gebhart/patrepeval huggingface dataset:
Proteolytic processing of TAR DNA binding protein‐43 by caspases produces C‐terminal fragments with disease defining properties independent of progranulin (2009)

Neuronal and glial deposition of misfolded, proteolytically processed, polyubiquitinated and abnormally phosphorylated C-terminal fragments (CTFs) of the TAR DNA binding protein-43 (TDP-43) is a pathological hallmark of frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U) and certain cases of amyotrophic lateral sclerosis. We demonstrate that TDP-43 can be proteolytically processed by caspases upon induction of apoptosis to a major 35 kDa and a minor 25 kDa CTF. These fragments are initially soluble, but over time they accumulate as insoluble and pathologically phosphorylated derivatives. However, proteolytic processing appears not to be absolutely required for the deposition of insoluble TDP-43 species, since a caspase resistant mutant of TDP-43 is also converted into insoluble species. Phosphorylation at S409/410 apparently occurs late during the conversion of soluble to insoluble TDP-43, suggesting that phosphorylation is not a prerequisite for aggregation. Loss of function of the progranulin (PGRN) gene causes FTLD-U with TDP-43 positive inclusions and has been suggested to lead to caspase activation and subsequent TDP-43 processing. However, siRNA-mediated knockdown of PGRN in cell culture as well as a PGRN gene knockout in mice failed to cause the formation of the disease characterizing CTFs of TDP-43. Our findings therefore suggest that caspase-mediated processing generates CTFs of similar biochemical properties as those occurring in nuclear and cytoplasmic deposits of FTLD-U patients independent of PGRN levels.
Role of Toll‐like Receptors in Adjuvant‐Augmented Immune Therapies (2006)

Effective therapeutic vaccines contain two primary constituents, antigen and adjuvant. Adjuvants consisting of microbial pattern molecules play a central role in vaccination. Successful vaccine requires efficient induction of antibody (Ab), type I interferons (IFN), cytokines/chemokines, cytotoxic T lymphocytes (CTL) and/or NK cells. Toll-like receptors (TLRs) in myeloid dendritic cells (mDC) essentially act as adjuvant receptors and sustain the molecular basis of adjuvant activity. Current consensus is that TLRs and their adapters introduce signals to preferentially induce IFN-alpha/beta, chemokines and proinflammatory cytokines, and mature mDC to augment antigen presentation. Although most of these data were obtained with mice, the results are presumed to be adaptable to humans. Whenever TLR pathway is activated in mDC, NK and/or CTL activation is promoted. For induction of antigen-specific CTL toward phagocytosed material, cross-priming must be induced in mDC, which is also sustained by TLR signaling in mDC. Since the TLR responses vary with different adjuvants, mDC functions are skewed depending on adjuvant-specific direction of mDC maturation. It appears that the directed maturation of mDC largely relies on selection of appropriate sets of TLRs and their adapter signaling pathways. Synthetic chimera molecules consisting of TLR agonists and target antigens are found to be effective in induction of CTL to eliminate target cells in vivo. Here, we review the role of human TLRs and adapters in a variety of host immune responses. We will also describe the relevance of adjuvants in the manipulation of receptors and adapters in vaccine therapy.
Structurally Diverse N-terminal Peptides of Parathyroid Hormone (PTH) and PTH-related Peptide (PTHRP) Inhibit the Na+/H+ Exchanger NHE3 Isoform by Binding to the PTH/PTHRP Receptor Type I and Activating Distinct Signaling Pathways (1996)

