gebhart/patrepeval huggingface dataset:
Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses (2010)

A key issue in advancing the use of adoptive cell transfer (ACT) of T cell receptor (TCR) engineered lymphocytes for cancer therapy is demonstrating how TCR transgenic cells repopulate lymphopenic hosts and target tumors in an antigen-specific fashion. ACT of splenocytes from fully immunocompetent HLA-A2.1/K(b) mice transduced with a chimeric murine/human TCR specific for tyrosinase, together with lymphodepletion conditioning, dendritic cell (DC)-based vaccination, and high-dose interleukin-2 (IL-2), had profound antitumor activity against large established MHC- and antigen-matched tumors. Genetic labeling with bioluminescence imaging (BLI) and positron emitting tomography (PET) reporter genes allowed visualization of the distribution and antigen-specific tumor homing of TCR transgenic T cells, with trafficking correlated with antitumor efficacy. After an initial brief stage of systemic distribution, TCR-redirected and genetically labeled T cells demonstrated an early pattern of specific distribution to antigen-matched tumors and locoregional lymph nodes, followed by a more promiscuous distribution 1 wk later with additional accumulation in antigen-mismatched tumors. This approach of TCR engineering and molecular imaging reporter gene labeling is directly translatable to humans and provides useful information on how to clinically develop this mode of therapy.
Phenotypic Differences In Cholinergic Markers Within The Nucleus Basalis In Individuals With Mild Cognitive Impairment (2001)

Major tenet in Alzheimer's disease research has been that cholinergic neurons within the nucleus basalis degenerate, resulting in a cortical cholinergic deficit. Cholinergic innervation to the entire cortical mantle and the loss of choline acetyltransferase (ChAT) activity is consistently correlated.
Index distribution technique for efficient search on unstructured peer-to-peer networks (2008)

Resource indexing is an effective technique for fast, successful search on decentralized, unstructured peer-to-peer (P2P) networks. An index is a summary of resources owned by a node, and is distributed over the P2P network; any node having the index can answer queries on the location of the resources. While more thoroughly distributed indices can make queries answered more quickly with a small hop count, in large-scale networks, such a scheme may not be always effective due to the large space requirement for keeping indices at each node. We propose a new index distribution technique that aims to minimize the hop count required for each query by distributing indices over the network as uniformly as possible, but still in a space-efficient way. To do so, we compute the weight of each index that estimates how many unique resources each index can locate. We give a large weight to an index if it can locate many resources that others cannot. On the other hand, if a resource can be located from an index, we decrease the weights of other indices that can also locate it. Each node selectively keeps the indices with the largest weights, thus increasing the chance of successful queries at the node, while keeping the space requirement minimum. Simulation studies show that our distribution technique is effective in decreasing hop counts and messages needed for resolving queries. It decreases the average hop count by up to 44% with 75%-less messages when used with flooding based queries. Random-walk with our technique also decrease the average hop count by up to 58% with 82%-less messages. Furthermore, the query success rate with a limited timeout condition also increases, approaching nearly to 100%.
Molecular cloning of the CD3 eta subunit identifies a CD3 zeta-related product in thymus-derived cells. (1990)

The CD3 eta subunit of the T-cell antigen receptor forms a heterodimeric structure with the CD3 zeta subunit in thymus-derived lymphoid cells and is apparently involved in signal transduction through the receptor. Here we report the primary structure of murine CD3 eta as deduced from protein microsequencing and cDNA cloning. The mature protein is divided into three domains: a 9-amino acid extracellular segment, a 21-amino acid transmembrane segment including a negatively charged residue characteristic of CD3 subunits, and a 155-amino acid cytoplasmic tail. The NH2-terminal sequences of CD3 eta and CD3 zeta are identical through amino acid 122 of each mature protein but then diverge in the remainder of their respective COOH-terminal regions, consistent with alternatively spliced products of a common gene. The cytoplasmic domain of CD3 eta is 42 amino acids larger than that of CD3 zeta but lacks one of six potential tyrosine phosphorylation sites as well as a putative nucleotide binding site previously identified in CD3 zeta. These structural features presumably account for the difference between CD3 eta and CD3 zeta function and are consistent with the notion that CD3 eta may be an important component of a T-cell receptor isoform(s) during thymic development.
Transgenic mice carrying the human poliovirus receptor: new animal models for study of poliovirus neurovirulence (1994)

