gebhart/patrepeval huggingface dataset:
The interaction of synaptic vesicle‐associated membrane protein/synaptobrevin with botulinum neurotoxins D and F (1997)

Botulinum neurotoxins type D and F are zinc-endopeptidases with a unique specificity for VAMP/synaptobrevin, an essential component of the exocytosis apparatus. VAMP contains two copies of a nine residue motif, termed V1 and V2, which are determinants of the interaction with tetanus and botulinum B and G neurotoxins. Here, we show that V1 plays a major role in VAMP recognition by botulinum neurotoxins D and F and that V2 is also involved in F binding. Site-directed mutagenesis of V1 and V2 indicates that different residues are the determinants of the VAMP interaction with the two endopeptidases. The study of the VAMP-neurotoxins interaction suggest a pairing of the V1 and V2 segments.
Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis (2009)

Abstract Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora. Reduction of gut commensal bacteria impaired the development of EAE. Intraperitoneal antibiotic-treated mice showed no significant decline in the gut microflora and developed EAE similar to untreated mice, suggesting that reduction in disease activity was related to alterations in the gut bacterial population. Protection was associated with a reduction of proinflammatory cytokines and increases in IL-10 and IL-13. Adoptive transfer of low numbers of IL-10-producing CD25+CD4+ T cells (&amp;gt;75% FoxP3+) purified from cervical lymph nodes of commensal bacteria reduced mice and in vivo neutralization of CD25+ cells suggested the role of regulatory T cells maintaining peripheral immune homeostasis. Our data demonstrate that antibiotic modification of gut commensal bacteria can modulate peripheral immune tolerance that can protect against EAE. This approach may offer a new therapeutic paradigm in the treatment of multiple sclerosis and perhaps other autoimmune conditions.
Electrical Impedance Tomography (2006)

The specific conductance (conductivity) of human tissues varies from 15.4 mS/cm for cerebrospinal fluid to 0.06 mS/cm for bone. The difference in the value of conductivity is large between different tissues (Table 17.1). Cross-sectional images of the distribution of conductivity, or alternatively specific resistance (resistivity), should show good contrast. The aim of electrical impedance tomography (EIT) is to produce such images. It has been shown [Kohn and Vogelius, 1984a,b; Sylvester and Uhlmann, 1986] that for reasonable isotropic distributions of conductivity it is possible in principle to reconstruct conductivity images from electrical measurements made on the surface of an object. Electrical impedance tomography (EIT) is the technique of producing these images. In fact, human tissue is not simply conductive. There is evidence that many tissues also demonstrate a capacitive component of current flow and therefore, it is appropriate to speak of the specific admittance (admittivity) or specific impedance (impedivity) of tissue rather than the conductivity; hence the use of the world impedance in electrical impedance tomography.Tissue consists of cells with conducting contents surrounded by insulating membranes embedded in a conducting medium. Inside and outside the cell wall is conducting fluid. At low frequencies of applied current, the current cannot pass through the membranes, and conduction is through the extracellular space. At high frequencies, current can flow through the membranes, which act as capacitors. A simple
The cellular basis of allograft rejection in vivo. I. The cellular requirements for first-set rejection of heart grafts. (1978)

The nature of the cells required for first-set graft rejection in vivo was examined by using an adoptive transfer system to restore heart-graft rejection in irradiated rats. Highly purified inocula of peripheral T lymphocytes were shown to quantitatively account for the restorative ability of adoptively transferred cells. These T cells were shown to be long-lived small lymphocytes which are not recently derived from the thymus during adult life. They belong to the pool of T cells which constantly recirculate from blood to lymph as shown by their rapid appearance in the lymph of iradiated syngeneic rats after intravenous injection. Neither B lymphocytes nor antibodies in the circulation or in the graft itself are required for first-set graft rejection.
Site‐specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity (2011)

