gebhart/patrepeval huggingface dataset:
Consequences of Aging on Memory CD4 T-Cell Responses (2012)

Previous studies have shown an accumulation of memory CD4+ T cells (TMs) that was associated with aging. Although aging has been linked to a shift from naïve to a memory-dominant population, very little is known about the consequences of those changes on CD4 driven alloimmune responses. We studied age-dependent immune responses to cardiac allografts from DBA/2 donor mice into old and young B6 recipients during a primary immune response and following sensitization. Cardiac transplant survival data reflected age-specific modifications of CD4+ TMs during an initial alloantigen encounter and following sensitization. Primary allografts were rejected in a significantly slower fashion in older recipients (6.8 ± 0.7 vs. 10.0 ± 1.3d, p< 0.001). In sharp contrast, cardiac allografts transplanted following an initial sensitization with donor-specific skin grafts at -4 wks were rejected at a comparable and accelerated tempo in both, old and young recipients (4.9 ± 0.1 vs. 5.6 ± 0.6 d, p=ns). Next, wE delineated the impact of aging on CD4+ TMs before and following donor-specific sensitization. We found that the frequency of CD4+ TMs increased significantly with age in naive mice. However, old naive CD4+ TMs expressed less IFN-γ, IL-2 and IL-17 (IFN-γ, IL-17, p< 0.01; IL-2; p< 0.05 compared to young CD4+ TMs). Of note, following sensitization, old CD4+ TMs demonstrated increased IL-17 and IFN-γ but decreased IL-2 levels (IFN-γ, p< 0.05; IL-17, p< 0.01; IL-2, p< 0.05). Moreover, peripheral memory like CD4+CD25+CD44hiFoxp3+ Tregs which have the capacity to secret IL-17 had significantly increased following donor-specific sensitization in old recipients (p< 0.01). Next, we performed adoptive transfer experiments of old and young CD4+TMs from sensitized animals into RAG-1 KO mice testing their functional capacity in vivo. We were able to confirm an age-independent capacity of effector memory CD4+ T cells following sensitization as skin transplants were effectively and rapidly rejected by both young and old primed effector memory CD4+T cells. In vitro, we observed a similar colonial expansion of old and young sensitized CD4+ memory T cells by 3H incorporation (p=ns). Old memory T-cells are functional compromised. However, effector capacities appeared intact and were age-independent following sensitization. The functional capacities of memory CD4+ T cells during primary and secondary immune responses are of critical clinical significance when transplanting older recipients.
Elimination of human leukemia cells in NOD/SCID mice by WT1-TCR gene–transduced human T cells (2005)

Abstract Cytotoxic T lymphocytes (CTLs) specific for an HLA-A2–presented peptide epitope of the Wilms tumor antigen-1 (WT1) can selectively kill immature human leukemia progenitor and stem cells in vitro. In this study we have used retroviral gene transfer to introduce a WT1-specific T-cell receptor (TCR) into T lymphocytes obtained from patients with leukemia and from healthy donors. TCR-transduced T cells kill leukemia cells in vitro and display WT1-specific cytokine production. Intravenous injection of TCR-transduced T cells into nonobese diabetic–severe combined immunodeficiency (NOD/SCID) mice harboring human leukemia cells resulted in leukemia elimination, whereas transfer of control T cells transduced with an irrelevant TCR was ineffective. The data suggest that adoptive immunotherapy with WT1-TCR gene–modified patient T cells should be considered for the treatment of leukemia.
Structure of a 16-nm Cage Designed by Using Protein Oligomers (2012)

Designing protein molecules that will assemble into various kinds of ordered materials represents an important challenge in nanotechnology. We report the crystal structure of a 12-subunit protein cage that self-assembles by design to form a tetrahedral structure roughly 16 nanometers in diameter. The strategy of fusing together oligomeric protein domains can be generalized to produce other kinds of cages or extended materials.
Molecular biology, genetics and biochemistry of the repulsive guidance molecule family (2009)

