gebhart/patrepeval huggingface dataset:
Screening‐based discovery of drug‐like O‐GlcNAcase inhibitor scaffolds (2009)

O-GlcNAcylation is an essential posttranslational modification in metazoa. Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. Here we report the discovery of novel, low molecular weight and drug-like O-GlcNAcase inhibitor scaffolds by high-throughput screening. Kinetic and X-ray crystallographic analyses of the binding modes with human/bacterial O-GlcNAcases identify some of these as competitive inhibitors. Comparative kinetic experiments with the mechanistically related human lysosomal hexosaminidases reveal that three of the inhibitor scaffolds show selectivity towards human OGA. These scaffolds provide attractive starting points for the development of non-carbohydrate, drug-like OGA inhibitors.
The replication initiation protein of the broad-host-range plasmid RK2 is activated by the ClpX chaperone (1997)

Initiation and control of replication of the broad-host-range plasmid RK2 requires two plasmid-encoded elements, the replication origin (oriV) and the initiation protein TrfA. Purified TrfA is largely in the form of a dimer; however, only the monomeric form of the protein can bind specifically to the direct repeats (iterons) at the RK2 origin. The largely dimeric form of wild-type TrfA is inactive in the initiation of replication of RK2 in an in vitro replication system reconstituted from purified components. However, preincubation of the TrfA protein with the ClpX molecular chaperone isolated from Escherichia coli activates the initiator protein for replication in the purified system. We further observed that ClpX, in an ATP-dependent reaction, greatly increases the proportion of TrfA monomers and, therefore, the ability of this protein to bind to iterons localized within RK2 origin. Finally, a copy-up mutant of the TrfA protein which is largely in the monomer form is active in the reconstituted in vitro replication system, and its activity is not affected by ClpX.
Biomarker end-points in cancer chemoprevention trials. (1997)

Over the last decade, the Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, USA, has been developing drugs that will slow or stop the progression to invasive cancer of precancerous (pre-invasive) lesions generally termed 'intraepithelial dysplasia' or 'dysplasia'. Over 40 short-term clinical trials are in progress, testing the following classes of agents on precancerous lesions in the different major organ systems: antimutagens (N-acetylcysteine, oltipraz), antiproliferatives (difluoromethylornithine, dehydroepiandrosterone, selenomethionine), antioxidants (vitamin E, curcumin), anti-inflammatories (aspirin, piroxicam, ibuprofen, sulindac sulfone) and hormonally active agents (tamoxifen in breast ductal carcinoma in situ and finasteride in prostatic intraepithelial neoplasia). Because of the strong practical need to keep so many clinical trials as short-term as possible, certain tissue changes known to be associated with high cancer risk were selected for use as biomarker end-points in the trials, such changes being quantitatively assayed by computer-assisted image analysis. These 'surrogate end-point biomarkers' (SEBs) are based on the individual cellular morphological and functional changes universally used by histopathologists to diagnose the lesion of intraepithelial neoplasia (Riddell, 1984; Boone et al., 1992; Wright et al., 1994). High grades of this lesion precede invasive cancer in the great majority of cases, and therefore SEBs based on them are linked to high cancer risk. Table 1 summarizes some of the short-term clinical trials now being monitored by the Chemoprevention Branch. The SEBs abbreviated 'PPNN' in the figure are: proliferative index (P); ploidy (DNA histogram) (P); nuclear morphometry and chromatin texture (N); and nucleolar size and frequency (N). Computer-assisted image analysis is used to assay these features quantitatively, which gives the SEBs increased objectivity, reproducibility and sensitivity. Further details concerned with cancer chemoprevention trials using SEBs, and their relation to the field of cancer epidemiology, are given below.
Efficacy of calcium channel blockers as maintenance therapy for asthma (2002)

Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.
Role of NAD(P)H:quinone oxidoreductase in the progression of neuronal cell death in vitro and following cerebral ischaemia in vivo (2003)

