gebhart/patrepeval huggingface dataset:
Development of preclinical diagnosis and preventive treatment of neurodegenerative diseases (2015)

Neurodegenerative diseases (NDD) are serious fatal neurological and mental diseases that resulted in disability and fethal outcome. Based on the advances of basic sciences over the last two decades, new knowledge on the risk factors for NDD and molecular mechanisms of the pathogenesis are obtained. It has been shown that the accelerated process of neuronal death which is the main cause of NDD development begins long before the appearance of clinical symptoms. The first symptoms appeared only after the death of most specific regulatory neurons and exhaustion of brain compensatory reserve. Only at that time, one can make the diagnosis and start traditional treatment of patients that accounts for the extremely low efficacy of the latter. Currently, complex preclinical diagnosis based on the identification of relatively specific clinical precursors and peripheral biomarkers has been developing. Development of preclinical diagnosis and preventive treatment is a strategic issue of modern neurology and psychiatry. The resolution of this issue allows to consider NDD as cured, but not fatal, diseases.
Review Th2 cytokines and asthma: an introduction (2001)

Asthma is a highly complex disease that is still poorly understood and whose cause remains unknown. One of the striking advances in the last decade has been the recognition that cytokines play a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. Indeed the increased and abnormal expression of cytokines in airway cells is one of the major targets of corticosteroid therapy, by far the most effective controller treatment for asthma currently available. Many cytokines and chemokines are involved in the pathophysiology of asthma [1,2]. While some of these cytokines, such as interleukin (IL)-1, tumour necrosis factor-α and IL-6, are involved in many inflammatory diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease, others are more specific
Sonar-based real-world mapping and navigation (1987)

A sonar-based mapping and navigation system developed for an autonomous mobile robot operating in unknown and unstructured environments is described. The system uses sonar range data to build a multileveled description of the robot's surroundings. Sonar readings are interpreted using probability profiles to determine empty and occupied areas. Range measurements from multiple points of view are integrated into a sensor-level sonar map, using a robust method that combines the sensor information in such a way as to cope with uncertainties and errors in the data. The resulting two-dimensional maps are used for path planning and navigation. From these sonar maps, multiple representations are developed for various kinds of problem-solving activities. Several dimensions of representation are defined: the abstraction axis, the geographical axis, and the resolution axis. The sonar mapping procedures have been implemented as part of an autonomous mobile robot navigation system called Dolphin. The major modules of this system are described and related to the various mapping representations used. Results from actual runs are presented, and further research is mentioned. The system is also situated within the wider context of developing an advanced software architecture for autonomous mobile robots.
Assessing serum cytokine profiles in breast cancer patients receiving a HER2/neu vaccine using Luminex® technology (2007)

We used the Luminex assay to compare serum cytokine profiles of breast cancer patients (BCa) to healthy controls, node-positive (NP) patients to node-negative (NN), and pre- and post-vaccination serum of BCa vaccinated with a HER2/neu E75 peptide vaccine. Sera from 36 pre- and post-vaccination BCa, (12 NP and 24 NN) and 13 healthy, female donors, were evaluated using Luminex technology. Levels of 22 cytokines consisting of interleukin (IL)-1alpha, -1beta, -2, -4, -5, -6, -7, -8, -10, -12, -13, -15, -17, IFN-gamma, G-CSF, GM-CSF, TNF-alpha, IP-10, MIP-1alpha, RANTES, eotaxin and monocyte chemotactic protein-1 (MCP-1) were assessed. Six of 22 cytokines showed significant differences between BCa and healthy controls. MCP-1, eotaxin, RANTES and GM-CSF levels were significantly elevated in BCa (P<0.009) and IL-1alpha and IL-4 levels were significantly decreased in BCa (P<0.015). Cytokine levels were generally elevated in NN patients compared to NP patients with the exception of eotaxin and IL-13, which were increased in NP patients. Three cytokines, IL-6, MIP-1alpha and G-CSF reached statistical significance (P<0.05). In 34 vaccinated BCa, MCP-1, eotaxin and IL-13 were significantly elevated post-vaccination with MCP-1 demonstrating the most significant response (median, 145.8-217.0 pg/ml, P=0.003). Using a multiplex assay we found significant differences in cytokine levels in sera of BCa compared to healthy controls, in NN compared to NP patients, and in vaccinated patients. Our results support an extended analysis of serum cytokine profiles for the potential development of predictive panels in diagnosis, staging and monitoring cancer vaccine trials.
Tandem AP-1-binding sites within the human beta-globin dominant control region function as an inducible enhancer in erythroid cells. (1990)