RGMs (repulsive guidance molecules) comprise a recently discovered family of GPI (glycosylphosphatidylinositol)-linked cell-membrane-associated proteins found in most vertebrate species. The three proteins, RGMa, RGMb and RGMc, products of distinct single-copy genes that arose early in vertebrate evolution, are approximately 40-50% identical to each other in primary amino acid sequence, and share similarities in predicted protein domains and overall structure, as inferred by ab initio molecular modelling; yet the respective proteins appear to undergo distinct biosynthetic and processing steps, whose regulation has not been characterized to date. Each RGM also displays a discrete tissue-specific pattern of gene and protein expression, and each is proposed to have unique biological functions, ranging from axonal guidance during development (RGMa) to regulation of systemic iron metabolism (RGMc). All three RGM proteins appear capable of binding selected BMPs (bone morphogenetic proteins), and interactions with BMPs mediate at least some of the biological effects of RGMc on iron metabolism, but to date no role for BMPs has been defined in the actions of RGMa or RGMb. RGMa and RGMc have been shown to bind to the transmembrane protein neogenin, which acts as a critical receptor to mediate the biological effects of RGMa on repulsive axonal guidance and on neuronal survival, but its role in the actions of RGMc remains to be elucidated. Similarly, the full spectrum of biological functions of the three RGMs has not been completely characterized yet, and will remain an active topic of ongoing investigation.
An Asn to Lys Polymorphism in the Third Intracellular Loop of the Human α2A-Adrenergic Receptor Imparts Enhanced Agonist-promoted Gi Coupling (2000)

alpha(2A)-Adrenergic receptors (alpha(2A)AR) are presynaptic autoinhibitory receptors of noradrenergic neurons in the central and peripheral sympathetic nervous systems, which act to dynamically regulate neurotransmitter release. Signaling through the G(i)/G(o) family of G-proteins, the receptor subserves numerous homeostatic and central nervous system functions. A single nucleotide polymorphism of this receptor, which results in an Asn to Lys substitution at amino acid 251 of the third intracellular loop, was identified in the human population. The frequency of Lys-251 was 10-fold greater in African-Americans than in Caucasians, but was not associated with essential hypertension. To determine the consequences of this substitution, wild-type and Lys-251 receptors were expressed in CHO and COS-7 cells. Expression, ligand binding, and basal receptor function were unaffected by the substitution. However, agonist-promoted [(35)S]GTPgammaS binding was approximately 40% greater with the Lys-251 receptor. This enhanced agonist function was observed with catecholamines, azepines, and imidazolines albeit to different degrees. In studies of agonist-promoted functional coupling to G(i), the polymorphic receptor displayed enhanced inhibition of adenylyl cyclase (60 +/- 4. 4 versus 46 +/- 4.1% inhibition) and markedly enhanced stimulation of MAP kinase (57 +/- 9 versus 15- +/- 2-fold increase over basal) compared with wild-type alpha(2A)AR. The potency of epinephrine in stimulating inositol phosphate accumulation was increased approximately 4 fold with the Lys-251 receptor. Unlike previously described variants of G-protein-coupled receptors, where the minor species causes either a loss of function or increased non-agonist function, Lys-251 alpha(2A)AR represents a new class of polymorphism whose phenotype is a gain of agonist-promoted function.
Targeting SDF-1/CXCL12 with a Ligand That Prevents Activation of CXCR4 through Structure-Based Drug Design (2010)

CXCL12 is an attractive target for clinical therapy because of its involvement in autoimmune diseases, cancer growth, metastasis, and neovascularization. Tyrosine sulfation at three positions in the CXCR4 N-terminus is crucial for specific, high-affinity CXCL12 binding. An NMR structure of the complex between the CXCL12 dimer and a sulfotyrosine-containing CXCR4 fragment enabled high-throughput in silico screening for inhibitors of the chemokine-receptor interface. A total of 1.4 million compounds from the ZINC database were docked into a cleft on the CXCL12 surface normally occupied by sulfotyrosine 21 (sY21), and five were selected for experimental screening. NMR titrations with CXCL12 revealed that four of the compounds occupy the sY21 site, one of which binds with a K(d) of 64 microM. This compound selectively inhibits SDF1-induced CXCR4 signaling in THP1 cells. Our results suggest that sulfotyrosine recognition sites can be targeted for the development of novel chemokine inhibitors.
Ground State of the Electron Gas by a Stochastic Method (1980)

An exact stochastic simulation of the Schroedinger equation for charged bosons and fermions has been used to calculate the correlation energies, to locate the transitions to their respective crystal phases at zero temperature within 10%, and to establish the stability at intermediate densities of a ferromagnetic fluid of electrons.
Analysis of Anti-drug Antibodies (ADA) to Adalimumab in Patient Serum Using a Novel Homogeneous Mobility Shift Assay (2010)

