gebhart/patrepeval huggingface dataset:
Nectin4/PRR4, a New Afadin-associated Member of the Nectin Family That Trans-interacts with Nectin1/PRR1 through V Domain Interaction (2001)

Nectins are adhesion molecules that participate in the organization of epithelial and endothelial junctions and serve as receptors for herpes simplex virus entry. They belong to the immunoglobulin superfamily, are homologues of the poliovirus receptor (PVR/CD155), and were also named poliovirus receptor-related (PRR) proteins. We identify a new member of the nectin family named nectin4. Peptide sequences of human and murine nectin4 share 92% identity, and as for other members, the ectodomain is made of three immunoglobulin-like domains of V, C, C types. In contrast to other nectin molecules, detection of nectin4 transcripts is mainly restricted to placenta in human tissues. Expression is broader in mouse, and interestingly nectin4 is detected at days 11, 15, and 17 during murine embryogenesis. Nectin4 interacts with afadin, a F-actin-associated molecule, via its carboxyl-terminal cytoplasmic sequence. Both molecules co-localize at cadherin-based adherens junctions in the MDCKII epithelial cell line. Nectins are homophilic adhesion molecules, and recently heterophilic interactions have been described between nectin3/nectin1 and nectin3/nectin2. We confirmed these trans-interactions and also described nectin3 as the PVR/CD155 ligand. By means of several approaches, we report on the identification of nectin4 as a new ligand for nectin1. First, a soluble chimeric recombinant nectin4 ectodomain (nectin4-Fc) trans-interacts with cells expressing nectin1 but not with cells expressing nectin2, nectin3, or PVR/CD155. Conversely, nectin1-Fc binds to cells expressing nectin4. Second, nectin1-Fc precipitates nectin4 expressed in COS cells. Third, reciprocal in vitro physical interactions were detected between nectin4-Fc and nectin1-Fc. The nectin4-Fc/nectin4-Fc interaction was detected suggesting that nectin4 exhibits both homophilic and heterophilic properties. Using the same approaches we demonstrate, for the first time, that the V domain of nectin1 acts as a major functional region involved in trans-heterointeraction with nectin4 and also nectin3.
A Pollen-specific Novel Calmodulin-binding Protein with Tetratricopeptide Repeats (2000)

Calcium is essential for pollen germination and pollen tube growth. A large body of information has established a link between elevation of cytosolic Ca(2+) at the pollen tube tip and its growth. Since the action of Ca(2+) is primarily mediated by Ca(2+)-binding proteins such as calmodulin (CaM), identification of CaM-binding proteins in pollen should provide insights into the mechanisms by which Ca(2+) regulates pollen germination and tube growth. In this study, a CaM-binding protein from maize pollen (maize pollen calmodulin-binding protein, MPCBP) was isolated in a protein-protein interaction-based screening using (35)S-labeled CaM as a probe. MPCBP has a molecular mass of about 72 kDa and contains three tetratricopeptide repeats (TPR) suggesting that it is a member of the TPR family of proteins. MPCBP protein shares a high sequence identity with two hypothetical TPR-containing proteins from Arabidopsis. Using gel overlay assays and CaM-Sepharose binding, we show that the bacterially expressed MPCBP binds to bovine CaM and three CaM isoforms from Arabidopsis in a Ca(2+)-dependent manner. To map the CaM-binding domain several truncated versions of the MPCBP were expressed in bacteria and tested for their ability to bind CaM. Based on these studies, the CaM-binding domain was mapped to an 18-amino acid stretch between the first and second TPR regions. Gel and fluorescence shift assays performed with CaM and a CaM-binding synthetic peptide further confirmed MPCBP binding to CaM. Western, Northern, and reverse transcriptase-polymerase chain reaction analysis have shown that MPCBP expression is specific to pollen. MPCBP was detected in both soluble and microsomal proteins. Immunoblots showed the presence of MPCBP in mature and germinating pollen. Pollen-specific expression of MPCBP, its CaM-binding properties, and the presence of TPR motifs suggest a role for this protein in Ca(2+)-regulated events during pollen germination and growth.
Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy (2020)

