gebhart/patrepeval huggingface dataset:
Recent Progress in the Design of Small Molecule Inhibitors of HIV RNase H (2006)

DNA polymerase and RNase H (RH) activities of HIV reverse transcriptase (RT) have been recognized as potential targets for antiretroviral therapy for more than 15 years. The development of medicines targeting the DNA polymerase activity has been highly successful, with currently 12 drugs approved for the treatment of HIV infection and more candidates in preclinical and clinical development. In contrast, the discovery of potent and selective inhibitors of HIV RH has been slow, and inhibitors of this enzyme function have yet to reach the clinical development stage. Selective HIV RH inhibitors are likely to provide significant clinical benefit in combination therapies, considering the high prevalence of HIV strains resistant to currently available antiretroviral therapies. Recent progress in a number of key areas has provided new impetus to the discovery of HIV RH inhibitors. High throughput assay systems based on fluorescence detection have been developed, which facilitate screening of inhibitor candidates. Substantial progress has been made in expression, purification, crystallisation and solution studies of HIV RT and RH, in particular with regards to aspects of structural dynamics. Crystal structures of active site binding and allosteric HIV RH inhibitors bound to HIV RT and RH have been obtained. Finally, an improved understanding of similarities and differences in enzymatic mechanisms between related nuclease enzymes has provided new concepts for achieving inhibitor selectivity. Together, these developments provide promising new starting points for the rational design of selective HIV RH inhibitors.
Trends in structure–toxicity relationships for carbonyl-containing α,β-unsaturated compounds (2004)

Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure-toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between alpha,beta-unsaturated carbonyl compounds with the carbon-carbon double bond on the end of the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of alpha,beta-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.
Aperture-coupled thin-film superconducting meander antennas (1999)

A thin-film superconducting meander patch antenna coupled by an H-shaped aperture is proposed. It is analyzed using a full wave electromagnetic simulator and the theory of cavity model for microstrip patch antennas. The meander patch was fabricated from a single-sided film of YBCO (YBa/sub 2/CU/sub 3/O/sub 7/) on MgO with a typical transition temperature of 90 K. Simulated results are presented for return loss, radiation pattern, and efficiency and these are shown in good agreement with the results obtained from network analyzer measurements. An array of a number of elements is also proposed for wide-band operation.
GaN Synthesis by Ammonothermal Method (1995)

It is shown that ammonothermal method can be successfully used to synthesize GaN powder of good crystallographic quality from ammonia solution at high pressure and a moderate temperature. The size of obtained GaN powder grains was of a few micrometers. The improvement of the powder crystalline quality (examined by X-ray rocking curve, scanning electroii microscopy and luminescence measurements) with increasing molar proportion of mineralizer was observed. It was therefore possible to conclude that high molar proportion of mineralizer in ammonia solution plays a crucial role in the polycrystal growth process. Visible luminescence of high efficiency from the GaN powder was found.
Thermophilic DNA ligase. Purification and properties of the enzyme from Thermus thermophilus HB8. (1984)

