gebhart/patrepeval huggingface dataset:
Reprogramming of tau alternative splicing by spliceosome-mediated RNA trans-splicing: Implications for tauopathies (2005)

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the gene encoding the microtubule-associated protein, tau. Some FTDP-17 mutations affect exon 10 splicing. To correct aberrant exon 10 splicing while retaining endogenous transcriptional control, we evaluated the feasibility of using spliceosome-mediated RNA trans-splicing (SMaRT) to reprogram tau mRNA. We designed a pre-trans-splicing molecule containing human tau exons 10 to 13 and a binding domain complementary to the 3' end of tau intron 9. A minigene comprising tau exons 9, 10, and 11 and minimal flanking intronic sequences was used as a target. RT-PCR analysis of SH-SY5Y cells or COS cells cotransfected with a minigene and a pre-trans-splicing molecule using primers to opposite sides of the predicted splice junction generated products containing exons 9 to 13. Sequencing of the chimeric products showed that an exact exon 9-exon 10 junction had been created, thus demonstrating that tau RNA can be reprogrammed by trans-splicing. Furthermore, by using the same paradigm with a minigene containing full-length intronic sequences, we show that cis-splicing exclusion of exon 10 can be by-passed by trans-splicing and that conversion of exon 10(-) tau RNA into exon 10(+) tau RNA could be achieved with approximately 34% efficiency. Our results demonstrate that an alternatively spliced exon can be replaced by trans-splicing and open the way to novel therapeutic applications of SMaRT for tauopathies and other disorders linked to aberrant alternative splicing.
Aminopyrazole Carboxamide Bruton’s Tyrosine Kinase Inhibitors. Irreversible to Reversible Covalent Reactive Group Tuning (2018)

Potent covalent inhibitors of Bruton's tyrosine kinase (BTK) based on an aminopyrazole carboxamide scaffold have been identified. Compared to acrylamide-based covalent reactive groups leading to irreversible protein adducts, cyanamide-based reversible-covalent inhibitors provided the highest combined BTK potency and EGFR selectivity. The cyanamide covalent mechanism with BTK was confirmed through enzyme kinetic, NMR, MS, and X-ray crystallographic studies. The lead cyanamide-based inhibitors demonstrated excellent kinome selectivity and rat pharmacokinetic properties.
One-step preparation of competent Escherichia coli: transformation and storage of bacterial cells in the same solution. (1989)

We have developed a simple, one-step procedure for the preparation of competent Escherichia coli that uses a transformation and storage solution [TSS; 1 x TSS is LB broth containing 10% (wt/vol) polyethylene glycol, 5% (vol/vol) dimethyl sulfoxide, and 50 mM Mg2+ at pH 6.5]. Cells are mixed with an equal volume of ice-cold 2 x TSS and are immediately ready for use. Genetic transformation is equally simple: plasmid DNA is added and the cells are incubated for 5-60 min at 4 degrees C. A heat pulse is not necessary and the incubation time at 4 degrees C is not crucial, so there are no critical timing steps in the transformation procedure. Transformed bacteria are grown and selected by standard methods. Thus, this procedure eliminates the centrifugation, washing, and long-term incubation steps of current methods. Although cells taken early in the growth cycle (OD600 0.3-0.4) yield the highest transformation efficiencies (10(7)-10(8) transformants per micrograms of plasmid DNA), cells harvested at other stages in the growth cycle (including stationary phase) are capable of undergoing transformation (10(5)-10(7) transformants per micrograms of DNA). For long-term storage of competent cells, bacteria can be frozen in TSS without addition of other components. Our procedure represents a simple and convenient method for the preparation, transformation, and storage of competent bacterial cells.
A wide-FSR waveguide double-ring resonator for optical FDM transmission systems (1991)

A wide free-spectral-range (FSR) waveguide double-ring resonator (DRR) is investigated for use in optical frequency-division multiplexing (OFDM) transmission systems. It consists of two ring resonators with different radii and three directional couplers. The FSR is determined by the least common multiple of the FSRs of the two ring resonators. In order to determine the parameters of the DRR, transmission equations of the DRR, which have different radii, are derived by using the scattering matrix. The dependence of the transmittance characteristics of the DRR on the amplitude coupling coefficients of directional couplers and on the propagation loss of the ring waveguides is studied. The design guidelines for OFDM transmission systems are described.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Going Back to the Street: Revisiting Lipsky’s Street-level Bureaucracy (2012)