The exocrine pancreas expresses the highest concentrations of fibroblast growth factor 21 (FGF21) in the body, where it maintains acinar cell proteostasis. Here, we showed in both mice and humans that acute and chronic pancreatitis is associated with a loss of FGF21 expression due to activation of the integrated stress response (ISR) pathway. Mechanistically, we found that activation of the ISR in cultured acinar cells and mouse pancreata induced the expression of ATF3, a transcriptional repressor that directly bound to specific sites on the <i>Fgf21</i> promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human <i>FGF21</i> promoter. Consistent with the mouse studies, we also observed the reciprocal expression of ATF3 and FGF21 in the pancreata of human patients with pancreatitis. Using three different mouse models of pancreatitis, we showed that pharmacologic replacement of FGF21 mitigated the ISR and resolved pancreatitis. Likewise, inhibition of the ISR with an inhibitor of the PKR-like endoplasmic reticulum kinase (PERK) also restored FGF21 expression and alleviated pancreatitis. These findings highlight the importance of FGF21 in preserving exocrine pancreas function and suggest its therapeutic use for prevention and treatment of pancreatitis.
[Living epidermal and dermal substitutes for treatment of severely burned patients]. (1998)

Epidermal and dermal cells can be multiplied in vitro using different techniques. Under particular conditions, the structure and the function of the original tissues are partly recreated. Autologous epidermal substitutes for wound coverage in deep burns are prepared in less than three weeks. Bilayered skin equivalents containing a dermal component are obtained by growing epidermal cells on a reconstructed dermal substitute or by juxtaposing stratified cultures of keratinocytes and fibroblasts. New technologies are required to optimise the nutrition of three-dimensional cultures of skin cells, which should lead to further progress in the area of skin reconstruction.
Lipid modification of the 17-kilodalton membrane immunogen of Treponema pallidum determines macrophage activation as well as amphiphilicity (1993)

A murine monoclonal antibody specific for a 17-kDa major membrane immunogen of Treponema pallidum was used to select recombinant Escherichia coli clones expressing the molecule from a T. pallidum genomic library. Sequence analysis of the structural gene for the immunogen (designated tpp17) revealed a 468-bp open reading frame encoding a polypeptide of 156 amino acids with a calculated molecular mass of 16,441 Da. The deduced amino acid sequence included a putative leader peptide terminated by a consensus tetrapeptide for the modification and processing of prokaryotic lipoproteins. Immunoprecipitation of the cloned immunogen radiolabeled with [3H]palmitate confirmed that it was a lipoprotein. The amino acid sequence also predicted that the mature protein contains four cysteine residues in addition to the lipid-modified cysteine of the N terminus. The existence of disulfide-bonded multimeric forms of the native immunogen was demonstrated by immunoblotting T. pallidum solubilized in the presence and absence of 2-mercaptoethanol. Triton X-114 phase partitioning of a nonlipidated form of the 17-kDa immunogen cleaved from a glutathione S-transferase fusion protein demonstrated that lipid modification is responsible for the immunogen's hydrophobic character. The same nonlipidated form of the immunogen also was used to demonstrate that lipid modification is essential for the molecule's ability to stimulate production of tumor necrosis factor alpha by murine macrophages. We conclude that covalently attached fatty acids not only anchor T. pallidum lipoproteins to spirochetal membranes but also confer upon these molecules the ability to activate immune effector cells.
Pulse treatment of human vascular endothelial cells with high doses of tumor necrosis factor and interferon‐gamma results in simultaneous synergistic and reversible effects on proliferation and morphology (1998)

Regional administration of high doses of tumor necrosis factor (TNF), interferon gamma (IFNγ) and melphalan to patients with advanced cancers of the limbs, results in rapid and specific tumor necrosis, while the normal adjacent tissues remain unaffected. The tumor vasculature is selectively destroyed by this treatment, and neovascular endothelial cells appear to be an early and specific target of TNF and IFNγ. To further understand some of the cellular events underlying these in vivo effects, we have investigated the response of human macro- and microvascular endothelial cells in vitro, after exposure to high doses of TNF and IFNγ (up to 40 × 103 U/ml each). TNF and IFNγ synergistically inhibited endothelial-cell proliferation by up to 80% after 72 hr of treatment. Achievement of synergy required the simultaneous presence of both cytokines. A cytokine pulse as short as 30 min was sufficient to induce maximal growth inhibition measured after 48 hr. Both cytokines also induced progressive and dose-dependent elongation of the endothelial-cell morphology. The effects on endothelial-cell proliferation and morphology were reversible upon removal of the cytokines. Moreover, replating of treated cells onto a fresh substrate immediately resulted in re-acquisition of their normal shape. In contrast to the effect on cell proliferation, there was little or no effect on the rate of endothelial-cell apoptosis. The presented data extend reports on the effects of TNF and IFNγ on human endothelial cells in vitro, and suggest that the in vivo disruption of the tumor vasculature caused by high doses of TNF and IFNγ is not due to a direct cytotoxic effect on endothelial cells but occurs through an indirect mechanism. Int. J. Cancer 77:592–599, 1998. © 1998 Wiley-Liss, Inc.
Integrating innate and adaptive immunity in the whole animal (1999)

