gebhart/patrepeval huggingface dataset:
Predominant Role for Directly Transfected Dendritic Cells in Antigen Presentation to CD8+ T Cells after Gene Gun Immunization (1998)

Cutaneous gene (DNA) bombardment results in substantial expression of the encoded antigen in the epidermal layer as well as detectable expression in dendritic cells (DC) in draining lymph nodes (LNs). Under these conditions, two possible modes of DC antigen presentation to naive CD8+ T cells might exist: (a) presentation directly by gene-transfected DC trafficking to local lymph nodes, and (b) cross-presentation by untransfected DC of antigen released from or associated with transfected epidermal cells. The relative contributions of these distinct modes of antigen presentation to priming for cytotoxic T cell (CTL) responses have not been clearly established. Here we show that LN cells directly expressing the DNA-encoded antigen are rare; 24 h after five abdominal skin bombardments, the number of these cells does not exceed 50-100 cells in an individual draining LN. However, over this same time period, the total number of CD11c+ DC increases more than twofold, by an average of 20,000-30,000 DC per major draining node. This augmentation is due to gold bombardment and is independent of the presence of plasmid DNA. Most antigen-bearing cells in the LNs draining the site of DNA delivery appear to be DC and can be depleted by antibodies to an intact surface protein encoded by cotransfected DNA. This finding of predominant antigen presentation by directly transfected cells is also consistent with data from studies on cotransfection with antigen and CD86-encoding DNA, showing that priming of anti-mutant influenza nucleoprotein CTLs with a single immunization is dependent upon coexpression of the DNAs encoding nucleoprotein and B7.2 in the same cells. These observations provide insight into the relative roles of direct gene expression and cross-presentation in CD8+ T cell priming using gene gun immunization, and indicate that augmentation of direct DC gene expression may enhance such priming.
DNA sequence and expression analysis of algP and algQ, components of the multigene system transcriptionally regulating mucoidy in Pseudomonas aeruginosa: algP contains multiple direct repeats (1990)

The complete nucleotide sequence of a 3.2-kilobase-pair chromosomal region containing the algP and algQ genes was determined. The algQ gene encodes an acidic 18-kilodalton polypeptide required for transcriptional activation of the algD gene. The algD gene product catalyzes a critical step in alginate biosynthesis, and its overproduction is necessary for the emergence of mucoid Pseudomonas aeruginosa during chronic infections in cystic fibrosis. A novel genetic element, algP, was identified immediately downstream of algQ. This gene appears to act synergistically with algQ. Unlike a biosynthetic gene, algD, and another regulatory gene, algR, which undergo transcriptional activation in mucoid cells, both algP and algQ are equally transcribed in mucoid and nonmucoid isogenic strains of P. aeruginosa. The promoter regions of algP and algQ were mapped by using S1 nuclease protection analysis. The algQ promoter was also analyzed and showed activity in an in vitro transcriptional runoff assay with major RNA polymerase species from P. aeruginosa and Escherichia coli. The putative algQ and algP promoter sequences, unlike algD and algR, resemble sigma 70-utilized promoters from E. coli and appeared constitutively transcribed at a low level in P. aeruginosa. The algP gene has an unusual DNA sequence, with multiple direct repeats organized in six highly conserved, tandemly arranged, 75-base-pair (bp) units. At a lower level, this sequence had 45 degenerate repeats of 12 bp overlapping with the 75-bp repeats and extending beyond the region of 75-bp repeats. The algP repeats appeared important for the function of the algQ-algP regulatory region in maintaining mucoidy.
Syn5 RNA polymerase synthesizes precise run-off RNA products (2013)

The enzyme predominantly used for in vitro run-off RNA synthesis is bacteriophage T7 RNA polymerase. T7 RNA polymerase synthesizes, in addition to run-off products of precise length, transcripts with an additional non-base-paired nucleotide at the 3'-terminus (N+1 product). This contaminating product is extremely difficult to remove. We recently characterized the single-subunit RNA polymerase from marine cyanophage Syn5 and identified its promoter sequence. This marine enzyme catalyses RNA synthesis over a wider range of temperature and salinity than does T7 RNA polymerase. Its processivity is >30,000 nt without significant intermediate products. The requirement for the initiating nucleotide at the promoter is less stringent for Syn5 RNA polymerase as compared to T7 RNA polymerase. A major difference is the precise run-off transcripts with homogeneous 3'-termini synthesized by Syn5 RNA polymerase. Therefore, the enzyme is advantageous for the production of RNAs that require precise 3'-termini, such as tRNAs and RNA fragments that are used for subsequent assembly.
Therapeutic Targeting of the Interleukin-6 Receptor (2011)

