gebhart/patrepeval huggingface dataset:
Protease Inhibitors: Part 4. Synthesis of Weakly Basic Thrombin Inhibitors Incorporating Pyridinium-Sulfanilylaminoguanidine Moieties (2000)

Three series of derivatives have been prepared by reaction of sulfanilylaminoguanidine with pyrylium salts, with the pyridinium derivatives of glycine and with the pyridinium derivatives of beta-alanine, respectively. The new compounds were assayed as inhibitors of two serine proteases, thrombin and trypsin. The study showed that in contrast to the leads, possessing KI's around 100-300 nM against thrombin, and 450-1420 nM against trypsin, respectively, the new derivatives showed inhibition constants in the range of 15-50 nM against thrombin, whereas their affinity for trypsin remained relatively low. Derivatives of beta-alanine were more active than the corresponding glycine derivatives, which in turn were more inhibitory than the pyridinium derivatives of sulfanilylaminoguanidine possessing the same substitution pattern at the pyridinium ring. Thus, the present study proposes two novel approaches for the preparation of high affinity, specific thrombin inhibitors: a novel S1 anchoring moiety in the already large family of arginine/amidine-based inhibitors, i.e., the SO2NHNHC(=NH)NH2 group, and novel non-peptidomimetic scaffolds obtained by incorporating alkyl-/aryl-substituted-pyridinium moieties in the hydrophobic binding site(s). The first one is important for obtaining bioavailable thrombin inhibitors, devoid of the high basicity of the commonly used arginine/amidine-based inhibitors, whereas the second one may lead to improved water solubility of such compounds.
Bactericidal Effects of a Fusion Protein of Llama Heavy-Chain Antibodies Coupled to Glucose Oxidase on Oral Bacteria (2004)

Enzymes such as lactoperoxidase and glucose oxidase (GOx) are used as antimicrobial agents in oral care products. Their low specificities and substantiveness can be reduced by covalent coupling of antimicrobial molecules to antibodies. Variable domains (V(HH)) derived from llama heavy-chain antibodies are particularly suited for such an approach. The antibodies are composed solely of heavy-chain dimers; therefore, production of active fusion proteins by using molecular biology-based techniques is less complicated than production by use of conventional antibodies. In this study, a fusion protein consisting of V(HH) and GOx was constructed and expressed by Saccharomyces cerevisiae. A llama was immunized with Streptococcus mutans strain HG982. Subsequently, B lymphocytes were isolated and cDNA fragments encoding the V(HH) fragments were obtained by reverse transcription-PCR. After construction of a V(HH) library in Escherichia coli and screening of the library against mutans group streptococci and Streptococcus sanguinis strains, we found two V(HH) fragments with high specificities for S. mutans strains. A GOx gene was linked to the two V(HH) genes and cloned into S. cerevisiae yeasts. The yeasts expressed and secreted the recombinant proteins into the growth medium. The test of binding of fusion proteins to oral bacteria through their V(HH) fragments showed that S. mutans had been specifically targeted by GOx-S120, one of the fusion protein constructs. A low concentration of the fusion protein was also able to selectively kill S. mutans within 20 min in the presence of lactoperoxidase and potassium iodide. These findings demonstrate that the fusion protein GOx-V(HH) is potentially valuable in the selective killing of target bacteria such as S. mutans.
REVERSAL OF HYPERGLYCEMIA IN MICE AFTER SUBCUTANEOUS TRANSPLANTATION OF MACROENCAPSULATED ISLETS1 (1999)

Macroencapsulated islets transplanted into the s.c. space were able to survive and regulate blood glucose levels in mice. The observed differences in glucose metabolism between normal and transplanted mice may be attributed to the site of transplantation and to the use of rat islets, which have a different set point for glucose induced insulin release.
A Guide to Physical Examination and History Taking, Sixth Edition (1995)

Home Healthcare Nurse: The Journal for the Home Care and Hospice Professional: November 1995 - Volume 13 - Issue 6 - p 81
The non-immunosuppressive cyclosporin A analogue SDZ NIM 811 inhibits cyclophilin A incorporation into virions and virus replication in human immunodeficiency virus type 1-infected primary and growth-arrested T cells. (1997)

