gebhart/patrepeval huggingface dataset:
Engineered antibody intervention strategies for Alzheimer's disease and related dementias by targeting amyloid and toxic oligomers (2008)

Most neurodegenerative disorders, such as Alzheimer's (AD), Parkinson's, Huntington's and Creutzfeldt-Jakob disease, are characterised by the accumulation of insoluble filamentous aggregates known as amyloid. These pathologies share common pathways involving protein aggregation which can lead to fibril formation and amyloid plaques. The 4 kDa Abeta peptide (39-43 amino acids) derived from the proteolysis of the amyloid precursor protein is currently a validated target for therapy in AD. Both active and passive immunisation studies against Abeta are being trialled as potential AD therapeutic approaches. In this study, we have characterised engineered antibody fragments derived from the monoclonal antibody, WO-2 which recognises an epitope in the N-terminal region of Abeta (amino acids 2-8 of Abeta). A chimeric recombinant Fab (rFab) and single chain fragments (scFvs) of WO-2 were constructed and expressed in Escherichia coli. Rationally designed mutants to improve the stability of antibody fragments were also constructed. All antibody formats retained high affinity (K(D) approximately 8 x 10(-9) M) for the Abeta peptide, comparable with the intact parental IgG as measured by surface plasmon resonance. Likewise, all engineered fragments were able to: (i) prevent amyloid fibrillisation, (ii) disaggregate preformed Abeta(1-42) fibrils and (iii) inhibit Abeta(1-42) oligomer-mediated neurotoxicity in vitro as efficiently as the whole IgG molecule. These data indicate that the WO-2 antibody and its fragments have immunotherapeutic potential. The perceived advantages of using small Fab and scFv engineered antibody formats which lack the effector function include more efficient passage across the blood-brain barrier and minimising the risk of triggering inflammatory side reactions. Hence, these recombinant antibody fragments represent attractive candidates and safer formulations of passive immunotherapy for AD.
Substrate Specificity of the Escherichia coli Outer Membrane Protease OmpP (2006)

ABSTRACT Escherichia coli OmpP is an F episome-encoded outer membrane protease that exhibits 71% amino acid sequence identity with OmpT. These two enzymes cleave substrate polypeptides primarily between pairs of basic amino acids. We found that, like OmpT, purified OmpP is active only in the presence of lipopolysaccharide. With optimal peptide substrates, OmpP exhibits high catalytic efficiency ( k cat / K m = 3.0 × 10 6 M −1 s −1 ). Analysis of the extended amino acid specificity of OmpP by substrate phage revealed that both Arg and Lys are strongly preferred at the P1 and P1′ sites of the enzyme. In addition, Thr, Arg, or Ala is preferred at P2; Leu, Ala, or Glu is preferred at P4; and Arg is preferred at P3′. Notable differences in OmpP and OmpT specificities include the greater ability of OmpP to accept Lys at the P1 or P1′, site as well as the prominence of Ser at P3 in OmpP substrates. Likewise, the OmpP P1 site could better accommodate Ser; as a result, OmpP was able to cleave a peptide substrate between Ser-Arg about 120 times more efficiently than was OmpT. Interestingly, OmpP and OmpT cleave peptides with three consecutive Arg residues at different sites, a difference in specificity that might be important in the inactivation of cationic antimicrobial peptides. Accordingly, we show that the presence of an F′ episome results in increased resistance to the antimicrobial peptide protamine both in ompT mutants and in wild-type E. coli cells.
DDB2 Suppresses Epithelial-to-Mesenchymal Transition in Colon Cancer (2013)

Colon cancer is one of the deadliest cancers worldwide because of its metastasis to other essential organs. Metastasis of colon cancer involves a complex set of events, including epithelial-to-mesenchymal transition (EMT) that increases invasiveness of the tumor cells. Here, we show that the xeroderma pigmentosum group E (XPE) gene product, damaged DNA-binding protein (DDB)-2, is downregulated in high-grade colon cancers, and it plays a dominant role in the suppression of EMT of the colon cancer cells. Depletion of DDB2 promotes mesenchymal phenotype, whereas expression of DDB2 promotes epithelial phenotype. DDB2 constitutively represses genes that are the key activators of EMT, indicating that DDB2 is a master regulator of EMT of the colon cancer cells. Moreover, we observed evidence that DDB2 functions as a barrier for EMT induced by hypoxia and TGF-β. Also, we provide evidence that DDB2 inhibits metastasis of colon cancer. The results presented here identify a transcriptional regulatory pathway of DDB2 that is directly linked to the mechanisms that suppress metastasis of colon cancer.
In vivo examination of membrane protein localization and degradation with green fluorescent protein. (1996)

