gebhart/patrepeval huggingface dataset:
The EphA2 Receptor and EphrinA1 Ligand in Solid Tumors: Function and Therapeutic Targeting (2008)

The Eph receptor tyrosine kinases and ephrin ligands have been studied extensively for their roles in developmental processes. In recent years, Eph receptors and ephrins have been found to be integral players in cancer formation and progression. Among these are EphA2 and ephrinA1, which are involved in the development and maintenance of many different types of solid tumors. The function of EphA2 and ephrinA1 in tumorigenesis and tumor progression is complex and seems to be dependent on cell type and microenvironment. These variables affect the expression of the EphA2 and ephrinA1 proteins, the pathways through which they induce signaling, and the functional consequences of that signaling on the behavior of tumor cells and tumor-associated cells. This review will specifically focus on the roles that EphA2 and ephrinA1 play in the different cell types that contribute to the malignancy of solid tumors, with emphasis on the opportunities for therapeutic targeting.
Increases in tyrosine phosphorylation are detectable before phospholipase C activation after T cell receptor stimulation. (1990)

Antiphosphotyrosine immunoblots were used to characterize tyrosine phosphorylated proteins after stimulation of the human TCR. Increased tyrosine phosphorylation was evident on at least 12 substrates within 2 min after ligation of the TCR with mAb. Analysis of the time course for increased tyrosine phosphorylation revealed distinct patterns. Increased phosphorylation of 135-kDa and 100-kDa substrates was evident within 5 s, whereas increased phosphorylation of the TCR-zeta-chain required several minutes after treatment with anti-CD3 mAb. This rapid cellular tyrosine phosphorylation occurred independent of the cell cycle, as it occurred after stimulation of resting T cells, T cell blasts, and the Jurkat T cell leukemia line. When the TCR complex was cross-linked together with the CD4 receptor by heteroconjugate anti-CD3/CD4 mAb, an increased magnitude of tyrosine phosphorylation occurred, although no new substrates could be detected. The increased tyrosine phosphorylation of the 135-kDa and 100-kDa substrates was specific in that anti-HLA class I, anti-CD6, anti-CD7, and anti-CD28 antibodies did not cause increased tyrosine phosphorylation. Anti-CD4 stimulation of resting T cells did not cause increased tyrosine phosphorylation of pp100 and pp135, suggesting that the CD4-associated kinase, lck, does not account for the tyrosine phosphorylation observed after TCR stimulation. Similarly, pharmacologic treatment of cells with phorbol ester and calcium ionophore did not cause increased tyrosine phosphorylation of these substrates, indicating that activation of protein kinase C or phospholipase C does not account for these early increases in tyrosine phosphorylation. The time of onset of pp100 phosphorylation, and the magnitude of phosphorylation correlated with the magnitude of calcium mobilization when cells were stimulated with different forms of TCR stimulation. When cells were labeled with [3H]myoinositol and analyzed after stimulation by anti-CD3 mAb, increased tyrosine phosphorylation of the 135-kDa and 100-kDa substrates preceded the activation of phospholipase C, as measured by the appearance of inositol 1,4,5-trisphosphate. This occurred in both T cell blasts and in the Jurkat T cell line. Thus, these findings show that increased tyrosine phosphorylation is the earliest yet detected signal observed after ligation of the TCR complex, and furthermore suggest that tyrosine phosphorylation might link the TCR to the phosphatidylinositolbisphosphate hydrolysis signaling pathway.
Proinflammatory responses are efficiently induced by homotrimeric but not heterotrimeric lymphotoxin ligands. (1997)

