gebhart/patrepeval huggingface dataset:
In Vivo Evaluation of Cysteine-Based Chelators for Attachment of 99mTc to Tumor-Targeting Affibody Molecules (2007)

Affibody molecules present a new class of affinity proteins, which utilizes a scaffold based on a 58-amino acid domain derived from protein A. The small (7 kDa) Affibody molecule can be selected to bind to cell-surface targets with high affinity. An Affibody molecule (ZHER2:342) with a dissociation constant (Kd) of 22 pM for binding to the HER2 receptor has been reported earlier. Preclinical and pilot clinical studies have demonstrated the utility of radiolabeled ZHER2:342 in imaging of HER2-expressing tumors. The small size and cysteine-free structure of Affibody molecules enable complete peptide synthesis and direct incorporation of radionuclide chelators. The goal of this study was to evaluate if incorporation of the natural peptide sequences cysteine-diglycine (CGG) and cysteine-triglycine (CGGG) sequences would enable labeling of Affibody molecules with 99mTc. In a model monomeric form, the chelating sequences were incorporated by peptide synthesis. The HER2-binding affinity was 280 and 250 pM for CGG-ZHER2:342 and CGGG-ZHER2:342, respectively. Conjugates were directly labeled with 99mTc with 90% efficiency and preserved the capacity to bind specifically to HER2-expressing cells. The biodistribution in normal mice showed a rapid clearance from the blood and the majority of organs (except kidneys). In the mice bearing SKOV-3 xenografts, tumor uptake of 99mTc-CGG-ZHER2:342 was HER2-specific and a tumor-to-blood ratio of 9.2 was obtained at 6 h postinjection. Gamma-camera imaging with 99mTc-CGG-ZHER2:342 clearly visualized tumors at 6 h postinjection. The results show that the use of a cysteine-based chelator enables 99mTc-labeling of Affibody molecules for imaging.
Analytical luminescence: its potential in the clinical laboratory. (1979)

The various types of chemiluminescent and bioluminescent reactions are described. Applications of luminescence in the analysis of substancs of clinical interest are surveyed. The advantages, disadvantages, and prospects for luminescent assays are discussed.
Evidence-based treatments for cluster headache (2015)

Cluster headache (CH), one of the most painful syndromes known to man, is managed with acute and preventive medications. The brief duration and severity of the attacks command the use of rapid-acting pain relievers. Inhalation of oxygen and subcutaneous sumatriptan are the two most effective acute therapeutic options for sufferers of CH. Several preventive medications are available, the most effective of which is verapamil. However, most of these agents are not backed by strong clinical evidence. In some patients, these options can be ineffective, especially in those who develop chronic CH. Surgical procedures for the chronic refractory form of the disorder should then be contemplated, the most promising of which is hypothalamic deep brain stimulation. We hereby review the pathogenesis of CH and the evidence behind the treatment options for this debilitating condition.
Constitutive Activation of Extracellular Signal-regulated Kinase 2 by Synergistic Point Mutations (2001)

Constitutively active mutant forms of signaling enzymes provide insight into mechanisms of activation as well as useful molecular tools for probing downstream targets. In this study, point mutations in ERK2 at conserved residues L73P and S151D were identified that individually led to 8-12-fold increased specific activity and in combination reached 50-fold, indicating synergistic interactions between these residues. Examination by mass spectrometry, phosphatase sensitivity, and Western blotting revealed that the mutations enhanced ERK2 activity by facilitating intramolecular autophosphorylation predominantly at Tyr-185 and to a lesser extent at Thr-183 and that phosphorylation at both sites is required for activation. A set of short molecular dynamics simulations were carried out using different random seeds to sample locally accessible configurations. Simulations of the active mutant showed potential hydrogen bonding interactions between the phosphoryl acceptor and catalytic nucleophile, which could account for enhanced intramolecular autophosphorylation. In intact cells, the ERK2 mutants were functionally active in phosphorylating Elk-1 and RSK1 and activating the c-fos promoter. This activity was only partially reduced upon treatment of cells with the MKK1/2 inhibitor, U0126, indicating that in vivo the mechanism of ERK2 activation occurs substantially through autophosphorylation and partially through phosphorylation by MKK1/2.
A general strategy for generating intact, full-length IgG antibodies that penetrate into the cytosol of living cells (2014)

