. Among these agents, autonomous parvoviruses have attracted the attention of researchers for their ability to preferentially replicate in and kill transformed cells, and to suppress tumors in the absence of adverse reactions in various animal models. We have previously shown that lethally irradiated autologous tumor cells can support parvovirus H-1PV production and serve as carriers to deliver progeny H-1PV into the vicinity of lung metastases in a rat tumor model, resulting in H-1PV infection of and multiplication in metastatic cells. It is known that irradiated autologous (neoplastic) cells can also act as a therapeutic vaccine against the original tumor. Yet the ability of these cells to suppress metastases in the above model was found to be much increased as a result of their H-1PV infection. This prompted us to determine whether H-1PV boosted the tumor-suppressing capacity of the autologous vaccine by increasing its immunogenic potential and/or by making it a factory of oncolytic viruses able to reach and destroy the metastases. Both effects could be dissociated in the presence of neutralising antibodies which either prevent the progeny viruses from spreading to metastatic cells, or deplete the CD8 effector cells from the immune system. This strategy revealed that the H-1PV infection of tumor cells enhanced their ability to trigger an immune response for which uninfected tumor cells could be the targets, thereby amplifying and taking over from the direct viral oncolytic activity. This dual oncolytic/vaccinal effect of H-1PV holds out promises of clinical applications to cancer therapy.
Computed tomography fluoroscopy‐guided chemical lumbar sympathectomy: Simple, safe and effective (2002)

Demographic, clinical and laboratory data were retrospectively collected from records of 146 cases of CT fluoroscopy-guided chemical lumbar sympathectomy for the palliation of inoperable peripheral vascular disease (PVD) between January 1997 and August 1999. Of these, 16% had claudication, 39% had rest pain and 44% had ischaemic ulcers or gangrene. Seventy-three percent of elective cases were outpatients. At 3 months, 27 cases were lost to follow up, leaving 119 cases. Within 3 months, improvement, defined as doubling of the walking distance, cessation of rest pain or healing of ulcers, occurred in 30.3% of cases. No change was observed in 45.4% of cases and 24.3% of cases deteriorated. Patients with ulcers or gangrene had significantly poorer results than those without any ischaemic lesions, as only 19% versus 39% of patients improved (P < 0.05). The presence of hypertension, diabetes mellitus, hyperlipidaemia and smoking had no value in predicting clinical outcome (P > 0.05). There were no major complications noted. CT fluoroscopy-guided chemical lumbar sympathectomy is safe and effective, with a complication rate of less than 1%, and efficacy of at least 30% measured within 3 months. It is a simple and minimally invasive procedure, easily performed on an outpatient basis. CT fluoroscopy-guided chemical lumbar sympathectomy should be considered for all patients in the early stages of inoperable PVD.
Reduction of UHF power transistor distortion with a nonuniform collector doping profile (2001)

The linearity of a class-A, bipolar UHF power transistor is investigated. The device is intended for transmission of signals with multiple (TV) channels. Mixing between the various channels must be suppressed, which makes linearity an important parameter. This paper presents a novel approach, where process technology is specifically optimized to minimize distortion. It is shown that particularly the nonlinear collector-base capacitance strongly affects the linearity of this type of device. With a modified collector-base doping profile, the capacitance is manipulated. A nonuniform profile is introduced that significantly reduces third-order intermodulation. The profile consists of an arsenic doped spike that is grown epitaxially into the (otherwise) lightly doped collector. This reduces the bias dependence of C/sub cb/ and improves the tradeoff between linearity and breakdown or ruggedness. The reduction in third-order intermodulation is demonstrated both experimentally and by mixed-level MDS/MAIDS simulations.
Protection from Herpes Simplex Virus (HSV)–2 Infection with Replication‐Defective HSV‐2 or Glycoprotein D2 Vaccines in HSV‐1–Seropositive and HSV‐1–Seronegative Guinea Pigs (2009)

dl5-29 Is an effective vaccine in both HSV-1-seropositive and HSV-1-seronegative guinea pigs and was superior to gD2 vaccines in reducing virus shedding after challenge in both groups of animals. dl5-29 Might reduce transmission of HSV-2.
Potentiation of pentazocine analgesia by low-dose naloxone. (1988)

The analgesia produced by combinations of low-dose naloxone with pentazocine or morphine was studied in 105 patients with moderately severe postoperative pain after standardized surgery for removal of impacted third molars. Pain intensity was quantified using a visual-analogue scale. To eliminate the release of endogenous opioids produced by the placebo component of open drug administration, all injections were made by a preprogrammed infusion pump. The analgesia produced by pentazocine, an agonist-antagonist opiate-analgesic acting predominantly at the kappa opiate receptor, was potentiated by low-dose naloxone, whereas the analgesia produced by morphine, a mu-agonist, was attenuated by low-dose naloxone. To evaluate whether similar potentiation would be present in an animal model, and specifically, in the absence of diazepam, which patients receive, we performed an analogous experiment in rats in which nociceptive threshold was determined using the Randall-Selitto paw-withdrawal test. The results were completely analogous to the clinical results: pentazocine analgesia was potentiated by low-dose naloxone, whereas morphine analgesia was attenuated by low-dose naloxone. These data demonstrate a novel interaction between opiates, and suggest a rationale for opiate combinations to produce potent analgesia with fewer autonomic side effects and less abuse potential than presently available analgesics.
The older person within a changing society. -editorial- (2003)

The following are the five major foci the Singapore centres will be undertaking for the next two years: 1. Improving the availability and utilisation of rehabilitation community aged care and post acute community care services needed by patients and older people with complex and chronic health conditions. 2. Assuring that all older patients have access to affordable community rehabilitative, geriatric and post acute community care. 3. Promoting the importance of good physical, mental and social health, and, healthy lifestyles and preventing and detecting diseases. 4. Networking with various community groups and schools to provide better outreach to encourage older people and the community to take part in the centre's activities. 5. Increasing and improving partnerships between volunteers and professionals in community health initiatives and fund raising efforts. 6. Last but not least, providing training, education and consultancy services for other health and social care providers. (non-author abstract)
Hormone replacement therapies in women at risk of cardiovascular disease and osteoporosis in South Australia in 1997 (1999)

OBJECTIVE To describe changes in use of hormone replacement therapy (HRT) in an Australian population and to determine HRT use in women at risk of cardiovascular disease and osteoporotic fracture. DESIGN Data were derived from the 1997 South Australian Health Omnibus Survey (a representative population survey) and compared with data from 1991, 1993 and 1995 Omnibus Surveys. SETTING South Australia, 1997. PARTICIPANTS 1049 women aged 40 years and over from a random selection of 4400 households. RESULTS Among women aged 55-64 years (and thus likely to be postmenopausal), 60% had used HRT (ever use). Nearly two-thirds of these women used it currently. In this age group, mean length of HRT use had increased to 70 months (median, 60 months). Rates of HRT use had not changed significantly between 1991 and 1997 in women under 55 years, but had increased significantly in women aged 55 years or over (P < or = 0.01). Among women currently using HRT, 5.4% had used testosterone therapy, while 4% used unregistered products purported to contain hormones. Rates of ever use of HRT in women with zero, one, two, or three or more cardiovascular risk factors were 33%, 37%, and 45%, respectively. Among women with a diagnosis of osteoporosis, 52% had used HRT, with a mean length of use of 86 months (median, 60 months). CONCLUSION HRT use is increasing in older-age groups. Longer-term therapy with potential for primary prevention is now occurring, but half of those with osteoporosis and more than half of those with risk factors for cardiovascular disease have not used HRT.