The mammalian defense system can respond to a variety of threats, but this capability is not just a simple alarm system for triggering antigen-presenting cells and initiating cellular immunity. Instead, the body is an integrated system in which nearly every cell type can relay the alarm through the production of chemokines, which recruit specific inflammatory cells to the target tissues. This chemokine production is carefully regulated at several levels so that the kinetics and character of local tissue inflammation is tailored to the specific threat. First, the production of nuclear factor-kappa B-regulated chemokines can be modulated in non-bone marrow-derived cells through transcriptional repression mediated by RelB. RelB is also implicated in the differentiation of lymphoid dendritic cells, suggesting that this gene regulates the transition from acute inflammation to adaptive immunity. Second, tissue parenchymal cells, in their capacity as sentinel cells, are able to produce different patterns of chemokines in response to different alarm stimuli. Third, cells from different tissues also show distinct potentials for chemokine responses so that the non-specific damage from inflammation might be avoided in some cases. Finally, the differentiation of T-cell effectors allows for further regulation of local inflammation as their cytokines can also affect chemokine production. This integration of innate and adaptive immunity allows for both rapid responses and dynamic regulation of inflammation in vivo.
Differences in MHC class I self peptide repertoires among HLA-A2 subtypes (1995)

To investigate how single amino acid substitutions in MHC class I molecules affect differences in peptide repertoires, we eluted and sequenced the naturally processed peptides from three HLA-A2 subtypes (HLA-A*0204, -A*0206, and -A*0207) that differ by a single amino acid residue substitution each with HLA-A*0201 at the floor of the binding groove. Allele-specific peptide motifs for each HLA-A2 subtype substantially differed from that of HLA-A*0201 in the dominant anchor residues. The relative signal intensities for 18 self peptides, determined by mass spectrometry, precisely reflected these peptide motifs. Some overlapping peptides were isolated from both HLA-A*0201 and a single HLA-A2 variant, but no peptide was ubiquitously found across all variants. To rationalize the differences in peptide motifs, possible conformations of each allele were computer modeled by energy minimization calculations based on the reported crystal structure of HLA-A*0201. According to our models, the differences in peptide motifs could be explained by substituted-residue-driven conformational changes for each MHC-peptide complex. These results demonstrate the fine differences between HLA-A2 subtype self peptide repertoires and contribute to the prediction of antigenic peptides.
Systemic Delivery of shRNA by AAV9 Provides Highly Efficient Knockdown of Ubiquitously Expressed GFP in Mouse Heart, but Not Liver (2013)

AAV9 is a powerful gene delivery vehicle capable of providing long-term gene expression in a variety of cell types, particularly cardiomyocytes. The use of AAV-delivery for RNA interference is an intense area of research, but a comprehensive analysis of knockdown in cardiac and liver tissues after systemic delivery of AAV9 has yet to be reported. We sought to address this question by using AAV9 to deliver a short-hairpin RNA targeting the enhanced green fluorescent protein (GFP) in transgenic mice that constitutively overexpress GFP in all tissues. The expression cassette was initially tested in vitro and we demonstrated a 61% reduction in mRNA and a 90% reduction in GFP protein in dual-transfected 293 cells. Next, the expression cassette was packaged as single-stranded genomes in AAV9 capsids to test cardiac GFP knockdown with several doses ranging from 1.8×10(10) to 1.8×10(11) viral genomes per mouse and a dose-dependent response was obtained. We then analyzed GFP expression in both heart and liver after delivery of 4.4×10(11) viral genomes per mouse. We found that while cardiac knockdown was highly efficient, with a 77% reduction in GFP mRNA and a 71% reduction in protein versus control-treated mice, there was no change in liver expression. This was despite a 4.5-fold greater number of viral genomes in the liver than in the heart. This study demonstrates that single-stranded AAV9 vectors expressing shRNA can be used to achieve highly efficient cardiac-selective knockdown of GFP expression that is sustained for at least 7 weeks after the systemic injection of 8 day old mice, with no change in liver expression and no evidence of liver damage despite high viral genome presence in the liver.
Isoflavone concentrations in the leaves of the species of the genus Trifolium , section Calycomorphum (1971)