A powerful enhancer has been mapped to an 18-bp DNA segment located 11 kb 5' to the human epsilon-globin gene within the dominant control or locus-activating region. This enhancer is inducible in K562 human erythroleukemia cells, increasing linked gamma-globin promoter/luciferase gene expression to 170-fold over an enhancerless construct. The enhancer consists of tandem AP-1-binding sites, phased 10 bp apart, which are both required for full activity. DNA-protein binding assays with nuclear extracts from induced cells demonstrate a high molecular weight complex on the enhancer. The formation of this complex also requires both AP-1 sites and correlates with maximal enhancer activity. Induction of the enhancer may have a role in the increase in globin gene transcription that characterizes erythroid maturation. Enhancer activity appears to be mediated by the binding of a complex of proteins from the jun and fos families to tandem AP-1 consensus sequences.
Protein H, an Antiphagocytic Surface Protein inStreptococcus pyogenes (1999)

Surface-associated M protein is a major virulence factor in Streptococcus pyogenes which confers bacterial resistance to phagocytosis. However, many S. pyogenes strains also express additional structurally related so-called M-like proteins. The strain studied here is of the clinically important M1 serotype and expresses two structurally related surface proteins, the M1 protein and protein H. Mutants were generated that expressed only one or none of these proteins at the bacterial surface. For survival in human blood either protein H or M1 protein was sufficient, whereas the double mutant was rapidly killed. The protein-binding properties of protein H, M1 protein, and the mutants suggest that bacterial binding of immunoglobulin G and factor H or factor H-like protein 1, which are regulatory proteins in the complement system, contribute to the antiphagocytic property.
Improving the biodistribution of PSMA-targeting tracers with a highly negatively charged linker (2014)

Placement of multiple negative charges in the linker region of PSMA tracers significantly reduced the non-specific background binding without significant reduction of binding affinity. This increased tumor/background contrast in positron emission tomography promises to provide more sensitive tumor detection while decreasing the overall radiation exposure to patients.
Delineation of an enhancerlike positive regulatory element in the interleukin-2 receptor alpha-chain gene. (1990)

We have delineated a positive regulatory element in the interleukin-2 receptor alpha-chain gene (IL-2R alpha) between positions -299 and -243 that can potently activate a heterologous (herpesvirus thymidine kinase [tk]) promoter in phorbol myristate acetate (PMA)-induced Jurkat T cells and is functional when cloned in either orientation. This enhancerlike element contains a site (-268/-257) that can bind NF-kappa B; however, unlike the immunoglobulin kappa gene kappa B enhancer element, the IL-2R alpha kappa B-like site alone can only weakly activate a heterologous promoter. Adjacent 5' and 3' sequences also weakly activate the tk-CAT vector, but constructs combining the IL-2R alpha kappa B-like site plus adjacent 5' and 3' sequences potently activate gene expression. This combination of regions is essential for potent PMA-induced transcription from the tk promoter. Experiments using constructs in which IL-2R alpha upstream sequences are sequentially deleted suggested that there is a region 5' of position -299 which can suppress IL-2R alpha promoter and/or enhancer activity. Thus, it is possible that both positive and negative elements may be important in the regulation of IL-2R alpha gene transcription.
Soft Micro- and Nanorobotics (2018)

Micro- and nanorobots can perform a number of tasks at small scales, such as minimally invasive diagnostics, targeted drug delivery, and localized surgery. During the past decade, the field has been transformed in many ways, one of the most significant being a transition from hard and rigid micro- and nanostructures to soft and flexible architectures. Inspired by the dynamics of flexible microorganisms, researchers have focused on developing miniaturized soft components such as actuators, sensors, hinges, joints, and reservoirs to create soft micro- and nanoswimmers. The use of organic structures such as polymers and supramolecular ensembles as functional components has brought more complex features to these devices, such as advanced locomotion strategies and stimulus-triggered shape transformations, as well as other capabilities. A variety of microorganisms and contractile mammalian cells have also been utilized as microengines and integrated with functional synthetic materials, producing bending or deformation of the functional materials to initiate motion. In this review, we consider several types of soft micro- and nanorobots in terms of their architecture and design, and we describe their locomotion mechanisms and applications.
High-Sensitivity C-Reactive Protein Is the Most Effective Prognostic Measurement of Acute Coronary Events (2002)

