gebhart/patrepeval huggingface dataset:
Evaluation of Hexadecyloxypropyl-9- R -[2-(Phosphonomethoxy)Propyl]- Adenine, CMX157, as a Potential Treatment for Human Immunodeficiency Virus Type 1 and Hepatitis B Virus Infections (2007)

9-R-[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC(50)s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC(50), and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.
A Generalized Symbolic Notation for Mechanisms (1971)

Revisions of the Denavit-Hartenberg symbolic notation are proposed which extend its use to the entire domain of rigid link mechanisms. The extended notation provides a clear separation of the pair variables and the invariant parameters of a mechanism and thus provides a framework in which higher pairs can be systematically modeled. The new symbolism can be used directly with the existing matrix methods of kinematic analysis, and a numerical scheme is presented to reduce the task of data collection for these methods.
Structural and Functional Analysis of a Lytic Polysaccharide Monooxygenase Important for Efficient Utilization of Chitin in Cellvibrio japonicus (2016)

Cellvibrio japonicusis a Gram-negative soil bacterium that is primarily known for its ability to degrade plant cell wall polysaccharides through utilization of an extensive repertoire of carbohydrate-active enzymes. Several putative chitin-degrading enzymes are also found among these carbohydrate-active enzymes, such as chitinases, chitobiases, and lytic polysaccharide monooxygenases (LPMOs). In this study, we have characterized the chitin-active LPMO,CjLPMO10A, a tri-modular enzyme containing a catalytic family AA10 LPMO module, a family 5 chitin-binding module, and a C-terminal unclassified module of unknown function. Characterization of the latter module revealed tight and specific binding to chitin, thereby unraveling a new family of chitin-binding modules (classified as CBM73). X-ray crystallographic elucidation of theCjLPMO10A catalytic module revealed that the active site of the enzyme combines structural features previously only observed in either cellulose or chitin-active LPMO10s. Analysis of the copper-binding site by EPR showed a signal signature more similar to those observed for cellulose-cleaving LPMOs. The full-length LPMO shows no activity toward cellulose but is able to bind and cleave both α- and β-chitin. Removal of the chitin-binding modules reduced LPMO activity toward α-chitin compared with the full-length enzyme. Interestingly, the full-length enzyme and the individual catalytic LPMO module boosted the activity of an endochitinase equally well, also yielding similar amounts of oxidized products. Finally, gene deletion studies show thatCjLPMO10A is needed byC. japonicusto obtain efficient growth on both purified chitin and crab shell particles.
Chemical stability of peptides in polymers. 2. Discriminating between solvent and plasticizing effects of water on peptide deamidation in poly(vinylpyrrolidone) (1999)

The mechanistic role of water in the deamidation of a model asparagine-containing hexapeptide (Val-Tyr-Pro-Asn-Gly-Ala) in lyophilized formulations containing poly(vinylpyrrolidone) (PVP) and glycerol was investigated. Glycerol was used as a plasticizer to vary formulation glass transition temperature (T(g)) without significantly changing water content or activity. Increases in moisture and glycerol contents increased the rate of peptide deamidation. This increase was strongly correlated with T(g) at constant water content and activity, suggesting that increased matrix mobility facilitates deamidation. In rubbery systems (T > T(g)), deamidation rates appeared to be independent of water content and activity in formulations with similar T(g)s. However, in glassy formulations with similar T(g)s, deamidation increased with water content, suggesting a solvent/medium effect of water on reactivity in this regime. An increase in water content also affected the degradation product distribution; less of the cyclic imide intermediate and more of the hydrolytic products, isoAsp- and Asp-hexapeptides, were observed as water content increased. Thus, residual water appears to facilitate deamidation in these solid PVP formulations both by enhancing molecular mobility and by solvent/medium effects, and also participates as a chemical reactant in the subsequent breakdown of the cyclic imide.
Cancer Immunotherapy Using a Bispecific NK Receptor Fusion Protein that Engages both T Cells and Tumor Cells (2011)

T-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)-activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand-positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand-positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv-NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host-specific immunologic memory response had been generated. Host adaptive immunity including γδ T cells was required for scFv-NKG2D-mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand-negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv-NKG2D as a promising biological fusion protein to induce effective antitumor immunity.
Antimalarial Iron Chelator, FBS0701, Shows Asexual and Gametocyte Plasmodium falciparum Activity and Single Oral Dose Cure in a Murine Malaria Model (2012)