Seventy-six lines of various clovers, representing all extant species of the section Calycomorphum, were assayed at the commencement of flowering stage for their concentrations of the oestrogenic isoflavones formononetin, genistein, and biochanin A. All species tested contained substantial quantities of isoflavone, a characteristic rarely found outside this section. Although most species showed considerable variation in concentrations of the different isoflavones, there does appear to be a characteristic pattern for some of them, and in most of the species there was at least one line with an acceptably low formononetin concentration. T. batmanicum lines generally were high in genistein and low in biochanin A, a characteristic shared with T. subterraneum subsp. brachycalycinurn. This supports other evidence that T. batmanicum is the ancestral species of T. subterraneum, and suggests that T. subterraneum subsp. brachycalycinum may have been the earliest form of subterranean clover.
Proteins of the membrane skeleton in rat sertoli cells (1986)

Analogues of the alpha, beta and gamma subunits of human spectrin and erythroid protein 4.1 have been detected in rat Sertoli cell primary cultures. Immunofluorescence of permeabilized cells showed that erythroid type spectrin, protein 4.1 and actin co-distribute within the cells as filamentous structures. Fodrin-like molecules were distributed in a diffuse manner, mostly associated with the plasma membrane. Immunoprecipitation and immunoblotting experiments indicated that the polypeptides present in rat Sertoli cells are immunologically related and display molecular weights similar to their analogues in the human erythroid and non-erythroid membrane skeleton.
Molecular and Quantitative Analysis of Helper T Cell-Replacing Factors on the Induction of Antigen-Sensitive B and T Lymphocytes (1979)

Abstract Murine spleen cells activated by the T cell mitogen concanavalin A (Con A) secrete factors that exhibit biologic activity on both bone-marrow (B) and thymus-derived (T) lymphocytes. In the presence of heterologous erythrocyte antigens, these factors stimulate antibody synthesis in T cell-depleted spleen cultures. In the presence of Con A, these factors stimulate mitogenic responses in thymocyte cultures where the cell density is too low to support mitogenic responses to Con A alone. Both culture systems have been developed as quantitative assays for the activities of the Con A factors. Purification of the biologic activities by salt precipitation, gel filtration, ion-exchange chromatography, and isoelectric focusing (IEF) establish that the molecules responsible for effects on B and T lymphocytes in these assay systems are identical. The quantitative assays performed reveal that these factors are active in each culture system at concentrations below 10-9 M. The IEF-purified factors also stimulate the specific generation of cytotoxic lymphocytes to allogeneic tumor cells in culture. These experiments reveal a requirement for helper T cells in the induction of antibody synthesis in B lymphocytes, mitogenic responses to Con A in T lymphocytes, and cytotoxic T cell precursors to effector cells. Each assay system may be a measure of the induction of antigen-sensitive lymphocytes, suggesting that B and T lymphocytes respond to similar, if not identical, helper T cell activity.
Nanotechnology Foresight: How Can We Explore Employment and Skills Implications? (2010)