SDZ NIM 811 is a cyclosporin A (CsA) analogue that is completely devoid of immunosuppressive capacity but exhibits potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity. Binding to cyclophilin A, the intracellular receptor for cyclosporins, is a prerequisite for HIV-1 inhibition by cyclosporins. Cyclophilin A was demonstrated to bind to HIV-1 p24gag and this cyclophilin-Gag interaction leads to the incorporation of cyclophilin A into HIV-1 virions. SDZ NIM 811 inhibits this protein interaction, and this is likely to be the molecular basis for its antiviral activity. Here, we show that in activated primary T cells SDZ NIM 811 interferes with two stages of the virus replication cycle: (i) translocation of pre-integration complexes into the nucleus and (ii) production of infectious virus particles. SDZ NIM 811 not only inhibits translocation of HIV-1 pre-integration complexes in primary T cells, but also in a growth-arrested T cell line. In vivo, most T lymphocytes are quiescent, but serve nevertheless as a major and inducible HIV-1 reservoir in infected individuals. Significant amounts of cyclophilin A were found to be associated with virus particles propagated in primary T cells. SDZ NIM 811 caused a strong reduction in the amount of incorporated cyclophilin A, thereby reducing infectivity. Thus, cyclophilin A seems to be necessary for HIV-1 replication in primary T cells.
Molecular wall effects: Are conditions at a boundary “boundary conditions”? (2000)

This paper addresses and answers "no" to the question of whether the literal molecular-dynamically-derived species velocities prevailing at a solid surface bounding a two-component fluid continuum undergoing molecular diffusion constitute the appropriate species-velocity boundary conditions to be imposed upon the fluid continuum. In a broader context, generic boundary condition issues arising from the presence of different length scales in continuum-mechanical descriptions of physical phenomena are clarified. This is achieved by analyzing a model problem involving the steady-state diffusion of a dilute system of Brownian spheres (the latter envisioned as tractable models of solute "molecules") through a quiescent viscous solvent continuum bounded laterally by solid plane walls. Both physicochemical (potential energy) and hydrodynamic (steric) wall interaction effects experienced by the Brownian spheres are explicitly accounted for in our refined, microscale continuum model of the diffusion process. Inclusion of these "solid-wall-fluid" (s-f ) boundary-generated forces [above and beyond the usual "fluid-fluid" (f-f ) intermolecular forces implicit in the conventional Fick's law macroscale continuum description] serves to simulate the comparable s-f molecular boundary forces modeled in molecular dynamics simulations of the diffusional process. A singular perturbation framework is used to clarify the physical interpretation to be ascribed to "continuum-mechanical boundary conditions." In this same spirit we also clearly identify the origin of the physical concept of a "surface field" as well as of the concomitant surface transport conservation equation for strongly adsorbed species at solid walls. Our analysis of such surface phenomena serves to emphasize the fact that these are asymptotic, surface-excess, macroscale concepts assigned to a surface, rather than representing literal molecular material entities physically confined to the surface. Overall, this paper serves to illustrate the manner in which molecular simulations need to account for these different length scales and corresponding scale-dependent concepts if such analyses are to avoid drawing incorrect inferences regarding the molecular origins of continuum-mechanical boundary conditions.
Carbonic Anhydrase Inhibitors:  Water-Soluble 4-Sulfamoylphenylthioureas as Topical Intraocular Pressure-Lowering Agents with Long-Lasting Effects (2000)

