gebhart/patrepeval huggingface dataset:
Wortmannin Inactivates Phosphoinositide 3-Kinase by Covalent Modification of Lys-802, a Residue Involved in the Phosphate Transfer Reaction (1996)

Wortmannin at nanomolar concentrations is a potent and specific inhibitor of phosphoinositide (PI) 3-kinase and has been used extensively to demonstrate the role of this enzyme in diverse signal transduction processes. At higher concentrations, wortmannin inhibits the ataxia telangiectasia gene (ATM)-related DNA-dependent protein kinase (DNA-PKcs). We report here the identification of the site of interaction of wortmannin on the catalytic subunit of PI 3-kinase, p110alpha. At physiological pH (6.5 to 8) wortmannin reacted specifically with p110alpha. Phosphatidylinositol-4,5-diphosphate, ATP, and ATP analogs [adenine and 5'-(4-fluorosulfonylbenzoyl)adenine] competed effectively with wortmannin, while substances containing nucleophilic amino acid side chain functions had no effect at the same concentrations. This suggests that the wortmannin target site is localized in proximity to the substrate-binding site and that residues involved in wortmannin binding have an increased nucleophilicity because of their protein environment. Proteolytic fragments of wortmannin-treated, recombinant p110alpha were mapped with anti-wortmannin and anti-p110alpha peptide antibodies, thus limiting the target site within a 10-kDa fragment, colocalizing with the ATP-binding site. Site-directed mutagenesis of all candidate residues within this region showed that only the conservative Lys-802-to-Arg mutation abolished wortmannin binding. Inhibition of PI 3-kinase occurs, therefore, by the formation of an enamine following the attack of Lys-802 on the furan ring (at C-20) of wortmannin. The Lys-802-to-Arg mutant was also unable to bind FSBA and was catalytically inactive in lipid and protein kinase assays, indicating a crucial role for Lys-802 in the phosphotransfer reaction. In contrast, an Arg-916-to-Pro mutation abolished the catalytic activity whereas covalent wortmannin binding remained intact. Our results provide the basis for the design of novel and specific inhibitors of an enzyme family, including PI kinases and ATM-related genes, that play a central role in many physiological processes.
Notch signaling induces cell cycle arrest in small cell lung cancer cells. (2001)

Among the various forms of human lung cancer, small cell lung cancer (SCLC) exhibits a characteristic neuroendocrine (NE) phenotype. Neural and NE differentiation in SCLC depend, in part, on the action of the basic-helix-loop-helix (bHLH) transcription factor human achaete-scute homologue-1 (hASH1). In nervous system development, the Notch signaling pathway is a critical negative regulator of bHLH factors, including hASH1, controlling cell fate commitment and differentiation. To characterize Notch pathway function in SCLC, we explored the consequences of constitutively active Notch signaling in cultured SCLC cells. Recombinant adenoviruses were used to overexpress active forms of Notch1, Notch2, or the Notch effector protein human hairy enhancer of split-1 (HES1) in DMS53 and NCI-H209 SCLC cells. Notch proteins, but not HES1 or control adenoviruses, caused a profound growth arrest, associated with a G1 cell cycle block. We found up-regulation of p21(waf1/cip1) and p27kip1 in concert with the cell cycle changes. Active Notch proteins also led to dramatic reduction in hASH1 expression, as well as marked activation of phosphorylated extracellular signal-regulated kinase (ERK)1 and ERK2, findings that have been shown to be associated with cell cycle arrest in SCLC cells. These data suggest that the previously described function of Notch proteins as proto-oncogenes is highly context-dependent. Notch activation, in the setting of a highly proliferative hASH1-dependent NE neoplasm, can be associated with growth arrest and apparent reduction in neoplastic potential.
A new approach to the maximum-flow problem (1988)

