gebhart/patrepeval huggingface dataset:
Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response (2004)

The skin is an important immunological organ with an outer protective layer, the stratum corneum forming a barrier between the skin-associated lymphoid tissue and the environment. We show that gently removing the stratum corneum with adhesive tape permits potent epicutaneous immunization to protein antigens. IL-4 secretion by T cells from draining lymph nodes and high levels of specific IgE and IgG1 with no IgG2a showed that the immune responses induced following epicutaneous antigen exposure are strongly Th2 biased. Similar responses were obtained with different antigens and mouse strains. In contrast, subcutaneous immunization with antigen delivery into the dermis was less potent and gave predominantly Th1 responses. Removal of the stratum corneum increased expression of MHC class II, CD86, CD40, CD54 and CD11c on Langerhans cells, but did not cause them to migrate. Rapid migration from epidermis to draining lymph node was obtained, however, by exposure to antigen after removal of the stratum corneum, suggesting that maturation and migration of Langerhans cells are independently regulated events. These results suggest that antigen presentation by Langerhans cells gives predominantly Th2 responses. This may provide an explanation for allergic sensitization to some antigens. It may also be a useful non-invasive, non-adjuvant-dependent method of vaccination.
Manufacturing a green service: engaging the TRIZ model of innovation (2001)

Following a number of years in incremental improvements in eco-design, it is now frequently hypothesised that step changes in environmental impact are required via the generation of innovative new products or a transition to services. The paper begins by addressing the definition of needs and functionalities as important precursors to product creation. The generation of innovative environmentally friendly solutions via TRIZ models, based on the theory of inventive problem solving by Altshuller, are assessed for their ability to systematise this approach. The principles of TRIZ, derived from the study of patents and observed trends in the evolution of technical systems, will also be explored in terms of its applicability to provide an eco-centered service solution. Four product service combinations have been outlined as a basis to establish the operational characteristics of infrastructural based services. These concepts are further illustrated via service centered scenarios including those from telecommunications, car sharing and launderette facilities.
Chemokine C Receptor 7 Expression and Protection of Circulating CD8+ T Lymphocytes from Apoptosis (2005)

Chemokine C receptor 7 (CCR7) expression is important for lymphocyte homing to tissues. We hypothesized that CCR7 also plays a role in CD8(+) T-cell protection from apoptosis. Its expression was determined on circulating T cells in patients with cancer and related to that of molecules responsible for lymphocyte susceptibility/resistance to apoptosis. Peripheral blood mononuclear cells were obtained from 36 patients with squamous cell carcinoma of the head and neck and 16 normal controls. Multicolor flow cytometry was used to evaluate CCR7, Fas, Bax, and Bcl-2 expression in CD8(+) T cells. Annexin V binding to CD8(+)CCR7(+) and CD8(+)CCR7(-) T-cell subsets was compared. Fewer CD8(+)CCR7(+) T cells bound Annexin V than CD8(+)CCR7(-) T cells in normal control and patients (P < 0.0001). CCR7 expression correlated with higher Bcl-2 but lower Bax and Fas expression levels in CD8(+) T cells in both normal control and patients (P < 0.0001). In patients, the CD8(+)CCR7(+) subset was reduced relative to normal control (P = 0.008) and replaced with an excess of apoptosis-sensitive CD8(+)CCR7(-) T cells. To study CCR7 signaling, CD8(+) T cells were stimulated with CCR7 ligands, chemokine C ligands 19 or 21. Ligand binding to CCR7 resulted in phosphorylation of Akt and increased Bcl-2 expression in CD8(+)CCR7(+) T cells, suggesting that CCR7 protects effector T cells from apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. The absence of CCR7 expression on the majority of CD8(+) T cells in the peripheral circulation of patients with squamous cell carcinoma of the head and neck contributes to apoptosis and a rapid turnover of these effector cells.
Neutralization of heparin activity by neutrophil lactoferrin (1995)