BACKGROUND AND PURPOSE Exenatide is a 39‐amino‐acid peptide widely used to manage type 2 diabetes mellitus. However, it has a short plasma half‐life and requires a twice daily injection regime. To overcome these drawbacks we used maleimide‐polyethylene glycol to induce site‐specific PEGylation. EXPERIMENTAL APPROACH The analogue PB‐105 (ExC39) was produced by replacing cysteine at position 39 of exenatide to provide a free thiol group. PB‐105 showed the same glucoregulatory activity as exenatide in mice. Site‐specific PEGylation of PB‐105 was performed to produce PB‐110 (ExC39PEG5kDa), PB‐106 (ExC39PEG20kDa), PB‐107 (ExC39PEG30kDa) and PB‐108 (ExC39PEG40kDa). Their effects on intracellular cAMP, acute glucoregulatory activity and pharmacokinetic profile were compared in mice and rats. KEY RESULTS PEGylation shifted the concentration–response curve of PB‐105 to the right in a parallel, polyethylene glycol mass‐dependent manner but with an inflexion point of at least 20 kDa. The activities of PB‐107 and PB‐108 but not PB‐106 were reduced by 90% and 99%. PEGylation affected in vivo glucoregulatory activity in the same ‘Inflexion‐Shift’ fashion at least at 20 kDa, but linearly increased plasma duration and systemic exposure without inflexion. PB‐106 had a plasma t 1/2 approximately 10‐fold that of PB‐105, and exhibited superior glucoregulatory activity compared with PB‐105 in normal and diabetic mice. CONCLUSIONS AND IMPLICATIONS Site‐specific PEGylation of exenatide with a permanent amide linkage affects its activity in a new type of ‘Inflexion‐Shift’ fashion. PB‐106 is a putative new analogue for treating diabetes; it possesses no loss of in vitro activity, prolonged plasma duration and superior, improved in vivo glucoregulatory activity compared with exenatide.
Replication of Influenza A and B Viruses in Human Diploid Cells (1983)

Under optimal conditions, of high multiplicities of infection and with trypsin included in the medium throughout the incubation period, high yields of infectious influenza A and B viruses (10(6 . 5) p.f.u./ml) and of antigenically active haemagglutinin (HA)(1 microgram/HA/10(6) cells) were produced in human diploid MRC-5 cells. Budding virus particles were seen as spherical or short rod-like protrusions on the surface of the infected cells, and also on cell filopodia. Virus-induced cytoplasmic and nuclear inclusions were present in infected cells. This virus-human cell system may be suitable for studies of influenza virus persistence and for production of immunologically active HA antigen.
Treatment-Resistant Major Depressive Disorder: New Developments in 2006 (2006)

Despite the progressive increase in the number of available antidepressants, many patients with depression continue to be symptomatic.
Induction of KDR expression in bovine arterial endothelial cells by thrombin: Involvement of nitric oxide (2002)

Thrombin, a multifunctional serine protease, is generated at the site with vascular injuries. It not only participates in the coagulation cascade, but also can induce a lot of events related to cell mitogenesis and migration. In this study, we investigated the effect of thrombin on endothelial cell proliferation induced by vascular endothelial growth factor (VEGF). Thrombin promoted proliferation of cultured bovine carotid endothelial cells in a time- and dose-dependent manner. Moreover, it drastically enhanced the cell growth stimulated by VEGF. This stimulatory effect was reduced by inhibitors of either protein kinase C (PKC) or mitogen-activated protein kinase kinase (MAPKK). Thrombin induced a significant increase in the level of mRNA of the kinase domain-containing receptor (KDR), but not tms-like tyrosine kinase (Flt-1), in a time-dependent manner, which reached the maximum after 24 h of stimulation. This increase coincides well with the KDR protein expression. The luciferase assay showed that thrombin induced an about 7.5-fold increase in the KDR promoter activity compared with the control. This enhanced KDR promoter activity was also abolished by inhibitors of either PKC or MAPKK. The deletion analyses indicated that the region between -115 and -97 (containing Sp1 binding region) within the KDR promoter gene was required for the enhanced KDR expression induced by thrombin and VEGF. Moreover, the nitric oxide synthase (NOS) inhibitor abolished both the accelerated cell proliferation and the increased KDR expression induced by thrombin and VEGF. This inhibition was abrogated by DETA NONOate, a NO donor with long half-life. These findings suggest that thrombin might potentiate the VEGF-induced angiogenic activity through increasing the level of the VEGF receptor KDR, in which production of NO is involved.
Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells (2003)