A series of sulfonamides has been obtained by reaction of 4-isothiocyanatobenzenesulfonamide with amines, amino acids, and oligopeptides. The new thiourea derivatives showed strong affinities toward isozymes I, II, and IV of carbonic anhydrase (CA, EC 4.2.1.1). In vitro inhibitory power was good (in the low-nanomolar range) for the derivatives of beta-phenylserine and alpha-phenylglycine, for those incorporating hydroxy and mercapto amino acids (Ser, Thr, Cys, Met), hydrophobic amino acids (Val, Leu, Ile), aromatic amino acids (Phe, His, Trp, Tyr, DOPA), and dicarboxylic amino acids as well as di/tri/tetrapeptides among others. Such CA inhibitors displayed very good water solubility (in the range of 2-3%) mainly as sodium (carboxylate) salts, with pH values of the obtained solutions being 6.5-7.0. Some of these preparations (such as the derivatives of Ser, beta-Ph-Ser, Leu, Asn, etc.) strongly lowered intraocular pressure (IOP) when applied topically, directly into the normotensive/glaucomatous rabbit eye, as 2% water solutions. It is interesting to note that not all the powerful CA inhibitors designed in the present study showed topical IOP-lowering effects (such as, for instance, the Cys and Lys derivatives, devoid of such properties) whereas the Pro, Arg, and oligopeptidyl thiourea derivatives showed reduced efficacy when administered topically. This may be due to the very hydrophilic nature of some of these compounds, whereas inhibitors with balanced hydro- and liposolubility also showed optimal in vivo effects. The interesting pharmacological properties of this new type of CA inhibitors, correlated with the neutral pH of their solutions used in ophthalmologic applications, make them attractive candidates for developing novel antiglaucoma drugs devoid of major ocular side effects.
Quantifying Point-Prediction Uncertainty in Neural Networks via Residual\n Estimation with an I/O Kernel (2019)

Neural Networks (NNs) have been extensively used for a wide spectrum of\nreal-world regression tasks, where the goal is to predict a numerical outcome\nsuch as revenue, effectiveness, or a quantitative result. In many such tasks,\nthe point prediction is not enough: the uncertainty (i.e. risk or confidence)\nof that prediction must also be estimated. Standard NNs, which are most often\nused in such tasks, do not provide uncertainty information. Existing approaches\naddress this issue by combining Bayesian models with NNs, but these models are\nhard to implement, more expensive to train, and usually do not predict as\naccurately as standard NNs. In this paper, a new framework (RIO) is developed\nthat makes it possible to estimate uncertainty in any pretrained standard NN.\nThe behavior of the NN is captured by modeling its prediction residuals with a\nGaussian Process, whose kernel includes both the NN's input and its output. The\nframework is evaluated in twelve real-world datasets, where it is found to (1)\nprovide reliable estimates of uncertainty, (2) reduce the error of the point\npredictions, and (3) scale well to large datasets. Given that RIO can be\napplied to any standard NN without modifications to model architecture or\ntraining pipeline, it provides an important ingredient for building real-world\nNN applications.\n
Dextran-Conjugated Vascular Endothelial Growth Factor Receptor Antibody for In Vivo Melanoma Xenografted Mouse Imaging (2011)

Intact immunoglobulin G antibody has a relatively large molecule size of approximately 150 kDa that remains in the bloodstream for many weeks, which is a considerable disadvantage when it is used to carry radioactive materials for imaging. To lower background activity and increase the contrast of images, we investigated antivascular endothelial growth factor (VEGF) receptor 2 antibody (DC101) conjugated dextran for VEGF receptor 2 imaging in tumor xenografted mice. DTPA-conjugated aminodextran was synthesized, reacted with sulfo-LC-SPDP, and then reacted with DC101. The binding affinity of DTPA-dextran-DC101 to Flk-1 was measured. The gamma imaging and biodistributions of (99m)Tc-DTPA-dextran-DC101, (99m)Tc-DTPA-DC101, and (125)I-DC101 were studied in B16F10 melanoma xenografted mice. The dissociation values for DC101, DTPA-DC101, and DTPA-dextran-DC101 were 22.48, 3.05, and 14.74 pM, respectively. In gamma images, (99m)Tc-DTPA-dextran-DC101 showed weak liver uptake and rapid kidney elimination. In biodistribution results, the liver uptake of (99m)Tc-DTPA-dextran-DC101 was similar with that of (99m)Tc-DTPA-DC101 at each time point. However, the blood activity of (99m)Tc-DTPA-dextran-DC101 has shown significant differences, compared with (99m)Tc-DTPA-DC101 at all time points. The tumor accumulation of dextran-conjugated antibody was increased with time, whereas that of dextran nonconjugated antibody decreased. In particular, the pattern of tumor uptake of (99m)Tc-DTPA-dextran-DC101 was similar to that of (125)I-DC101, so this was thought to reflect the kinetics of DC101, unlike the nonconjugated form. The results of this study suggested that introduction of dextran moiety to make (99m)Tc-radiolabeled DC101 imaging agent could provide better images with the impaired background and the steady increasing binding to the receptor. However, further studies are necessary to improve clinical pharmacokinetics, such as enhancement of tumor uptake and impaired renal uptake.
Antisense treatment of caliciviridae: an emerging disease agent of animals and humans. (2002)