The cytokine, lymphotoxin [LT, tumor necrosis factor beta (TNF beta)] is a potent mediator of proinflammatory and tumoricidal activities. Soluble lymphotoxin is a complex of three LT alpha chains. Its receptors, TNF-R55 and TNF-R75, bind in clefts formed by adjacent identical LT alpha monomers. LT also exists as membrane anchored heterotrimers comprised of LT alpha and LT beta chains. The major and minor membrane forms, LT alpha 1 beta 2 and LT alpha 2 beta 1, respectively, bind a unique receptor, LT beta-R. As LT alpha 2 beta 1 expresses an LT alpha-alpha cleft, it also binds TNF-R. In this report we have compared the effects of ligand engagement of TNF-R and LT beta-R by evaluating the ability of soluble LT alpha beta complexes to initiate activities of human umbilical vein endothelial cells which are characteristically signalled by TNF. We recently reported that soluble LT alpha 1 beta 2 signals via LT beta-R to mediate cytotoxicity of a subset of gamma interferon (IFN-gamma) treated carcinomas. We now show that human LT alpha beta heterotrimers do not efficiently activate LT beta-R+, TNF-R+ human endothelial cells in vitro and only inefficiently mediates lethal toxicity in mice. We also show that neither LT alpha beta heterotrimer signals via TNF-R; in fact LT alpha 2 beta 1 trimers fail to activate NF-kappa B and rather inhibit ligand-induced TNF-R signalling supporting the role for aggregation in TNF-R signalling. Thus, the ability of LT alpha beta complexes to efficiently initiate tumoricidal but not inflammatory activities distinguishes the LT/LT beta-R from the LT/TNF-R pathways and suggest novel strategies for exploiting the LT ligands in tumor therapy and for inhibiting TNF-R-mediated inflammatory sequellae.
Discovery and Development of GS 4104 (oseltamivir) An Orally Active Influenza Neuraminidase Inhibitor (2000)

Rational drug design utilizing available X-ray crystal structures of sialic acid analogues bound to the active site of influenza virus neuraminidase has led to the discovery of a series of potent carbocyclic influenza neuraminidase inhibitors. From this series, GS 4104 (oseltamivir, TAMIFLU ) has emerged as a promising antiviral for the treatment and prophylaxis of human influenza infection. This article will summarize the design, discovery, and development of oseltamivir as an oral therapeutic to treat influenza infection.
Proposed structure for the DNA-binding domain of the Myb oncoprotein based on model building and mutational analysis (1991)

Myb-related proteins from plants to humans are characterized by a DNA-binding domain which contains two to three imperfect repeats of approximately 50 amino acids each. Based on the evolutionary conservation of specific residues, secondary structural predictions suggest an arrangement of alpha helices homologous to that seen in the homeodomains, members of the helix-turn-helix family of DNA-binding proteins. We have used molecular modelling in conjunction with site-directed mutagenesis to test the feasibility of this structure. We propose that each Myb repeat consists of three alpha helices packed over a hydrophobic core which is built around the three highly conserved tryptophan residues. The C-terminal helix forms part of the helix-turn-helix motif and can be positioned into the major groove of B-form DNA, allowing prediction of residues critical for specificity of interaction. Modelling also allowed positioning of adjacent repeats around the major groove over an 8 bp binding site.
Dynamics of Thymocyte-Stromal Cell Interactions Visualized by Two-Photon Microscopy (2002)

Thymocytes are selected to mature according to their ability to interact with self major histocompatibility complex (MHC)-peptide complexes displayed on the thymic stroma. Using two-photon microscopy, we performed real-time analysis of the cellular contacts made by developing thymocytes undergoing positive selection in a three-dimensional thymic organ culture. A large fraction of thymocytes within these cultures were highly motile. MHC recognition was found to increase the duration of thymocyte-stromal cell interactions and occurred as both long-lived cellular associations displaying stable cell-cell contacts and as shorter, highly dynamic contacts. Our results identify the diversity and dynamics of thymocyte interactions during positive selection.
Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection (1995)