N-terminal peptides of parathyroid hormone (PTH) and PTH-related peptide (PTHRP) elicit a wide variety of biological responses in target cells, including the inhibition of Na+/H+ exchanger NHE3 activity in renal cells. This response is believed to be mediated by ligand binding to a common receptor (i.e. PTH/PTHRP receptor type I) and activation of cAMP-dependent and/or Ca2+/phospholipid-dependent protein kinases (PKA and PKC, respectively). However, the mechanism of action of these N-terminal peptides is now unclear because of recent data reporting the existence of additional receptor isoforms. Therefore, to directly examine the ligand binding and signaling characteristics of the PTH/PTHRP receptor type I and its ability to elicit a biological response, cDNAs encoding the rat type I receptor and the rat NHE3 isoform were transfected into Chinese hamster ovary (AP-1) cells that lack endogenous expression of these proteins. Competition binding assays using [125I-Tyr36]PTHRP-(1-36)-NH2 radioligand indicated that several biologically active human N-terminal PTH and PTHRP fragments (PTH-(1-34), PTH-(3-34), PTH-(28-42), PTH-(28-48), and PTHRP-(1-34)) were capable of binding to the type I receptor. Both PTH-(1-34) and PTHRP-(1-34) stimulated adenylate cyclase and PKC activities in these cells, whereas PTH-(3-34), PTH-(28-42), and PTH-(28-48) selectively enhanced only PKC activity. PTHRP-(1-16), a biologically inert fragment, was incapable of binding to this receptor and influencing either the PKA or PKC pathway. Furthermore, all the analogues with the exception of PTHRP-(1-16) inhibited NHE3 activity. Inhibition of PKC by the potent antagonist chelerythrine chloride abolished the depression of NHE3 activity by PTH-(3-34), PTH-(28-42), and PTH-(28-48) but did not alleviate the effects of PTH-(1-34). Likewise, antagonism of PKA by H-89 was unable to prevent the inhibition caused by PTH-(1-34). However, inhibition of both PKA and PKC by the nonselective protein kinase antagonist H-7 abolished the reduction of NHE3 activity by PTH-(1-34). These data indicate that discrete N-terminal analogues of PTH and PTHRP can interact with the classical PTH/PTHRP receptor type I and activate PKA and/or PKC. Activation of either signaling pathway independently leads to inhibition of NHE3.
Regulation of striatal dopamine neurotransmission by nitric oxide: Effector pathways and signaling mechanisms (2002)

An important role for the reactive gas nitric oxide (NO) in regulating striatal dopaminergic neurotransmission was identified shortly after initial observations indicated that this unorthodox neurotransmitter mediates many of the influences of glutamatergic neurotransmission in the cerebellum, cortex, and hippocampus. While the precise actions of NO on striatal presynaptic and postsynaptic elements remain to be fully characterized, the recent application of sophisticated anatomical, neurochemical, and electrophysiological approaches to the study of nitrergic signaling has revealed that NO exerts a powerful influence both on tonic extracellular dopamine (DA) levels and phasic DA neuron spike activity via the modulation of intrinsic striatal mechanisms and striatonigral feedback loops. Although the nature of the NO-mediated modulatory influence on DA neurotransmission was initially clouded by seemingly conflicting neurochemical observations, a growing body of literature and understanding of the diverse signaling mechanisms and effector pathways utilized by NO indicates that NO exerts a primary facilitatory influence over tonic and phasic dopaminergic neurotransmission under physiological conditions. A review of neurochemical and electrophysiological studies examining the influence of endogenous and exogenous NO on DA neurotransmission indicates that NO signaling exerts multiple effects on local striatal circuits and projection neurons involved in regulating basal ganglia output and nigrostriatal DA neuron activity. In addition to summarizing these influences, the current review focuses on the mechanisms utilized by striatal NO signaling pathways involved in modulating DA transmission at the level of the terminal and cell body and attempts to integrate these observations into a functional model of NO-dependent regulation of basal ganglia systems.
Killing of African Trypanosomes by Antimicrobial Peptides (2003)