The Earth's oceans are the primary reservoir for an emerging family of RNA viruses, the Caliciviridae, which can cause a spectrum of diseases in marine animals, wildlife, farm animals, pets and humans. Certain members of this family have unusually broad host ranges, and some are zoonotic (transmissible from animals to humans). The RNA virus replicative processes lack effective genetic repair mechanisms, and, therefore, virtually every calicivirus replicate is a mutant. Hence, traditional therapeutics dependent on specific nucleic acid sequences or protein epitopes lack the required diversity of sequence or conformational specificity that would be required to reliably detect, prevent or treat infections from these mutant clusters (quasi-species) of RNA viruses, including the Caliciviridae. Antisense technology using phosphorodiamidate morpholino oligomers shows promise in overcoming these current diagnostic and therapeutic problems inherent with newly emerging viral diseases.
Inhibitory and stimulatory effects of glucocorticoid on androgen-induced growth of murine Shionogi carcinoma 115 in vivo and in cell culture. (1987)

It has been generally accepted for 20 years that the growth of Shionogi carcinoma 115 (SC115) is stimulated only by androgen in vivo and in cell culture. However, we recently found that the growth of SC115 is also stimulated by pharmacological, but not physiological, doses of glucocorticoid both in vivo and in cell culture and by pharmacological doses of estrogen only in vivo. In the present study, therefore, we investigated the effect of dexamethasone on androgen-induced growth of SC115 cells in vivo and in cell culture. In a serum-free medium [Ham's F-12:Eagle's minimum essential medium (1:1, v/v) containing 0.1% bovine serum albumin], the proliferation of SC-3 cells (a cloned cell line from SC115 cells) estimated by cell number and DNA synthesis reached a plateau at 10(-8) M testosterone (up to 93-fold) or 10(-6) M dexamethasone (up to 7.2-fold); high stimulation induced by higher than 10(-8) M testosterone was inhibited by the addition of 10(-5)-10(-8) M dexamethasone in a concentration-dependent manner, whereas low stimulation induced by lower than 10(-10) M testosterone was significantly enhanced by the addition of dexamethasone. The presence of typical glucocorticoid and androgen receptors in SC-3 cells was also demonstrated; dexamethasone did not bind to androgen receptor and testosterone did not bind to glucocorticoid receptor. In castrated mice, the concomitant administration of dexamethasone again significantly inhibited the high growth of SC115 tumors induced by high doses of androgen but significantly enhanced the low growth induced by low doses of androgen. The present results demonstrate both inhibitory and stimulatory effects of glucocorticoid on androgen-induced proliferation of SC115 cells in cell culture and probably in vivo.
Multivalent Interactions: Synthesis and Evaluation of Melanotropin Multimers—Tools for Melanoma Targeting (2012)

In order to develop agents for early detection and selective treatment of melanomas, high affinity and high specificity molecular tools are required. Enhanced specificity may be obtained by simultaneously binding to multiple cell surface targets <i>via</i> the use of multimeric analogs of naturally occurring ligands. Trimers targeting overexpressed melanocortin receptors have been found to be potential candidates for this purpose. In the present letter, we describe the synthesis and study of multimers based on a dendrimer-like scaffold. The binding affinity and activity results revealed that dendrimers promote multivalent interactions via statistical and/or cooperative effects on binding. Moreover, viability studies showed no significant toxicity at micromolar concentrations, which will allow these molecular complexes to be used <i>in vivo</i>. Finally, imaging studies showed effective internalization for all the molecules confirming their potential as delivery agents.
Predicting Blood-Brain Barrier Permeability of Drugs: Evaluation of Different In Vitro Assays (2002)