Full-length IgG antibodies cannot cross cell membranes of living cells; this limits their use for direct targeting of cytosolic proteins. Here, we describe a general strategy for the generation of intact, full-length IgG antibodies, herein called cytotransmabs, which internalize into living cells and localize in the cytosol. We first generated a humanized light chain variable domain (VL) that could penetrate into the cytosol of living cells and was engineered for association with various subtypes of human heavy chain variable domains (VHs). When light chains with humanized VL were co-expressed with 3 heavy chains (HCs), including 2 HCs of the clinically approved adalimumab (Humira®) and bevacizumab (Avastin®), all 3 purified IgG antibodies were internalized into the cytoplasm of living cells. Cytotransmabs primarily internalized into living cells by the clathrin-mediated endocytic pathway through interactions with heparin sulfate proteoglycan that was expressed on the cell surface. The cytotransmabs escaped into the cytosol from early endosomes without being further transported into other cellular compartments, like the lysosomes, endoplasmic reticulum, Golgi apparatus, and nucleus. Furthermore, we generated a cytotransmab that co-localized with the targeted cytosolic protein when it was incubated with living cells, demonstrating that the cytotransmab can directly target cytosolic proteins. Internalized cytotransmabs did not show any noticeable cytotoxicity and remained in the cytosol for more than 6 h before being degraded by proteosomes. These results suggest that cytotransmabs, which efficiently enter living cells and reach the cytosolic space, will find widespread uses as research, diagnostic, and therapeutic agents.
Retrovirus-mediated transfer of viral IL-10 gene prolongs murine cardiac allograft survival (1996)

A murine heterotopic, nonvascularized cardiac allograft model was used to examine the effects of the immunosuppressive cytokine, viral IL-10 (vIL-10), delivered by gene transfer on graft rejection. Retroviral-mediated gene transfer and expression of vIL-10 significantly prolonged allograft survival, without conventional systemic immunosuppression, from 12.1 +/- 0.8 days to 39.4 +/- 2.5 days (p < 0.0001). The effect was specific, dose dependent, and restricted to the site of transplantation. PCR analysis demonstrated specific expression of the transferred gene within the allograft. Analysis of the cellular infiltrate in the allografts showed a reduction in T cells and alloantigen-specific cytotoxic T cells and IL-2 producing helper T cells. Thus, the transient local expression of a gene encoding an immunosuppressive protein within a graft can generate local immunosuppression, making gene therapy a viable approach for facilitating transplantation.
103 Modulation of Human Basophilic Responses by a Fibroleukin-Allergen Fusion Protein (2012)

BACKGROUND: Fibroleukin or fibrinogen-like protein-2 is a immunomodulatory protein that was described to bind to Fcgamma-receptor-IIb and III. In the present study the effects of a fusion protein consisting of fibroleukin and the major allergen of shrimp, tropomyosin, on human basophilic responses were investigated in vitro. METHODS: The fusion molecule was generated by molecular cloning and expressed in E. coli. Receptor binding studies were performed by immunoblot, ELISA, and flow cytometry. Activation of basophils was studied by basophil activation test (BAT) with blood from shrimp allergic individuals. RESULTS: Tropomyosin and the C-terminal part of fibroleukin were fused by a short flexible linker consisting of the amino acids RADAAP. The fusion protein bound to the human Fcgamma-receptor-IIb in immunoblot and ELISA and binding of the fusion protein to human B-cells was shown by flow-cytometry. Shortening of the allergen into a peptide covering one-fifth of whole tropomyosin increased the binding to B-cells. Futhermore, a decrease in the activation of basophils to shrimp tropomyosin was observed in presence of the fusion protein. CONCLUSIONS: Here we describe a novel fusion protein based on fibroleukin and shrimp tropomyosin that may have tolerizing effects on basophils and B-cells in shrimp allergic individuals.
A human immunodeficiency caused by mutations in the PIK3R1 gene (2014)

Recently, patient mutations that activate PI3K signaling have been linked to a primary antibody deficiency. Here, we used whole-exome sequencing and characterized the molecular defects in 4 patients from 3 unrelated families diagnosed with hypogammaglobulinemia and recurrent infections. We identified 2 different heterozygous splice site mutations that affect the same splice site in PIK3R1, which encodes the p85α subunit of PI3K. The resulting deletion of exon 10 produced a shortened p85α protein that lacks part of the PI3K p110-binding domain. The hypothetical loss of p85α-mediated inhibition of p110 activity was supported by elevated phosphorylation of the known downstream signaling kinase AKT in patient T cell blasts. Analysis of patient blood revealed that naive T and memory B cell counts were low, and T cell blasts displayed enhanced activation-induced cell death, which was corrected by addition of the PI3Kδ inhibitor IC87114. Furthermore, B lymphocytes proliferated weakly in response to activation via the B cell receptor and TLR9, indicating a B cell defect. The phenotype exhibited by patients carrying the PIK3R1 splice site mutation is similar to that of patients carrying gain-of-function mutations in PIK3CD. Our results suggest that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
Expression of the Epstein--Barr Virus Envelope Fusion Glycoprotein gp85 Gene by a Recombinant Baculovirus (1994)

