gebhart/patrepeval huggingface dataset:
RTL551 Treatment of EAE Reduces CD226 and T-bet+ CD4 T Cells in Periphery and Prevents Infiltration of T-bet+ IL-17, IFN-γ Producing T Cells into CNS (2011)

Recombinant T cell receptor ligands (RTLs) that target encephalitogenic T-cells can reverse clinical and histological signs of EAE, and are currently in clinical trials for treatment of multiple sclerosis. To evaluate possible regulatory mechanisms, we tested effects of RTL therapy on expression of pathogenic and effector T-cell maturation markers, CD226, T-bet and CD44, by CD4+ Th1 cells early after treatment of MOG-35-55 peptide-induced EAE in C57BL/6 mice. We showed that 1-5 daily injections of RTL551 (two-domain I-A(b) covalently linked to MOG-35-55 peptide), but not the control RTL550 ("empty" two-domain I-A(b) without a bound peptide) or Vehicle, reduced clinical signs of EAE, prevented trafficking of cells outside the spleen, significantly reduced the frequency of CD226 and T-bet expressing CD4+ T-cells in blood and inhibited expansion of CD44 expressing CD4+ T-cells in blood and spleen. Concomitantly, RTL551 selectively reduced CNS inflammatory lesions, absolute numbers of CNS infiltrating T-bet expressing CD4+ T-cells and IL-17 and IFN-γ secretion by CNS derived MOG-35-55 reactive cells cultured ex vivo. These novel results demonstrate that a major effect of RTL therapy is to attenuate Th1 specific changes in CD4+ T-cells during EAE and prevent expansion of effector T-cells that mediate clinical signs and CNS inflammation in EAE.
Isoreticular expansion of polyMOFs achieves high surface area materials (2017)

The concept of isoreticular chemistry has become a core principle in metal-organic framework (MOF) materials. Isoreticular chemistry has shown that organic ligands of different sizes, but with a common geometry/symmetry can be used to generate MOFs of related topologies, but with expanded pore sizes and volumes. In this report, polymer-MOF hybrid materials (polyMOFs) with a UiO (UiO = University of Oslo) architecture are shown to adhere to the principle of isoreticular expansion, generating polyMOFs with large surface areas and enhanced stability.
Cd8+ T Cells Can Block Herpes Simplex Virus Type 1 (HSV-1) Reactivation from Latency in Sensory Neurons (2000)

Recurrent herpes simplex virus type 1 (HSV-1) disease usually results from reactivation of latent virus in sensory neurons and transmission to peripheral sites. Therefore, defining the mechanisms that maintain HSV-1 in a latent state in sensory neurons may provide new approaches to reducing susceptibility to recurrent herpetic disease. After primary HSV-1 corneal infection, CD8(+) T cells infiltrate the trigeminal ganglia (TGs) of mice, and are retained in latently infected ganglia. Here we demonstrate that CD8(+) T cells that are present in the TGs at the time of excision can maintain HSV-1 in a latent state in sensory neurons in ex vivo TG cultures. Latently infected neurons expressed viral genome and some expressed HSV-1 immediate early and early proteins, but did not produce HSV-1 late proteins or infectious virions. Addition of anti-CD8alpha monoclonal antibody 5 d after culture initiation induced HSV-1 reactivation, as demonstrated by production of viral late proteins and infectious virions. Thus, CD8(+) T cells can prevent HSV-1 reactivation without destroying the infected neurons. We propose that when the intrinsic capacity of neurons to inhibit HSV-1 reactivation from latency is compromised, production of HSV-1 immediate early and early proteins might activate CD8(+) T cells aborting virion production.
Expression of platelet-derived growth-factor B-chain mRNA and tumor angiogenesis in invasive transitional cell carcinoma of the upper urinary tract. (1997)