Thermophilic and thermostable DNA ligase was purified to near homogeneity from the extract of Thermus thermophilus HB8. The purified enzyme has an isoelectric point at pH 6.6 and consists of a single polypeptide of about 79,000 in molecular weight on the bases of sodium dodecyl sulfate-polyacrylamide gel electrophoresis data and an equilibrium sedimentation method. The enzyme requires divalent cations, Mg2+ or Mn2+, and the optimum concentration of these ions being 5-9 X 10(-3) M and 3-6 X 10(-3) M, respectively. The enzyme also requires NAD as a cofactor. The apparent Km for NAD is 1.85 X 10(-8) M and that of (dT)10 is 1.4 X 10(-4) M. The pH optimum is 7.4-7.6 in Tris-HCl and 8.0 in collidine/HCl buffer. The joining reaction is activated by K+ and NH+4 at a concentration of 2-100 mM and inhibited by Na+ above 25 mM. The optimum temperatures of the joining of thymidylate oligomers in the presence of poly(dA) as a template are 27.5 degrees C for p(dT)s, 34.5 degrees C for p(dT)10, and 37 degrees C for p(dT)12-18 and that of cohesive-end DNA restriction fragments is 24-37 degrees C. The nick-closing activity of the enzyme was observed over a wide range of the temperature from 15 to 85 degrees C and the optimum temperature is 65-72 degrees C. The temperature dependency of ligation with HB8 DNA ligase for various substrates was found to shift to a region of 7-10 degrees C higher than that of T4 DNA ligase and the activity of HB8 DNA ligase decreased remarkably below 4 degrees C. The enzyme was stable for 1 week at 37 degrees C, its activity dropped by 50% within 2 days at 65 degrees C.
Therapeutic Potential of Antisense Nucleic Acid Molecules (2003)

Elucidation of many disease-related signal transduction and gene expression pathways has provided unparalleled opportunities for the development of targeted therapeutics. The types of molecules in development are increasingly varied and include small-molecule enzyme inhibitors, humanized antibodies to cell surface receptors, and antisense nucleic acids for silencing the expression of specific genes. This Perspective reviews the basis for various antisense strategies for modulating gene expression, including RNA interference, and discusses the prospects for their clinical use.
Beyond multiple-choice questions and essays (1993)

This essay reviews the influence that research on psychological processes in clinical reasoning has had upon the characteristics and formats of licensing examinations such as the new United States Medical Licensing Examination (USMLE) and its predecessors, emphasizes the implications of such research for the assessment of clinical competence at all levels of medical education, and proposes a challenging new direction for educational research that could make clinical assessment more effective. Specifically, (1) factors are discussed that support the continued judicious use of multiple-choice questions (MCQs); and (2) emphasis is given to the need to assess the clinician's ability to analyze controversial clinical situations, where no single answer is agreed upon as "most nearly correct," for even though essay questions and oral examinations are better suited than MCQs to assess such questions, they have been replaced by MCQs largely because of problems of consistency in grading, breadth of domain sampling, and cost. Because of these limits on essays and oral examinations, a program of educational research is advocated to develop a test format that can effectively assess the clinician's abilities to deliberate among alternatives, to recognize the role of values and preferences in decisions, and to weigh risks and benefits. Just how much this new tool could be used for national certification and licensing examinations would have to be determined, but it is important that some component be included to signal to educators and new physicians that medical practice is, at least in part, concerned with matters for which final answers are not available.
Quantitation of the Myelin‐Associated Glycoprotein in Human Nervous Tissue from Controls and Multiple Sclerosis Patients (1986)

Myelin-associated glycoprotein (MAG) was measured by radioimmunoassay in the human CNS and peripheral nervous system (PNS). The level of MAG, expressed as ng/microgram of total protein, was approximately 20-fold higher in whole homogenates of cerebral white matter (4.7 +/- 0.60) than of peripheral nerve (0.12-0.28). MAG concentrations were only slightly higher in the isolated myelin fractions from these tissues: CNS myelin, 5.6 ng/microgram; PNS myelin, 0.37 ng/microgram. The levels of MAG were measured in nine plaques, periplaque regions, and areas of macroscopically normal-appearing white matter (NAWM) from six separate multiple sclerosis brains and compared with the levels of other myelin proteins in the same samples. MAG and other myelin proteins were reduced to very low levels in plaques. The levels of MAG and basic protein (BP) and the activity of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) in periplaque areas were significantly lower than those in control white matter, and MAG and BP levels were also significantly reduced in NAWM. In a periplaque region and NAWM from the most rapidly progressing case of multiple sclerosis examined, the MAG content was between 30 and 35% of the control level, whereas BP and PLP levels and CNP activity were between 50 and 85% of control values. The reduction of MAG content in periplaque regions from all nine multiple sclerosis plaques examined was significantly greater than the reductions of BP level and CNP activity. In NAWM samples, the mean reduction of MAG content was also greater than the reductions of BP level and CNP activity, but the difference was only statistically significant in comparison to CNP.(ABSTRACT TRUNCATED AT 250 WORDS)
An Oral ApoJ Peptide Renders HDL Antiinflammatory in Mice and Monkeys and Dramatically Reduces Atherosclerosis in Apolipoprotein E–Null Mice (2005)