This article reviews Lipsky's Street-level Bureaucracy, a classic work of central importance to the discipline and teaching of public administration. The paper argues that Lipsky's portrayal of the dilemmas faced by front line workers challenges us to focus on the ethical, professional and personal development of student-practitioners.
DNA electrodiffusion in a 2D array of posts (1994)

We consider some of the fundamental statistical mechanics of the electrodiffusion of a long polyelectrolyte, DNA, in a microlithographically constructed 2D rectangular array of cylindrical posts. The DNA polymer is shown to be free draining when not hooked on a post, and the mean time to unhook is explicitly calculated and compared to our measurements.
Organogelators for making porous sol–gel derived silica at two different length scales (2000)

New sol–gel derived silicas made with a double porous network with pore sizes on two very different length scales (typically several nm and several µm) are reproducibly synthesised using molecular 2,3-di-n-decyloxyanthracene (DDOA) organogelators. The micron sized fibrous patterns made in methanol by DDOA aggregates are used as a blueprint for the growing of porous silica fibres. At the same time the mesoporous silica network seems to be templated by smaller DDOA aggregates. By varying the DDOA concentration, the mean size of the mesoporous network increases from 50 to 120 Å and the pore shape changes from a ink-bottle to a cylindrical type.
Size-selected cluster beam source based on radio frequency magnetron plasma sputtering and gas condensation (2005)

We report on a source for producing size-selected nanoclusters based on the combination of radio frequency magnetron plasma sputtering and gas condensation. The use of plasma sputtering to vaporize a target is applicable to a large range of materials; Ag, Au, Cu, and Si have been attempted to date. The source, combined with a time-of-flight mass filter, can produce clusters in the size range from 2 up to at least 70 000 atoms, depending on the target material, with a constant mass (M) resolution (M∕ΔM∼25) at an intensity that produces atomic monolayer coverage in as little as a few minutes. The source is also attached to an ultrahigh vacuum analysis chamber, which allows in situ surface chemical and structural analysis. Examples of cluster deposition experiments with the source are also presented.
Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans (2006)

Interleukin-10 (IL-10)-secreting T regulatory type 1 (Tr1) cells are defined by their specific cytokine production profile, which includes the secretion of high levels of IL-10 and transforming growth factor-beta(TGF-beta), and by their ability to suppress antigen-specific effector T-cell responses via a cytokine-dependent mechanism. In contrast to the naturally occurring CD4+ CD25+ T regulatory cells (Tregs) that emerge directly from the thymus, Tr1 cells are induced by antigen stimulation via an IL-10-dependent process in vitro and in vivo. Specialized IL-10-producing dendritic cells, such as those in an immature state or those modulated by tolerogenic stimuli, play a key role in this process. We propose to use the term Tr1 cells for all IL-10-producing T-cell populations that are induced by IL-10 and have regulatory activity. The full biological characterization of Tr1 cells has been hampered by the difficulty in generating these cells in vitro and by the lack of specific marker molecules. However, it is clear that Tr1 cells play a key role in regulating adaptive immune responses both in mice and in humans. Further work to delineate the specific molecular signature of Tr1 cells, to determine their relationship with CD4+ CD25+ Tregs, and to elucidate their respective role in maintaining peripheral tolerance is crucial to advance our knowledge on this Treg subset. Furthermore, results from clinical protocols using Tr1 cells to modulate immune responses in vivo in autoimmunity, transplantation, and chronic inflammatory diseases will undoubtedly prove the biological relevance of these cells in immunotolerance.
Expressions of survivin in primary hepatocellular carcinoma and para-carcinoma tissues (2013)