The gp85 envelope glycoprotein of Epstein-Barr virus (EBV) has a role in the molecular mechanism of infection, enabling fusion between the viral and host cell envelopes, a role in common with the homologous gH glycoproteins in other herpesviruses. A glutathione S-transferase bacterial fusion protein (GST85N-S) was generated, containing 178 amino acids from the C terminus of gp85 and including a known gp85 linear epitope. A panel of EBV-positive human antisera contained no antibodies to linear epitopes presented on the purified GST85N-S protein, indicating that primary protein structure in this region of gp85 is not a B cell target. This bacterial fusion protein was used to raise a rabbit monospecific polyclonal antiserum capable of detecting gp85 in a Western blot. The majority of recombinant baculovirus-expressed gp85 obtained from cell extracts prepared with SDS appeared on Western blots as heterogeneous high M(r) protein aggregates and consistently included 84K, 81K and 70K bands. Recombinant gp85 aggregation was increased by boiling the sample prior to gel electrophoresis. The 84K and 81K proteins were completely sensitive to endoglycosidase H treatment, indicating that these glycosylated species did not undergo further post-translational processing. Immunofluorescence studies revealed that recombinant gp85 was not transported to the insect cell surface. It reacted only with antibodies recognizing denatured gp85 and not with antibody to native gp85. Therefore expression of the gene encoding gp85, BXLF2, alone in the baculovirus expression system is insufficient for the synthesis of a correctly transported, processed, folded and antigenically native form of recombinant gp85.
Proteinuria-Lowering Effect of Heparin Therapy in Diabetic Nephropathy without Affecting the Renin-Angiotensin-Aldosterone System (2006)

Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I-hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.
Entrainment and Transport of Laser Ablated Plumes for Subsequent Elemental Analysis (1988)

Several cell designs have been systematically evaluated for gas flow entrainment and transport of laser ablated material to a secondary excitation source for elemental analysis. The best cell is not limited to samples of particular size or shape and is insensitive to sample surface irregularity. An annular gas sheath around the cell results in a transient response sufficiently fast to permit depth and lateral sampling of single samples or rapid throughput of different samples but slow enough to give a steady signal with laser repetition rates ≥10 Hz. Entrainment and transport of ablated particulates have been investigated experimentally and by model calculation for a test material (Mo metal). The equations for predicting diffusive and gravitational loss of particles in a horizontal tube are presented and discussed. The major loss mechanism appears to be gravitational deposition of relatively large particles formed during ablation and possibly by coalescence within the transfer tube. Entrainment of ablated Mo by the cell and mass transport from the cell to the secondary source were determined to be ∼90% and ∼40% efficient, respectively. Shot-to-shot fluctuation in particle size may cause corresponding variation in transport efficiency when the upper end of the ablated particle size distribution exceeds the size limit for particle transport.
On Improved Single Viewpoint Constraint Calibration for Catadioptric Omnidirectional Vision (2009)

The single viewpoint constraint (SVC) is a principal optical characteristic for most catadioptric omni-directional vision (COV). Precise calibration for SVC is needed during system assembling. However, owning to the nonlinear distortion in the imaging system, the calibration precision based on ideal perspective imaging model is often poor. In this paper, a new calibration method of SVC for the COV is proposed. Firstly, an image correction algorithm is obtained by training a neural network (NN). Then, according to characteristics of space circular perspective projection, the corrected image of the mirror boundary is used to estimate whose position and attitude relative to the camera to guide calibration. Since the estimate is conducted based on actual image model rather than the simplified model, the estimate error is largely reduced, and the calibration accuracy is clearly improved. Experiments are conducted on simulated images and real images to show the accuracy and the effectivity of the proposed method.
Zonula Occludens-1 Alters Connexin43 Gap Junction Size and Organization by Influencing Channel Accretion (2005)

Regulation of gap junction (GJ) organization is critical for proper function of excitable tissues such as heart and brain, yet mechanisms that govern the dynamic patterning of GJs remain poorly defined. Here, we show that zonula occludens (ZO)-1 localizes preferentially to the periphery of connexin43 (Cx43) GJ plaques. Blockade of the PDS95/dlg/ZO-1 (PDZ)-mediated interaction between ZO-1 and Cx43, by genetic tagging of Cx43 or by a membrane-permeable peptide inhibitor that contains the Cx43 PDZ-binding domain, led to a reduction of peripherally associated ZO-1 accompanied by a significant increase in plaque size. Biochemical data indicate that the size increase was due to unregulated accumulation of gap junctional channels from nonjunctional pools, rather than to increased protein expression or decreased turnover. Coexpression of native Cx43 fully rescued the aberrant tagged-connexin phenotype, but only if channels were composed predominately of untagged connexin. Confocal image analysis revealed that, subsequent to GJ nucleation, ZO-1 association with Cx43 GJs is independent of plaque size. We propose that ZO-1 controls the rate of Cx43 channel accretion at GJ peripheries, which, in conjunction with the rate of GJ turnover, regulates GJ size and distribution.
Calculation of winding losses in high-frequency toroidal inductors using single strand conductors (1994)