Lactoferrin is a prominent component of neutrophil secondary granules, and its blood concentration is increased in certain inflammatory diseases. In contrast to the well-described biochemical characterization of lactoferrin as an iron-binding protein, its physiologic role in the regulation of inflammation and other host defense mechanisms is unclear. In this report, we provide evidence that lactoferrin has a potent heparin-neutralizing activity during thrombin inhibition by the serine proteinase inhibitors (serpins) antithrombin and heparin co-factor II. Activated neutrophil supernatant, which contains lactoferrin and other heparin-binding proteins, could neutralize the heparin-dependent antithrombin-thrombin inhibition reaction. The addition of lactoferrin to plasma corrected the heparin-induced prolongation of blood plasma coagulation as measured by the activated partial thromboplastin time (aPTT). Treatment of whole blood with specific inflammatory mediators, fMLP, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) increased the concentration of both plasma lactoferrin and platelet factor 4 while inhibiting the blood anticoagulant activity of heparin as measured by the aPTT. These results suggest that the prothrombotic sequelae of some inflammatory processes may be partly due to various agonists that release neutrophil lactoferrin, which can then neutralize glycosaminoglycan-dependent serpin-thrombin inhibition reactions.
Dystrophic neurites express C9orf72 in Alzheimer's disease brains (2012)

These results suggest a general role of C9orf72 in the process of neurodegeneration in a range of human neurodegenerative diseases.
Role of Genes That Modulate Host Immune Responses in the Immunogenicity and Pathogenicity of Vaccinia Virus (2005)

Poxvirus vaccine vectors, although capable of eliciting potent immune responses, pose serious health risks in immunosuppressed individuals. We therefore constructed five novel recombinant vaccinia virus vectors which contained overlapping deletions of coding regions for the B5R, B8R, B12R, B13R, B14R, B16R, B18R, and B19R immunomodulatory gene products and assessed them for both immunogenicity and pathogenicity. All five of these novel vectors elicited both cellular and humoral immunity to the inserted HIV-BH10 env comparable to that induced by the parental Wyeth strain vaccinia virus. However, deletion of these immunomodulatory genes did not increase the immunogenicity of these vectors compared with the parental vaccinia virus. Furthermore, four of these vectors were slightly less virulent and one was slightly more virulent than the Wyeth strain virus in neonatal mice. Attenuated poxviruses have potential use as safer alternatives to current replication-competent vaccinia virus. Improved vaccinia virus vectors can be generated by deleting additional genes to achieve a more significant viral attenuation.
Hidden Markov Models and their Applications in Biological Sequence Analysis (2009)

Hidden Markov models (HMMs) have been extensively used in biological sequence analysis. In this paper, we give a tutorial review of HMMs and their applications in a variety of problems in molecular biology. We especially focus on three types of HMMs: the profile-HMMs, pair-HMMs, and context-sensitive HMMs. We show how these HMMs can be used to solve various sequence analysis problems, such as pairwise and multiple sequence alignments, gene annotation, classification, similarity search, and many others.
Long-Term Therapy with Deferiprone (1996)

Data from several trials have provided direct and supportive evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has been shown to induce sustained decreases in body iron to concentrations associated with survival free from the complications of iron overload in deferoxamine (DFO)-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation in patients willing and able to use DFO. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy and the United States, under corporate sponsorship (Apotex Research, Canada). The results of this study should determine the risk associated with the use of this agent, and may provide the data required for an FDA decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.
N-Methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism (2004)

MEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of the fibrosis pathway even without relief from mechanical stress.
cAMP-DEPENDENT PROTEIN KINASE: FRAMEWORK FOR A DIVERSE FAMILY OF REGULATORY ENZYMES (1990)

cAPK has provided many insights into the functioning of the diverse family of eukaryotic protein kinases. The fact that a particular amino acid in the catalytic core is conserved is an indication that the residue plays an important role; however, questions concerning function remain obscure. With the catalytic subunit, the assignment of amino acids that participate in catalysis has begun, and in many instances that function appears to be conserved in the other protein kinases. Although the regulatory subunit and the use of cAMP to release its inhibitor effects is unique to cAPK, the general mechanism of a small autoinhibitory region occupying the peptide binding site and thus preventing access of other substrates may be invoked frequently by other protein kinases. Coupling recombinant approaches with protein chemistry is allowing us to decipher at least some of the molecular events associated with cAMP-binding and holoenzyme activation. Although the next chapter in the history of cAPK will undoubtedly include three-dimensional structures, the chemical information remains as an essential complement for interpreting those structures and eventually understanding the molecular events associated with catalysis and activation.
Drug-resistance in human melanoma (2001)