Purpose: Anti-TNF-α drugs such as infliximab (IFX) and adalimumab have been shown to be effective in treating inflammatory bowel disease (IBD). However, induction of ADA in the treated patients may reduce the drug's efficacy and/or induce adverse effects. Indeed, ADAs have been found not only in patients treated with IFX, but also in patients treated with adalimumab. Monitoring of ADA and drug levels in individual patients may help optimize treatment and dosing of the patient. We have developed a proprietary mobility shift assay to accurately measure in the serum both HACA (Human Anti-Chimeric Antibody) and IFX from IFX-treated patients. This assay overcame the major limitation of the current solid-phase assays for detecting HACA, namely the inability to accurately detect HACA in the presence of IFX in circulation. In the present study, we have evaluated this new assay to measure serum ADA and drug levels in patients treated with the humanized antibody drug, adalimumab. Methods: The mobility shift assay was based on the shift in retention time of a free antigen versus the antigen-antibody immunocomplex on size-exclusion chromatography. Fluorophore-labeled adalimumab or TNF-α and internal control were mixed with serum samples to measure the mobility shift of free adalimumab and TNF-α in the presence of ADA or drug. The changes in the ratio of free adalimumab or TNF-α to internal control are the indicators of the immunocomplex formation. Serum concentrations of ADA or adalimumab were determined with standard curves generated by incubating with different concentrations of anti-human IgG antibody or purified adalimumab. Using this assay, we measured adalimumab and ADA levels in sera collected from IBD patients treated with adalimumab. Results: Dose-response curves were generated with anti-human IgG antibody for the measurement of mobility shift of labeled adalimumab. The detection limit of the assay was 1 ng of anti-human IgG. Detection of ADA was also demonstrated in the presence of exogenously added adalimumab. Sera from fifty healthy controls were tested for the ADA and all of the samples had the ADA levels below the detection limit. To measure the drug concentration in patients treated with adalimumab, we generated a standard curve with different amount of adalimumab on the mobility shift of labeled TNF-α and the detection limit of adalimumab is 10 ng. Conclusion: We have applied our proprietary mobility shift assay to measure the ADA and adalimumab levels in serum samples from patients treated with adalimumab. The assay was found to be reproducible with high sensitivity and accuracy, and can be used to evaluate ADA and drug levels in serum samples from patient treated with adalimumab. Disclosure: Dr Wang - Employee: Prometheus Laboratories, Inc. Mrs. Ohrmund - Employee: Prometheus Laboratories, Inc. Dr Ling - Consultant: Prometheus Laboratories, Inc. Dr Singh - Employee: Prometheus Laboratories, Inc.
Control of Stochasticity in Eukaryotic Gene Expression (2004)

Noise, or random fluctuations, in gene expression may produce variability in cellular behavior. To measure the noise intrinsic to eukaryotic gene expression, we quantified the differences in expression of two alleles in a diploid cell. We found that such noise is gene-specific and not dependent on the regulatory pathway or absolute rate of expression. We propose a model in which the balance between promoter activation and transcription influences the variability in messenger RNA levels. To confirm the predictions of our model, we identified both cis- and trans-acting mutations that alter the noise of gene expression. These mutations suggest that noise is an evolvable trait that can be optimized to balance fidelity and diversity in eukaryotic gene expression.
Neutrophils That Infiltrate the Central Nervous System Regulate T Cell Responses (2005)

Regulation of inflammatory responses is critical to progression of organ-specific autoimmune disease. Although many candidate cell types have been identified, immunoregulatory activity has rarely been directly assayed and never from the CNS. We have analyzed the regulatory capability of Gr-1high neutrophils isolated from the CNS of mice with experimental autoimmune encephalomyelitis. Proportions of neutrophils were markedly increased in the CNS of IFN-gamma-deficient mice. Strikingly, CNS-derived neutrophils, whether or not they derived from IFN-gamma-deficient mice, were potent suppressors of T cell responses to myelin or adjuvant Ags. Neutrophil suppressor activity was absolutely dependent on IFN-gamma production by target T cells, and suppression was abrogated by blocking NO synthase. These data identify an immunoregulatory capacity for neutrophils, and indicate that interplay between IFN-gamma, NO, and activated Gr-1high neutrophils within the target organ determines the outcome of inflammatory and potentially autoimmune T cell responses.
Cloning and Bacterial Expression of a Sesquiterpene Cyclase from Hyoscyamus muticus and Its Molecular Comparison to Related Terpene Cyclases (1995)