Inflammation plays a major role in the pathogenesis of arterial atherosclerosis. The stages of atheroma development from early recruitment of leukocytes and fatty streaks to the unstable plaque and finally rupture are mediated by the inflammatory process. Several markers of vascular wall inflammation that can predict future risk of plaque rupture have been identified. However, these lack the specificity of CRP. Numerous large-scale prospective studies established hs-CRP as a strong biochemical marker for the prediction of future first or recurrent coronary events. A Food and Drug Administration-approved method for measuring hs-CRP is currently available.
Differing characteristics of human papillomavirus rna-positive and rna-negative anal carcinomas (1991)

Anal carcinomas were tested for the presence of human papillomavirus (HPV) RNA transcripts by in situ hybridization using 125I-labeled RNA probes. The HPV transcripts were detected in 73.2% of 41 nonglandular anal carcinomas but in none of six anal or 11 rectal adenocarcinomas. In anal nonglandular carcinomas, no difference in the percentage of tumors that were HPV RNA positive was observed between tumors classed as basaloid carcinomas or squamous cell carcinomas. Patients with HPV RNA-negative tumors were significantly older (9.2 years) than those with HPV RNA-positive tumors. Anal intraepithelial neoplasia Grade 3 in the surrounding epithelium was seen in 14 of 25 assessable HPV RNA-positive tumors and in none of nine assessable HPV RNA-negative tumors. Anal tumors may include two separate clinical and biologic groups distinguished by their dependence, or lack of dependence, on HPV RNA expression for maintenance of the neoplastic state.
DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard, 1,3-bis(2-chloroethyl)-1-nitrosourea, and other nitrosoureas. (1977)

Summary The technique of alkaline elution was applied to studies of DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard (HN2) and nitrosoureas. DNA cross-linking was measured in terms of the reduction in the effect of X-ray on the kinetics of DNA elution and was observed in cells treated with HN2 and three chloroethylnitrosoureas: 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and chlorozotocin. Evidence was obtained that cross-links are of two types, DNA interstrand cross-links and DNA-protein cross-links, distinguishable on the basis of sensitivity to proteinase-K. HN2 and 1,3-bis(2-chloroethyl)-1-nitrosourea each produced both types of cross-links. In most of the studies reported, the combined effect of the two types of cross-links was measured. With HN2, cross-linking was observed at subtoxic doses, and the cross-links were fully repaired by 24 hr. At higher HN2 doses, which reduced colony-forming ability, cross-links were not fully repaired by 24 hr. Cross-linking by chloroethylnitrosoureas differed from that by HN2 in that the effect increased for about 6 hr after removal of the drug (treatment times were 0.5 hr for HN2 and 1 hr for nitrosoureas). The chloroethylnitrosoureas, but not HN2, also produce DNA single-strand breaks or lesions, which were converted to single-strand breaks in alkali. Methylnitrosourea produced little or no cross-linking for at least 6 hr after treatment but did produce extensive DNA damage of the alkali-labile type; this damage was repairable and had little efect on colony-forming ability. Fluoroethylnitrosourea, the fluoro analog of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, was much less effective than 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in producing cross-links. The findings on the kinetics and structure dependence of cross-linking are similar to the previously reported findings on interstrand cross-linking of purified DNA and support a two-step reaction mechanism involving a chloroethylated intermediate.
Preparation, Properties, Reactions, and Adenosine Receptor Affinities of Sulfophenylxanthine Nitrophenyl Esters:  Toward the Development of Sulfonic Acid Prodrugs with Peroral Bioavailability (2004)