Advanced malignant melanoma has a poor prognosis since chemotherapy is mostly ineffective due in part to the intrinsic and/or extrinsic resistance of melanoma cells to systemic treatment with anti-neoplastic agents. The reasons for the chemoresistant phenotype are unknown. The relevance of well-analyzed drug-resistance mechanisms, e.g., intracellular/extracellular transport and induction of certain enzyme systems, is reviewed. Most anti-cancer drugs kill susceptible cells through induction of apoptosis. Therefore, it appears that differences in the apoptotic pathways which lead to apoptotic deficiency may account for the ability of some tumor cells to resist drug therapy. Human melanomas, which are characteristically drug-resistant, are more likely to have altered apoptotic pathways and fewer pro-apoptotic molecules. Tumor cells with these characteristics are seldom sensitive to drugs. The complexity of the molecular variants involved in signal transduction along apoptotic pathways suggests that the cell may have a variety of possibilities for regulating apoptosis and generating apoptotic deficiency. Thus, apoptosis and apoptotic deficiency should be analyzed to better clarify the mechanisms of melanoma resistance.
Comparative Analyses of the Proteins and Antigens of Five Herpesviruses (1977)

Summary The proteins of five herpesviruses — herpes simplex types 1 and 2 (HSV-1 and HSV-2), bovine mammillitis virus (BMV), pseudorabies virus (PRV) and equine abortion virus (EAV) — have been compared by polyacrylamide gel electrophoresis of purified virus and by antigenic analysis using virus neutralization and agar-gel immunodiffusion tests. Although there were general similarities in the number, size range and overall complexity of polypeptides separated by polyacrylamide gel electrophoresis from purified particles of the five viruses, no single component of identical mobility was present in all viruses. The major capsid polypeptide from each of the five viruses comprised about 10% of virion protein mass but had distinctive mol. wt. of 158000 to 160000 (HSV-2 and BMV), 145000 (EAV) and 140000 (PRV) relative to 155000 for HSV-1. Despite differences of apparent mol. wt. there was a one-for-one correspondence for the majority of structural polypeptides of HSV-1 and HSV-2 and many polypeptides of BMV were recognizably analogous to those of HSV-1 and HSV-2. In contrast the polypeptides of PRV and, more particularly, EAV differed markedly from those of all the other viruses. The antigenic analysis complemented these results; HSV-1, HSV-2 and BMV all cross-neutralized, whereas PRV and EAV were only neutralized by homologous antisera. Agar gel immunodiffusion tests with extracts of infected cells demonstrated at least one antigen common to all five viruses and showed BMV to be more closely related to HSV-1 and HSV-2 than were PRV or EAV although less closely related than HSV-1 to HSV-2. PRV and EAV share more antigens with each other than with the other viruses.
Automated high throughput RT-PCR (1996)

AMGEN's genome project is designed to discover and assess genes that may be of therapeutic value. As an early screen, novel genes of potential importance are investigated by analysis of their in vivo expression pattern using reverse transcriptase-polymerase chain reaction (RT-PCR). We describe the automation pathway taken to provide high throughput screening of mRNA from human, mouse, and rat species. High throughput was achieved using the Beckman Biomek™ 2000 robot, large-capacity gel electrophoresis trays, an imaging station and custom image analysis software written in Visual Basics™ (VB). © 1996 John Wiley & Sons, Inc.
Evolution of MHC class I genes in higher primates (1996)