The paper is concerned with the optimisation of inductor design to improve the design capability for these large, expensive and heat-producing magnetic components in power electronic circuits. The work focuses on toroidal inductors which consist of uniformly distributed, solid conductor windings on low permeability toroidal cores. It develops methods of calculating the eddy current losses in the windings. The basic analytical equations for losses in the windings are evolved and the problem of variable turn pitch that arises in the toroidal geometry is dealt with by means of an effective core diameter concept. Effective core diameters are presented graphically in terms of normalised parameters. The theoretical and graphical results given in the paper enable toroidal inductor designs to be optimised, and losses to be calculated in a rapid and convenient way. Experimental results are shown to agree well with the theoretical results presented in the paper.
Enabling Technologies for Direct Detection Optical Phase Modulation Formats (2009)

Phase modulation formats are believed to be one of the key enabling techniques for next generation high speed long haul fiber-optic communication systems due to the following main advantages: (1) with a balanced detection, a better receiver sensitivity over conventional intensity modulation formats, e.g., a ~3 dB sensitivity improvement using differential phase shift keying (DPSK) and a ~1.3 dB sensitivity improvement using differential quadrature phase shift keying (DQPSK); (2) excellent robustness against fiber nonlinearities; (3) high spectrum efficiency when using multilevel phase modulation formats, such as DQPSK. As the information is encoded in the phase of the optical field, the phase modulation formats are sensitive to the phase-related impairments and the deterioration induced in the phase-intensity conversion. This consequently creates new challenging issues. The research objective of this thesis is to depict some of the challenging issues and provide possible solutions.
Enthalpy and entropy effects for homologous solutes in HPLC with alkali chain bonded phases (1989)

Retention for homologous solutes in reversed phase high performance liquid chromatography is studied using C 1 , C 4 , C 8 and C 18 alkyl chain bonded phases. For three homologous series the capacity ratios measured at different temperatures are analyzed in order to estimate the enthalpy and entropy effects in reversed phase HPLC
Thermoresponsive core–shell magnetic nanoparticles for combined modalities of cancer therapy (2009)

Thermoresponsive polymer-coated magnetic nanoparticles loaded with anti-cancer drugs are of considerable interest for novel multi-modal cancer therapies. Such nanoparticles can be used for magnetic drug targeting followed by simultaneous hyperthermia and drug release. Gamma-Fe(2)O(3) iron oxide magnetic nanoparticles (MNP) with average sizes of 14, 19 and 43 nm were synthesized by high temperature decomposition. Composite magnetic nanoparticles (CNP) of 43 nm MNP coated with the thermoresponsive polymer poly-n-isopropylacrylamide (PNIPAM) were prepared by dispersion polymerization of n-isopropylacrylamide monomer in the presence of the MNP. In vitro drug release of doxorubicin-(dox) loaded dehydrated CNP at temperatures below and above the lower critical solution temperature of PNIPAM (34 degrees C) revealed a weak dependence of drug release on swelling behavior. The particles displayed Fickian diffusion release kinetics; the maximum dox release at 42 degrees C after 101 h was 41%. In vitro simultaneous hyperthermia and drug release of therapeutically relevant quantities of dox was achieved, 14.7% of loaded dox was released in 47 min at hyperthermia temperatures. In vivo magnetic targeting of dox-loaded CNP to hepatocellular carcinoma (HCC) in a buffalo rat model was studied by magnetic resonance imaging (MRI) and histology. In summary, the good in vitro and in vivo performance of the doxorubicin-loaded thermoresponsive polymer-coated magnetic nanoparticles suggests considerable promise for applications in multi-modal treatment of cancer.
Increased expression of the src proto-oncogene in hairy cell leukemia and a subgroup of B-cell lymphomas. (1993)

The c-src proto-oncogene encodes a M(r) 60,000 phosphoprotein, pp60c-src, with tyrosine-specific protein kinase activity. We have used an immune complex protein kinase assay for pp60c-src to analyze a spectrum of B-cell neoplasms. pp60c-src activity was elevated in all five hairy cell leukemia specimens and in a number of the large cell and immunoblastic lymphomas; neoplasms representing later stages in B-cell development. pp60c-src activity was low in neoplastic cells which correspond to early and intermediate stages in B-cell development (acute and chronic lymphatic leukemia, lymphoblastic lymphoma, small lymphocytic lymphoma). The enhanced pp60c-src activity was associated with high levels of pp60c-src protein. However, increased expression of c-src was not associated with amplification or gross structural rearrangement of the c-src gene. This preliminary study demonstrates elevated levels of pp60c-src protein and tyrosine protein kinase activity in neoplasms corresponding to the later stages of B-cell ontogeny.