Many currently known antagonists for P2 purinergic receptors are anionic molecules bearing one or several phenylsulfonate groups. Among the P1 (adenosine) receptor antagonists, the xanthine phenylsulfonates are a potent class of compounds. Due to their high acidity, phenylsulfonates are negatively charged at physiologic pH values and do not easily penetrate cell membranes. The present study was aimed at developing lipophilic, perorally bioavailable prodrugs of sulfonates by converting them into chemically stable nitrophenyl esters. Initial stability tests at different pH values using nitrophenyl tosylates as model compounds showed that m-nitrophenyl esters were stable over a wide pH range, while the ortho and para isomers were less stable under strongly acidic or basic conditions. A series of m- and p-nitrophenyl esters of p-sulfophenylxanthine derivatives were synthesized as model compounds. The target xanthine derivatives were obtained in high yields by condensation of the appropriate 5,6-diaminouracils with 4-(nitrophenoxysulfonyl)benzoic acids in the presence of a carbodiimide, followed by ring closure with polyphosphoric acid trimethylsilyl ester. The chemical and enzymatic stability of the m-nitrophenyl esters was investigated in vitro by means of capillary electrophoresis. High stability in aqueous solution, in artificial gastric acid, and in serum was observed. However, compound 5d, used as a prototypic xanthine m-nitrophenylsulfonate, was hydrolyzed by rat liver homogenate indicating an enzymatic pathway of hydrolysis. Thus, nitrophenyl esters of sulfonic acids have a potential as peroral prodrugs of drugs bearing a sulfonate group. The nitrophenyl esters of sulfophenylxanthines were additionally investigated for their adenosine receptor affinities. They showed high affinity at A(1), A(2A), and A(2B), but not at A(3) ARs. One of the most potent compounds was 1-propyl-8-[4-[[p-nitrophenoxy]sulfonyl]phenyl]xanthine (9d), a mixed A(1)/A(2B) antagonist (K(i)A(1) 3.6 nM, K(i)A(2B) 5.4 nM) selective versus the other subtypes. As a further result of this study, the m-nitrophenoxy group was found to be a suitable protecting group for sulfonates in organic synthesis due to its high lipophilicity and stability; it can be split off under strongly basic conditions. This new protection strategy allowed for the upscaling of the synthesis of 1-propyl-8-p-sulfophenylxanthine (PSB-1115), a selective A(2B) antagonist.
Structure of Atg5·Atg16, a Complex Essential for Autophagy (2006)

Atg5 is covalently modified with a ubiquitin-like modifier, Atg12, and the Atg12-Atg5 conjugate further forms a complex with the multimeric protein Atg16. The Atg12-Atg5.Atg16 multimeric complex plays an essential role in autophagy, the bulk degradation system conserved in all eukaryotes. We have reported here the crystal structure of Atg5 complexed with the N-terminal region of Atg16 at 1.97A resolution. Atg5 comprises two ubiquitin-like domains that flank a helix-rich domain. The N-terminal region of Atg16 has a helical structure and is bound to the groove formed by these three domains. In vitro analysis showed that Arg-35 and Phe-46 of Atg16 are crucial for the interaction. Atg16, with a mutation at these residues, failed to localize to the pre-autophagosomal structure and could not restore autophagy in Atg16-deficient yeast strains. Furthermore, these Atg16 mutants could not restore a severe reduction in the formation of the Atg8-phosphatidylethanolamine conjugate, another essential factor for autophagy, in Atg16-deficient strains under starvation conditions. These results taken together suggest that the direct interaction between Atg5 and Atg16 is crucial to the performance of their roles in autophagy.
Identification of CD137 as a potent monocyte survival factor (1999)

CD137 (ILA/4-1BB), a member of the tumor necrosis factor (TNF) receptor family, promotes adherence and prolongs survival of human peripheral monocytes. It induces a strong expression of macrophage colony-stimulating factor (M-CSF), an essential monocyte survival factor. Monocyte survival induced by CD137 is primarily mediated by M-CSF and to a lesser extent by granulocyte-macrophage colony-stimulating factor and IL-3. Survival and induction of M-CSF are mediated via reverse signaling through a CD137 ligand expressed constitutively by peripheral monocytes.
Three different ways to decorrelate two closely spaced monopoles for MIMO applications (2005)

This work describes three different ways for obtaining low correlation for a closely spaced two-antenna system. They are a particular implementation of more general approach to MIMO antenna decorrelation. Each solution results in different antenna parameters, therefore their behaviour in a system has to be assessed in order to conclude their suitability.
Immunization with haptenized, autologous tumor cells induces inflammation of human melanoma metastases. (1991)