Genomic and cDNA clones for vetispiradiene synthase, a sesquiterpene cyclase found in Hyoscyamus muticus, were isolated using a combination of reverse transcription-polymerase chain reactions and conventional cloning procedures. RNA blot hybridization demonstrated an induction of mRNA consistent with the induction of cyclase enzyme activity in elicitor-treated cells, DNA blot hybridization indicated a gene family of 6 to 8 members, and bacterial expression of 3 cDNA clones indicated that each coded for a vetispiradiene synthase enzyme activity catalyzing the synthesis of a single reaction product. Intron-exon organization of the vetispiradiene synthase gene was identical with that previously described for 5-epi-aristolochene synthase (tobacco sesquiterpene cyclase) and casbene synthase (castor bean diterpene cyclase), and the vetispiradiene synthase amino acid sequence was 77% identical with and 81% similar to the tobacco sesquiterpene cyclase. Regions of the vetispiradiene synthase sequence centered around amino acids 60, 100, and 370 were conspicuously different relative to the tobacco sesquiterpene cyclase. The sequence similarity between the tobacco and H. muticus enzymes is suggested to be reflective of the conservation of several partial reactions common to both enzymes, and the differences may be reflective of a partial reaction unique to each enzyme.
Submicron-resolved relief formation in poled glasses and glass-metal nanocomposites (2008)

The formation of a spatial relief reproducing that of the anode as a result of the thermal poling of glasses and glass-metal nanocomposites in a strong electric field has been studied by atomic force microscopy. The anode surface patterns exhibited either a square grid or a rectangular grating with a depth of 120 nm, a strip width of 0.5 μm, and a period of 1 μm manufactured using electron-beam lithography and ion etching on the surface of an n-type single crystal silicon wafer. The relief depth formed on the surface of poled samples varied within 5–15 nm, depending on the experimental conditions. The mechanism of relief formation in this system is discussed.
Clinical applications of dendritic cell vaccines. (2000)

Dendritic cells play a central role in the presentation of antigen to naïve T-cells and the induction of primary immune responses. Preclinical studies have established that dendritic cells loaded with antigens ex vivo induce potent antitumor and antiviral immune responses in vitro and in vivo. This has lead to a proliferation of clinical trials testing their effectiveness in humans, particularly with advanced malignancies. The few reported studies suggest that clinically relevant immune responses may be induced against some types of malignancies. Many questions regarding the best type of dendritic cell, degree of maturity, choice of antigen, route and schedule of administration, targeting to lymphoid tissue and use of additional adjuvants will need to be answered in preclinical and clinical studies as the field of dendritic cell-based immunotherapy progresses.
Role of vascular cell adhesion molecule 1/very late activation antigen 4 and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 interactions in antigen-induced eosinophil and T cell recruitment into the tissue. (1994)

To determine the role of vascular cell adhesion molecule 1 (VCAM-1)/very late activation antigen 4 (VLA-4) and intercellular adhesion molecule 1 (ICAM-1)/lymphocyte function-associated antigen 1 (LFA-1) interactions in causing antigen-induced eosinophil and T cell recruitment into the tissue, we studied the effect of the in vivo blocking of VCAM-1, ICAM-1, VLA-4, and LFA-1 by pretreatment with monoclonal antibodies (mAb) to these four adhesion molecules on the eosinophil and T cell infiltration of the trachea induced by antigen inhalation in mice. The in vivo blocking of VCAM-1 and VLA-4, but not of ICAM-1 and LFA-1, prevented antigen-induced eosinophil infiltration into the mouse trachea. On the contrary, the in vivo blocking of VCAM-1 and VLA-4, but not of ICAM-1 and LFA-1, increased blood eosinophil counts after antigen challenge, but did not affect blood eosinophil counts without antigen challenge in sensitized mice. Furthermore, the expression of VCAM-1 but not ICAM-1 was strongly induced on the endothelium of the trachea after antigen challenge. In addition, pretreatment with anti-IL-4 mAb decreased the antigen-induced VCAM-1 expression only by 27% and had no significant effect on antigen-induced eosinophil infiltration into the trachea. The in vivo blocking of VCAM-1 and VLA-4 inhibited antigen-induced CD4+ and CD8+ T cell infiltration into the trachea more potently than that of ICAM-1 and LFA-1. In contrast, regardless of antigen challenge, the in vivo blocking of LFA-1, but not of ICAM-1, increased blood lymphocyte counts more than that of VCAM-1 and VLA-4. These results indicate that VCAM-1/VLA-4 interaction plays a predominant role in controlling antigen-induced eosinophil and T cell recruitment into the tissue and that the induction of VCAM-1 expression on the endothelium at the site of allergic inflammation regulates this eosinophil and T cell recruitment.
Dynamic channel resource allocation in frequency hopped wireless communication systems (2002)

