gebhart/patrepeval huggingface dataset:
IL‐21 regulates experimental colitis by modulating the balance between T reg and Th17 cells (2007)

Regulatory T (T(reg)) cells play a key role in the maintenance of the immune system homeostasis. T(reg) cells can be generated in the periphery under control of TGF-beta, a cytokine involved in the negative control of the immune system. However, TGF-beta cooperates with IL-6 in the generation of Th17 cells, a novel class of effector cells involved in numerous inflammatory diseases, including colitis. Therefore, TGF-beta emerges as a mediator of both anti-inflammatory and pro-inflammatory processes, depending on the local cytokine milieu. Here we demonstrate that IL-21, a type-1 cytokine produced by T cells and involved in the pathogenesis of immune-mediated diseases, prevents the TGF-beta-dependent expression of FoxP3, the master regulator of T(reg) cell commitment, and the induction of suppressive capacity in naive CD4(+) T cells, while promoting the differentiation of Th17 cells. In vivo, CD4(+) naive T cells activated in the presence of TGF-beta and IL-21 failed to suppress colitis while inducing an inflammatory response characterized by high levels of IL-17 and RORgammat, the transcription factor expressed by Th17 cells. Therefore, IL-21 emerges as a key modulator of TGF-beta signaling, leading to the reciprocal differentiation of T(reg) and Th17 cells.
Bits y algoritmos: algunas reflexiones sobre el futuro carácter de la guerra (2021)

El carácter de la guerra está experimentando profundos cambios como resultado de dos factores fundamentales; el cambio de escenario geopolítico y la revolución tecno­lógica en la que estamos inmersos. El escenario geopolítico actual, caracterizado por una potencia aun hegemónica que afronta la creciente competición de otras emergen­tes, está evolucionando hacia otro orden internacional multipolar con varias potencias con capacidades equilibradas, con numerosos estados fallidos y un creciente papel de organizaciones no estatales. Esta situación favorecerá los conflictos en la denominada zona gris. El otro factor lo constituye el ritmo acelerado del actual desarrollo tecno­lógico que estamos experimentando y en particular en el campo digital. El campo de batalla del futuro estará definido por los avances en la conectividad, la automatización y la robotización y por el traslado del conflicto al ciberespacio.
Strapdown Inertial Navigation Technology (2004)

Inertial navigation is widely used for the guidance of aircraft, missiles ships and land vehicles, as well as in a number of novel applications such as surveying underground pipelines in drilling operations. This book discusses the physical principles of inertial navigation, the associated growth of errors and their compensation. It draws current technological developments, provides an indication of potential future trends and covers a broad range of applications. New chapters on MEMS (microelectromechanical systems) technology and inertial system applications are included.
Raf‐1 provides a dominant but not exclusive signal for the induction of CD69 expression on T cells (1995)

Stimulation of the T cell antigen receptor (TCR) induces a number of intracellular signaling pathways which lead to the transcription of a variety of new genes. Of the newly synthesized proteins, the earliest to be detected on the cell surface is the type II integral membrane protein CD69. Cross-linking of this activation antigen induces signaling events related to T cell activation. The proto-oncogene product Ras has been reported to up-regulate CD69. However, which of the potential effectors of Ras induces the expression of CD69 has remained unclear. Using transient transfection, we have shown a constitutively active form of the serine/threonine kinase Raf-1 to be sufficient to induce CD69 expression in human Jurkat T cells. Raf-1 was further shown to be necessary for PMA-induced CD69 expression, since transfection of a dominant inhibitory form of Raf-1 blocked the up-regulation of CD69 by PMA. In addition, studies with the calcium ionophore ionomycin identified a previously uncharacterized pathway regulating the expression of CD69 in T cells. Elevation of intracellular calcium induced the expression of CD69 in both Jurkat cells and peripheral blood T cells. This effect was sensitive to the immunosuppressive drug cyclosporin A, indicating that calcium-induced CD69 expression is mediated by the protein phosphatase calcineurin. Taken together, these results define Raf-1 as the major signaling mediator of CD69 expression in T cells and suggest that multiple mechanisms exist to regulate the level of CD69 expression following TCR stimulation.
Can Biomarkers Differentiate Pain and No Pain Subgroups of Nonverbal Children with Cerebral Palsy? A Preliminary Investigation Based on Noninvasive Saliva Sampling (2014)