Mouse embryonic stem (ES) cells differentiate into cells of all three primary germ layers including endodermal cells that produce insulin in vitro. We show that constitutive expression of Pax4 (Pax4(+)), and to a lesser extent Pdx1 (Pdx1(+)), affects the differentiation of ES cells and significantly promote the development of insulin-producing cells. In Pax4 overexpressing R1 ES cells, isl-1, ngn3, insulin, islet amyloid polypeptide, and glucose transporter 2 (Glut-2) mRNA levels increase significantly. The number of nestin-expressing (nestin+) cells also increases. Constitutive Pax4 expression combined with selection of nestin+ cells and histotypic culture conditions give rise to spheroids containing insulin-positive granules typical of embryonal and adult beta cells. In response to glucose, Pax4(+) and wild-type ES-derived cells release insulin. Transplantation of these cells into streptozotocin-treated diabetic mice results in a normalization of blood glucose levels. We conclude that constitutive expression of Pax4 in combination with histotypic cultivation facilitates ES cell differentiation into the pancreatic lineage, which leads to the formation of islet-like spheroid structures that produce increased levels of insulin.
Scaling optoelectronic-VLSI circuits into the 21st century: a technology roadmap (1996)

Technologies now exist for implementing dense surface-normal optical interconnections for silicon CMOS VLSI using hybrid integration techniques. The critical factors in determining the performance of the resulting photonic chip are the yield on the transceiver device arrays, the sensitivity and power dissipation of the receiver and transmitter circuits, and the total optical power budget available. The use of GaAs-AlGaAs multiple-quantum-well p-i-n diodes for on-chip detection and modulation is one effective means of implementing the optoelectronic transceivers. We discuss a potential roadmap for the scaling of this hybrid optoelectronic VLSI technology as CMOS linewidths shrink and the characteristics of the hybrid optoelectronic transceiver technology improve. An important general conclusion is that, unlike electrical interconnects, such dense optical interconnections directly to an electronic circuit will likely be able to scale in capacity to match the improved performance of future CMOS technology.
Chronic Lymphocytic Leukemia (2002)

Chronic lymphocytic leukemia (CLL) is one of the most commonly diagnosed leukemias managed by practicing hematologists. For many years patients with CLL have been viewed as similar, with a long natural history and only marginally effective therapies that rarely yielded complete responses. Recently, several important observations related to the biologic significance of V(H) mutational status and associated ZAP-70 overexpression, disrupted p53 function, and chromosomal aberrations have led to the ability to identify patients at high risk for early disease progression and inferior survival. Concurrent with these investigations, several treatments including the nucleoside analogues, monoclonal antibodies rituximab and alemtuzumab have been introduced. Combination of these therapies in clinical trials has led to high complete and overall response rates when applied as initial therapy for symptomatic CLL. Thus, the complexity of initial risk stratification of CLL and treatment has increased significantly. Furthermore, when these initial therapies do not work, approach of the CLL patient with fludarabine-refractory disease can be quite challenging. This session will describe the natural history of a CLL patient with emphasis on important decision junctures at different time points in the disease. In Section I, Dr. Stephan Stilgenbauer focuses on the discussion that occurs with CLL patients at their initial evaluation. This includes a review of the diagnostic criteria for CLL and prognostic factors utilized to predict the natural history of the disease. The later discussion of risk stratification focuses on molecular and genomic aberrations that predict rapid progression, poor response to therapy, and inferior survival. Ongoing and future efforts examining early intervention strategies in high risk CLL are reviewed. In Section II, Drs. Ian Flinn and Jesus G. Berdeja focus on the discussion of CLL patients when symptomatic disease has developed. This includes an updated review of monotherapy trials with nucleoside analogs and recent trials that have combined these with monoclonal antibodies and/or alternative chemotherapy agents. Appropriate application of more aggressive therapies such as autologous and allogeneic immunotherapy and less aggressive treatments for appropriate CLL patient candidates are discussed. In Section III, Dr. John Byrd focuses on the discussion that occurs with CLL patients whose disease is refractory to fludarabine. The application of genetic risk stratification in choosing therapy for this subset of patients is reviewed. Available data with conventional combination based therapies and monoclonal antibodies are discussed. Finally, alternative promising investigational therapies including new antibodies, kinase inhibitors (CDK, PDK1/AKT, PKC) and alternative targeted therapies (DNA methyltransferase inhibitors, histone deacetylase inhibitors, etc.) are reviewed with an emphasis on the most promising agents for this patient population.
Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90, and hsp70. (1994)