Iron chelators for the treatment of malaria have proven therapeutic activity in vitro and in vivo in both humans and mice, but their clinical use is limited by the unsuitable absorption and pharmacokinetic properties of the few available iron chelators. FBS0701, (S)3"-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator currently in Phase 2 human studies for the treatment of transfusional iron overload. The drug has very favorable absorption and pharmacokinetic properties allowing for once-daily use to deplete circulating free iron with human plasma concentrations in the high µM range. Here we show that FBS0701 has inhibition concentration 50% (IC(50)) of 6 µM for Plasmodium falciparum in contrast to the IC(50) for deferiprone and deferoxamine at 15 and 30 µM respectively. In combination, FBS0701 interfered with artemisinin parasite inhibition and was additive with chloroquine or quinine parasite inhibition. FBS0701 killed early stage P. falciparum gametocytes. In the P. berghei Thompson suppression test, a single dose of 100 mg/kg reduced day three parasitemia and prolonged survival, but did not cure mice. Treatment with a single oral dose of 100 mg/kg one day after infection with 10 million lethal P. yoelii 17XL cured all the mice. Pretreatment of mice with a single oral dose of FBS0701 seven days or one day before resulted in the cure of some mice. Plasma exposures and other pharmacokinetics parameters in mice of the 100 mg/kg dose are similar to a 3 mg/kg dose in humans. In conclusion, FBS0701 demonstrates a single oral dose cure of the lethal P. yoelii model. Significantly, this effect persists after the chelator has cleared from plasma. FBS0701 was demonstrated to remove labile iron from erythrocytes as well as enter erythrocytes to chelate iron. FBS0701 may find clinically utility as monotherapy, a malarial prophylactic or, more likely, in combination with other antimalarials.
Effect of diosgenin on lipid metabolism in rats. (1979)

The purpose of this study was to determine whether diosgenin suppresses cholesterol absorption in rats, and to examine relevant changes in cholesterol and bile acid metabolism. Diosgenin fed with the diet for 1 week inhibited cholesterol absorption as determined by the serum isotope ratio technique, as well as by measuring in the feces the amount of unabsorbed radioactivity from orally administered [3H]cholesterol. In addition, diosgenin suppressed the serum and liver uptake of radioactivity from co-administered [3H]cholesterol as well as the accumulation of liver cholesterol in the cholesterol-fed rat; diosgenin was substantially more active than cholestyramine or beta-sitosterol. In vitro, diosgenin had no effect on the activity of rat pancreatic esterase. Diosgenin decreased the elevated cholesterol in serum LDL and elevated cholesterol in the HDL fraction of cholesterol-fed rats; diosgenin had no effect on serum cholesterol in normocholesterolemic rats. In contrast to cholestyramine, diosgenin markedly increased neutral sterol excretion without altering bile acid excretion; in vitro, diosgenin had no effect on bile acid binding. Diosgenin treatment increased hepatic and intestinal cholesterol synthesis as well as the activity of hepatic HMG CoA reductase. This was accompanied by increased biliary concentration of cholesterol, but not of bile acids. Diosgenin had no effect on cholesterol synthesis when added to normal rat liver homogenates. It was concluded that diosgenin interferes with the absorption of cholesterol of both exogenous and endogenous origin; such interference is accompanied by derepressed, i.e., increased, rates of hepatic and intestinal cholesterol synthesis. The increased unabsorbed cholesterol together with enhanced secretion of cholesterol into bile resulted in increased excretion of neutral sterols without affecting the biliary and fecal excretion of bile acids.
Initiation of Phage Infection by Partial Unfolding and Prolyl Isomerization (2013)

Infection of Escherichia coli by the filamentous phage fd starts with the binding of the N2 domain of the phage gene-3-protein to an F pilus. This interaction triggers partial unfolding of the gene-3-protein, cis → trans isomerization at Pro-213, and domain disassembly, thereby exposing its binding site for the ultimate receptor TolA. The trans-proline sets a molecular timer to maintain the binding-active state long enough for the phage to interact with TolA. We elucidated the changes in structure and local stability that lead to partial unfolding and thus to the activation of the gene-3-protein for phage infection. Protein folding and TolA binding experiments were combined with real-time NMR spectroscopy, amide hydrogen exchange measurements, and phage infectivity assays. In combination, the results provide a molecular picture of how a local unfolding reaction couples with prolyl isomerization not only to generate the activated state of a protein but also to maintain it for an extended time.
Using multiple structure alignments, fast model building, and energetic analysis in fold recognition and homology modeling (2003)