The ease of collection and noninvasive manner in which the samples were collected and analyzed support the possibility of the regular predictive use of this novel biomarker-monitoring method in clinical practice.
Discovery of GSK2126458, a Highly Potent Inhibitor of PI3K and the Mammalian Target of Rapamycin (2010)

Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative efficacy of PI3K/AKT pathway inhibition. 2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide (GSK2126458, 1) has been identified as a highly potent, orally bioavailable inhibitor of PI3Kα and mTOR with in vivo activity in both pharmacodynamic and tumor growth efficacy models. Compound 1 is currently being evaluated in human clinical trials for the treatment of cancer.
Characterization of human hybridomas secreting antibody to tetanus toxoid. (1983)

We have selected a thioguanine-resistant lymphoblastoid cell line (LTR228) that forms human-human hybrids with high efficiency. Fusions with peripheral B cells consistently yield one colony per 10(5) cells plated. To produce antitetanus monoclonal antibodies, we withdrew blood from persons who had recently received booster injections of tetanus toxoid. T cells were separated from peripheral mononuclear cells by 2-aminoethylisothiouronium bromide-induced rosette formation, given 1,500 rads (1 rad = 0.01 gray), and cultured in a 1:1 ratio with nonrosetting cells. After 3 days of pokeweed mitogen stimulation, heterokaryons were produced by a plate-fusion technique and cultured in Iscove's Dulbecco's minimal essential medium for 24 hr prior to hybrid selection. Colonies appeared after 10-14 days in hypoxanthine/azaserine supplemented medium. A direct binding enzyme-linked immunosorbent assay with specific tetanus toxoid inhibition identified positive wells. The hybridomas were cloned twice in soft agarose and by limiting dilution. The subcloned hybridomas double every 26 hr (vs. every 16 hr for LTR228) and produce 1-5 micrograms of specific IgG, kappa antibody per 10(6) cells per ml per 24 hr. All subclones (almost 200) continue to secrete antibody after 11 months of continuous culture. Twelve representative subclones have near tetraploid amounts of DNA. From hybridomas grown in 5-liter spinner flasks, milligram quantities of the IgG, kappa antibody were purified by staphylococcus protein A affinity chromatography. Specific antibody from hybridoma cultures protected mice injected with 1,000 times the LD50 of tetanus toxin. Our cell line and associated techniques should permit the production of therapeutically important human monoclonal antibodies.
Heavy chain–only antibodies are spontaneously produced in light chain–deficient mice (2007)

In healthy mammals, maturation of B cells expressing heavy (H) chain immunoglobulin (Ig) without light (L) chain is prevented by chaperone association of the H chain in the endoplasmic reticulum. Camelids are an exception, expressing homodimeric IgGs, an antibody type that to date has not been found in mice or humans. In camelids, immunization with viral epitopes generates high affinity H chain-only antibodies, which, because of their smaller size, recognize clefts and protrusions not readily distinguished by typical antibodies. Developmental processes leading to H chain antibody expression are unknown. We show that L(-/-) (kappa(-/-)lambda(-/-)-deficient) mice, in which conventional B cell development is blocked at the immature B cell stage, produce diverse H chain-only antibodies in serum. The generation of H chain-only IgG is caused by the loss of constant (C) gamma exon 1, which is accomplished by genomic alterations in C(H)1-circumventing chaperone association. These mutations can be attributed to errors in class switch recombination, which facilitate the generation of H chain-only Ig-secreting plasma cells. Surprisingly, transcripts with a similar deletion can be found in normal mice. Thus, naturally occurring H chain transcripts without C(H)1 (V(H)DJ(H)-hinge-C(H)2-C(H)3) are selected for and lead to the formation of fully functional and diverse H chain-only antibodies in L(-/-) animals.
Probing the Non-covalent Structure of Proteins by Amide Hydrogen Exchange and Mass Spectrometry (1997)