Abstract A direct involvement of the antioxidant enzyme NAD(P)H:quinone oxidoreductase (NQO1) in neuroprotection has not yet been shown. The aim of this study was to examine changes, localization and role of NQO1 after different neuronal injury paradigms. In primary cultures of rat cortex the activity of NQO1 was measured after treatment with ethylcholine aziridinium (AF64A; 40 µ m ), inducing mainly apoptotic cell death, or oxygen‐glucose deprivation (OGD; 120 min), which combines features of apoptotic and necrotic cell death. After treatment with AF64A a significant NQO1 activation started after 24 h. Sixty minutes after OGD a significant early induction of the enzyme was observed, followed by a second increase 24 h later. Enzyme activity was preferentially localized in glial cells in control and injured cultures, however, expression also occurred in injured neuronal cells. Inhibition of the NQO1 activity by dicoumarol, cibacron blue or chrysin (1–100 n m ) protected the cells both after exposure to AF64A or OGD as assessed by the decreased release of lactate dehydrogenase. Comparable results were obtained in vivo using a mouse model of focal cerebral ischaemia. Dicoumarol treatment (30 nmol intracerebroventricular) reduced the infarct volume by 29% ( p = 0.005) 48 h after the insult. After chemical induction of NQO1 activity by t ‐butylhydroquinone in vitro neuronal damage was exaggerated. Our data suggest that the activity of NQO1 is a deteriorating rather than a protective factor in neuronal cell death.
Electroporation: a method for transferring genes into the gametes of zebrafish (Brachydanio rerio), channel catfish (Ictalurus punctatus), and common carp (Cyprinus carpio). (1993)

Recombinant plasmids containing the Rous sarcoma virus long-terminal repeat (RSVLTR) promoter linked to either rainbow trout (Oncorhyncus mykiss) growth hormone 1 (rtGH1) or growth hormone 2 (rtGH2) cDNA were linearized and introduced into the fertilized eggs of zebrafish (Brachydanio rerio), channel catfish (Ictalurus punctatus), and common carp (Cyprinus carpio) by both electroporation and microinjection. The latter two species had these rainbow trout constructs (RSVLTR-rtGH1cDNA or RSVLTR-rtGH2) electroporated into both gametes (i.e., sperm and unfertilized eggs) prior to fertilization, into eggs shortly after fertilization, and at the first cell division stage. Survival was determined just after hatching and again between 3 and 5 months after hatching. Polymerase chain reactions and Southern blot analyses were used to detect those individuals carrying the introduced foreign genes 3 to 5 months after hatching, respectively. Individuals analyzed by both methods yielded identical results in a double-blind study. The electroporation results were compared with groups that were microinjected. Although survival was similar, electroporation tended to produce a greater number of transgenic individuals than the microinjection procedure, and many more eggs could be treated per unit time by electroporation than microinjection. Survival was better for common carp when electroporation was performed shortly after fertilization, whereas channel catfish fared better at the first cell division stage. Electroporation prior to and shortly after fertilization, and at the first cell stage appeared to generate a large fraction of transgenic fish. We cautiously conclude that electroporation is an efficient method for introducing foreign DNA into fish gametes and embryos and may be an ideal method for treating large numbers of gametes in a modest period.
Malaria chemotherapy: Resistance to quinoline containing drugs inPlasmodium falciparum (1993)

Resistance to quinoline containing drugs, particularly chloroquine (CQ), is a major impediment to the successful chemotherapy and prophylaxis of malaria. CQ-resistant parasites fail to accumulate as much drug as their sensitive counterparts and two major hypotheses have been proposed to account for this phenomenon. CQ-resistant parasites are thought to maintain lower intracellular drug levels by means of an active efflux system, similar to that found in multi-drug resistant cancer cells, despite major differences in both the genetic and biochemical manifestations of drug resistance in the two cell types. Alternatively, CQ-resistance could be linked to a defective CQ uptake mechanism, possibly an impaired acidification process in the food vacuole of the resistant parasite. These two theories are discussed in detail in the following review. The potential of pharmacological intervention to override these resistance mechanisms is also discussed.
Fluoxetine-clonazepam cotherapy for anxious depression: an exploratory, post-hoc analysis of a randomized, double blind study (2009)

Anxious depression, defined as major depressive disorder (MDD) accompanied by high levels of anxiety, seems to be both common and difficult to treat, with antidepressant monotherapy often yielding modest results. We sought to examine the relative benefits of antidepressant-anxiolytic cotherapy versus antidepressant monotherapy for patients with anxious depression versus without anxious depression. We conducted a post-hoc analysis of an existing dataset (N=80), from a 3-week, randomized, double-blind trial which demonstrated cotherapy with fluoxetine and clonazepam to result in superior efficacy than fluoxetine monotherapy in MDD. The present analysis involved examining whether anxious depression status served as a predictor and moderator of symptom improvement. Anxious depression status was not found to predict symptom improvement, or serve as a moderator of clinical improvement to cotherapy versus monotherapy. However, the advantage in remission rates in favor of cotherapy versus monotherapy was, numerically, much larger for patients with anxious depression (32.2%) than it was for patients without anxious MDD (9.7%). The respective number needed to treat statistic for these two differences in response rates were, approximately, one in three for patients with anxious depression versus one in 10 for patients without anxious depression. The efficacy of fluoxetine-clonazepam cotherapy compared with fluoxetine monotherapy was numerically but not statistically enhanced for patients with anxious depression than those without anxious depression.
Photo navigator (2008)