Oral D- [113-122]apoJ significantly improves HDL inflammatory properties in mice and monkeys and inhibits lesion formation in apoE-null mice.
Cautionary Tail: The Presence of an N-Terminal Tag on Dynein Light-Chain Roadblock/LC7 Affects Its Interaction with a Functional Partner (2007)

As part of structural investigations of components of the molecular motor, dynein, we prepared the light chain, Robl1_mouse, with and without an N-terminal His-tag. We found that the His-tag introduced a spurious binding site for a second protein, IC74. We propose a molecular mechanism for functional interference by the His-tag.
Implants of Encapsulated Human CNTF-Producing Fibroblasts Prevent Behavioral Deficits and Striatal Degeneration in a Rodent Model of Huntington’s Disease (1996)

Delivery of neurotrophic molecules to the CNS has gained considerable attention as a potential treatment strategy for neurological disorders. In the present study, a DHFR-based expression vector containing the human ciliary neurotrophic factor (hCNTF) was transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting hCNTF (BHK-hCNTF) were transplanted unilaterally into the rat lateral ventricle. Twelve days later, the same animals received unilateral injections of quinolinic acid (QA; 225 nmol) into the ipsilateral striatum. After surgery, animals were behaviorally tested for apomorphine-induced rotation behavior and for skilled forelimb function using the staircase test. Rats receiving BHK-hCNTF cells rotated significantly less than animals receiving BHK-control cells. No behavioral effects of hCNTF were observed on the staircase test. Nissl-stained sections demonstrated that BHK-hCNTF cells significantly reduced the extent of striatal damage produced by QA. Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase- and GAD-immunoreactive neurons were protected by BHK-hCNTF implants. In contrast, a similar loss of NADPH-diaphorase-positive cells was observed in the striatum of both implant groups. Analysis of retrieved capsules revealed numerous viable and mitotically active BHK cells that continued to secrete hCNTF. These results support the concepts that implants of polymer-encapsulated hCNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage and that this strategy may ultimately prove relevant for the treatment of Huntington's disease.
Specific inhibition of pathological prion protein accumulation by small interfering RNAs (2003)

Development of transmissible spongiform encephalopathies (TSEs) pathogenesis requires the presence of both the normal host prion protein (PrP-sen) and the abnormal pathological proteinase-K resistant isoform (PrP-res). PrP-res forms highly insoluble aggregates, with self-perpetuating properties, by binding and converting PrP-sen molecules into a likeness of themselves. In the present report, we show that small interfering RNA (siRNA) duplexes trigger specific Prnp gene silencing in scrapie-infected neuroblastoma cells. A non-passaged, scrapie-infected culture transfected with siRNA duplexes is depleted of PrP-sen and rapidly loses its PrP-res content. The use of different murine-adapted scrapie strains and host cells did not influence the siRNA-induced gene silencing efficiency. More than 80% of transfected cells were positive for the presence of fluorescein-labeled siRNA duplexes. No cytotoxicity associated with the use of siRNA was observed during the time course of these experiments. Despite a transient abrogation of PrP-res accumulation, our results suggest that the use of siRNA may provide a new and promising therapeutic approach against prion diseases.
Activity of a newly identified serine protease in CNS demyelination (2002)