The classical major histocompatibility complex (MHC) class I genes are conserved in higher primates. Motifs common to human, chimpanzee and gorilla alleles indicate that class I alleles diverged from ancestral sequences that existed before separation of these species. Analysis of native human populations such as Australian Aborigines and Amerindians shows that HLA-B is characterized by rapid generation of new alleles. HLA-A and -C appear to be evolving more slowly. Comparison of alleles for orthologous class I genes in humans and other primates confirms that similar mechanisms contribute to the generation of new alleles in these species.
Vascular Endothelial Growth Factor Activates PI3K/Akt/Forkhead Signaling in Endothelial Cells (2003)

These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway.
Severe Vasospasm Mimics Hypotension After High-Dose Intrauterine Vasopressin (2011)

Intramyometrial vasopressin injection reduces bleeding during myomectomy. Subsequent loss of peripheral pulses and nonmeasurable arterial blood pressure have been attributed to cardiovascular collapse or hypotension. When interpreted as global hypotension, treatment with vasopressors or according to Advanced Cardiac Life Support resuscitation protocols has been associated with cardiac complications. We describe a patient who developed loss of peripheral pulses and nonmeasurable blood pressure by noninvasive means after myometrial administration of 60 U vasopressin, with documented severe peripheral arterial vasospasm and elevated proximal blood pressure. We discuss the pathophysiology and emphasize the danger of misinterpreting pulselessness as global hypotension instead of vasospasm in this setting.
The Development of Amplifiable and Evolvable Unnatural Molecules (2003)

Abstract : We have developed a new approach to (i) controlling chemical reactivity and (ii) discovering functional synthetic molecules that is based on biosynthesis and molecular evolution in nature. Our approach uses DNA-templated organic synthesis as a surprisingly general means of translating an amplifiable information carrier into a synthetic structure. We have integrated insights into DNA-templated synthesis with synthetic organic chemistry and molecular biology to develop (a) new modes of controlling reactivity that are not possible using existing synthetic methods, (b) multistep small molecule syntheses programmed by DNA sequences, (c) a model for stereoselectivity in DNA-templated synthesis, (d) DNA-templated library synthesis of complex small molecules, and (e) selections for DNA-linked synthetic molecules with protein binding affinity and specificity. These studies have enabled synthetic molecules to participate in powerful processes including translation, selection, and amplification previously available only to biological macromolecules. Our studies represent an entirely new approach to synthesis and discovery that may lead to new synthetic small molecules and polymers with desired properties, as well as to the discovery of new chemical reactions.
Hydromorphone-naloxone combinations in opioid-dependent humans under naloxone novel-response discrimination procedure. (1998)

Naloxone-hydromorphone combinations were tested in participants trained to discriminate naloxone from placebo under a novel-response drug discrimination procedure while maintained on methadone. Naloxone alone produced dose-related increases in naloxone-appropriate responding, little or no "novel"-appropriate responding, and increases in opioid antagonist adjective ratings (n = 5). Hydromorphone alone produced dose-related increases in novel-appropriate responding, little or no naloxone-appropriate responding, and increases in opioid agonist adjective ratings (n = 6). When combined with naloxone, hydromorphone produced dose-related decreases in naloxone-appropriate responding and antagonist adjective ratings (n = 6). These findings are consistent with nonhuman data and suggest that this procedure may be useful as a human laboratory model of opioid withdrawal.
The bromodomain: a conserved sequence found in human,Drosophilaand yeast proteins (1992)