All previously known efficient maximum-flow algorithms work by finding augmenting paths, either one path at a time (as in the original Ford and Fulkerson algorithm) or all shortest-length augmenting paths at once (using the layered network approach of Dinic). An alternative method based on the preflow concept of Karzanov is introduced. A preflow is like a flow, except that the total amount flowing into a vertex is allowed to exceed the total amount flowing out. The method maintains a preflow in the original network and pushes local flow excess toward the sink along what are estimated to be shortest paths. The algorithm and its analysis are simple and intuitive, yet the algorithm runs as fast as any other known method on dense graphs, achieving an O ( n 3 ) time bound on an n -vertex graph. By incorporating the dynamic tree data structure of Sleator and Tarjan, we obtain a version of the algorithm running in O ( nm log( n 2 / m )) time on an n -vertex, m -edge graph. This is as fast as any known method for any graph density and faster on graphs of moderate density. The algorithm also admits efficient distributed and parallel implementations. A parallel implementation running in O ( n 2 log n ) time using n processors and O ( m ) space is obtained. This time bound matches that of the Shiloach-Vishkin algorithm, which also uses n processors but requires O ( n 2 ) space.
Gardnerella vaginalis: characteristics, clinical considerations, and controversies. (1992)

The clinical significance, Gram stain reaction, and genus affiliation of Gardnerella vaginalis have been controversial since Gardner and Dukes described the organism as the cause of "nonspecific vaginitis," a common disease of women which is now called bacterial vaginosis. The organism was named G. vaginalis when taxonomic studies showed that it was unrelated to bacteria in various genera including Haemophilus and Corynebacterium. Electron microscopy and chemical analyses have elucidated the organism's gram-variable reaction. Controversy over the etiology of bacterial vaginosis was largely resolved by (i) studies using improved media and methods for the isolation and identification of bacteria in vaginal fluids and (ii) standardization of criteria for clinical and laboratory diagnosis. Besides G. vaginalis, Mobiluncus spp., Mycoplasma hominis, and certain obligate anaerobes are now acknowledged as participants in bacterial vaginosis. The finding that G. vaginalis, Mobiluncus spp., and M. hominis inhabit the rectum indicates a potential source of autoinfection in addition to sexual transmission. Extravaginal infections with G. vaginalis are increasingly recognized, especially when the toxic anticoagulant polyanetholesulfonate is omitted from blood cultures and when urine cultures are incubated anaerobically for 48 h. The finding that mares harbor G. vaginalis suggests that an equine model can be developed for studies of Gardnerella pathogenesis.
Acoustic Loci and Transitional Cues for Consonants (1955)

Previous studies with synthetic speech have shown that second-formant transitions are cues for the perception of the stop and nasal consonants. The results of those experiments can be simplified if it is assumed that each consonant has a characteristic and fixed frequency position, or locus, for the second formant, corresponding to the relatively fixed place of production of the consonant. On that basis, the transitions may be regarded as “movements” from the locus to the steady state of the vowel. The experiments reported in this paper provide additional evidence concerning the existence and positions of these second-formant loci for the voiced stops, b, d, and g. There appears to be a locus for d at 1800 cps and for b at 720 cps. A locus for g can be demonstrated only when the adjoining vowel has its second formant above about 1200 cps; below that level no g locus was found. The results of these experiments indicate that, for the voiced stops, the transition cannot begin at the locus and go from there to the steady-state level of the vowel. Rather, if we are to hear the appropriate consonant, the first part of the transition must be silent. The voiced stops are best synthesized by making the duration of the silent interval equal to the duration of the transition itself. An experiment on the first formant revealed that its locus is the same for b, d, and g.
High-Yield, Nondestructive Purification and Quantification Method for Multiwalled Carbon Nanotubes (2002)