In several types of carcinoma, angiogenesis is associated with metastasis and might be a prognostic indicator. Platelet-derived growth factor (PDGF) is one of several growth factors known; it is involved in the regulation of cell migration and proliferation. There have been few reports, however, dealing with the expression of PDGF B-chain mRNA and angiogenesis in transitional cell carcinoma. We evaluated both the expression of PDGF B-chain mRNA and angiogenesis in transitional cell carcinoma of the upper urinary tract and examined their interrelation with metastasis, patient prognosis, and other established clinicopathologic parameters. For this purpose, formalin-fixed, paraffin-embedded tumor tissues from 91 patients with invasive tumors were analyzed with in situ hybridization for PDGF B-chain mRNA and immunohistochemical staining of Factor VIII-related antigen to assess angiogenesis. The expression of PDGF B-chain mRNA was positive in 59 (66%) of the 91 patients. Microvessel density was significantly increased in positive PDGF B-chain mRNA cases (P < .0001). There was no significance, however, in any relationship between the expression of PDGF B-chain mRNA or between the microvessel density and the clinicopathologic findings, metastasis, or prognosis. Assessment of the expression of PDGF B-chain mRNA and microvessel density seems to be of no real value in predicting either the risk of metastasis or the prognosis in transitional cell carcinoma of the upper urinary tract.
Chemo-enzymatic synthesis of 4-methylumbelliferyl β-(1→4)-d-xylooligosides: new substrates for β-d-xylanase assays (2004)

Transglycosylation catalyzed by a beta-D-xylosidase from Aspergillus sp. was used to synthesize a set of 4-methylumbelliferyl (MU) beta-1-->4-D-xylooligosides having the common structure [beta-D-Xyl-(1-->4)]2-5-beta-D-Xyl-MU. MU xylobioside synthesized chemically by the condensation of protected MU beta-D-xylopyranoside with ethyl 2,3,4-tri-O-acetyl-1-thio-beta-D-xylopyranoside was used as a substrate for transglycosylation with the beta-D-xylosidase from Aspergillus sp. to produce higher MU xylooligosides. The structures of oligosaccharides obtained were established by 1H and 13C NMR spectroscopy and electrospray tandem mass spectrometry. MU beta-D-xylooligosides synthesized were tested as fluorogenic substrates for the GH-10 family beta-D-xylanase from Aspergillus orizae and the GH-11 family beta-D-xylanase I from Trichoderma reesei. Both xylanases released the aglycone from MU xylobioside and the corresponding trioside. With substrates having d.p. 4 and 5, the enzymes manifested endolytic activities, splitting off MU, MUX, and MUX2 primarily.
Zinc(II)-Templated Synthesis of a [2]-Catenane Consisting of a 2,2‘,6‘,2‘ ‘-Terpyridine-Incorporating Cycle and a 1,10-Phenanthroline-Containing Ring (2003)

A nonsymmetrical [2]-catenane has been synthesized, with a 5-coordinated metal center (Zn(2+)) as template. One of the two rings contains a terdentate ligand (2,2',6',2' '-terpyridine) and the other one incorporates a bidentate chelate (1,10-phenanthroline). The first ring was prepared separately and, subsequently, Zn(2+) was used as the gathering and threading element to pass the stringlike component through the ring. This open-chain species bears two terminal olefins, which were reacted with Grubbs first-generation catalyst (ring-closing metathesis) to afford the desired catenane. Hydrogenation of the double bond and removal of the zinc(II) template afforded the final free [2]-catenane in 40% yield from the terdentate ligand-containing cycle and the diolefinic compound. Complexation studies on this new pentacoordinating catenane were carried out with Fe(II) or Cu(II). The most interesting observation is that the 5-coordinated complexes obtained are strongly stabilized. Their electrochemical reduction occurs at negative potentials.
Failure of feedback as a putative common mechanism of spreading depolarizations in migraine and stroke (2008)

The stability of cortical function depends critically on proper regulation. Under conditions of migraine and stroke a breakdown of transmembrane chemical gradients can spread through cortical tissue. A concomitant component of this emergent spatio-temporal pattern is a depolarization of cells detected as slow voltage variations. The propagation velocity of approximately 3 mm/min indicates a contribution of diffusion. We propose a mechanism for spreading depolarizations (SD) that rests upon a nonlocal or noninstantaneous feedback in a reaction-diffusion system. Depending upon the characteristic space and time scales of the feedback, the propagation of cortical SD can be suppressed by shifting the bifurcation line, which separates the parameter regime of pulse propagation from the regime where a local disturbance dies out. The optimization of this feedback is elaborated for different control schemes and ranges of control parameters.
Implantable Parylene MEMS for Glaucoma Therapy (2005)