Objective To analyze the survivin expressions in primary hepatocellular carcinoma(HCC) tissue and para-carcinoma tissue,and to investigate the effects of survivin on tumor blood vessel growth and inhibiting apoptosis of tumor endothelial cells.Methods The human HCC,para-carcinoma and normal liver tissues were collected,and the relationship between the positive rate of survivin protein expression and pathological parameters of HCC was analyzed by immunohistochemitry,and the survivin protein expression levels in different tissues were detected by flow cytometry,and the survivin gene expression levels in different tissues were measured by quantitative real-time PCR(qRT-PCR).Results The survivin protein expression in HCC tissue was related to portal vein tumor thrombus formation(P0.05),and had no relationship with tumor size,casple,AFP level and pathological stages of HCC(P0.05).The flow cytometry results showed that the survivin protein expression in HCC tissue was higher than those in para-carcinoma and normal liver tissues(P0.05);the survivin protein expression in para-carcinoma tissue was higher than that in normal liver tissues,but there was no significant difference(P0.05).The qRT-PCR results showed that the survivin mRNA was only detected in HCC tissue,not detectable in para-carcinoma or normal liver tissues.Conclusion Survivin is highly expressed in HCC tissue,but the survivin gene is not expressed in para-carcinoma tissue,and the survivin protein may transport through a paracrine manner from HCC.
Amino acid composition in parenteral nutrition: what is the evidence? (2010)

Despite routine use of parenteral nutrition, surprisingly little clinical efficacy data are available to guide total or specific amino acid dosing in adult and pediatric patients requiring this therapy. This warrants increased attention by the research community and funding agencies to better define optimal amino acid administration strategies in patient subgroups requiring parenteral nutrition.
Adaptive time-frequency resolution in modulated transform at reduced delay (2008)

Cosine-modulated transforms such as the Modified Discrete Cosine Transform (MDCT) are key elements in audio coding. They allow efficient energy compaction and perceptual irrelevancy reduction. The frequency localization can be adapted to the signal characteristics and fast implementations exist. All of this has made MDCT the most popular transform in audio coding. In this paper we solve a problem never addressed in the literature: in order to enable variable MDCT sizes in communication codecs, we demonstrate how frequency resolution can be adapted on the fly without using transition windows hence decreasing coding delay. A low complexity implementation of the method is also proposed.
Drug evaluation: Volociximab, an angiogenesis-inhibiting chimeric monoclonal antibody. (2007)

PDL Biopharma Inc (formerly Eos Biotechnology Inc) and Biogen Idec Inc are developing volociximab, an angiogenesis-inhibiting chimeric mAb that targets AAB1, a component protein of alpha5/beta1 integrin, for the potential treatment of solid tumors, including renal cell carcinoma. Two phase II clinical trials evaluating volociximab in solid tumors are underway. Volociximab is also under investigation for the treatment of age-related macular degeneration.
An ancient system of host defense (1998)

Research over the past few years has begun to provide significant advances in our understanding of the interplay between the innate and adaptive immune systems. New findings in several model systems reveal remarkable parallels and conservation of ancient host defense pathways in organisms separated by over a billion years of evolution.
Stereospecific production of the herbicide phosphinothricin (glufosinate) by transamination: isolation and characterization of a phosphinothricin-specific transaminase from Escherichia coli (1990)

An aminotransferase capable of transaminating 2-oxo-4-[(hydroxy)(methyl)phosphinoyl]butyric acid to L-phosphinothricin [L-homoalanine-4-yl-(methyl)phosphinic acid], the active ingredient of the herbicide Basta (Hoechst AG), was purified to apparent homogeneity from Escherichia coli K-12. The enzyme catalyzes the transamination of L-phosphinothricin and various analogs with 2-ketoglutarate as the amino group acceptor. The transaminase has a molecular mass of 43 kilodaltons by sodium dodecyl sulfate-gel analysis and an isoelectric point of 4.35. The enzyme was most active in the high-pH region, with a maximum at pH 8.0 to 9.5, and had a temperature optimum of 55 degrees C. Heat stability was observed up to 70 degrees C. Substrate specificity studies suggested that the enzyme is identical with the 4-aminobutyrate:2-ketoglutarate transaminase (EC 2.6.1.19). The first 30 amino acids of the N terminus of the protein were determined by gas phase sequencing. The transaminase was immobilized by coupling to the epoxy-activated carrier VA-Biosynth (Riedel de Haen) and used in a column reactor for the continuous production of L-phosphinothricin. The enzyme reactor was operated for 7 weeks with only a slight loss of catalytic capacity. Production rates of more than 50 g of L-phosphinothricin per liter of column per h were obtained.
Computer Simulation of HRTFs for Personalization of 3D Audio (2008)