Policymakers responsible for improving the skill base needed for future economic development must assess the implications of radical technological change in the future. The example selected here is in nanoscience and nanotechnology. The objective of this paper is to demonstrate the importance of using more than one scenario of long term development when assessing such a complex issue as technology development and the demand for skills. Scenario forecasting is appropriately based on assessing plausible alternatives combined with horizon-scanning and determination of “weak signals”. This procedure will provide early warning about how far the key elements of various scenarios become manifest and those with maximum influence on emerging trends. This procedural approach for forecasting future skills needs in a particular technology is to estimate short-term and medium-term prospects for its development from concrete scenarios. Nanotechnology, the paper shows, due to its relative infancy, its composition of numerous lines of knowledge development, and the many contested claims about the scope and speed of its evolution, poses particular challenges. The paper assesses how confident we can be about skill and employment projections related to nanoindustries – and industrial applications of nanotechnology, i.e. in medicine; chemistry and the environment; energy; information and communication; heavy industry; and consumer goods. It proposes ways in which to provide more policy-relevant intelligence. Future skills forecasts, it argues, can be shaped using familiar ideas from innovation research - about technological paradigms and trajectories, and about diffusion and industry life-cycles. Requirements for skills will vary depending on how revolutionary nanotechnologies will be. Will innovation essentially extend existing nanoengineering techniques or embody more radical visions of molecular engineering and “bottom up” nanotechnologies? Responses to these questions can be derived from expert-based alternative scenarios.
A Cellular Trojan Horse for Delivery of Therapeutic Nanoparticles into Tumors (2007)

Destruction of hypoxic regions within tumors, virtually inaccessible to cancer therapies, may well prevent malignant progression. The tumor's recruitment of monocytes into these regions may be exploited for nanoparticle-based delivery. Monocytes containing therapeutic nanoparticles could serve as "Trojan Horses" for nanoparticle transport into these tumor regions. Here we report the demonstration of several key steps toward this therapeutic strategy: phagocytosis of Au nanoshells, and photoinduced cell death of monocytes/macrophages as isolates and within tumor spheroids.
Abstract LB-330: Therapeutic activity of a combination of immunostimulatory monoclonal antibodies (anti-B7-H1, CD137 and OX40) on a c-myc-driven spontaneous transgenic model of hepatocellular carcinoma. (2013)

Abstract Several immunostimulatory monoclonal antibodies (ISmAbs) that derepress and unleash antitumor immune responses are showing efficacy in cancer clinical trials. MAbs anti-B7-H1 (PD-L1) block a critical inhibitory pathway for T cells, while antibodies anti-CD137 and OX40 provide intense T cell costimulation. Documenting efficacy of immunotherapies on spontaneous tumors arising in oncogene transgenic mice is considered more predictive than experiments on transplanted tumors. A combination of these ISmAbs has been tested on a transgenic mouse model of spontaneous primary liver cancer in which c-myc drives transformation and the tumor cells express ovalbumin as a surrogate transgenic antigen. The induced tumor lymphocyte infiltrates and immune mechanisms of action were studied. The triple combination of mAbs clearly extended survival of mice bearing hepatocellular carcinomas (HCC) and synergized with adoptive T cell therapy with activated TCR-transgenic T cells that recognize OVA. Mice undergoing therapy showed a clear increase in the tumor tissue infiltration by activated and blastic CD8 T lymphocytes expressing the ISmAb-targeted receptors. The triple combination of ISmAbs did not result in enhanced OVA-specific CTL activity but other antigens in cell lines derived from such HCC were recognized by the elicited tumor infiltrating T lymphocytes. Indeed adoptive transfer of OT-1 cells to tumor bearing mice resulted in their tolerization, unless the triple mAb therapy was instigated. Our results emphasize the role of combinational immunotherapy approaches including ISmAbs to impact on agressive and highly T cell-tolerizing hepatocellular carcinomas. Citation Format: Aizea Morales-Kastresana, Miguel F. Sanmamed, Inmaculada Rodriguez, Asis Palazon, Ivan Martinez-Forero, Sara Labiano, Sandra Hervas-Stubbs, Bruno Sangro, Carmen Ochoa, Arantza Azpilikueta, Elixabet Bolaños, Ines Gütgemann, Ignacio Melero. Therapeutic activity of a combination of immunostimulatory monoclonal antibodies (anti-B7-H1, CD137 and OX40) on a c-myc-driven spontaneous transgenic model of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-330. doi:10.1158/1538-7445.AM2013-LB-330
Seeds: Physiology of Development and Germination. (1995)

Seeds: Germination, Structure, and Composition. Seed Development and Maturation. Development-Regulation and Maturation. Cellular Events during Germination and Seedling Growth. Dormancy and the Control of Germination. Some Ecophysiological Aspects of Germination. Mobilization of Stored Seed Reserves. Control of the Mobilization of Stored Reserves. Seeds and Germination: Some Agricultural and Industrial Aspects. Index.