We tested the ability of vaccination with virus-like particles (VLPs) to protect domestic rabbits against papillomas induced by the cottontail rabbit papillomavirus (CRPV). A recombinant baculovirus system that expressed only the L1 major papillomavirus structural protein or L1 plus the minor L2 protein was used in insect cells as the source of VLPs. Groups of 10 rabbits were immunized with native or denatured VLPs from CRPV or type 1 bovine papillomavirus by using Freund's adjuvant. Alum was used as the adjuvant for an additional group immunized with CRPV L1-L2 VLPs. Animals were challenged with 5 x 10(10) and 2 x 10(11) particles on opposing flanks. No protection was seen in rabbits immunized with native or denatured bovine papillomavirus L1-L2 or with denatured CRPV L1-L2. In these groups, the lower and higher challenge doses resulted in 27 of 30 animals with extensive papillomas, with each of the remaining animals having a smaller number of persistent papillomas. Progression to carcinoma developed in 20 rabbits. Animals inoculated with native CRPV VLPs composed of L1 alone or L1-L2 developed many fewer lesions; the lower and higher challenge doses resulted in 17 of 29 and 5 of 29 rabbits, respectively, with no lesions, and the remainder developed only one to eight papillomas, which all regressed except for those on 1 rabbit. None developed cancer within 1 year of infection. Rabbits vaccinated with native CRPV VLPs developed high-titer antibodies in an enzyme-linked immunosorbent assay based on native VLPs, and passive transfer of serum or immunoglobulin G from rabbits immunized with CRPV VLPs protected against CRPV challenge. We conclude that native VLPs can induce antibody-mediated, type-specific protection against experimental papillomavirus infection.
Resonance in nonlinear bubble oscillations (1991)

In two recent papers (Longuet-Higgins 1989 a,b ) the author showed that the shape oscillations of bubbles can emit sound like a monopole source, at second order in the distortion parameter ε. In the second paper (LH2) it was predicted that the emission would be amplified when the second harmonic frequency 2σ n of the shape oscillation approaches the frequency ω of the breathing mode. This ‘resonance’ would however be drastically limited by damping due to acoustic radiation and thermal diffusion. The predictions were confirmed by further numerical calculations in Longuet-Higgins (1990 a ). Ffowcs Williams &amp; Guo (1991) have questioned the conclusions of LH2 on the grounds that near resonance there is a slow (secular) transfer of energy between the shape oscillation and the volumetric mode which tends to diminish the amplitude of the shape oscillation and hence falsify the perturbation analysis. They have also argued that the volumetric mode never grows sufficiently to produce sound of the stated order of magnitude. In the present paper we show that these assertions are unfounded. Ffowcs Williams &amp; Guo considered only undamped oscillations. Here we show that when the appropriate damping is included in their analysis the secular transfer of energy becomes completely insignificant. The resulting pressure pulse (figure 5 below) is found to be essentially identical to that calculated in LH2, figure 3. Moreover, in the initial-value problem considered in LH2, the excitation of the volumetric mode takes place not by a secular energy transfer but by a resonance during the first few cycles of the shape oscillation. This accounts for the amplification near resonance found in Longuet-Higgins (1990 a ). Finally, it is pointed out that the initial energy of the shape oscillations is far greater than is required to produce the O (ε 2 ) volume pulsations that were studied in LH2, and which were used for a comparison with field data. This acoustic radiation was not calculated by Ffowcs Williams &amp; Guo.
Cell-Replacement and Gene-Therapy Strategies for Parkinson‘s and Alzheimer‘s Disease (2007)

Parkinson's disease and Alzheimer's disease are the most common neurodegenerative diseases in the elderly population. Given that age is the most important risk factor in these diseases, the number of patients is expected to rise dramatically in the coming years. Therefore, an effective therapy for these diseases is highly sought. Current treatment brings only temporary symptomatic relief and does not result in halting the progression of these diseases. The increasing knowledge on the molecular mechanisms that underlie these diseases enables the design of novel therapies, targeted at degenerating neurons by creating an optimal regenerative cellular environment. Here, we review the progress made in the field of cell-replacement and gene-therapy strategies. New developments in the application of embryonic stem cells and adult neuronal progenitors are discussed. We also discuss the use of genetically engineered cells in neuronal rescuing strategies that have recently advanced into the clinic. The first trials for the treatment of Alzheimer's disease and Parkinson's disease with this approach are ongoing.
Epidermal Cell Differentiation in Arabidopsis Determined by a Myb Homolog, CPC (1997)