The ability of a drug to penetrate the blood-brain barrier (BBB) is essential for its use in the pharmaceutical treatment of CNS disorders. Five different in vitro methods to predict BBB permeability of drugs were compared and evaluated in the present study. All assays were performed with a consistent set of seven compounds and in the same physiological buffer to provide a basis for direct comparison of the results. Octanol-buffer and liposome-buffer partition coefficients were most conveniently obtained but failed to predict BBB permeability for certain drugs. The incorporation of drugs into lipid monolayers at the air-buffer interface was found to be a poor predictor of BBB permeability and was furthermore not considered suitable for screening due to the demanding experimental requirements. Permeability studies using Caco-2 cell monolayers provided a good correlation to an in vitro model of the BBB, which was based on primary cultured porcine brain capillary endothelial cells (PBCEC). However, differences in drug permeability between the intestine and brain derived cells were detected, limiting the advantages of the easy handling of the Caco-2 cell line compared to the more time-consuming primary culture of the BCEC.
Ultrabroadband femtosecond lasers (1994)

The exploitation of soliton-like pulse shaping mechanisms and the optimization of phase dispersion in broadband self-modelocked solid state laser oscillators have led to unprecedented advances in ultrafast laser technology. This paper reviews the basic physical mechanisms governing pulse formation and addresses the requirements for optimum performance of these novel ultrashort pulse laser sources. These considerations together with the demonstration of /spl ap/10 fs pulse generation from a Ti:sapphire laser suggest that a family of solid-state laser oscillators with comparable performance can be developed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Deaths: leading causes for 2001. (2003)

In 2001, the 10 leading causes of death were (in rank order) Diseases of heart; Malignant neoplasms; Cerebrovascular diseases; Chronic lower respiratory diseases; Accidents (unintentional injuries); Diabetes mellitus; Influenza and pneumonia; Alzheimer's disease; Nephritis, nephrotic syndrome and nephrosis; and Septicemia and accounted for nearly 80 percent of all deaths occurring in the United States. Differences in the rankings are evident by age, sex, race, and Hispanic origin. Leading causes of infant death for 2001 were (in rank order) Congenital malformations, deformations and chromosomal abnormalities; Disorders related to short gestation and low birth weight, not elsewhere classified; Sudden infant death syndrome; Newborn affected by maternal complications of pregnancy; Newborn affected by complications of placenta, cord and membranes; Respiratory distress of newborn; Accidents (unintentional injuries); Bacterial sepsis of newborn; Diseases of the circulatory system; and Intrauterine hypoxia and birth asphyxia. Important variation in the leading causes of infant death is noted for the neonatal and postneonatal periods.
An Efficient Sol−Gel Reactor for Antibody-Catalyzed Transformations (1997)

The first successful sol−gel entrapment of monoclonal catalytic antibodies is described. Antibodies which catalyze various hydrolytic reactions were entrapped directly in a tetramethoxysilane-derived silica sol−gel matrix, retaining their activity. The catalytic reactions were carried out either batchwise or in a continuous flow apparatus, demonstrating the utility of these novel biocatalysts for preparative scale organic synthesis.
MYC regulates the antitumor immune response through CD47 and PD-L1 (2016)

The MYC oncogene codes for a transcription factor that is overexpressed in many human cancers. Here we show that MYC regulates the expression of two immune checkpoint proteins on the tumor cell surface: the innate immune regulator CD47 (cluster of differentiation 47) and the adaptive immune checkpoint PD-L1 (programmed death-ligand 1). Suppression of MYC in mouse tumors and human tumor cells caused a reduction in the levels of CD47 and PD-L1 messenger RNA and protein. MYC was found to bind directly to the promoters of the Cd47 and Pd-l1 genes. MYC inactivation in mouse tumors down-regulated CD47 and PD-L1 expression and enhanced the antitumor immune response. In contrast, when MYC was inactivated in tumors with enforced expression of CD47 or PD-L1, the immune response was suppressed, and tumors continued to grow. Thus, MYC appears to initiate and maintain tumorigenesis, in part, through the modulation of immune regulatory molecules.
Geometrical proportions (2012)

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