To give listeners a vivid sense of 3D spatial audio, virtual auditory display technology relies crucially on head related transfer functions (HRTFs). However, as each person has unique morphological characteristics of their head and ears, for a realistic auditory experience it is important to use personalized HRTFs. Our approach to HRTF personalization is first to measure a listener's head and ear morphology, currently by magnetic resonance imaging (MRI); then to use the 3D morphological data in computer simulation of sound wave propagation, by the finite difference time domain (FDTD) method. This paper summarizes our methods and recent improvements, which have led to obtaining more faithful, personalized HRTFs by FDTD simulation.
Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia (2008)

DT(388)IL3 fusion protein containing the catalytic and translocation domains of diphtheria toxin fused to human interleukin 3 was administered in an inter-patient dose escalation trial by 15 min i.v. infusions every other day for up to 6 doses to patients with chemo-refractory acute myeloid leukemia (AML) and myelodysplasia (MDS). The maximal tolerated dose was >12.5 microg/kg/dose. Transient grade 3 transaminasemia and grade 2 fevers, chills, hypoalbuminemia, and hypotension occurred. Peak DT(388)IL3 levels correlated with dose and day of administration but not antibody titer. Anti-DT(388)IL3 antibodies developed in most patients between day 15 and 30. Of 40 evaluable AML patients, 1 had a CR (8 months) and 1 had PR (3 months). Of 5 MDS patients, 1 had a PR (4 months). Because of the prolonged infusion schedule, many patients failed to receive six doses. DT(388)IL3 produces remissions in patients with relapsed/refractory AML and MDS with minimal toxicities, and alternate schedules of administration are needed to enhance the response rate.
In situ assembly of macromolecular complexes triggered by light (2010)

Chemical biology aims for a perfect control of protein complexes in time and space by their site-specific labeling, manipulation, and structured organization. Here we developed a self-inactivated, lock-and-key recognition element whose binding to His-tagged proteins can be triggered by light from zero to nanomolar affinity. Activation is achieved by photocleavage of a tethered intramolecular ligand arming a multivalent chelator head for high-affinity protein interaction. We demonstrate site-specific, stable, and reversible binding in solution as well as at interfaces controlled by light with high temporal and spatial resolution. Multiplexed organization of protein complexes is realized by an iterative in situ writing and binding process via laser scanning microscopy. This light-triggered molecular recognition should allow for a spatiotemporal control of protein-protein interactions and cellular processes by light-triggered protein clustering.
Supernatant of stored platelets causes lung inflammation and coagulopathy in a novel in vivo transfusion model (2010)

Transfusion-related acute lung injury is suggested to be a "2-hit" event resulting from priming and activation of pulmonary neutrophils. Activation may result from infusion of lysophosphatidylcholines (LysoPCs), which accumulate during storage of blood products. In the present study, we developed a syngeneic in vivo transfusion model to test whether storage of platelet concentrates (PLTs) results in lung injury in healthy rats as well as in a "2-hit" model using lipopolysaccharide-pretreated rats. In addition, the effect of washing of platelets was studied. In healthy rats, transfusion of aged PLTs caused mild lung inflammation. In LPS-pretreated rats, transfusion of aged PLTs, but not fresh PLTs, augmented pulmonary systemic coagulopathy. When PLTs components were transfused separately, supernatant of aged PLTs, but not washed aged platelets, induced pulmonary injury in the "2-hit" model. Supernatants of aged PLTs contained increased concentrations of LysoPCs compared with fresh PLTs, which enhanced neutrophil priming activity in vitro. We conclude that transfusion of aged PLTs induces lung inflammation in healthy rats. In a "2-hit" model, aged PLTs contribute to pulmonary and systemic coagulopathy, which may be mediated by LysoPCs, which accumulate in the supernatant of PLTs during storage.
Gene Expression Changes and Signaling Events Associated with the Direct Antimelanoma Effect of IFN-γ (2005)