An implantable glaucoma management system is presented for the first time. Glaucoma is an incurable disease characterized by gradual visual field loss that eventually results in blindness. Studies indicate that reduction of intraocular pressure reduces the rate of disease progress. A passive parylene MEMS pressure sensor and drainage shunt comprise a complete system for the detection and alleviation of elevated intraocular pressure. Tissue anchors for securing the pressure sensor to the iris have been developed to facilitate direct and convenient optical monitoring of intraocular pressure.
Cold-sensitive mutants of Taq DNA polymerase provide a hot start for PCR (2003)

Although the thermophilic bacterium Thermus aquaticus grows optimally at 70 degrees C and cannot grow at moderate temperatures, its DNA polymerase I has significant activity at 20-37 degrees C. This activity is a bane to some PCRs, since it catalyzes non-specific priming. We report mutations of Klentaq (an N-terminal deletion variant) DNA polymerase that have markedly reduced activity at 37 degrees C yet retain apparently normal activity at 68 degrees C and resistance at 95 degrees C. The first four of these mutations are clustered on the outside surface of the enzyme, nowhere near the active site, but at the hinge point of a domain that has been proposed to move at each cycle of nucleotide incorporation. We show that the novel cold-sensitive mutants can provide a hot start for PCR and exhibit slightly improved fidelity.
Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation (2010)

CD8+ T cells play a critical role in the immune response to viral pathogens. Persistent human cytomegalovirus (HCMV) infection results in a strong increase in the number of virus-specific, quiescent effector-type CD8+ T cells with constitutive cytolytic activity, but the molecular pathways involved in the induction and maintenance of these cells are unknown. We show here that HCMV infection induced acute and lasting changes in the transcriptomes of virus-reactive T cells collected from HCMV-seropositive patients at distinct stages of infection. Enhanced cell cycle and metabolic activity was restricted to the acute phase of the response, but at all stages, HCMV-specific CD8+ T cells expressed the Th1-associated transcription factors T-bet (TBX21) and eomesodermin (EOMES), in parallel with continuous expression of IFNG mRNA and IFN-γ-regulated genes. The cytolytic proteins granzyme B and perforin as well as the fractalkine-binding chemokine receptor CX3CR1 were found in virus-reactive cells throughout the response. During HCMV latency, virus-specific CD8+ T cells lacked the typical features of exhausted cells found in other chronic infections. Persistent effector cell traits together with the permanent changes in chemokine receptor usage of virus-specific, nonexhausted, long-lived CD8+ T cells may be crucial to maintain lifelong protection from HCMV reactivation.
Overexpressed P-Cadherin/CDH3 Promotes Motility of Pancreatic Cancer Cells by Interacting with p120ctn and Activating Rho-Family GTPases (2005)

P-Cadherin/CDH3 belongs to the family of classic cadherins that are engaged in various cellular activities including motility, invasion, and signaling of tumor cells, in addition to cell adhesion. However, the biological roles of P-cadherin itself are not fully characterized. Based on information derived from a previous genome-wide cDNA microarray analysis of microdissected pancreatic ductal adenocarcinoma (PDAC), we focused on P-cadherin as one of the genes most strongly overexpressed in the great majority of PDACs. To investigate the consequences of overexpression of P-cadherin in terms of pancreatic carcinogenesis and tumor progression, we used a P-cadherin-deficient PDAC cell line, Panc-1, to construct a cell line (Panc1-CDH3) that stably overexpressed P-cadherin. Induction of P-cadherin in Panc1-CDH3 increased the motility of the cancer cells, but a blocking antibody against P-cadherin suppressed the motility in vitro. Overexpression of P-cadherin was strongly associated with cytoplasmic accumulation of one of the catenins, p120ctn, and cadherin switching in PDAC cells. Moreover, P-cadherin-dependent activation of cell motility was associated with activation of Rho GTPases, Rac1 and Cdc42, through accumulation of p120ctn in cytoplasm and cadherin switching. These findings suggest that overexpression of P-cadherin is likely to be related to the biological aggressiveness of PDACs; blocking of P-cadherin activity or its associated signaling could be a novel therapeutic approach for treatment of aggressive pancreatic cancers.
Neuropeptides and the puzzle of bone remodeling: State of the art (1996)