We have described a one-step, high-yield, nondestructive purification and processing method for multiwalled carbon nanotube (MWNT) containing soot using a conjugated organic polymer host. This host selectively suspends nanotubes relative to impurities. The fraction of available MWNTs suspended can be measured using electron paramagnetic resonance (EPR) and rises with increasing polymer mass before saturating at approximately 50% by mass for a soot to polymer mass ratio of 1:5. Thermogravimetric analysis can then be used to calculate the mass of nanotubes suspended and hence the purity of the original soot. Furthermore, this allows the calculation of numerical constants relating the EPR signal intensity to the nanotube mass, allowing the routine calculation of nanotube content. Finally the host polymer was removed by filtration, giving 91% pure nanotube material. In this case a yield of 17% pristine nanotubes was reclaimed from the soot. Full optimization of this process could lead to yields of up to 40%.
Periodontal regeneration with an autogenous bone-Bio-Oss composite graft and a Bio-Gide membrane. (2001)

This study evaluated the clinical, radiographic, and histologic response to the composite use of Bio-Oss porous bone mineral and autogenous bone in combination with a Bio-Gide bilayer collagen membrane to achieve regeneration when treating human periodontal bone defects. Preoperative recordings for four treatment areas included radiographs, clinical probing depths, and attachment levels; these recordings were repeated at 9 months. Histologic evaluation revealed new cementum with inserting collagen fibers and new bone formation on the surface of both types of graft materials. This grafting combination not only compared favorably with the previous use of Bio-Oss and Bio-Gide, but exceeded that result with almost complete periodontal regeneration. This human histologic study demonstrates that autogenous bone in combination with porous bone mineral matrix, together with the Bio-Gide collagen membrane, has the capacity to stimulate substantial new bone and cementum formation with Sharpey's fiber attachment.
Atmospheric-Pressure Dielectric Barrier Discharge for Surface Processing of Polymer Films and Fibers (2009)

This paper presents results on surface processing of polymeric materials using a particular plasma reactor configuration. An atmospheric-pressure plasma beam is used to create a surface discharge with an axially symmetric profile. The exposure to He and mixtures of He with reactive gases allows combined functionalization and cross linking on polymers in film and fiber forms.
Identification of Mycobacterial σ Factor Binding Sites by Chromatin Immunoprecipitation Assays (2006)

Mycobacterium tuberculosis and Mycobacterium bovis are responsible for infections that cause a substantial amount of death, suffering, and loss around the world. Still, relatively little is known about the mechanisms of gene expression in these bacteria. Here, we used genome-wide location assays to identify direct target genes for mycobacterial sigma factors. Chromatin immunoprecipitation assays were performed with M. bovis BCG for Myc-tagged proteins expressed using an anhydrotetracycline-inducible promoter, and enriched DNA fragments were hybridized to a microarray representing intergenic regions from the M. tuberculosis H37Rv genome. Several putative target genes were validated by quantitative PCR. The corresponding transcriptional start sites were identified for sigma(F), sigma(C), and sigma(K), and consensus promoter sequences are proposed. Our conclusions were supported by the results of in vitro transcription assays. We also examined the role of each holoenzyme in the expression of sigma factor genes. Our results revealed that many sigma factors are expressed from autoregulated promoters.
Signed Vector Timestamps: A Secure Protocol for Partial Order Time. Revision. (1993)

Abstract : The language of partial order time expresses the issues central to many problems in asynchronous distributed systems. A secure partial order time service would provide a general method to develop secure protocols for these problems. In this paper, we sketch out these issues and develop one such protocol: signed vector timestamps. The majority of this paper is drawn verbatim from the first author's October 1991 thesis proposal, the first research into security issues for non-scalar time services and the original presentation of the SVT protocol.
Chorioallantoic Membrane Angiogenesis Model for Tissue Engineering: A New Twist on a Classic Model (2003)