In a conventional TDMA wireless system, the blocking probability is affected by the worst case interference statistics. Modifying the system to a frequency-hopped CDMA (CDMA-FH) system can change the blocking probability to be determined by average statistics. Hopping patterns can be implemented easily using Latin squares. A system using Latin squares of size n guarantees no users in the same cell share any slots and a user and all users in different cells share only one out of every n slots. Channel coding over hops then suppresses the worst interference. Further improvements may be obtained by allowing users to occupy M out of N slots where M/spl les/N. Centralized and distributed dynamic channel allocation (DCA) algorithms which allow users to have different SIR requirements have been developed to maximize the capacity of the system under a desired blocking probability.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Total Excitation of the Isolated Human Heart (1970)

To obtain information concerning the time course and instantaneous distribution of the excitatory process of the normal human heart, studies were made on isolated human hearts from seven individuals who died from various cerebral conditions, but who had no history of cardiac disease. Measurements were made from as many as 870 intramural terminals. In the isolated human hearts three endocardial areas were synchronously excited 0 to 5 msec after the start of the left ventricular activity potential. These areas increased rapidly in size during the next 5 to 10 msec and became confluent in 15 to 20 msec. The left ventricular areas first excited were (1) high on the anterior paraseptal wall just below the attachment of the mitral valve; (2) central on the left surface of the interventricular septum and (3) posterior paraseptal about one third of the distance from apex to base. The last part of the left ventricle to be activated usually was the posterobasal area. Endocardial activation of the right ventricle was found to start near the insertion of the anterior papillary muscle 5 to 10 msec after onset of the left ventricular cavity potential. Septal activation started in the middle third of the left side of the interventricular septum, somewhat anteriorly, and at the lower third at the junction of the septum and posterior wall. The epicardial excitation pattern reflected the movements of the intramural excitation wave. Conduction velocity was determined in one heart by an appropriate stimulation technic. Atrial excitation, explored in two hearts, spread more or less according to concentric isochronic lines. Control studies, carried out on five canine hearts, disclosed that the pattern of ventricular excitation did not change after isolation and perfusion. However, total excitation was completed earlier in the isolated heart, and conduction velocity increased. Careful mapping illustrations are presented.
Design and Synthesis of [111In]DTPA−Folate for Use as a Tumor-Targeted Radiopharmaceutical (1997)

Folate-conjugated metal chelates have been proposed as potential imaging agents for cancers that overexpress folate receptors. In a previous study, folic acid was linked through its gamma-carboxyl group to deferoxamine (DF), and the 67Ga-labeled complex ([67Ga]DF-folate) was examined for in vivo tumor targeting efficiency in athymic mice with a human tumor cell implant. Although superb tumor-to-background contrast was obtained, slow hepatobiliary clearance would compromise imaging of abdominal tumors such as ovarian cancer. In the present study, folic acid was conjugated to an alternative chelator, diethylenetriaminepentaacetic acid (DTPA), via an ethylenediamine spacer. The desired DTPA-folate (gamma) regioisomer was synthesized by two different approaches, purified by reversed phase column chromatography, and characterized mainly by analytical HPLC, mass spectroscopy, and NMR. In cultured tumor cells, uptake of [111In]DTPA-folate (gamma) was found to be specific for folate receptor-bearing cells, and the kinetics of uptake were similar to those of free folate and other folate-conjugated molecules. In the normal rat, intravenously administered [111In]DTPA-folate (gamma) was found to be rapidly excreted into the urine, giving intestinal levels of radiotracer 10-fold lower than those observed with [67Ga]DF-folate (gamma) at 4 h. In a preliminary mouse imaging study, a folate receptor-positive KB cell tumor was readily visualized by gamma scintigraphy 1 h following intravenous administration of [111In]DTPA-folate (gamma).