IFN-gamma plays a role in the response to melanoma indirectly through its effect on the immune system and directly through its antiproliferative and proapoptotic effects on melanoma cells. To understand the molecular basis for the direct antimelanoma effect of IFN-gamma, we studied IFN-induced changes in gene expression and signaling among three human melanoma cell lines (DM6, DM93, and 501mel). These were resistant to the antimelanoma effect of IFN-alpha, and only DM6 cells exhibited growth inhibition and apoptosis with IFN-gamma. Through DNA microarray analysis, we found that the antimelanoma effect of IFN-gamma in DM6 was associated with the down-regulation of multiple genes involved in G-protein signaling and phospholipase C activation (including Rap2B and calpain 3) as well as the down-regulation of genes involved in melanocyte/melanoma survival (MITF and SLUG), apoptosis inhibition (Bcl2A1 and galectin-3), and cell cycling (CDK2). The antimelanoma effect of IFN-gamma was also associated with the up-regulation of the proapoptotic dependence receptor UNC5H2 and the Wnt inhibitor Dkk-1. Whereas both IFNs were able to activate Stat1 in all cell lines, the delayed activation of the extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase mitogen-activated protein kinases occurred only in DM6 with IFN-gamma, and the effect of IFN-gamma on cell growth and survival as well as gene expression in DM6 was dependent on the coordinate activation of MEK1 and p38. These findings provide new insights into the signaling events and gene expression changes associated with growth inhibition and apoptosis in melanoma and may thereby assist in identifying new targets for the treatment of melanoma.
A canine model of chronic heart failure produced by multiple sequential coronary microembolizations (1991)

A canine model of chronic heart failure was produced by multiple sequential intracoronary embolizations with microspheres. Twenty closed-chest dogs underwent three to nine intracoronary embolizations performed 1-3 wk apart. Embolizations were discontinued when left ventricular (LV) ejection fraction was less than 35%. LV ejection fraction was 64 +/- 2% at baseline and decreased to 21 +/- 1% at 3 mo after the last embolization (P less than 0.001). During the same period, LV end-diastolic pressure increased from 6 +/- 1 to 22 +/- 3 mmHg (P less than 0.001); LV end-diastolic volume increased from 64 +/- 3 to 101 +/- 6 6 ml (P less than 0.001), and cardiac output decreased from 2.9 +/- 0.2 to 2.3 +/- 0.1 l/min (P less than 0.01). These changes were accompanied by significant increases of pulmonary artery wedge pressure and systemic vascular resistance. Plasma norepinephrine increased from 332 +/- 17 pg/ml at baseline to 791 +/- 131 pg/ml at 3 mo after the last embolization (P less than 0.01); plasma levels of atrial natriuretic factor increased from 12.7 +/- 10.0 to 28.8 +/- 8.6 pmol/l (P less than 0.01), whereas plasma renin activity remained unchanged. Gross and microscopic postmortem examination showed patchy myocardial fibrosis and LV hypertrophy. We conclude that multiple intracoronary embolizations with microspheres, separated in time, can lead to chronic heart failure in dogs. The preparation is stable and reproducible and manifests many of the sequelae of heart failure that result from loss of contractile myocardium.
Vaccination with Dukoral®against travelers’ diarrhea (ETEC) and cholera (2008)

There is currently only one vaccine available that provides protection against diarrhea caused by Vibrio cholerae and, to a lesser degree, enterotoxigenic Escherichia coli (ETEC). Adverse events of this oral whole-cell/recombinant B-subunit vaccine have been negligible. Protective efficacy against cholera is 85%, while protection against the heat-labile toxin of ETEC reaches 67%. There is still a need for data on protection of Western travelers against travelers' diarrhea in general by Dukoral vaccination. However, current studies show a protective effect of up to 43%. Although the vaccine is only licensed for vaccination against cholera in most Western countries, there is mounting evidence that the oral cholera vaccine is a valuable option to those traveling to high-risk endemic areas. Vaccination against cholera and ETEC should be recommended for at-risk travelers, in particular those with high exposure at their travel destination or high personal risks through fluid loss.