Tissue-engineering (TE) applications include the isolation, culture, and seeding of cells into a suitable matrix or scaffold before in vivo transplantation. After transplantation, vascularization of the scaffold is a principal limiting factor for cell viability for the first 6-8 days posttransplantation. A model for systematic analysis of this process has been developed. Fertilized White Leghorn eggs were incubated (at 37.8 degrees C in 60% relative humidity) and opened on day 3 of incubation. Preadipocyte-seeded fibrin constructs were implanted in a specially designed plastic cylinder and placed through the opening on the surface of the chorioallantoic membrane (CAM) on day 8 of incubation. Vascularization of the constructs by chorioallantoic blood vessels was assessed for up to 8 days posttransplantation. The survival rate for embryos receiving transplanted constructs was about 90%. Histology confirmed transplant cell viability at day 4 posttransplantation and vascularization of the constructs by avian endothelial cells began at this time. A new in vivo model to study the effect of angiogenesis in TE constructs, including assessments of viability, proliferation, and differentiation of transplanted cells and biomaterial properties, is presented. Advantages include easy access to the vascular network of the CAM, lack of immunocompetence, low costs, and avoidance of animal experiments.
Reactions of cyclotron-produced [18F]fluoride with diaryliodonium salts—a novel single-step route to no-carrier-added [18]fluoroarenes (1995)

Treatment of diaryliodonium salts with cyclotron-produced [18]fluoride in the presence of potassium carbonate–aminopolyether 2.2.2 constitutes a new single-step route to no-carrier-added [18F]fluoroarenes.
Propionibacterium acnes infected intervertebral discs cause vertebral bone marrow lesions consistent with Modic changes (2016)

Modic type I change (MC1) are vertebral bone marrow lesions adjacent to degenerated discs that are specific for discogenic low back pain. The etiopathogenesis is unknown, but occult discitis, in particular with Propionibacteria acnes (P. acnes), has been suggested as a possible etiology. If true, antibiotic therapy should be considered for patients with MC1. However, this hypothesis is controversial. While some studies report up to 40% infection rate in herniated discs, others fail to detect infected discs and attribute reports of positive cultures to contamination during sampling procedure. Irrespective of the clinical controversy, whether it is biologically plausible for P. acnes to cause MC1 has never been investigated. Therefore, the objective of this study was to test if P. acnes can proliferate within discs and cause reactive changes in the adjacent bone marrow. P. acnes was aseptically isolated from a symptomatic human L4/5 disc with MC1 and injected into rat tail discs. We demonstrate proliferation of P. acnes and up-regulation of IL-1 and IL-6 within three days of inoculation. At day-7, disc degeneration was apparent along with fibrotic endplate erosion. TNF-α immunoreactivity was enhanced within the effected endplates along with cellular infiltrates. The bone marrow appeared normal. At day-14, endplates and trabecular bone close to the disc were almost completely resorbed and fibrotic tissue extended into the bone marrow. T-cells and TNF-α immunoreactivity were identified at the disc/marrow junction. On MRI, bone marrow showed MC1-like changes. In conclusion, P. acnes proliferate within the disc, induce degeneration, and cause MC1-like changes in the adjacent bone marrow. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1447-1455, 2016.
Interaction proteome of human H ippo signaling: modular control of the co‐activator YAP 1 (2013)

Tissue homeostasis is controlled by signaling systems that coordinate cell proliferation, cell growth and cell shape upon changes in the cellular environment. Deregulation of these processes is associated with human cancer and can occur at multiple levels of the underlying signaling systems. To gain an integrated view on signaling modules controlling tissue growth, we analyzed the interaction proteome of the human Hippo pathway, an established growth regulatory signaling system. The resulting high-resolution network model of 480 protein-protein interactions among 270 network components suggests participation of Hippo pathway components in three distinct modules that all converge on the transcriptional co-activator YAP1. One of the modules corresponds to the canonical Hippo kinase cassette whereas the other two both contain Hippo components in complexes with cell polarity proteins. Quantitative proteomic data suggests that complex formation with cell polarity proteins is dynamic and depends on the integrity of cell-cell contacts. Collectively, our systematic analysis greatly enhances our insights into the biochemical landscape underlying human Hippo signaling and emphasizes multifaceted roles of cell polarity complexes in Hippo-mediated tissue growth control.
Alphavirus vectors and vaccination (2002)