The rates at which hydrogens located at peptide amide linkages in proteins undergo isotopic exchange when a protein is exposed to D2O depend on whether these amide hydrogens are hydrogen bonded and whether they are accessible to the aqueous solvent. Hence, amide hydrogen exchange rates are a sensitive probe for detecting changes in protein conformation and dynamics. Hydrogen exchange rates in proteins are most often measured by NMR or Fourier transform IR spectroscopy. After a brief introduction to model kinetics used to relate amide hydrogen exchange rates to protein structure and dynamics, information required to understand and implement a new method that uses acid proteases and mass spectrometry to determine amide hydrogen exchange rates in proteins is presented. Structural and dynamic features affecting isotopic exchange rates can be detected and localized from the deuterium levels detected by mass spectrometry in proteolytic fragments of the protein. Procedures used to adjust for isotopic exchange occurring during the analysis, to extract isotope exchange rate constants from mass spectra and to link bimodal isotope patterns to protein unfolding and structural heterogeneity are also discussed. In addition, the relative merits of using mass spectrometry or NMR combined with amide hydrogen exchange to study protein structure and dynamics are discussed. The spatial resolution of hydrogen exchange results obtained by this method is typically in the range of 1-10 residues, which is substantially less than that obtained by high-resolution NMR, but sufficient to detect many functionally significant structural changes. Advantages in the areas of sensitivity, protein solubility, detection of correlated exchange and high molecular mass proteins make this approach particularly attractive for a wide range of studies.
Structure of the filamentous bacteriophage fl. Location of the A, C, and D minor coat proteins. (1981)

The location within the virion of the A, C, and D minor coat proteins of the filamentous bacteriophage fl has been analyzed. The A protein is present in approximately 5 copies/particle and is located at the tip of normal length phage, miniphage, and fl/pBR322 chimeric phage, a longer than normal length phage. The mole ratios of the A, C, and D proteins are the same for each type of particle, consistent with a model of phage organization in which the minor coat proteins are clustered near or at the ends of the phage. Normal length phage were fragmented by passing them through a French press, and those fragments that contained the A protein were separated from those that did not by treating the mixture with anti-A protein antibody. Analysis of the protein compositions of the two populations of fragments showed that the A and D proteins were found together in one population of fragments and that most, it not all, of the C protein was found in the other. These results show that the D protein is located near or at the A protein end of the phage and that the C protein is located in a region near or at the opposite end. Treatment of the virion with proteases which lowered the infectivity of the phage resulted in particles in which only the A protein was cleaved to any detectable extent. These particles remained resistant to the action of micrococcal nuclease.
Facet selection algorithms for web product search (2013)

Multifaceted search is a commonly used interaction paradigm in e-commerce applications, such as Web shops. Because of the large amount of possible product attributes, Web shops usually make use of static information to determine which facets should be displayed. Unfortunately, this approach does not take into account the user query, leading to a nonoptimal facet drill down process. In this paper, we focus on automatic facet selection, with the goal of minimizing the number of steps needed to find the desired product. We propose several algorithms for facet selection, which we evaluate against the state-of-the-art algorithms from the literature. We implement our approach in a Web application called faccy.net. The evaluation is based on simulations employing 1000 queries, 980 products, 487 facets, and three drill down strategies. As evaluation metrics we use the average number of clicks, the average utility, and the top-10 promotion percentage. The results show that the Probabilistic Entropy algorithm significantly outperforms the other considered algorithms.
The highly selective mGlu 2 receptor positive allosteric modulator LY‐487,379 alleviates l ‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease (2020)

l-3,4-Dihydroxyphenylalanine (l-DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu<sub>2/3</sub> ) receptor activation with LY-354,740 alleviates dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset and the 6-hydroxydopamine (6-OHDA)-lesioned rat. Here, we sought to determine the role played by selective mGlu<sub>2</sub> activation in the anti-dyskinetic effect of mGlu<sub>2/3</sub> stimulation and have investigated the effect of the highly selective mGlu<sub>2</sub> positive allosteric modulator LY-487,379 at alleviating established, and preventing the development of, l-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat. First, dyskinetic 6-OHDA-lesioned rats were administered l-DOPA in combination with LY-487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6-OHDA-lesioned rats were administered LY-487,379 (0.1 or 1 mg/kg), started concurrently with l-DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY-487,379 on l-DOPA anti-parkinsonian effect. We found that acute challenges of LY-487,379 0.1 mg/kg in combination with l-DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l-DOPA/LY-487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l-DOPA/vehicle. LY-487,379 did not impair l-DOPA anti-parkinsonian activity. These results suggest that mGlu<sub>2</sub> activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.
Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. (1989)