To test the utility of green fluorescent protein (GFP) as an in vivo reporter protein when fused to a membrane domain, we made a fusion protein between yeast hydroxymethylglutaryl-CoA reductase and GFP. Fusion proteins displayed spatial localization and regulated degradation consistent with the native hydroxymethylglutaryl-CoA reductase proteins. Thus, GFP should be useful in the study of both membrane protein localization and protein degradation in vivo.
Systemic Acquired Resistance inArabidopsisRequires Salicylic Acid but Not Ethylene (1995)

Systemic acquired resistance (SAR) is an inducible plant response to infection by a necrotizing pathogen. In the induced plant, SAR provides broad-spectrum protection against not only the inducing pathogen, but also against other, unrelated pathogens. Both salicylic acid (SA) and SAR-gene expression have been implicated as playing important roles in the initiation and maintenance of SAR. Here, we describe the characterization of transgenic Arabidopsis plants that express the bacterial nahG gene encoding salicylate hydroxylase, an enzyme that can metabolize SA. Strong, constitutive expression of this gene prevents pathogen-induced accumulation of SA and the activation of SAR by exogenous SA. We show that SAR in Arabidopsis can be induced by inoculation with Pseudomonas syringe pv. tomato against infection by a challenge inoculation with Peronospora parasitica. This response is abolished in transgenic, nahG-expressing Arabidopsis, but not in ethylene-insensitive mutants. These experiments support the critical role of SA in SAR and show that ethylene sensitivity is not required for SAR induction. The NahG Arabidopsis plants will be important for future studies aimed at understanding the role of SA in plant disease resistance mechanisms.
Clinical radiation oncology : indications, techniques, and results (1988)

Basic concepts of clinical radiation oncology radiation biology for radiation oncologists physical aspects of radiation therapy cancer of the skin cancers of the head and neck - thyroid carcinomas cancers of the breast cancer of the thorax GI malignancies GU malignancies GYN malignancies sarcomas CNS tumors lymphomas paediatric tumours novel radiotherapeutic approaches.
T-Cell Immunity to the Folate Receptor Alpha Is Prevalent in Women With Breast or Ovarian Cancer (2006)

These findings demonstrate that the FRalpha is a target of the immune system in breast and ovarian cancer patients. Understanding which antigens are targeted by the immune system may be important for prognosis or immune-based therapies.
Expression of human IL-1 beta in Salmonella typhimurium. A model system for the delivery of recombinant therapeutic proteins in vivo (1992)

The feasibility of using Salmonella typhimurium aroA mutant (SL3261) to deliver protein therapeutic agents was investigated in a murine model system. We have constructed an Escherichia coli expression plasmid designed to express the human protein IL-1 beta. This plasmid expresses IL-1 beta to high levels (greater than 30% total cell protein) in E. coli. In Salmonella the IL-1 beta is expressed constitutively to about 10% total cell protein, as verified by Western blotting analysis using polyclonal rabbit anti-IL-1 beta antibody. The protein is produced in a soluble and biologically active form. BALB/c mice administered orally or i.v. with S. typhimurium aroA mutants carrying the plasmid produced highly significant antibody responses against human IL-1 beta as determined by a solid-phase RIA. Furthermore, mice injected with the construct were significantly protected against lethal gamma-irradiation (850 rad). This study therefore demonstrates that the vaccine strain of Salmonella mutants can also be used effectively to deliver therapeutic proteins in vivo.
Widespread Coronary Inflammation in Unstable Angina (2002)

The widespread activation of neutrophils across the coronary vascular bed in patients with unstable angina, regardless of the location of the culprit stenosis, challenges the concept of a single vulnerable plaque in unstable coronary syndromes.
Non-muscle myosin heavy chain IIA and IIB interact and co-localize in living cells: Relevance for MYH9-related disease (2006)