Antimicrobial peptides are components of the innate immune systems of a wide variety of eukaryotic organisms and are being developed as antibiotics in the fight against bacterial and fungal infections. We explored the potential activities of antimicrobial peptides against the African trypanosome Trypanosoma brucei, a vector-borne protozoan parasite that is responsible for significant morbidity and mortality in both humans and animals. Three classes of mammalian antimicrobial peptides were tested: alpha-defensins, beta-defensins, and cathelicidins. Although members of all 3 classes of antimicrobial peptides showed activity, those derived from the cathelicidin class were most effective, killing both insect and bloodstream forms of the parasite. The mechanism of action of the cathelicidins against T. brucei involves disruption of surface membrane integrity. Administration of cathelicidin antimicrobial peptides to mice with late-stage T. brucei infection acutely decreased parasitemia and prolonged survival. These results highlight the potential use of antimicrobial peptides for the treatment of African trypanosomiasis.
CD4+Foxp3+ T-Regulatory Cells in Noninfectious Uveitis (2009)

T-regulatory cells are reduced in patients with active compared with inactive disease. Severe depletion of CD4(+)Foxp3(+) T cells and Foxp3 mRNA in 2 patients with severe uveitis suggests that loss of the T-regulatory cells of uveitis may be a salient feature in certain patients.
Problems in construction of subsidy system for agricultural product identification and counter measures - a case study of Xingjiang. (2012)

In line with current situations of extension of Xinjiangâ€™s agricultural products, the paper put forward and analyzed existing problems in extension works of agricultural product identification. The problems mainly include: (i) general identification of agricultural products is basically blank and both producers and consumers lack awareness of identification; (ii) creating (famous) brand is a weak point of agriculture in Xinjiang; (iii) certification of non-hazard, green and organic agricultural products lags behind; (iv) it neglects problem of agricultural product packaging. On the basis of these problems, we present our recommendations: (i) government provides financial subsidy to actively guide certification of agricultural products; (ii) it should increase financial fund input in brand construction and support (famous) brand construction of agricultural products; (iii) it should provide subsidy for those enterprises creating famous brand, to encourage agricultural producing and processing enterprises to strive for famous brands; (vi) it should stress agricultural product packaging from the source and provide subsidy for agricultural producers who have affixed the identification; (v) it should gradually promote agricultural product identification, to constantly improve the farmersâ€™ awareness of agricultural product identification.
Protective effects of selectin chimeras in neutrophil-mediated lung injury. (1993)

Recombinant selectin chimeric molecules featuring the joining of the extracellular domains of L-, P-, and E-selectin to the CH2 and CH3 domains of human IgG1 have been evaluated for their ability to protect against neutrophil-dependent lung injury in rats after systemic activation of C caused by vascular infusion of cobra venom factor (CVF) or lung injury that follows intrapulmonary deposition of IgG immune complexes. Previous studies using anti-selectin antibodies have suggested that the former model is P-selectin dependent, whereas the latter is E-selectin dependent. Requirements for L-selectin have not been identified because of lack of reagents. For the current studies employing the CVF model of lung injury, infusion of P-selectin-Ig chimera reduced injury (as assessed by changes in permeability and hemorrhage) in a dose-dependent manner, with parallel reductions in lung myeloperoxidase (MPO) content. Similar results were obtained with the L-selectin-Ig chimera, whereas the E-selectin-Ig chimera was not protective and failed to alter MPO content. In contrast, in the IgG immune complex model of lung injury, the L- and E-selectin-Ig chimeras both showed dose-related protective effects and reductions in MPO content, whereas the P-selectin-Ig chimera failed to protect against injury and did not alter MPO content in this model of lung injury. In all cases of blocking of injury, this was incomplete, suggesting multi-selectin engagement or inadequate amounts of selectin-Ig chimeras employed. These data indicate that neutrophil recruitment and attendant lung injury in the CVF model are L- and P-selectin dependent and E-selectin-independent, whereas in the IgG immune complex model, neutrophil recruitment and lung injury are L- and E-selectin-dependent but independent of P-selectin. Thus, differing selectin requirements for acute inflammatory lung injury have been identified.
The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity (2005)

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of approximately 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.
Role of Histone Acetylation in the Assembly and Modulation of Chromatin Structures (2001)