Bone metabolism is dependent on cells of the osteoblast and osteoclast lineage. These cells play a major role in the synthesis and degradation of osteoid and in its mineralization and demineralization. Bone cells are under the influence of various systemic and local auto/paracrine factors. One further regulatory element that can play both a sensory/ afferent and a regulatory/efferent role, consists of neuropeptide-containing nerves. In particular, the calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) have been implicated; their distribution in bone and their molecular biology are discussed in some detail. Bone neuropeptides can function as direct bone cell regulators, with additional amplifying indirect effects mediated by vascular endothelial cells, monocyte/macrophages and mast cells and their mediators. Recent experimental and clinical work has implicated bone nerves in processes varying from normal remodelling to fracture healing and non-union. Apart from systemic endocrine influences on bone stock and osteoclast/ osteoblast coupling (activation-resorption-formation cycle) mediated by local auto/paracrine factors, bone nerves/neuropeptides may explain why various inputs/outputs are transformed in a meaningful way to altered mass and quality of bone.
Flavan-3-ols Isolated from Some Medicinal Plants Inhibiting COX-1 and COX-2 Catalysed Prostaglandin Biosynthesis (1998)

Extracts from the four plant species Atuna racemosa Raf. ssp. racemosa, Syzygium corynocarpum (A. Gray) C. Muell., Syzygium malaccense (L.) Merr. & Perry and Vantanea peruviana Macbr., traditionally used for inflammatory conditions, were fractionated using a cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro assay. The flavan-3-ol derivatives (+)-catechin, (+)-gallocatechin, 4'-O-Me-ent-gallocatechin, ouratea-catechin and ouratea-proanthocynidin A were isolated as active principles. The IC50 values ranged from 3.3 microM to 138 microM whilst indomethacin under the same test conditions had an IC50 value of 1.1 microM. The flavonol rhamnosides mearnsitrin, myricitrin and quercitrin were also isolated. When further tested for inhibitory effect on cyclooxygenase-2 catalysed prostaglandin biosynthesis, the five flavan-3-ol derivatives exhibited from equal to weaker inhibitory potencies, as compared to their cyclooxygenase-1 inhibitory effects. The flavonol rhamnosides were inactive towards both enzymes.
Cloning of the human IL‐13Rα1 chain and reconstitution with the IL‐4Rα of a functional IL‐4/IL‐13 receptor complex (1997)

The human homologue of the recently cloned murine IL-13 binding protein (IL-13R alpha1) was cloned from a cDNA library derived from the carcinoma cell line CAKI-1. The cloned cDNA encodes a 427 amino acid protein with two consensus patterns characteristic of the hematopoietic cytokine receptor family and a short cytoplasmic tail. The human protein is 74% identical to the murine IL-13R alpha1, and 27% identical to the human IL-13R alpha2. CHO cells expressing recombinant hIL-13R alpha1 specifically bind IL-13 (Kd approximately 4 nM) but not IL-4. Co-expression of the cloned cDNA with that of IL-4R alpha resulted in a receptor complex that displayed high affinity for IL-13 (Kd approximately 30 pM), and that allowed cross-competition of IL-13 and IL-4. Electrophoretic mobility shift assay showed that IL-13 and IL-4 were able to activate Stat6 in cells expressing both IL-4R alpha and IL-13R alpha1, while no activation was observed in cells expressing either one or the other alone.
A CRISPR design for next-generation antimicrobials (2014)

Two recent publications have demonstrated how delivering CRISPR nucleases provides a promising solution to the growing problem of bacterial antibiotic resistance.
Mesenchymal stem cells' interaction with skin: Wound-healing effect on fibroblast cells and skin tissue (2010)

Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to secrete growth factors. Because wound healing is associated with fibroblast cells and extracellular matrix (ECM) in the dermis and epidermis, we used fibroblast cells to resolve the question of whether or not MSCs regulate wound healing in vitro via a regenerative function. Using a cell proliferation assay, we demonstrated that conditioned media (CM) obtained from MSCs significantly enhanced the cell survival ability of fibroblast cells. Moreover, by measurement of mRNA and protein, we observed that CM also promoted the production or secretion of collagen, elastin, and fibronectin. To better understand the effects of ECM-related wound healing, we measured the level of collagen-degradative enzyme (matrix metalloprotease-1), and observed that CM suppressed matrix metalloprotease-1 expression. For the determination of oxidative stress, which has an influence on wound healing, we performed the superoxide dismutase and glutathione peroxidase assays; our results suggested that CM inhibited the oxidative stress of fibroblast cells. In order to widely investigate the wound-healing effects of MSCs, we performed in vivo experiments, and observed that MSCs stimulated wound healing. In summary, the results of this study suggest that MSCs inhibit the loss of fibroblast cells and ECM, and accumulation of oxidative stress. We found that MSCs stimulate wound healing in vitro and in vivo, suggesting that MSCs have the potential to enhance wound healing.
Ionotropic and metabotropic glutamate receptor protein expression in glioneuronal tumours from patients with intractable epilepsy (2001)