Alphaviruses are positive-stranded RNA viruses that have a broad host range and therefore are capable of replicating in many vertebrate and invertebrate cells. The single-stranded alphavirus genome is divided into two ORFs. The first ORF encodes the nonstructural proteins that are translated upon entry of the virus into the cytoplasm and are responsible for transcription and replication of viral RNA. The second ORF is under the control of a subgenomic promoter and normally encodes the structural proteins, which are responsible for encapsidation of viral RNA and final assembly into enveloped particles. Expression vectors have been engineered from at least three alphaviruses in which the structural protein gene region has been replaced by heterologous genes and have been shown to express high levels of the heterologous protein in cultured cells. These RNA vectors, known as replicons, are capable of replicating on their own but are not packaged into virus-like particles unless the structural proteins are provided in trans. Thus, replicons are single cycle vectors incapable of spreading from infected to noninfected cells. Because of these features, alphavirus replicon vectors are being developed as a platform vaccine technology for numerous viral, bacterial, protozoan and tumour antigens where they have been shown to be efficient inducers of both humoral and T cell responses. In addition, as the alphavirus structural proteins are not expressed in vaccine recipients, antivector immune responses are generally minimal, allowing for multiple effective immunisations of the same individual.
Targeting Neuronal Nicotinic Receptors: a Path to New Therapies (2002)

The structural heterogeneity, the ubiquity of anatomical distribution, and the demonstrated modulation of biological functions is consistent with the view that nicotinic cholinergic signaling plays a key regulatory role in the brain and influences a number of neuronal processes including sensory processing, motor activity, and cognitive function. It has become evident that perturbation of nicotinic cholinergic neurotransmission can result in diverse CNS pathologies providing the potential for therapeutic intervention in a number of neurodegenerative, neuropsychiatric and neurological disorders. This review will provide a status on the rationale for neuronal therapies targeting neuronal nicotinic receptors (nAChRs) and discusses the multifaceted beneficial effects than can be achieved through manipulation of cholinergic pharmacology. Recent advances and issues relating to rational drug design based on the structure of acetylcholine binding protein are discussed.
BONE MARROW TRANSPLANTATION FOR SEVERE APLASTIC ANEMIA (1990)

Twenty-nine patients with severe aplastic anemia were entered into a study of pre- and posttransplant immunosuppressive therapy for bone marrow transplantation. Four of twenty-five previously transfused recipients prepared with cyclophosphamide 200 mg/kg and total-lymphoid irradiation 3 Gy experienced graft failure, indicating that this regimen was inadequate to ensure sustained engraftment. Posttransplant treatment with cyclosporine and methotrexate resulted in an actuarial incidence for grade greater than or equal to 2 graft-versus-host disease of 22 +/- 16%. Actuarial survival was 78 +/- 15%. These data indicate that more effective treatment is necessary to prevent graft failure, but since many patients can be successfully retransplanted, overall survival is comparable to other recent studies.
Virus Evolution Reveals an Exclusive Role for LEDGF/p75 in Chromosomal Tethering of HIV (2007)

Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T-cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75-integrase interface provides in vivo evidence for previously reported crystallographic data. Moreover, the complementary inhibition by LEDGF/p75 knockdown and mutagenesis at the integrase-LEDGF/p75 interface points to the incapability of HIV to circumvent LEDGF/p75 function during proviral integration. Altogether, the data provide a striking example of the power of viral molecular evolution. The results underline the importance of the LEDGF/p75 HIV-1 interplay as target for innovative antiviral therapy. Moreover, the role of LEDGF/p75 in targeting integration will stimulate research on strategies to direct gene therapy vectors into safe landing sites.