The roots of plants normally carry small hairs arranged in a regular pattern. Transfer DNA-tagged lines of Arabidopsis thaliana included a mutant with few, randomly distributed root hairs. The mutated gene CAPRICE (CPC) encoded a protein with a Myb-like DNA binding domain typical of transcription factors involved in animal and plant development. Analysis in combination with other root hair mutations showed that CPC may work together with the TTG gene and upstream of the GL2 gene. Transgenic plants overexpressing CPC had more root hairs and fewer trichomes than normal. Thus, the CPC gene determines the fate of epidermal cell differentiation in Arabidopsis.
Substitution of an Aspartic Acid Results in Constitutive Activation of c-<i>kit</i>Receptor Tyrosine Kinase in a Rat Tumor Mast Cell Line RBL-2H3 (1995)

The c-kit protooncogene encodes a receptor tyrosine kinase that mediates signals required for differentiation, proliferation and survival of mast cells. We have already shown the constitutive activation of c-kit receptor tyrosine kinase (KIT) in a human mast cell leukemia line (HMC-1) and a murine mastocytoma cell line (P-815). We here examined whether such constitutive activation of KIT occurred in the rat tumor mast cell line RBL-2H3 as well, which is frequently used as a tool for studying functions of mast cells. In RBL-2H3 cells, KIT was constitutively phosphorylated on tyrosine and activated in the absence of autocrine production of its ligand, stem cell factor (SCF). Sequencing analysis revealed that one of c-kit genes of RBL-2H3 cells had a point mutation, resulting in amino acid substitution of Tyr for Asp in codon 817. When rat wild-type c-kit cDNA and mutant-type c-kit cDNA encoding KITTyr817 were transfected into cells of a human embryonic kidney cell line (293T), only mutant form KITTyr817 was constitutively phosphorylated on tyrosine and activated in the absence of SCF. Since mutations at the same Asp codon constitutively activated KIT in all the human HMC-1, murine P-815, and rat RBL-2H3 cell lines, and since the incorporation of antisense oligonucleotides of c-kit messenger RNA significantly suppressed the proliferation of RBL-2H3 cells, the activating mutations in the Asp codon of the c-kit gene appeared to be involved in neoplastic growth of mast cells.
Sculpting the band gap: a computational approach (2015)

Materials with optimized band gap are needed in many specialized applications. In this work, we demonstrate that Hellmann-Feynman forces associated with the gap states can be used to find atomic coordinates that yield desired electronic density of states. Using tight-binding models, we show that this approach may be used to arrive at electronically designed models of amorphous silicon and carbon. We provide a simple recipe to include a priori electronic information in the formation of computer models of materials, and prove that this information may have profound structural consequences. The models are validated with plane-wave density functional calculations.
Stabilization of RNA stacking by pseudouridine (1995)

The effect of the modified nucleoside pseudouridine (psi) on RNA structure was compared with uridine. The extent of base stacking in model RNA oligonucleotides was measured by 1H NMR, UV, and CD spectroscopy. The UV and CD results indicate that the model single-stranded oligoribonucleotides AAUA and AA psi A form stacked structures in solution and the CD results for AA psi A are consistent with a general A-form helical conformation. The AA psi A oligomer exhibits a greater degree of UV hypochromicity over the temperature range 5-55 degrees C, consistent with a better stacked, more A-form structure compared with AAUA. The extent of stacking for each nucleotide residue was inferred from the percent 3'-endo sugar conformation as indicated by the H1'-H2' NMR scalar coupling. This indirect indication of stacking was confirmed by sequential NOE experiments. NMR measurements as a function of temperature indicate that pseudouridine forms a more stable base stacking arrangement than uridine, an effect that is propagated throughout the helix to stabilize stacking of neighboring purine nucleosides. The N1-H imino proton in AA psi A exchanges slowly with solvent, suggesting a role for the extra imino proton in stabilizing the conformation of pseudouridine. These results show that the conformational stabilization is an intrinsic property of pseudouridine occurring at the nucleotide level. The characteristics of pseudouridine in these models are consistent with earlier studies on intact rRNA, indicating that pseudouridine probably performs the same stabilizing function in most structural contexts.
Roles of Oxytocin Neurones in the Control of Stress, Energy Metabolism, and Social Behaviour (2012)