Glioneuronal tumours are an increasingly recognized cause of chronic pharmaco-resistant epilepsy. In the present study the immunocytochemical expression of various glutamate receptor (GluR) subtypes was investigated in 41 gangliogliomas (GG) and 16 dysembryoplastic neuroepithelial tumours (DNT) from patients with intractable epilepsy. Immunocytochemistry with antibodies specific for ionotropic NR1, NR2A/B (NMDA) GluR1, GluR2 (AMPA), GluR5-7 (kainate), and metabotropic mGluR1, mGluR2-3, mGluR5, mGluR7a subtypes demonstrated in both GG and DNT the presence of an highly differentiated neuronal population, containing subunits from each receptor class. More than 50% of tumours contained a high percentage of neuronal cells immunolabelled for NMDA, AMPA and kainate receptor subunits. A high percentage of neurones showed strong expression of NR2A-B, which co-localized with NR1. Group I mGluRs (mGluR1 and mGluR5) were highly represented in the neuronal component of the tumours. Immunolabelling for several GluRs was also present in the glial component. Increased expression of mGluR2-3, mGluR5 and GluR5-7 was observed in reactive astrocytes in the perilesional zone compared to normal cortex. The neurochemical profile of glioneuronal tumours, with high expression of specific GluR subtypes, supports the central role of glutamatergic transmission in the mechanisms underlying the intrinsic and high epileptogenicity of these lesions.
Pseudomonas aeruginosa possesses homologues ofmammalian phenylalanine hydroxylase and 4 alpha-carbinolamine dehydratase/DCoHas part of a three-component gene cluster. (1994)

Pseudomonas aeruginosa possesses a multigene operon that includes phenylalanine hydroxylase (PhhA; phenylalanine 4-monooxygenase, EC 1.14.16.1). phhA encodes PhhA (M(r) = 30,288), phhB (M(r) = 13,333) encodes a homologue of mammalian 4 alpha-carbinolamine dehydratase/homeodomain protein transregulator, and phhC encodes an aromatic aminotransferase (M(r) = 43,237). The reading frames specifying phhB and phhC overlap by 2 bases. The P. aeruginosa PhhA appears to contain iron and is pterin dependent. Unlike the multimeric mammalian hydroxylase, the native P. aeruginosa enzyme is a monomer. The P. aeruginosa PhhA is homologous with mammalian PhhA, tryptophan hydroxylase, and tyrosine hydroxylase. Expression of PhhA from its native promoter required phhB. This may suggest a positive regulatory role for phhB, consistent with the dual catalytic and regulatory roles of the corresponding mammalian homologue.
Immunomodulatory therapy of eosinophil‐associated gastrointestinal diseases (2008)

Eosinophil-associated gastrointestinal disorders (EGIDs), including eosinophilic esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of increasingly recognized inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Significant morbidity is associated with the development of esophageal strictures in some patients. Immune-mediated reactions to food allergens appear to drive the inflammation in a subset of patients, especially those with solitary EE, but dietary interventions remain difficult in EE and are less effective in EG. Despite the increasing incidence of these disorders and their increased recognition by physicians, there are currently no medications that either United States or European Union regulatory agencies have specifically approved for use in EGIDs. This lack of safe and effective therapies for EGIDs is a major obstacle in the care of these patients and underscores the need for new therapeutic approaches. This review briefly discusses the currently available 'off label' drug treatments for EGIDs, most notably topical and systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible therapeutic targets, and conversely, clinical trials of mechanistically-targeted therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is discussed as an introduction to mechanistically-targeted immunotherapeutics. The two biologic categories that have been used in EGIDs, anti-IgE (omalizumab) and anti-IL-5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis, biologic therapeutics currently in early trials for asthma management are also briefly discussed as potential therapeutic agents for EGIDs. Given the deficiencies of current therapeutics and the rapidly advancing knowledge of the pathogenesis of these disorders, EGIDs are an ideal model for translating recent advances in understanding immunopathogenesis into mechanistically-based therapeutics. Further understanding of the early events in pathogenesis is also needed to develop preventive and disease-modifying treatments.