Interleukin (IL)-6 is a typical cytokine featuring redundancy and pleiotropic activity. It contributes to host defense against pathogens, but dysregulation of IL-6 production plays a significant pathological role in various autoimmune and inflammatory diseases. Because IL-6 blockade was expected to constitute a novel strategy for the treatment of such diseases, tocilizumab, a humanized anti-IL-6 receptor antibody (anti-IL-6RAb), was developed. Clinical trials have demonstrated the efficacy of anti-IL-6RAb for patients with rheumatoid arthritis, Castleman's disease, and juvenile idiopathic arthritis, resulting in approval of this innovative biologic for the treatment of these diseases, and it can be expected to become a novel drug for various other autoimmune and inflammatory diseases. In murine models of autoimmune diseases, anti-IL-6RAb induces Treg and inhibits Th17 and/or Th1 differentiation, indicating that anti-IL-6RAb may be able to repair Th17/Treg imbalance in human diseases as well.
Simultaneous Truth and Performance Level Estimation (STAPLE): An Algorithm for the Validation of Image Segmentation (2004)

Characterizing the performance of image segmentation approaches has been a persistent challenge. Performance analysis is important since segmentation algorithms often have limited accuracy and precision. Interactive drawing of the desired segmentation by human raters has often been the only acceptable approach, and yet suffers from intra-rater and inter-rater variability. Automated algorithms have been sought in order to remove the variability introduced by raters, but such algorithms must be assessed to ensure they are suitable for the task. The performance of raters (human or algorithmic) generating segmentations of medical images has been difficult to quantify because of the difficulty of obtaining or estimating a known true segmentation for clinical data. Although physical and digital phantoms can be constructed for which ground truth is known or readily estimated, such phantoms do not fully reflect clinical images due to the difficulty of constructing phantoms which reproduce the full range of imaging characteristics and normal and pathological anatomical variability observed in clinical data. Comparison to a collection of segmentations by raters is an attractive alternative since it can be carried out directly on the relevant clinical imaging data. However, the most appropriate measure or set of measures with which to compare such segmentations has not been clarified and several measures are used in practice. We present here an expectation-maximization algorithm for simultaneous truth and performance level estimation (STAPLE). The algorithm considers a collection of segmentations and computes a probabilistic estimate of the true segmentation and a measure of the performance level represented by each segmentation. The source of each segmentation in the collection may be an appropriately trained human rater or raters, or may be an automated segmentation algorithm. The probabilistic estimate of the true segmentation is formed by estimating an optimal combination of the segmentations, weighting each segmentation depending upon the estimated performance level, and incorporating a prior model for the spatial distribution of structures being segmented as well as spatial homogeneity constraints. STAPLE is straightforward to apply to clinical imaging data, it readily enables assessment of the performance of an automated image segmentation algorithm, and enables direct comparison of human rater and algorithm performance.
Approaches toward the Genetic Analysis of Complex Traits (1997)

With the challenges emerging from the analysis and interpretation of the human genome, and the specific issues pertinent to pursuing the Genome Project itself, it is truly an exciting time in the development of the biological sciences. The occasion is certainly ripe for the emergence of new concepts and ideas, as the theories of complexity, natural selection, and reductionism become integrated into a new whole. We need to learn how to approach the analysis of the complex data sets that will be generated by the Genome Project and address, more generally, the problems inherent in the analysis of the complex diseases such as asthma. Finally, we need to consider how the recent advances in genetics and genomics will affect biomedical research into the next millennium and beyond.
Reactions of amidines with some carboxylic acid hydrazides (2005)

Ten amidrazone derivatives (seven new compounds) and twelve 1,2,4-triazole derivatives (five new compounds) are synthesized and their structures are established by elemental analysis, IR, 1 H NMR and 1 3 C NMR spectral data.
NF-κB-inducing kinase activates IKK-α by phosphorylation of Ser-176 (1998)