Nowadays, travel has become a popular activity for people to relax their body and mind. Taking photos is then often an inevitable and frequent event during one's trip for recording the enjoyable experience. To help people to relive the wonderful travel experience they had recorded in photos, this paper presents a system, Photo Navigator, for enhancing the photo browsing experience by creating a new browsing style with a realistic feel to users as being into the scenes and taking a trip back in time to revisit the place. The proposed system is characterized by two main features. First, it better reveals the spatial relations among photos and offers a strong sense of space by taking users to fly into the scenes. Second, it is fully automatic and makes plausible for novice users to utilize the 3D technologies that are traditionally complex to manipulate. The proposed system is compared with two other photo browsing tools, ACDSee's photo slideshow and Microsoft's PhotoStory. User studies show that people would comparatively favor the browsing style we offer and appreciate the ease to create such a style.
Fused Heteroaromatic Dihydrosiloles: Synthesis and Double-Fold Modification (2013)

An efficient method for the synthesis of fused heteroaromatic dihydrosiloles via Ni-catalyzed hydrosilylation/intramolecular Ir-catalyzed dehydrogenative coupling of the Si-H bond with the heteroaromatic C-H bond has been developed. The method is efficient for both electron-deficient and -rich heterocycles. It exhibits high functional group tolerance and good regioselectivity. Fused heteroaromatic dihydrosiloles can be smoothly halogenated and then oxidized or arylated. Application of these transformations allows obtaining highly functionalized heteroaromatic structures. A gram-scale synthesis of dihydropyridinosilole has also been accomplished using reduced amounts of Ni- and Ir-catalysts.
Structure and Function of TolC: The Bacterial Exit Duct for Proteins and Drugs (2004)

The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded alpha/beta barrel, comprising an alpha-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous beta-barrel channel. This structure establishes a 140 A long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance alpha-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
Efficacy of Bladder Training in Older Women With Urinary Incontinence (1991)

The efficacy of bladder training was evaluated in a randomized clinical trial involving 123 noninstitutionalized women 55 years and older with urinary incontinence. Subjects were urodynamically categorized as those with urethral sphincteric incompetence (N = 88) and those with detrusor instability with or without concomitant sphincteric incompetence (N = 35). Bladder training reduced the number of incontinent episodes by 57%; the effect was similar for both urodynamic diagnostic groups. The quantity of fluid loss was reduced by 54%. This was greater for patients with detrusor instability than for those without it. Diurnal and nocturnal voluntary micturitions were also reduced. The effect on nocturnal micturition, however, was not observed in subjects with unstable detrusor function. It is recommended that bladder training be considered as an initial step in treatment of women with urinary incontinence. Provided prior comprehensive clinical evaluation is done, it can be prescribed without the need for urodynamic characterization.
Magnetic Levitation camera robot for endoscopic surgery (2011)

A wired miniature surgical camera robot with a novel Magnetic Levitation System (MLS) was modeled, designed and fabricated. A simple analysis and a theoretical model were developed in order to describe and predict basic behavior for different structural parameters of the system. The robot is composed of two main parts (head and tail) linked by a thin elastic flexible joint. The tail module embeds two magnets for anchoring and manual rough translation. The head module incorporates two motorized donut-shaped magnets and a miniaturized vision system at the tip. The MLS can exploit the external magnetic field to induce a smooth bending of the robotic head, guaranteeing a high span tilt motion of the point of view (0°-80°). The device is 100 mm long and 12.7 mm in diameter. Use of such a robot in single port or standard multiport laparoscopy could enable reduction of number/size of ancillary trocars, and/or increase the number of working devices that can be deployed, thus paving the way for multiple point of view laparoscopy.
Immunostimulant Patch Containing Heat-Labile Enterotoxin fromEscherichia coliEnhances Immune Responses to Injected Influenza Virus Vaccine through Activation of Skin Dendritic Cells (2003)