Recombinant viruses between the virulent Mahoney and attenuated Sabin 1 strains of poliovirus type 1 were subjected to neurovirulence tests using a transgenic (Tg) mouse line, ICR-PVRTg1, that carried the human poliovirus receptor gene. The Tg mice were inoculated intracerebrally with these recombinant viruses and observed for clinical signs, histopathological lesions, and viral antigens as parameters of neurovirulence of the viruses. These parameters observed in the Tg mice were different for different inoculated viruses. Dose-dependent incidences of paralysis and of death were observed in the Tg mice inoculated with any viruses used. This indicates that values of 50% lethal dose are useful to score a wide range of neurovirulence of poliovirus. The neurovirulence of individual viruses estimated by the Tg mouse model had a strong correlation with those estimated by monkey model. Consequently, the mouse tests identified the neurovirulence determinants on the genome of poliovirus that had been identified by monkey tests. In addition, the mouse tests revealed new neurovirulence determinants, that is, different nucleotides between the two strains at positions 189 and 21 and/or 935 in the 5'-proximal 1,122 nucleotides. The Tg mice used in this study may be suitable for replacing monkeys for investigating poliovirus neurovirulence.
Crystal Structure of 1-Deoxy-d-xylulose 5-Phosphate Synthase, a Crucial Enzyme for Isoprenoids Biosynthesis (2006)

Isopentenyl pyrophosphate (IPP) is a common precursor for the synthesis of all isoprenoids, which have important functions in living organisms. IPP is produced by the mevalonate pathway in archaea, fungi, and animals. In contrast, IPP is synthesized by a mevalonate-independent pathway in most bacteria, algae, and plant plastids. 1-Deoxy-D-xylulose 5-phosphate synthase (DXS) catalyzes the first and the rate-limiting step of the mevalonate-independent pathway and is an attractive target for the development of novel antibiotics, antimalarials, and herbicides. We report here the first structural information on DXS, from Escherichia coli and Deinococcus radiodurans, in complex with the coenzyme thiamine pyrophosphate (TPP). The structure contains three domains (I, II, and III), each of which bears homology to the equivalent domains in transketolase and the E1 subunit of pyruvate dehydrogenase. However, DXS has a novel arrangement of these domains as compared with the other enzymes, such that the active site of DXS is located at the interface of domains I and II in the same monomer, whereas that of transketolase is located at the interface of the dimer. The coenzyme TPP is mostly buried in the complex, but the C-2 atom of its thiazolium ring is exposed to a pocket that is the substrate-binding site. The structures identify residues that may have important roles in catalysis, which have been confirmed by our mutagenesis studies.
A Novel Engineered Peptide, a Narrow-Spectrum Antibiotic, is Effective against Vancomycin-Resistant Enterococcus faecalis (2005)

A novel antienterococcal peptide was prepared by fusing the enterococcal cCF10 pheromone to the channel-forming domain of colicin Ia, forming Enterococcus faecalis pheromonicin (PMC-EF). This peptide was bactericidal against vancomycin-resistant Enterococcus faecalis (VRE) organisms. Electron microscopy and vital dyes confirmed increased membrane permeability. All mice made bacteremic with VRE strains survived when they were treated with PMC-EF, while all controls died.
Concanavalin A-induced Hepatitis in Mice is Prevented by Interleukin (IL)-10 and Exacerbated by Endogenous IL-10 Deficiency (1999)