We participated in the fold recognition and homology sections of CASP5 using primarily in-house software. The central feature of our structure prediction strategy involved the ability to generate good sequence-to-structure alignments and to quickly transform them into models that could be evaluated both with energy-based methods and manually. The in-house tools we used include: a) HMAP (Hybrid Multidimensional Alignment Profile)-a profile-to-profile alignment method that is derived from sequence-enhanced multiple structure alignments in core regions, and sequence motifs in non-structurally conserved regions. b) NEST-a fast model building program that applies an "artificial evolution" algorithm to construct a model from a given template and alignment. c) GRASP2-a new structure and alignment visualization program incorporating multiple structure superposition and domain database scanning modules. These methods were combined with model evaluation based on all atom and simplified physical-chemical energy functions. All of these methods were under development during CASP5 and consequently a great deal of manual analysis was carried out at each stage of the prediction process. This interactive model building procedure has several advantages and suggests important ways in which our and other methods can be improved, examples of which are provided.
A common-path optical coherence tomography distance-sensor based surface tracking and motion compensation hand-held microsurgical tool (2011)

Microsurgery requires constant attention to the involuntary motion due to physiological tremors. In this work, we demonstrated a simple and compact hand-held microsurgical tool capable of surface tracking and motion compensation based on common-path optical coherence tomography (CP-OCT) distance-sensor to improve the accuracy and safety of microsurgery. This tool is miniaturized into a 15mm-diameter plastic syringe and capable of surface tracking at less than 5 micrometer resolution. A phantom made with Intralipid layers is used to simulate a real tissue surface and a single-fiber integrated micro-dissector works as a surgical tip to perform tracking and accurate incision on the phantom surface. The micro-incision depth is evaluated after each operation through a fast 3D scanning by the Fourier domain OCT system. The results using the surface tracking and motion compensation tool show significant improvement compared to the results by free-hand.
A fully programmable system for the study of catalytic gas reactions (1985)

The design of a fully programmable reaction system is described which allows the control and study of several gas reactions in parallel. In analogy to a microprocessor system it is based on a bus principle. Its inherent advantages are: the hardware is not restricted to the solution of one single problem, the course of an experiment is determined only by the software, and the bus system allows an easy extension of the system without much additional effort. Other advantages of the special system described are high speed and low cost.
High Heregulin Expression Is Associated with Activated HER3 and May Define an Actionable Biomarker in Patients with Squamous Cell Carcinomas of the Head and Neck (2013)

HRG expression levels define a biologically distinct subset of SCCHN patients. We propose that high-level expression of HRG is associated with constitutive activation of HER3 in SCCHN and thus defines an actionable biomarker for interventions targeting HER3.
Voltage Effects in Cholesteric Liquid Crystals (1966)

Abstract Liquid crystal mixtures were sandwiched between two transparent electrodes on glass and a direct or alternating potential was applied. The light scattering property of the liquid crystal changes upon application of voltage, the intensity varying from 1 to 10% of that scattered by a MgO diffuse surface. The maximum increase in intensity due to voltage was a factor of about six. The maximum wavelength shift was 40 nm to the blue by 80 V applied to a layer 10 μ thick. The response time varied from 0.03 to 0.5 sec.
Psychiatric Diagnosis and Behavioral Characteristics of Phenylketonuric Children (1986)

This study evaluated the psychiatric characteristics and the behavioral effects of an acute load of phenylalanine on phenylketonuric children. The sample consisted of 13 normal-IQ children who were identified at birth as having phenylketonuria and were subsequently treated with a strict low phenylalanine diet. After baseline measurements, the subjects were loaded with placebo or phenylalanine following a double-blind design. Behavioral and metabolic variables were monitored at hourly intervals for five subsequent hours. The effects of acute loading were measured by changes in a standardized Continuous Performance Task (CPT). Psychiatric symptoms were compiled through a structured psychiatric interview of the child and the parent. Results demonstrated that phenylalanine loading, compared to placebo, caused a nonsignificant decrement in performance on CPT testing. Psychiatric disorders were found in six of the 13 subjects with three currently meeting criteria for attention deficit disorder (ADD). In addition, six other subjects were diagnosed in the past as having ADD using DSM-III criteria.
Bioreactivity of the crystalline silica polymorphs, quartz and cristobalite, and implications for occupational exposure limits (OELs) (2013)