The acetylation of the core histone N-terminal "tail" domains is now recognized as a highly conserved mechanism for regulating chromatin functional states. The following article examines possible roles of acetylation in two critically important cellular processes: replication-coupled nucleosome assembly, and reversible transitions in chromatin higher order structure. After a description of the acetylation of newly synthesized histones, and of the likely acetyltransferases involved, an overview of histone octamer assembly is presented. Our current understanding of the factors thought to assemble chromatin in vivo is then described. Genetic and biochemical investigations of the function the histone tails, and their acetylation, in nucleosome assembly are detailed, followed by an analysis of the importance of histone deacetylation in the maturation of newly replicated chromatin. In the final section the involvement of the histone tail domains in chromatin higher order structures is addressed, along with the role of histone acetylation in chromatin folding. Suggestions for future research are offered in the concluding remarks.
Aminoglycoside Antibiotics (2000)

In the 50 years since their discovery, the aminoglycoside antibiotics have seen unprecedented use. Discovered in the 1940s, they were the long-sought remedy for tuberculosis and other serious bacterial infections. The side effects of renal and auditory toxicity, however, led to a decline of their use in most countries in the 1970s and 1980s. Nevertheless, today the aminoglycosides are still the most commonly used antibiotics worldwide thanks to the combination of their high efficacy with low cost. This review first summarizes the history, chemistry, antibacterial actions and acute side effects of the drugs. It then details the pathophysiology of aminoglycoside ototoxicity including experimental and clinical observations, risk factors and incidence. Pharmacokinetics, cellular actions and our current understanding of the underlying molecular mechanisms of ototoxicity are discussed at length. The review concludes with recent advances towards therapeutic intervention to prevent aminoglycoside ototoxicity.
Different Effects of Class Ic and III Antiarrhythmic Drugs on Vagotonic Atrial Fibrillation in the Canine Heart (1998)

Effects of class Ic drug pilsicainide and class III drug MS-551 were determined in the canine model of atrial fibrillation (AF) induced under vagal stimulation. Pilsicainide injected intravenously at a dose of 1.0 mg/kg over 3 min terminated AF in six of six dogs. After pilsicainide injection, the effective refractory period (ERP) of the right atrium (RA) increased (104 +/- 22 to 122 +/- 31 ms; p < 0.05), and intraatrial conduction time (CT) increased (24%; p < 0.05) in the RA during vagal stimulation. Wavelength index (WLI; ERP/CT), an estimate of the wavelength for reentry, was decreased slightly but significantly (-2%; p < 0.05) in the RA after pilsicainide. MS-551 injected intravenously at a dose of 0.5 mg/kg over a 3-min period terminated AF in three of eight dogs. An additional dose of 0.5 mg/kg of MS-551 terminated AF in three of the remaining five dogs. After MS-551 injection, ERP increased (100 +/- 30 to 143 +/- 28 ms; p < 0.05), but CT remained unchanged in the RA, and therefore WLI was increased significantly (48%; p < 0.01). Immediately before termination of AF with test drugs, mean AF intervals (FF intervals) increased, whereas the standard deviation of FF intervals did not change significantly. In conclusion, both pilsicainide and MS-551 effectively terminated vagotonic AF after an increase in FF intervals. However, changes in WLI were different between the two test drugs. Vagotonic AF could, therefore, be terminated either by prolongation of ERP or suppression of conduction with antiarrhythmic drugs.
Interleukin-6 Levels in Tears of Contact Lens Wearers (2000)

The purpose of this study was to evaluate the presence of interleukin-6 (IL-6) in basal tears of contact lens wearers (n = 18) and nonlens wearers (n = 25). Samples (5 microl) were collected with a microcapillary pipette and evaluated using PAGE electrophoresis and immunoblot analysis. Contact lens-wearing patients had a mean IL-6 level of 43.8 +/- 5.3 pg/5 microl compared with nondetectable IL-6 levels throughout the noncontact lens-wearing population. IL-6 in several patients removed from contact lens wear for 6 days became nondetectable. When these patients were returned to wearing lenses, IL-6 levels increased to their original levels within 24 h. The data presented indicate that an ocular medical device may stimulate IL-6 production.
A novel approach for location promotion on location-based social networks (2015)