Myosins of class II constitute part of a superfamily of several classes of proteins expressed in almost all eukaryotic cell types. Differences in the heavy chains produce three isoforms of class II non-muscle myosins (A, B and C), which are widely distributed in most tissues and thought to be components of the cell motor systems, although specific functional roles are largely unknown. In particular, it is still a matter of debate whether they interact and have overlapping or distinct functions. This argument is relevant not only to cell physiology, but also to human pathology since mutations of the MYH9 gene encoding non-muscle myosin heavy chain II A (NMMHC-A) cause MYH9-related disease (MYH9-RD), an autosomal dominant disorder characterized by platelet macrocytosis, thrombocytopenia and leukocyte inclusions, variably associated with sensorineural hearing loss, cataracts and/or glomerulonephritis. In this study, we report the results of yeast two-hybrid screening showing that the C-terminals of NMMHC-A and -B interact. This interaction was confirmed by immunoprecipitation in transfected COS-7 cells and in skin fibroblasts naturally expressing both isoforms. Moreover, our immunomorphological study revealed that isoforms A and B co-localize in fibroblasts, erythroblasts and kidney cells. These results suggest that isoforms A and B are strictly related molecules and support the hypothesis that their interrelationship could be involved both in the variability of clinical phenotype and selectivity of tissue damage of MYH9-RD.
Areca nut extracts suppress the differentiation and functionality of human monocyte‐derived dendritic cells (2011)

Wang C‐C, Chen T‐Y, Wu H‐Y, Liu T‐Y, Jan T‐R. Areca nut extracts suppress the differentiation and functionality of human monocyte‐derived dendritic cells. J Periodont Res 2012; 47: 198–203. © 2011 John Wiley &amp; Sons A/S Background and Objective: Areca quid chewing, a major risk factor contributing to the occurrence of oral cancer and precancer, has been reported to be associated with the severity and high prevalence of periodontal diseases in areca quid chewers. As dendritic cells are critically involved in the regulation of innate and adaptive immunity in oral mucosa, the objective of the present study was to investigate the effect of areca nut extracts (ANE) on the differentiation and reactivity of dendritic cells derived from monocytes. Material and Methods: Human peripheral blood monocytes were cultured in the presence of granulocyte–monocyte colony‐stimulating factor and interleukin‐4 for 7 d to generate dendritic cells. To examine the effect of ANE on the generation of dendritic cells, the monocytes were exposed to ANE throughout the 7 d culture period. In addition, the effect of ANE on the maturation of monocyte‐derived dendritic cells induced by lipopolysaccharide (LPS) was examined. Results: Monocytes cultured in granulocyte–monocyte colony‐stimulating factor and interleukin‐4 exhibited a typical phenotype of dendritic cells, as evidenced by the heightened expression of human leukocyte antigen (HLA)‐DR, CD11c and the co‐stimulatory molecules CD40, CD80 and CD86. Exposure of the monocytes to ANE did not influence the expression of HLA‐DR and CD11c, but markedly attenuated the proportion of CD40‐positive cells and the mean fluorescence intensity of CD86. The expression of co‐stimulatory molecules in LPS‐activated dendritic cells was not affected, whereas the mRNA expression of interleukin‐12 induced by LPS was markedly suppressed by ANE treatment in a concentration‐dependent manner. Conclusion: These results suggest that ANE exposure interfered with the differentiation of dendritic cells from monocytes. Moreover, the functionality of mature monocyte‐derived dendritic cells was attenuated in the presence of ANE.
The use of severe combined immunodeficiency mice to study the metabolism of human immunoglobulin g (1994)

SCID mice provide an adequate initial animal model for the study of human-mouse chimeric antibodies. Further understanding of the factors governing immunoglobulin catabolism can be probed by study of recombinant human constant regions in this animal system.
A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE (1992)