Stress-induced proteins (or heat shock proteins (HSPs)) of 96 kDa size (gp96) have been shown previously to elicit specific immunity to tumors from which they are isolated. In this report, we show that in contrast to Meth A-derived gp96, gp96 preparations derived from normal tissues did not elicit immunity to Meth A sarcoma at any dose tested. Further, in light of recent studies showing that other major cellular HSPs hsp90 and hsp70 also elicit tumor-specific immunity, we have compared the relative immunogenicities of gp96, hsp90, and hsp70 derived from the Meth A sarcoma. The proteins gp96 and hsp70 were observed to be highly and equally immunogenic, whereas the immunogenicity of hsp90 was approximately 10% of that of gp96 or hsp70. It is suggested that the poor immunogenicity of hsp90 results from its lack of a measurable ATPase activity, which has been implicated in the ability of HSPs to transfer peptide to acceptor molecules. This is the first study that documents the lack of immunogenicity of gp96 preparations derived from normal tissues and compares the immunogenicity of each of the three major cellular HSPs in one tumor system.
Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. (2007)

Novel therapeutic agents that are safe and effective are needed for the treatment of pancreatic, ovarian, lung adenocarcinomas and mesotheliomas. Mesothelin is a glycosyl-phosphatidyl inositol (GPI)-linked membrane protein of 40 kDa over-expressed in all pancreatic adenocarcinoma and mesothelioma, in >70% of ovarian adenocarcinoma, and in non-small cell lung and colorectal cancers. The biological functions of mesothelin are not known, although it appears to be involved in cell adhesion via its interaction with MUC16. We have recently developed MORAb-009, a mouse-human chimeric IgG1kappa monoclonal antibody with an affinity of 1.5 nM for human mesothelin. Here we provide evidence that MORAb-009 prevents adhesion of mesothelin-bearing tumor cells to MUC16 positive cells and can elicit cell-mediated cytotoxicity on mesothelin-bearing tumor cells. Treatment that included MORAb-009 in combination with chemotherapy led to a marked reduction in tumor growth of mesothelin-expressing tumors in nude mice compared to chemotherapy or MORAb-009 treatment alone. No adverse effects of MORAb-009 were noted during toxicology studies conducted in non-human primates. The preclinical data obtained from our studies warrants pursuing clinical testing of MORAb-009. We have in fact initiated a Phase I clinical study enrolling patients with mesothelin-positive pancreatic, mesothelioma, non-small cell lung and ovarian cancers.
Interleukin-3/erythropoietin fusion proteins: in vitro effects on hematopoietic cells. (1993)

Erythropoietin (Epo) acts synergistically with interleukin-3 (IL-3) to induce proliferation and differentiation of erythroid progenitors. This synergy occurs at IL-3 concentrations that have little or no effect alone. To determine whether optimal expansion of erythroid cells results when they are targeted by a molecule with both IL-3 and Epo activities, fusion proteins were generated and analyzed. Expression vectors were constructed in which the coding regions of human IL-3 and Epo cDNAs were joined by either a short (2 to 3 amino acids) or long (23 amino acids) linker sequence and expressed in Chinese hamster ovary (CHO) cells. Analysis of equilibrium binding properties of the IL-3 and Epo moieties revealed that in all fusion proteins each retained the ability to bind receptor. When IL-3 was connected to Epo by a short linker, the binding affinity of the IL-3 moiety was lower. In vitro proliferative activity of each moiety was observed on cell lines responsive to IL-3, Epo or a combination of the two cytokines. Fusion of IL-3 to Epo through its amino terminus was found to result in partial loss of its function. All the fusion proteins were biologically active on human bone marrow. When IL-3 was located at the amino domain of the protein, induction of erythroid colonies was similar to that of a mixture of IL-3 and Epo. These results indicate that biological integrity of both IL-3 and Epo can be maintained when these cytokines are fused, but that enhancement of erythropoiesis over that observed with a mixture of the two cytokines cannot be achieved by their fusion alone. Other requirements such as the coexpression of the IL-3 and Epo receptors and the sharing of a receptor subunit are likely to be needed for an optimal cell response to the fusion growth factors.
Electrical Stimulation Promotes Motor Nerve Regeneration Selectivity Regardless of End-Organ Connection (2009)