One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mice provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-10 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL-10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h prior to Con A) and even "early" therapeutic fashion (30 min after Con A) reduced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers of liver injury were significantly increased both in IL-10 KO mice as well as in those receiving anti-IL-10 mAb. Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL-10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-10 deficiency were associated with profound and opposite modifications of the Con A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were diminished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL-10 mAb-treated mice. These results prove the physiological antiinflammatory role of endogenous IL-10 in Con A induced hepatitis and the beneficial effects of IL-10 treatment to prevent this condition.
Nonlinear image estimation using piecewise and local image models (1998)

We introduce a new approach to image estimation based on a flexible constraint framework that encapsulates meaningful structural image assumptions. Piecewise image models (PIMs) and local image models (LIMs) are defined and utilized to estimate noise-corrupted images, PIMs and LIMs are defined by image sets obeying certain piecewise or local image properties, such as piecewise linearity, or local monotonicity. By optimizing local image characteristics imposed by the models, image estimates are produced with respect to the characteristic sets defined by the models. Thus, we propose a new general formulation for nonlinear set-theoretic image estimation. Detailed image estimation algorithms and examples are given using two PIMs: piecewise constant (PICO) and piecewise linear (PILI) models, and two LIMs: locally monotonic (LOMO) and locally convex/concave (LOCO) models. These models define properties that hold over local image neighborhoods, and the corresponding image estimates may be inexpensively computed by iterative optimization algorithms. Forcing the model constraints to hold at every image coordinate of the solution defines a nonlinear regression problem that is generally nonconvex and combinatorial. However, approximate solutions may be computed in reasonable time using the novel generalized deterministic annealing (GDA) optimization technique, which is particularly well suited for locally constrained problems of this type. Results are given for corrupted imagery with signal-to-noise ratio (SNR) as low as 2 dB, demonstrating high quality image estimation as measured by local feature integrity, and improvement in SNR.
Effect of Intermittent Shear Stress on Mechanotransductive Signaling and Osteoblastic Differentiation of Bone Marrow Stromal Cells (2008)

Perfusion culture of osteoprogenitor cells seeded within porous scaffolds suitable for bone tissue engineering is known to enhance deposition of a bone-like extracellular matrix, and the underlying mechanism is thought to involve flow-induced activation of mechanotransductive signaling pathways. Basic studies have shown that mechanotransduction is enhanced by impulse flow and may be mediated through autocrine signaling pathways. To test this, an intermittent flow regimen (5 min on/5 min off ) that exerts impulses on adherent cells and permits accumulation of secreted factors in the cell microenvironment was compared to continuous flow for its ability to stimulate phosphorylation of ERK and p38, synthesis of prostaglandin E2 (PGE2), and expression of mRNA for collagen 1alpha1 (Col-1alpha1), osteopontin (OPN), bone sialoprotein (BSP), and osteocalcin (OCN). Studies were performed using bone marrow stromal cells cultured in osteogenic media, and parallel-plate flow chambers were used to exert a shear stress of 2.3 dyn/cm2 on cell layers. Results show that continuous flow significantly enhanced phosphorylation of ERK and p38 after 30 min relative to intermittent flow, while intermittent flow significantly increased accumulation of PGE2 in the circulating medium by 24 h relative to continuous flow. Neither continuous nor intermittent flow affected mRNA expression of Col-1alpha1 and OPN after 4 h, but when monolayers were stimulated for 24 h and then allowed to differentiate under static conditions for an additional 13 days, expression of Col-1alpha1, OPN, BSP, and OCN under continuous and intermittent flow was similar and significantly elevated relative to static controls. This study demonstrates that the variation of perfusion regimen modulates mechanotransductive signaling.
Production, characterization, and species specificity of monoclonal antibodies to Mycobacterium avium complex protein antigens (1990)