A model of allergic bronchopulmonary aspergillosis was developed by exposing BALB/c mice to Aspergillus fumigatus (AF) Ag. Animals immunized intranasally (i.n.) with soluble AF Ag produced low levels of serum IgE compared to animals given alum precipitated AF Ag i.p. The latter treatment also produced higher levels of serum IgG1 and AF-specific IgG1 than soluble AF given i.p. or i.n.. Blood and lung eosinophilia was detected in mice repeatedly exposed to AF by i.n. but not in the groups injected i.p. Particulate AF Ag-induced striking blood and lung eosinophilia and elevated levels of serum IgE in mice preexposed to AF Ag. The results indicate that route of inoculation and physical nature of Ag determine the immune response and can be manipulated to obtain enhanced IgE, eosinophils, or both in the animal model.
Sorafenib Induces Apoptosis Specifically in Cells Expressing BCR/ABL by Inhibiting Its Kinase Activity to Activate the Intrinsic Mitochondrial Pathway (2009)

Although the BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myelogenous leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia, relapse with emerging imatinib resistance mutations in the BCR/ABL kinase domain poses a significant problem. Here, we show that the multikinase inhibitor sorafenib inhibits proliferation and induces apoptosis at much lower concentrations in Ton.B210 cells when driven by inducibly expressed BCR/ABL than when driven by interleukin-3. The increased sensitivity to sorafenib was also observed in cells inducibly expressing BCR/ABL with the imatinib-resistant E255K or T315I mutation. Sorafenib-induced apoptosis in these cells and Ph+ leukemic cells was synergistically enhanced by rottlerin, bortezomib, or ABT-737 and inhibited by the pan-caspase inhibitor BOC-d-fmk or the overexpression of Bcl-XL. It was further revealed that sorafenib activates Bax and caspase-3 and reduces mitochondrial membrane potential specifically in BCR/ABL-driven cells. Sorafenib also inhibited BCR/ABL-induced tyrosine phosphorylation of its cellular substrates and its autophosphorylation in Ton.B210. It was finally shown that sorafenib inhibits the kinase activity of BCR/ABL as well as its E255K and T315I mutants in in vitro kinase assays. These results indicate that sorafenib induces apoptosis of BCR/ABL-expressing cells, at least partly, by inhibiting BCR/ABL to activate the mitochondria-mediated apoptotic pathway. Thus, sorafenib may provide an effective therapeutic measure to treat Ph+ leukemias, particularly those expressing the T315I mutant, which is totally resistant to imatinib and the second generation BCR/ABL inhibitors.
Ferroelectric liquid crystal spatial light modulator using a hydrogenated amorphous silicon as a photoconductor (1991)

Abstract A novel high speed, high contrast, high resolution ferroelectric liquid crystal spatial light modulator using hydrogenated amorphous silicon as a photoconductor (a-Si:H - FLC - SLM) is presented. This device is optically addressed and has good bistability. (1) Response time : Typical values are 500 and 250μsec for rise and decay time, respectively. (2) Contrast ratio : Typically 100 : 1 to 150 : 1, best result 200:1. (3) Resolution : 60∼80LP/mm observed from the USAF resolution test target. Interference fringes with a resolution of more than 120LP/mm are obtained by He-Ne laser.
Modification of Polypropylene Fibers by Acrylic Acid and its Influence on the Mechanical Property of Cement Mortar (2010)

The surface of the PP fibers were modified by acrylic acid and grafted by suspension in water medium. The effect of modified PP fibers on mechanical properties of cement mortar was studied. The microstructure of fibers surface, the active functional groups of fibers and the profile of cracked samples were analyzed by SEM and IR. The results show that, crylic acid was grafted on surface of PP fibers after modification; the flexural strength of cement mortar reinforced by modified PP fibers improved markedly, compared with cement mortar reinforced by ordinary PP fibers.
Design of an optical see-through head-mounted display with a low f-number and large field of view using a freeform prism (2009)