Maximizing the spread of influence was recently studied in several models of social networks. For location-based social networks, it also plays an important role, so a further research about this field is necessary. In this study, based on users' movement histories and their friendships, we first design the Predicting Mobility in the Near Future (PMNF) model to capture human mobility. Human mobility is inferred from the model by taking into account the following three features: (1) the regular movement of users, (2) the movement of friends of users, (3) hot regions, the most attractive places for all users. Second, from the result of predicting movements of users at each location, we determine influence of each user on friends with the condition that friends are predicted to come to the location. Third, the Influence Maximization (IM) algorithms are proposed to find a set of k influential users who can make the maximum influence on their friends according to either the number of influenced users (IM num) or the total of probability of moving the considered location of influenced users (IM score). The model and algorithms are evaluated on three large datasets collected by from 40,000 to over 60,000 users for each dataset over a period of two years in the real world at over 500,000 checked-in points as well as 400,000 to nearly 2,000,000 friendships also considered. The points are clustered into locations by density-based clustering algorithms such as OPTICS and GRID. As a result, our algorithms give an order of magnitude better performance than baseline approaches like choosing influential users based on the number of check-ins of users and selecting influential users by the number of friends of users. From the result of experiments, we are able to apply to some areas like advertisement to get the most efficient with the minimum costs. We show that our framework reliably determines the most influential users with high accuracy.
Human Herpesvirus 8-Encoded Thymidine Kinase and Phosphotransferase Homologues Confer Sensitivity to Ganciclovir (1999)

Human herpesvirus 8 (HHV-8) sensitivity to the nucleoside analog ganciclovir (GCV) suggests the presence of a virally encoded kinase that catalyzes the initial phosphorylation of GCV. Analysis of the HHV-8 genome identified two candidate kinases: proteins encoded by open reading frame (ORF) 21, with homology to the herpesvirus thymidine kinases (TK), and ORF 36, with homology to the herpesvirus phosphotransferases (PT). Experiments presented here show that both ORF 21 and ORF 36 encode GCV kinase activities as demonstrated by GCV phosphorylation and GCV-mediated cell death. In both regards the PT homologue ORF 36 was more active than the TK homologue ORF 21. ORF 21, but not ORF 36, weakly sensitized cells to killing by penciclovir. Neither ORF sensitized cells to killing by (E)-5-(2-bromovinyl)-2'-deoxyuridine.
Histopathological changes at central nodes of Ranvier after stretch-injury (1996)

While the brain readily deforms when exposed to rotational loads as experienced in violent movements of the head, axons are able only to sustain tensile loads. Two discrete classes of axonal injury have been posited: disruptive axonal injury, where axons are physically torn or fragmented at the time of the insult, and nondisruptive axonal injury, where there is a hypothesised "perturbation" of the axolemma which leads to a cascade of pathobiological changes which result in axotomy over a period between 2 and 24 h after the initial insult. In the latter, it is posited that the node of Ranvier is that part of the axon which is the initial locus of axonal damage/ histopathological change. This paper describes the ultrastructure of nodal blebs, axolemma limited protrusions of the nodal axoplasm into the perinodal space, in which the nodal dense undercoating has been lost and aggregates of membranous profiles occur within the axoplasm. In addition, this paper provides novel data for disruption of the axonal cytoskeleton in nodes where blebs occur within 15 min of stretch-injury. The cytoskeletal disruption is visualised in thin sections as an almost total loss of microtubules together with a reduced density of neurofilaments within the nodal axoplasm. The loss of microtubules is posited to result in a disruption of fast axonal transport which results in the focal accumulation of membranous organelles in adjacent paranodal regions of the axon to form so-called "axonal swellings." Cytochemical and freeze-fracture studies provide evidence for structural reorganisation of the nodal axolemma after stretch-injury, and it is posited that these changes provide a route for uncontrolled influx of calcium which leads to loss of axonal integrity which potentiates axotomy. It is suggested that increased understanding of regulatory mechanisms that control ion channel activity will greatly increase our understanding of responses of neurones to trauma.