Vaccine strategies, such as influenza virus vaccination of the elderly, are highly effective at preventing disease but provide protection for only the responding portion of the vaccinees. Adjuvants improve the magnitude and rates of responses, but their potency must be attenuated to minimize side effects. Topical delivery of strong adjuvants such as heat-labile enterotoxin from Escherichia coli (LT) induces potent immune responses. We hypothesized that LT delivered alone in an immunostimulating (LT-IS) patch placed on the skin at the site of injection could augment the immune response to injected vaccines. This was based on the observation that topically applied LT induces migration of activated antigen-presenting cells (APCs) from the skin to the proximal draining lymph node (DLN), and that APCs loaded with antigen by injection in the same anatomical region also migrate to the same DLN. We observed that when influenza virus vaccine is injected and an LT-IS patch is placed to target the same DLN, the influenza virus antibody response is enhanced. Similarly, influenza virus-specific T cells isolated from the lungs show increased levels of gamma interferon and interleukin-4 production. An LT-IS patch placed near an injected vaccine also leads to increased levels of hemagglutination inhibition titers, enhanced mucosal immunoglobulin A responses, and enhanced antigen presentation. Although the mechanisms by which an LT-IS patch exerts its enhancing effects need further study, the enhanced immune responses, ability to safely use potent adjuvants, and simplicity of LT-IS patch application address an important unmet need and provide a new immune enhancement strategy.
Efficient construction of a large nonimmune phage antibody library: The production of high-affinity human single-chain antibodies to protein antigens (1998)

A large library of phage-displayed human single-chain Fv antibodies (scFv), containing 6.7 x 10(9) members, was generated by improving the steps of library construction. Fourteen different protein antigens were used to affinity select antibodies from this library. A panel of specific antibodies was isolated with each antigen, and each panel contained an average of 8.7 different scFv. Measurements of antibody-antigen interactions revealed several affinities below 1 nM, comparable to affinities observed during the secondary murine immune response. In particular, four different scFv recognizing the ErbB2 protein had affinities ranging from 220 pM to 4 nM. Antibodies derived from the library proved to be useful reagents for immunoassays. For example, antibodies generated to the Chlamydia trachomatis elementary bodies stained Chlamydia-infected cells, but not uninfected cells. These results demonstrate that phage antibody libraries are ideally suited for the rapid production of panels of high-affinity mAbs to a wide variety of protein antigens. Such libraries should prove especially useful for generating reagents to study the function of gene products identified by genome projects.
Gene therapy: progress and challenges. (2001)

Gene therapy is the delivery of new genetic material into a patient's somatic cells for the treatment of disease and is made possible through the development of viral and non-viral gene transfer vectors. In the first five years of gene therapy, clinical studies failed to yield efficacy data with the vectors available at that time. The lack of consistent clinical benefit prompted the United States National Institute of Health Recombinant DNA Advisory Committee to evaluate gene therapy research and conclude that substantial improvements in gene transfer vectors were needed in the areas of vector safety and control of the level and duration of gene expression, and to increase the understanding of the biological interaction of gene transfer vectors with the host. We will describe the progress in development of gene delivery technology, focusing on improvements in vector safety, analysis of vector biodistribution and GMP manufacturing of viral and non-viral gene transfer systems over the last six years since the report. Whereas 5 years ago, investigators tested every vector for every potential disease indication, the accumulated database now enables investigators to select a single vector based upon it's known performance in a wide number of animal models and human clinical studies. We will also highlight several directions investigators have taken to improve the safety and efficacy of gene therapy vectors.
Stimulation of lung lysyl oxidase activity in hamsters with elastase-induced emphysema. (1985)

Lysyl oxidase activity was measured in lung extracts of hamsters with elastase-induced emphysema 8 days after administration of the enzyme and again after 2, 3, and 4 wk. Levels of activity rose rapidly to 7 times the base values determined in the lungs of saline-injected control animals. In parallel with the increase in lysyl oxidase activity, the rate of 14C-lysine incorporation into desmosine and isodesmosine was at its maximum 1 wk after elastase administration, reflecting the lysyl-oxidase-mediated cross-link formation, which is the final step in the resynthesis of the pulmonary elastin destroyed by the elastolytic insult.
Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. (1992)

A cDNA encoding the murine Ah receptor (Ahb-1 allele for aromatic hydrocarbon responsiveness) has been isolated and characterized. Analysis of the deduced protein sequence revealed a region with similarity to the basic region/helix-loop-helix (BR/HLH) motif found in many transcription factors that undergo dimerization for function. In addition to the BR/HLH domain, the N-terminal domain of the Ah receptor has extensive sequence similarity to the human ARNT (aryl hydrocarbon receptor nuclear translocator) protein and two regulatory proteins of Drosophila, Sim and Per. Photoaffinity labeling and peptide mapping studies indicate that the Ah receptor binds agonist at a domain that lies within this conserved N-terminal domain. The Ah receptor appears to be a ligand-activated transcription factor with a helix-loop-helix motif similar to those found in a variety of DNA-binding proteins, including Myc and MyoD.