It has been a challenge to design an optical see-through head-mounted display (OST-HMD) that has a wide field of view (FOV) and low f-number (f/#) while maintaining a compact, lightweight, and nonintrusive form factor. In this paper, we present an OST-HMD design using a wedge-shaped freeform prism cemented with a freeform lens. The prism, consisting of three freeform surfaces (FFSs), serves as the near-eye viewing optics that magnifies the image displayed through a microdisplay, and the freeform lens is an auxiliary element attached to the prism in order to maintain a nondistorted see-through view of a real-world scene. Both the freeform prism and the lens utilize plastic materials to achieve light weight. The overall dimension of the optical system per eye is no larger than 25 mm by 22 mm by 12 mm, and the weight is 8 g. Based on a 0.61 in. microdisplay, our system demonstrates a diagonal FOV of 53.5 degrees and an f/# of 1.875, with an 8 mm exit pupil diameter and an 18.25 mm eye relief.
The "beta-like-globin" gene domain in human erythroid cells. (1985)

We have mapped the distribution of the major and minor DNase I-hypersensitive sites in the human "beta-like-globin" gene domain. The minor DNase I-hypersensitive sites map close to the 5' end of each of the beta-like-globin genes. Their presence is specifically associated with the transcription of the immediate downstream beta-like-globin genes. The major DNase I-hypersensitive sites map in what appear to be the 5' and 3' boundary areas of the human beta-like-globin gene domain, a region estimated to span at least 90 kilobases of DNA. These major sites are present in various erythroid cells, which express predominantly either the embryonic, the fetal, or the adult beta-like-globin genes, and seem to be involved in defining the active beta-like-globin genes domain in cells of erythroid lineage. The four major DNase I-hypersensitive sites in the 5' boundary area, when correlated with sequencing data, are shown to be located in DNA regions containing enhancer core-like sequences and alternating purine and pyrimidine bases.
Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy (1999)

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.
Hepatitis B vaccine: Immunogenicity and follow‐up including two year booster doses in high‐risk health care personnel in a London teaching hospital (1987)

One hundred forty-four adult health care personnel (aged 18-62 years, median 33 years) considered at high risk of future HBV infection were vaccinated with a plasma-derived hepatitis B vaccine (20 micrograms HBVax at 0, 1, and 6 months) and followed-up for 2 years. Anti-HBs was present in only 6.9% prior to vaccination, and prescreening to detect this group would not have been cost-effective. At 9 months, 8.3% were nonresponders and a further 9% had anti-HBs levels less than 50 mIU/ml. Multivariate analysis showed that age was the single most important determinant of a poor response. In 47 of 52 individuals retested 2 years later, anti-HBs levels had fallen by 80% or more, and in four it had become undetectable. Response to a booster dose at this stage was excellent, with anti-HBs levels 3 months later much higher than at the end of the initial course. Additional booster doses of vaccine in two of the initial nonresponders at 14 and 22 months, respectively, also led to seroconversion. Although a significant proportion of health care workers in this study did not make a satisfactory response to the hepatitis B vaccine, later booster doses were very effective in subsequently increasing anti-HBs levels.
Effect of Interferon- γ on Allergic Airway Responses in Interferon- γ –deficient Mice (2002)

Interferon (IFN)-gamma reduces airway responses after allergen challenge in mice. The mechanisms of this effect are not clear. These studies investigate whether IFN-gamma can reverse prolonged airway responses after allergen challenge in IFN-gamma-deficient (IFN-gammaKO) mice. Sensitized mice (IFN-gammaKO and wild-type [WT]) were challenged with ovalbumin. Airway responsiveness, eosinophils in bronchoalveolar lavage fluid, and lung lymphocyte subsets (CD4(+) and CD8(+)) were measured 24 hours and 8 weeks after challenge. In further experiments, we treated IFN-gammaKO mice with recombinant IFN-gamma starting 4 weeks after the challenge for 1 week or 4 weeks. Airway responsiveness, bronchoalveolar lavage eosinophils, and lung CD4(+) cells were increased 8 weeks after challenge in IFN-gammaKO but not WT mice. IFN-gamma treatment returned lung CD4(+) cell numbers to values obtained in unchallenged mice. One week of IFN-gamma treatment also returned airway responsiveness to baseline levels; however, 4-week treatment with IFN-gamma failed to decrease airway responsiveness below levels observed in untreated animals. This suggests that IFN-gamma plays an essential role in reversing allergen-induced airway inflammation and hyperresponsiveness and that it may have dual actions on the latter. Observations that IFN-gamma reverses airway responses, even when administered after challenge, suggests that IFN-gamma treatment could control allergic disease, including asthma.