We have identified a novel serine protease, myelencephalon-specific protease (MSP), which is preferentially expressed in the adult CNS, and therein, is abundant in both neurones and oligodendroglia. To determine the potential activity of MSP in CNS demyelination, we examined its expression in multiple sclerosis lesions and in two animal models of multiple sclerosis: Theiler's murine encephalomyelitis virus (TMEV) and myelin oligodendrocyte glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE) in marmosets. High levels of MSP were present within infiltrating mononuclear cells, including macrophages and T cells, which characteristically fill sites of demyelination, both in multiple sclerosis lesions and in animal models of this disease. The functional consequence of excess MSP on oligodendroglia was determined in vitro by evaluating the effects of recombinant MSP (r-MSP) on oligodendrocyte survival and process number. Application of excess r-MSP resulted in a dramatic loss of processes from differentiated oligodendrocytes, and a parallel decrease in process outgrowth from immature cells. Transfection of oligodendrocyte progenitors with an MSP-green fluorescent protein construct produced similar changes in oligodendrocyte process number. Importantly, r-MSP did not affect oligodendrocyte survival or differentiation towards the sulphatide-positive lineage. We further demonstrate that myelin basic protein, and to a lesser extent myelin oligodendrocyte glycoprotein, can serve as MSP substrates. These studies support the hypothesis that excess MSP, as is present in inflammatory CNS lesions, promotes demyelination.
A simplified method to culture human ovarian surface epithelium. (1990)

The ovarian surface epithelium (OSE) is thought to give rise to over 85% of human ovarian carcinomas. In spite of its clinical importance, no animal models for the in vivo investigation of this tissue exist, and available culture methods have yielded limited success. In this study, OSE cells from 55 normal ovarian biopsy specimens were used to improve and simplify the methodology for OSE culture and to define the influence of clinical parameters on cultured OSE cells. An improved explanation method was developed which takes advantage of the tenuous attachment of OSE to underlying tissues: the surface epithelium was scraped off the ovarian surface with a rubber scraper, generating epithelial fragments which produced monolayers in culture, with little contamination by other cell types. The scrape method is superior to the explant method previously described (Siemens CH, Auersperg N: J Cell Physiol 134:347, 1988) in terms of speed, simplicity, higher purity of cultures, and increased cell yield. An improved nutrient medium (199/MCDB105/15%FBS) resulted in OSE lines that maintained the original epithelial phenotype for up to 12 population doublings. OSE, detached from the ovary, remained viable if frozen in liquid nitrogen either before culture or in primary culture on strips of plastic, providing OSE independently of the availability of surgical specimens. Growth was not influenced by diagnosis (nonmalignant gynecologic disorders), patient age (mean range: 40.5, 20 to 62 years), or the presence of inclusion cysts or large follicles in the biopsy specimen. This culture system provides conditions for in depth studies of OSE physiology and pathology.
Phenotypic and functional characterization of mast cells derived from renal tumor tissues. (1998)

Mast cells (MCs) originate from multipotent hematopoietic progenitor cells. However, MCs in various organs are heterogenous in terms of mediator or receptor expression and response to diverse stimuli. We characterized the phenotype and functional properties of human renal mast cells (HRMCs). Tissue was obtained from 17 patients suffering from renal tumors (transitional cell carcinoma, n = 4; renal cell carcinoma, n = 13). HRMCs were isolated by collagenase digestion. Double staining with toluidine blue and immunofluorescence using monoclonal antibodies (mAbs) revealed expression of stem cell factor (SCF)-receptor (c-kit/CD117), CD9, CD29, CD33, CD43, CD44, CD54, and CD63 on HRMCs. In contrast, HRMCs were not recognized by mAbs to CD2, CD3, CD4, CD11b, CD14, CD15, CD16, CDw17, CD19, or CD23. HRMCs were also negative for CD116 (granulocyte-macrophage colony-stimulating factor [GM-CSF] receptor alpha), CD123 (interleukin [IL]-3Ralpha), CD121a (IL-1R type I), CD122 (IL-2Rbeta), and CD127 (IL-7R) and were also found to lack C5aR (CD88). Ligand-induced activation of HRMCs through immunoglobulin (Ig)E-R or SCF-R (c-kit) resulted in histamine secretion (control: <10%; alphaIgE, 1 microg/mL: 50.12 +/-5.18%; rhSCF, 100 ng/mL: 29.24 +/- 22.39), whereas recombinant C5a, erythropoietin (EPO), IL-1 through 10, and GM-CSF exerted no effects. As determined by in situ staining, HRMCs contained tryptase, but only low or undetectable amounts of chymase. Electron microscopy confirmed the presence of MCs in renal tissues and revealed a scroll-rich granule population in HRMCs. Together, HRMCs are tryptase+, C5aR- mast cells exhibiting phenotypic and functional properties similar to those of lung MCs.
Remodeling of the transmembrane segment in human glycophorin by aberrant RNA splicing. (1994)