Previous studies have demonstrated that end-organ deprivation after peripheral nerve injury results in targeting of regenerating nerve fibers into inappropriate pathways, which leads to poor functional recovery. Here we studied the effect of electrical stimulation on the regeneration selectivity of motor nerves after peripheral nerve injury and end-organ deprivation. We found that end-organ deprivation reduced regenerating selectivity of motor nerves, total number of regenerating motoneurons, and level of neural trophic factors in the regenerating pathways after nerve injury (p < 0.05). Electrical stimulation successfully promoted motor nerve regeneration selectivity regardless of end-organ connections (p < 0.05). This increased selectivity was accompanied by an increase in the protein level of neural trophic factors in the distal nerve stumps by 3 weeks after nerve injury (p < 0.05). There was a similar increase in the protein level of these neural trophic factors in denervated muscle. However, the RNA level of these factors decreased both in the distal nerves and in the muscle. Despite the promising effect of promoting motor nerve regeneration selectivity, electrical stimulation did not prevent motoneuron loss caused by end-organ deprivation. The present study suggests that end organs contribute to the development of selective motor nerve regeneration by increasing the neurotrophic factors in the regeneration pathways. Electrical stimulation is an efficient strategy to ameliorate the deteriorated regeneration microenvironment caused by end-organ deprivation and to promote motor nerve regeneration selectivity when end-organ connections are deprived.
Postsynaptic Action of BDNF on GABAergic Synaptic Transmission in the Superficial Layers of the Mouse Superior Colliculus (2002)

The neurotrophin brain-derived neurotrophic factor (BDNF) is involved in numerous aspects of synapse development and plasticity. The present study was aimed at clarifying the significance of endogenous BDNF for the synaptically driven spontaneous network activity and GABAergic inhibition in the superficial layers of the mouse superior colliculus. In this structure neuron survival is unaffected by the absence of BDNF. Two experimental approaches were used: comparison of BDNF-deficient (-/-) and wild-type (+/+) mice and blockade of BDNF receptor signaling by the tyrosine kinase inhibitor K-252a. Patch-clamp recordings were performed on horizontal slices during postnatal days 15 and 16. The lack of BDNF in -/- mice caused a significant reduction of the spontaneous action potential frequency and an increase in the pharmacologically induced disinhibition of spike discharge. This change was accompanied by an increase in the amplitudes of GABAergic evoked, spontaneous, and miniature inhibitory postsynaptic currents (IPSCs). BDNF gene inactivation had no effect on the degree of paired-pulse facilitation or the frequency of miniature IPSCs. The increase of IPSC amplitudes by chronic BDNF deprivation was completely mimicked by acute exposure to K-252a in +/+ animals. The enhancement of GABAergic IPSCs in -/- animals was reversed by acute application of 100 ng/ml BDNF, but this rescue was completely prevented by blocking postsynaptic protein kinase C (PKC) activation with the PKC inhibitor peptide 19-31. From these results we conclude that BDNF increases spontaneous network activity by suppressing GABAergic inhibition, the site of action of BDNF is predominantly postsynaptic, BDNF-induced suppression of GABAergic synaptic transmission is caused by acute downregulation of GABA(A) receptors, and BDNF effects are mediated by its TrkB receptor and require PKC activation in the postsynaptic cell.
Comparison of enzyme: enhanced with conventional deinking of xerographic and laser: printed paper (1994)

This study examines seven commemial enzymes with cellulase activity xylanase activity or a combination of both applied to paper stock in the pulper at optimum conditions for each enzyme. Results of deinking efficiencyshowed that most enzyme preparations performed better than the conventional chemical method. Pilot results agreed with laboratory experiments for two enzymes. Dewatering and dispersion steps and subsequent reflotation and washing may therefore not be essential Their elimination could save capital costs and reduce electrical energy consumption.