Localization of the site of blood-retinal barrier breakdown in diabetes has been controversial. It has been particularly difficult to make assessments in clinical material where the use of tracer materials may not be practical. In this study, immunohistochemical staining for albumin was performed on paraffin-embedded eyes from patients with no known ocular disease and those with various stages of diabetic retinopathy. No extravascular albumin was detected in the retina or retinal pigment epithelium (RPE) of normal nondiabetics or diabetics with no ocular findings, but it was detected in 12.5% of mildly affected diabetics, 20% of background diabetic retinopathy cases, and 89% of proliferative diabetic retinopathy cases. The inner retinal vasculature appeared to be the primary site of leakage in diabetics because all cases demonstrating extravascular albumin-positivity expressed it in the inner retina. It usually permeated the vessel walls and spread along the inner surface of the retina. Some of these cases also contained albumin in the outer retina and RPE, suggesting that additional leakage also may occur through the RPE. A case of cytomegalovirus (CMV) retinitis showed albumin staining predominantly in the inner retina, whereas a rhegmatogenous retinal detachment showed only outer retina staining. These data suggest immunohistochemical staining for albumin may be a useful technique for localizing blood-retinal barrier breakdown.
Resonance Raman study of phenylhydrazonopropanedinitriles (1985)

Resonance Raman spectra and band assignments of some phenylhydrazonopropanedinitriles, including the 3-chloro and the 2-carboxy derivatives, in the 900–2300 cm −1 spectral range are presented and discussed. I5 N and 2 H isotopic shifts have been used to clarify the assignments, which have been made for both protonated and deprotonated forms of the compounds. The resonance Raman spectra of the protonated forms show strong coupling between NH deformation and hydrazone vibrations. This coupling is lost in the anionic forms, which are considered to have considerable carbanion character. By using the drastic changes between the resonance Raman spectra of protonated and deprotonated forms, the pK a value of the 2-carboxy derivative has been determined.
Double Blind Trial of L-Dopa in Chronic Schizophrenia (1975)

A double blind study in 28 patients with chronic schizophrenia was carried out comparing L-dopa (up to 1250 mgm daily) with placebo (both groups continuing to receive regular neuroleptic medication) over a six week period. Assessments by the psychiatrists and psychologist using Rockland and Pollin Rating Scale showed differential improvement of insignificant proportions but the nurse's ratings showed clearly significant improvement in the subject group.
Rapid Detection of Candida albicans in Clinical Blood Samples by Using a TaqMan-Based PCR Assay (2003)

We describe a rapid and reproducible PCR assay for quantitation of the Candida albicans ribosomal DNA (rDNA) in clinical blood samples based on the TaqMan principle (Applied Biosystems), in which a signal is generated by cleavage of a template-specific probe during amplification. We used two fluorogenic probes based on universal, fungus-specific primers, one for the detection of C. albicans species DNA and one for the detection of all Candida genus DNA. C. albicans blastoconidia mixed with whole blood in a titration experiment yielded a linear PCR signal over a range of 3 orders of magnitude. The TaqMan-based PCR assay for C. albicans exhibited a low limit of detection (5 CFU/ml of blood) and an excellent reproducibility (96 to 99%). While the C. albicans species-specific probe had 100% specificity for C. albicans, all Candida genus-specific probes cross-reacted with other organisms likely to coinfect patients with C. albicans infections. On the basis of these data, we determined the C. albicans loads with a species-specific probe from 122 blood samples from 61 hematology or oncology patients with clinically proven or suspected systemic Candida infections. Eleven positive samples exhibited a wide range of C. albicans loads, extending from 5 to 100,475 CFU/ml of blood. The sensitivity and specificity of the present assay were 100 and 97%, respectively, compared with the results of blood culture. These data indicate that the TaqMan-based PCR assay for quantitation of C. albicans with a species-specific probe provides an attractive alternative for the identification and quantitation of C. albicans rDNA in pure cultures and blood samples.
Biosynthesis of (1→3),(1→4)‐β‐glucan in developing endosperms of barley (Hordeum vulgare) (2005)