Silica or silicon dioxides (SiO₂) are naturally occurring substances that comprise the vast majority of the earth's crust. Because of their prevalence and commercial applications, they have been widely studied for their potential to induce pulmonary fibrosis and other disorders. Historically, the focus in the workplace has been on the development of inflammation and fibrotic lung disease, the basis for promulgating workplace standards to protect workers. Crystalline silica (CS) polymorphs, predominantly quartz and cristobalite, are used in industry but are different in their mineralogy, chemistry, surface features, size dimensions and association with other elements naturally and during industrial applications. Epidemiologic, clinical and experimental studies in the literature historically have predominantly focused on quartz polymorphs. Thus, in this review, we summarize past scientific evaluations and recent peer-reviewed literature with an emphasis on cristobalite, in an attempt to determine whether quartz and cristobalite polymorphs differ in their health effects, toxicity and other properties that may dictate the need for various standards of protection in the workplace. In addition to current epidemiological and clinical reports, we review in vivo studies in rodents as well as cell culture studies that shed light on mechanisms intrinsic to the toxicity, altered cell responses and protective or defense mechanisms in response to these minerals. The medical and scientific literature indicates that the mechanisms of injury and potential causation of inflammation and fibrotic lung disease are similar for quartz and cristobalite. Our analysis of these data suggests similar occupational exposure limits (OELs) for these minerals in the workplace.
Prostate Specific Antigen Decline after Antiandrogen Withdrawal: the Flutamide Withdrawal Syndrome (1993)

Post-therapy changes in prostate specific antigen (PSA) have been proposed as a surrogate end point for response in clinical trials of patients with hormone refractory prostatic cancer. While the specific criteria for response are evolving, there are concerns that changes in serum levels of PSA may be the result of changes in PSA expression or secretion independent of effects on cell growth and proliferation. We report 3 representative cases receiving complete androgen blockade with either gonadotropin-releasing hormone or orchiectomy plus the antiandrogen flutamide, which demonstrated sustained declines in serum PSA levels after discontinuation of the antiandrogen. Similar results have been observed in 6 additional patients. Whether this represents an agonist effect of the antiandrogen is unknown. The results suggest that a trial of flutamide withdrawal is justified in an asymptomatic patient with an increasing PSA before treatment with more toxic therapies. It also shows the importance of documenting sequential elevations in the marker before enrolling a patient in a clinical trial, and that changes in PSA must be interpreted cautiously in clinical trials when an antiandrogen is discontinued.
The blood factors I and i in primates including man, and in lower species (1965)

Abstract Human‐type blood factors I and i have been investigated in several primate species including man, and in other mammals. The anti‐I tests were performed with the original antiserum which led to the discovery of blood factor I. The anti‐i serum used was obtained from a patient with severe idiopathic hemolytic anemia. Both antisera were similar in serological reactivity, except for their difference of specificity. Human adults, in general, have blood factor I but lack factor i; those very rare adults of type i who lack factor I have the factor i instead. In newborn human infants the factor I is still undeveloped and blood factor i is present in its place. In all other species only juvenile and adult animals have so far been tested. Chimpanzees lack blood factor I but have the factor i, which could be interpreted as phylogeny paralleling ontogeny; however, gibbons lack both factors I and i while orangutan has an intermediate position. All Catarrhini tested, namely, yellow baboons, geladas, patas, mangabeys, macaques, African green, talapoin and Sykes monkeys lack blood factor I but have the factor i. Among Platyrrhini the results are less uniform: Capuchins have very strong blood factor I and a weak factor i, while squirrel and spider monkeys have factor i and little or no factor I. On the other hand, marmosets have both factors I and i well developed. Only two single prosimians were tested: slow loris had factor i but no factor I, while potto lacked both factors I and i. Among non‐primate animals, sheep, goat, deer, cat and South American agoutilack both factors I and i; dog and rat lack factor I but have a weak factor i, while rabbit has a very strong factor I but lacks the factor i. Bearing in mind the relatively small number of animals tested within each species, the present study indicates a heterophile behavior of the blood factors I and i in mammals, in that their distribution cuts across taxonomic lines.