This paper describes the identification in S-s-U-erythrocytes of a novel glycophorin (GP), He(P2), with structural variations in both its extracellular and transmembrane domains. In the exon II-intron 2 region, a sequence transfer from GPA to GPB, probably via the mechanism of gene conversion, was associated with the induction of multiple untemplated nucleotide replacements. These changes defined the sequence for the He epitope while concomitantly abolishing GPB-associated N antigenicity. Moreover, the GPHe(P2) gene carries two splice site mutations that coordinately affect the processing of exon V coding for the transmembrane segment. The C-->G transversion at the 3' end of exon V created a cryptic acceptor splice site, whereas the G-->T transversion at the +5 position of intron 5 altered the consensus of the donor splice site. Transcript sequencing revealed that neither site was utilized in the splicing of GPHe(P2) pre-mRNA. Rather, complete skipping of exon V and subsequent joining of exon IV to exon VI caused a shift in the open reading frame, which remodeled GPHe(P2) with an elongated new hydrophobic sequence for membrane anchoring. As a result, GPHe(P2) does not display the S and U epitopes although it still contains an intact linear sequence for the two antigens. These findings illustrate how exon and intron sequences concertedly determine the specificity of in vivo splice site selection. In addition, they pinpoint the conformational dependence of the S, s, and U antigens and the importance of the hinge region for their presentation.
Three approaches to the quantitative definition of information* (1968)

Click to increase image sizeClick to decrease image size *Here and in what follows f≈g indicates that the differencef—g is bounded, while f∼g indicates that the ratio f:g approaches one Notes *Here and in what follows f≈g indicates that the differencef—g is bounded, while f∼g indicates that the ratio f:g approaches one
Serum contents of IL-23 and IL-17 in the patients with ulcerative colitis and the clinical significance. (2011)

IL-23 and IL-17 participates in the pathogenesis of ulcerative colitis. IL-23 may play a critical role in the development of UC through inducing production of IL-17.
Prevention of ovarian cancer: intraepithelial neoplasia. (2003)

To reduce the incidence and mortality associated with invasive cancers, the Intraepithelial Neoplasia (IEN) Task Force recommends that carcinogenesis be viewed as a disease that requires treatment. This publication outlines the current knowledge of IEN of the ovary and reviews chemoprevention possibilities for ovarian cancer. Ovarian cancer has the highest mortality of all of the gynecological cancers and is the fourth leading cause of death from cancer in women. The IEN Task Force has defined precancer as a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer with a substantial likelihood of developing invasive cancer. The IEN Task Force recommends targeting moderate to severe dysplasia for new IEN treatment agents in clinical trials. Ovarian cancer does not have a clear preinvasive lesion yet merits considerable study for new prevention strategies because of the high mortality associated with ovarian cancer. There is a great unmet clinical need for treatments that can prevent ovarian cancer by providing nonsurgical options that treat the entire epithelial layer. New prevention strategies hold significant promise to reduce the mortality from ovarian cancer.