Oxytocin neurones are activated by stressful stimuli, food intake and social attachment. Activation of oxytocin neurones in response to stressful stimuli or food intake is mediated, at least in part, by noradrenaline/prolactin-releasing peptide (PrRP) neurones in the nucleus tractus solitarius, whereas oxytocin neurones are activated after social stimuli via medial amygdala neurones. Activation of oxytocin neurones induces the release of oxytocin not only from their axon terminals, but also from their dendrites. Oxytocin acts locally where released or diffuses and acts on remote oxytocin receptors widely distributed within the brain, resulting in anxiolytic, anorexic and pro-social actions. The action sites of oxytocin appear to be multiple. Oxytocin shows anxiolytic actions, at least in part, via serotoninergic neurones in the median raphe nucleus, has anorexic actions via pro-opiomelanocortin neurones in the nucleus tractus solitarius and facilitates social recognition via the medial amygdala. Stress, obesity and social isolation are major risk factors for mortality in humans. Thus, the oxytocin-oxytocin receptor system is a therapeutic target for the promotion of human health.
Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies (2008)

Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases.
The ‘Soft-Push’: Mining Internet Data for Marketing Intelligence (1997)

This paper examines the challenges that on-line shopping and other commercial transactions on the Internet pose for marketers in the retail industry. The Internet constitutes a whole new marketplace in its own right, and evidence exists that the traditional manipulation of the marketing mix has to be modified for this new environment. To place this paper in context, the authors describe the potential growth of electronic commerce on the Internet, how traditional marketing strategies can be adapted for the Internet and current Internet marketing techniques. This paper highlights how marketing professionals and retailers can exploit the tools of the Internet to move closer to their customers and add value to their products. It outlines the potential for applying data mining technology to the data that is collected as consumers browse and purchase goods and services in on-line shopping malls. The authors introduce a variation of the push promotional strategy - ‘the soft-push’ - a sales promotion strategy based on the navigational and purchasing behaviour of on-line shoppers. Data mining allows marketers to reveal customer profiles, helping to identify appropriate market segments. Different data algorithms are described and the data mining process is explained. A comparison is made between the ‘soft-push’ approach and other web mining approaches. In conclusion, key ethical questions are posed and the implications of data mining for marketers are summarised.
Intraductal Papillary Mucinous Neoplasms of the Pancreas (2004)

IPMNs continue to be recognized with increasing frequency. Five-year survival for those patients following resection of IPMNs with invasive cancer (43%) is improved compared with those patients with resected pancreatic ductal adenocarcinoma in the absence of IPMN (averages 15%-25%). Survival following resection of IPMNs without invasive cancer (regardless of degree of dyplasia) is good, but recurrent disease in the residual pancreas suggests that long-term surveillance is critical. Based on the age at resection data, there appears to be a 5-year lag time from IPMN adenoma (63.2 years) to invasive cancer (68.1 years).
Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. (1990)

A potent inhibitor of human leukocyte elastase (EC 3.4.21.37) and porcine pancreatic elastase (EC 3.4.21.36) was purified to homogeneity from human horny layers. It inhibits human leukocyte elastase and porcine pancreatic elastase in a 1:1 molar ratio and shows equilibrium dissociation constants of 6 x 10(-10) M and 1 x 10(-9) M, respectively. Inhibition of plasmin, trypsin, alpha-chymotrypsin, and cathepsin G was not observed. This inhibitor proved to be an acid stable basic peptide with an isoelectric point of 9.7. The complete amino acid sequence appears to be unique with 38% homology to the C-terminal half of antileukoprotease. The sequence shows that the inhibitor is composed of 57 amino acids and predicts a Mr of 7017. The high affinity as well as the apparent specificity for elastases suggests a functional role in preventing elastase-mediated tissue proteolysis. It is suggested that the term "elafin" be used to designate this inhibitor.