The incidence of Mycobacterium avium-Mycobacterium intracellulare complex infections has increased in recent years primarily because a significant proportion of acquired immunodeficiency syndrome patients develop disseminated M. avium complex disease. In an effort to develop new tools to study these infections, we have produced eight monoclonal antibodies directed against M. avium. Western blot (immunoblot) specificity analysis and protease sensitivity assays indicate that four of these antibodies recognize M. avium-specific protein epitopes and two react with M. avium complex-specific peptide determinants. These monoclonal antibodies may be useful clinically in the diagnosis of M. avium complex disease and in the laboratory for isolation and characterization of native and recombinant M. avium complex antigens.
A new synthesis of a steroid side chain via stereocontrolled protonation: synthesis of (–)-desmosterol (1983)

Protonation of the lactone enolate (9), obtained from the 20-cyano-steroid (3) and (R)-benzyl 2,3-epoxypropyl ether (6), with saturated aqueous sodium sulphate proceeds in a highly steroselective manner from the less hindered side to give the (20R)-lactone (10) which can be converted into the (20R)-steroid, desmosterol (17).
Insulin-Like Growth Factor I Has Independent Effects on Bone Matrix Formation and Cell Replication* (1988)

The effects of insulin-like growth factor-I (IGF-I) and insulin on bone matrix synthesis and bone cell replication were studied in cultured 21-day-old fetal rat calvariae. Histomorphometry techniques were developed to measure the incorporation of [2,3-3H]proline and [methyl-3H]thymidine into bone matrix and bone cell nuclei, respectively, using autoradiographs of sagittal sections of calvariae cultured with IGF-I, insulin, or vehicle for up to 96 h. To confirm an effect on bone formation, IGF-I was also studied for its effects on [3H]proline incorporation into collagenase-digestible protein (CDP) and noncollagen protein and on [3H]thymidine incorporation into acid-precipitable material (DNA). IGF-I at 10(-9)-10(-7) M significantly increased the rate of bone matrix apposition and CDP after 24 h by 45-50% and increased cell labeling by 8-fold in the osteoprogenitor cell zone, by 4-fold in the osteoblast cell zone, and by 2-fold in the periosteal fibroblast zone. Insulin at 10(-9)-10(-6) M also increased matrix apposition rate and CDP by 40-50%, but increased cell labeling by 2-fold only at a concentration of 10(-7) M or higher and then only in the osteoprogenitor cell zone. When hydroxyurea was added to IGF-I-treated bones, the effects of IGF-I on DNA synthesis were abolished, but the increase in bone matrix apposition induced by IGF-I was only partly diminished. In conclusion, IGF-I stimulates matrix synthesis in calvariae, an effect that is partly, although not completely, dependent on its stimulatory effect on DNA synthesis.
Ligand activation causes a phosphorylation-dependent change in platelet-derived growth factor receptor conformation. (1988)

The effect of ligand binding on platelet-derived growth factor (PDGF) receptor conformation was examined using peptide antibodies directed against specific receptor domains. Antiserum 83, which was directed to the receptor's carboxyl terminus (residues 934-951), preferentially immunoprecipitated the ligand-activated form of the PDGF receptor from 35S-labeled BALB/c 3T3 cells. By contrast, two antisera directed against other receptor sequences precipitated unactivated and activated receptors equally well. Denatured receptors were recognized equally by all antisera, even 83. Thus, ligand activation caused a change in PDGF receptor conformation that enhanced accessibility of the antibody to the carboxyl terminus. The activated receptor conformation was induced by three different forms of PDGF (AA and BB homodimers and AB heterodimers) and was reversed by suramin, a polyanionic compound that dissociates PDGF from the receptor. The inhibitory effect of suramin on receptor conformation was abolished by the phosphatase inhibitor, sodium orthovanadate, suggesting that receptor phosphorylation mediated the conformational change. In a cell-free assay, the change in receptor conformation was induced by PDGF only in the presence of ATP and was inhibited by adenyl-5'-yl imidodiphosphate, a nonhydrolyzable analog of ATP. The functional significance of receptor conformation was examined in Chinese hamster ovary fibroblasts transfected with wild-type or mutated forms of the PDGF receptor. When receptor tyrosine kinase activity was abolished by a mutation of the ATP binding site the receptor no longer underwent PDGF-induced conformational change and did not mediate PDGF-induced mitogenesis even though 125I-PDGF binding was normal. These findings show that ligand binding elicits a phosphorylation-dependent change in PDGF receptor conformation that may be important for receptor function.
Low intensity laser therapy: Still not an established clinical tool (1995)