Identification of conserved domains or motifs in proteins may aid in the localization and analysis of important structural and functional regions. We report here a protein sequence motif, called the bromodomain (1), that has been found in six genes from humans (CCG1 and RING3), Drosophila (fsh and brm), and yeast (SPT7 and SNF2). The fsh and brm genes are required maternally for proper expression of certain homeotic genes (1,2). The SPT7 and SNF2 genes of Saccharomyces cerevisiae encode transcriptional activators (3,4). The SNF2 and brm proteins have extensive sequence homology (1). It is not clear whether the two human genes are involved in processes. CCG1 is a DNA-binding protein that complements temperature sensitive mutations that cause cell cycle arrest in Gl (5). The RING3 gene is a newly identified human gene of unknown function, mapping to the class II region of the human major histocompatibility locus, that has substantial homology to the fsh gene (6). Each of these proteins has one or two copies of the 61 —63 amino acid bromodomain (Figure 1). The sequence identity is highest (~ 80%) between the corresponding fsh and RING3 repeats. More typically, any two motifs show 25-40% identity, with 50-60% identity between two repeats within the same protein. There are seven invariant residues, four of which are aromatic amino acids, and numerous conservative substitutions. The location of the motif(s) within the individual proteins is variable, and two motifs may be present in tandem or separated by sequences unrelated to the motif. Secondary structure prediction methods were applied to the bromodomain and revealed two strongly predicted amphipathic a helices followed by reverse turns. Four of the invariant residues are located within the turns, and the other three are located among four highly conserved proline residues at the N terminus. The functional significance of the bromodomain is unknown, and experiments with the two yeast proteins indicate that it may be dispensable in some cases (6; P.Tan and F.W., unpublished data). However, the widespread conservation of the bromodomain suggests that it is important for some aspects of protein function. We speculate that the hydrophobic surfaces of the helices and the invariant hydrophobic residues could serve as sites of intramolecular or intermolecular protein-protein interaction. Such interactions could influence the assembly or activity of multicomponent complexes involved in transcription activation or other cellular processes.
Adeno-Associated Virus-Mediated MicroRNA Delivery and Therapeutics (2015)

MicroRNAs (miRNAs) are 20 to 24 nt long, single-stranded RNAs that repress gene expression. Dysregulation of miRNA expression is associated with many human diseases. Modulating the level of endogenous miRNA alters gene profiling and can achieve therapeutic benefits. Here the authors review currently used methods of altering miRNA activity in vivo. They focus on the delivery of miRNAs and miRNA inhibitors using recombinant adeno-associated virus (rAAV). In general, rAAV-mediated miRNA inhibition or overexpression provides a simple, efficient, and informative way to study miRNA function in mammals. This method also provides the opportunity to explore potential miRNA therapeutics for many diseases.
Electrical stimulation of C2C12 myotubes induces contractions and represses thyroid-hormone-dependent transcription of the fast-type sarcoplasmic-reticulum Ca2+-ATPase gene (1997)

Chronic low-frequency contraction of skeletal muscle, either induced by a slow motor nerve or through direct electrical stimulation, generally induces expression of proteins associated with the slow phenotype, while repressing the corresponding fast isoforms. Contractions thereby counteract the primarily transcriptional effect of thyroid hormone (T3) which results in the selective induction and stimulation of expression of fast isoforms. We studied the regulation of expression of the fast-type sarcoplasmic-reticulum Ca2+-ATPase (SERCA1), a characteristic component of the fast phenotype. Previous work suggested that reduction of SERCA1 expression by contractile activity might result from interference with the T3-dependent transcriptional stimulation of the SERCA1 gene. The present study was set up to test this unexpected mode of action of contractile activity. We show that electrical stimulation of C2C12 mouse myotubes, which results in synchronous contractions at the imposed frequency, reduces basal but virtually abolishes T3-dependent SERCA1 expression. T3-dependent expression of a reporter gene driven by the SERCA1 promoter was similarly affected by electrical stimulation. This is the first demonstration that the counteracting effects on muscle gene expression of electrically induced contractions and T3 may interact at the transcriptional level.
Cleavage of Nuclear DNA into Oligonucleosomal Fragments during Cell Death Induced by Fungal Infection or by Abiotic Treatments (1996)

Douglas E. Ryerson, , Cleavage of Nuclear DNA into Oligonucleosomal Fragments during Cell Death Induced by Fungal Infection or by Abiotic Treatments, The Plant Cell, Vol. 8, No. 3 (Mar., 1996), pp. 393-402