Twenty-four patients with metastatic melanoma were treated with a novel form of active immunotherapy, autologous tumor cell vaccine conjugated to the hapten, dinitrophenyl. This approach is based on the idea, well established in animal systems, that presentation of tumor antigens in the context of a strongly immunogenic hapten augments the development of immunity to those antigens. After being sensitized to dinitrophenyl, patients were given injections of dinitrophenyl-vaccine every 28 days following pretreatment with low dose cyclophosphamide. The vaccine induced a striking inflammatory response in superficial metastases in 14 of 24 patients, consisting of erythema, swelling, warmth, and tenderness over tumor masses. Immunohistochemistry and flow cytometric analysis of biopsy specimens showed marked infiltration with lymphocytes, the majority of which were CD8+, HLA-DR+ T-cells. These observations suggest that a T-cell-mediated immune response against melanoma-associated antigens was facilitated by the "helper" effect of the anti-hapten response.
CD28 co-stimulatory regimes differ in their dependence on phosphatidylinositol 3-kinase: common co-signals induced by CD80 and CD86 (1996)

CD80 (B7-1) and CD86 (B7-2) ligation of CD28 provide co-stimulatory signals required for optimal lymphokine production in response to TCR zeta-CD3 ligation. CD28 binds to several intracellular proteins including phosphatidylinositol 3-kinase (Pl3-kinase), the tyrosine kinase ITK and the growth factor receptor-bound protein/Son of Sevenless (GRB-2/SOS) complex. Previously, we showed that TCR zeta-CD3 and CD28 co-stimulation required Pl3-kinase binding to the pYMNM motif of the cytoplasmic domain of the co-receptor. In this study, we have investigated whether CD28-associated Pl3-kinase is required for CD80 and CD86 co-stimulation, as well as in co-signaling that involves different primary signals (i.e. TCR zeta-CD3 versus phorbol ester/lonomycin). In the presence of anti-CD3, ligation of CD28 by both CD80 and CD86 was found to induce Pl3-kinase recruitment and IL-2 production. Furthermore, mutations at Y-191 and M-194 within the pYMNM motif blocked the ability of both ligands to induce IL-2. CD80 and CD86 therefore share a common signaling pathway leading to IL-2 production. By contrast, CD28 mediated co-stimulation involving receptor ligation plus phorbol ester/lonomycin induced IL-2 independent of Pl3-kinase binding to CD28. These data indicate that TCR zeta-CD3-dependent CD80 and CD86 co-signaling requires Pl3-kinase binding to the CD28pYMNM motif, while phorbol ester and lonomycin can bypass this requirement in CD28 co-stimulation.
Why Are the Hydroxy Groups of Partially Protected N-Acetylglucosamine Derivatives Such Poor Glycosyl Acceptors, and What Can Be Done about It? A Comparative Study of the Reactivity of N-Acetyl-, N-Phthalimido-, and 2-Azido-2-deoxy-glucosamine Derivatives in Glycosylation. 2-Picolinyl Ethers as Reactivity-Enhancing Replacements for Benzyl Ethers (2001)

Competition experiments were used to determine that the 4-OH of a 2-deoxy-2-azidoglucose derivative is more reactive than that of the corresponding N-phthalimido glucose derivative which, in turn, is more easily glycosylated than the N-acetyl derivative. Glycosylation of the 4-OH groups of the N,N-diacetyl and N-acetyl-N-benzyl glucosamine was also found to be superior to that of the simple N-acetyl substance. The 3-O-picolinyl ether of a 4,6-O-benzylidene-protected N-acetylglucosamine was shown to have a strong intramolecular hydrogen bond to the adjacent acetamide group. This interaction does not persist in the 3-O-picolinyl-6-O-benzyl N-acetylglucosamine derivative, owing to a probable competing hydrogen bond between the 4-OH and the picolinyl ether. However, in the 3-O-picolinyl-4-O-benzyl N-acetylglucosamine regioisomer the picolinyl-acetamide hydrogen bond persists and leads to an enhancement of reactivity of the 6-OH, over and above that in the corresponding 3-O-benzyl ether, due to disruption of the typical intermolecular amide hydrogen bonding scheme. It is demonstrated that the picolinyl ether is readily removed by hydrogenolysis at atmospheric pressure and room temperature.
Monoamine Transporter and Receptor Interaction Profiles in Vitro Predict Reported Human Doses of Novel Psychoactive Stimulants and Psychedelics (2018)

The rapid assessment of in vitro pharmacological profiles of new psychoactive substances can help to predict psychoactive doses and effects in humans and facilitate the appropriate scheduling of new psychoactive substances.