A (1→3),(1→4)‐β‐glucan synthase catalysing the synthesis of (1→3),(1→4)‐β‐glucan (mixed‐linkage glucan) was investigated using microsomal membranes prepared from developing barley ( Hordeum vulgare L. cv. Shikokuhadaka 97) endosperms harvested 21 days after flowering. The microsomal fraction produced (1→3),(1→4)‐β‐glucan by incorporation of [ 14 C]Glc from UDP‐[ 14 C]Glc. The production of (1→3),(1→4)‐β‐glucan was ascertained by specific enzymatic digestion with endo ‐(1→3),(1→4)‐β‐glucanase (lichenase; EC 3.2.1.73) from Bacillus amyloliquefaciens , which released a radiolabelled trisaccharide (3‐ O ‐β‐cellobiosyl‐glucose) and a tetrasaccharide (3‐ O ‐β‐cellotriosyl‐glucose), the diagnostic oligosaccharides for the identification of (1→3),(1→4)‐β‐glucan. Digestion of the products with exo ‐(1→3)‐β‐glucanase (EC 3.2.1.58) from Basidiomycete QM806 released radiolabelled Glc, indicating that not only (1→3),(1→4)‐β‐glucans but also (1→3)‐β‐glucans (callose) had been formed due to the presence of (1→3)‐β‐glucan (callose) synthase (EC 2.4.1.34) in the microsomal fraction. The activity of (1→3),(1→4)‐β‐glucan synthase was maximal at pH 9.0 and at 25°C and in the presence of at least 2 m M Mg 2+ . The apparent K m and V max values for UDP‐Glc were 0.33 m M and 480 pmol min −1 mg protein −1 , respectively. Investigating the dependence of enzyme activity on developmental stage (7–35 days after flowering) of the endosperms, we found an increase of activity during the initial development reaching a maximum at 19 days, followed by a gradual decrease as the endosperms matured. The amount of (1→3),(1→4)‐β‐glucan in the cell walls of the endosperms, however, increased gradually towards maturation, even after 19 days. Analysing the relationship between enzyme activity and (1→3),(1→4)‐β‐glucan deposition in cell walls of endosperms prepared from 12 different barley varieties harvested 11–22 days after flowering showed that some varieties had both low activity and low glucan content, and in some both were high. But for several other varieties, the availability of donor substrate and other factors seem to influence the production of (1→3),(1→4)‐β‐glucan as well.
ERK2 Mitogen-activated Protein Kinase Binding, Phosphorylation, and Regulation of the PDE4D cAMP-specific Phosphodiesterases (2000)

The cAMP-specific phosphodiesterase family 4, subfamily D, isoform 3 (PDE4D3) is shown to have FQF and KIM docking sites for extracellular signal-regulated kinase 2 (ERK2) (p42(MAPK)). These straddle the target residue, Ser(579), for ERK2 phosphorylation of PDE4D3. Mutation of either or both of these docking sites prevented ERK2 from being co-immunoprecipitated with PDE4D3, ablated the ability of epidermal growth factor to inhibit PDE4D3 through ERK2 action in transfected COS cells, and attenuated the ability of ERK2 to phosphorylate PDE4D3 in vitro. The two conserved NH(2)-terminal blocks of sequence, called upstream conserved regions 1 and 2 (UCR1 and UCR2), that characterize PDE4 long isoforms, are proposed to amplify the small, inherent inhibitory effect that ERK2 phosphorylation exerts on the PDE4D catalytic unit. In contrast to this, the lone intact UCR2 region found in PDE4D1 directs COOH-terminal ERK2 phosphorylation to cause the activation of this short isoform. From the analysis of PDE4D3 truncates, it is suggested that UCR1 and UCR2 provide a regulatory signal integration module that serves to orchestrate the functional consequences of ERK2 phosphorylation. The PDE4D gene thus encodes a series of isoenzymes that are either inhibited or activated by ERK2 phosphorylation and thereby offers the potential for ERK2 activation either to increase or decrease cAMP levels in cellular compartments.