The surgical, ophthalmological, and dermatological applications of high power lasers are well known and easily understood. What is neither as well known nor as easily understood is that lasers at powers that are orders of magnitude smaller have also been used in the laboratory and clinic for nearly 30 years to modulate cell function, lessen pain, and accelerate healing of soft tissue injuries. This article analyzes the rationale of this approach, examines the utility of laser therapy in its most common clinical applications, reviews and synthesizes the findings, and concludes that although laboratory findings seem authentic, clinical utility remains unestablished.
Synergy between chemotherapeutic agents and CTLA-4 blockade in preclinical tumor models (2013)

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) binding agent, has proven to be an effective monotherapy for metastatic melanoma and has shown antitumor activity in trials when administered with other therapeutic agents. We hypothesized that the combination of ipilimumab with chemotherapeutic agents, such as ixabepilone, paclitaxel, etoposide, and gemcitabine, may produce therapeutic synergy based on distinct but complementary mechanisms of action for each drug and unique cellular targets. This concept was investigated using a mouse homolog of ipilimumab in preclinical murine tumor models, including SA1N fibrosarcoma, EMT-6 mammary carcinoma, M109 lung carcinoma, and CT-26 colon carcinoma. Results of CTLA-4 blockade in combination with one of various chemotherapeutic agents demonstrate that synergy occurs in settings where either agent alone was not effective in inducing tumor regression. Furthermore, when combined with CTLA-4 blockade, ixabepilone, etoposide, and gemcitabine elicited prolonged antitumor effects in some murine models with induction of a memory immune response. Future investigations are warranted to determine which specific chemo-immunotherapy combinations, if any, will produce synergistic antitumor effects in the clinical setting.
Error characterization and coding schemes for flash memories (2010)

In this work, we use an extensive empirical database of errors induced by write, read, and erase operations to develop a comprehensive understanding of the error behavior of flash memories. Error characterization of MLC and SLC flash is given on the block, page, and bit level. Based on our error characterization in MLC flash, we propose an error-correcting scheme which outperforms the conventional BCH code. We compare several schemes which use an MLC block as an SLC block. Finally, an implementation of two-write WOM-codes in SLC flash is given as well as the BER for the first and second write.
Low Power Embedded Deterministic Test (2007)

This paper presents a novel low power test scheme integrated with the embedded deterministic test environment. It reduces switching rates in scan chains with no hardware modification. Experimental results obtained for industrial circuits indicate that switching activity can be reduced up to 23 times.
Molecular Interactions Mediating T Cell Antigen Recognition (2003)

Over the past decade, key protein interactions contributing to T cell antigen recognition have been characterized in molecular detail. These have included interactions involving the T cell antigen receptor (TCR) itself, its coreceptors CD4 and CD8, the accessory molecule CD2, and the costimulatory receptors CD28 and CTLA-4. A clear view is emerging of how these molecules interact with their ligands at the cell-cell interface. Structural and binding studies have confirmed that the proteins span small but comparable distances and that, overall, they interact very weakly. However, there have been important surprises as well: that TCR interactions with peptide-MHC are topologically constrained and characterized by considerable conformational flexibility at the binding interface; that coreceptors engage peptide-MHC with extraordinarily fast kinetics and at angles apparently precluding direct interactions with the TCR bound to the same peptide-MHC; that the structural mechanisms allowing recognition by costimulatory and accessory molecules to be weak and yet specific are very heterogeneous; and that because of differences in both binding affinity and stoichiometry, there is enormous variation in the stability of the various costimulatory receptor/ligand complexes. These studies provide the necessary framework for exploring how these molecular interactions initiate T cell activation.