Activation of the transcription factor NF-kappaB by inflammatory cytokines involves the successive action of NF-kappaB-inducing kinase (NIK) and two IkappaB kinases, IKK-alpha and IKK-beta. Here we show that NIK preferentially phosphorylates IKK-alpha over IKK-beta, leading to the activation of IKK-alpha kinase activity. This phosphorylation of IKK-alpha occurs specifically on Ser-176 in the activation loop between kinase subdomains VII and VIII. A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation. Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-alpha on Ser-176 by NIK may be required for cytokine-mediated NF-kappaB activation.
Methotrexate‐Immobilized Poly(ethylene glycol) Magnetic Nanoparticles for MR Imaging and Drug Delivery (2006)

Abstract We report the development of a biostable methotrexate‐immobilized iron oxide nanoparticle drug carrier that may potentially be used for real‐time monitoring of drug delivery through magnetic resonance imaging. Methotrexate (MTX) was immobilized on the nanoparticle surface via a poly(ethylene glycol) self‐assembled monolayer (PEG SAM). The cytotoxicity of the nanoparticle–drug conjugate (NP‐PEG‐MTX) to target cells was studied with 9L glioma cells. Cellular uptake experiments showed that the uptake of NP‐PEG‐MTX conjugates by glioma cells was considerably higher than that of control nanoparticles. Magnetic resonance imaging in 9L cells cultured with NP‐PEG‐MTX of various concentrations showed significant contrast enhancement. NP‐PEG‐MTX demonstrated higher cytotoxicity in 9L cells to free MTX in vitro. Leucovorin, an MTX antidote, was used to rescue the cells that had been exposed to NP‐PEG‐MTX or free MTX, and the experiment verified the biocompatibility of NP‐PEG‐MTX conjugates and the MTX on NP‐PEG‐MTX conjugates to be the true source of the cytotoxicity to the target cells. TEM results showed that NP‐PEG‐MTX conjugates were internalized into the 9L cellular cytoplasm and retained its crystal structure therein for up to 144 h, as identified by electron diffraction. This prolonged particle retention may allow physicians to image tumor cells exposed to the NP‐PEG‐MTX conjugate over an extended therapeutic time course.
Multimicrophone adaptive beamforming for interference reduction in hearing aids. (1987)

To reduce interference in monaural hearing aids from sound sources that are spatially separated from a target source, we are investigating methods for combining information from multiple microphones. In this paper, we describe an adaptive beamforming method that functions to preserve target signals arriving from straight-ahead of a microphone array while minimizing output power from off-axis interference sources. In a preliminary evaluation of a two-microphone system, sentence intelligibility tests were administered to normal-hearing subjects using processed and unprocessed materials from simulated environments in which the target was on-axis, the interference (speech babble) was 45 degrees off-axis, and the reverberation mimicked that of a living room, a conference room, and anechoic space. Compared to listening through a single microphone, the two-microphone beamformer reduced the target-to-interference ratio required to achieve 50 percent keyword intelligibility by 30, 14, and 0 dB in the anechoic, living-room, and conference-room conditions, respectively. The corresponding improvements over binaural listening (one microphone to each ear) were 24, 9, and 0 dB. Further tests in the living-room environment using the same beam-forming system but with filter impulse responses shortened by a factor of four (which would decrease the adaptation time by a factor of four) decreased the improvement by 5 dB. These results are sufficiently encouraging to warrant further tests involving more realistic reverberant conditions, multiple sources of interference, and time-varying acoustic environments.
Concurrent event handling through multithreading (1999)

Exceptions have traditionally been used to handle infrequently occurring and unpredictable events during normal program execution. Current trends in microprocessor and operating systems design continue to increase the cost of event handling. Because of the deep pipelines and wide out-of-order superscalar architectures of contemporary microprocessors, an event may need to nullify a large number of in-flight instructions. Large register files require existing software systems to save and restore a substantial amount of process state before executing an exception handler. At the same time, processors are executing in environments that supply higher event frequencies and demand higher performance. We have developed an alternative architecture, "concurrent event handling", that incorporates multithreading into event handling architectures. Instead of handling the event in the faulting thread's architectural and pipeline registers, the fault handler is forked into its own thread slot and executes concurrently with the faulting thread. Microbenchmark programs show a factor-of-3 speedup for concurrent event handling over a traditional architecture on code that takes frequent exceptions. We also demonstrate substantial speedups on two event-based applications. Concurrent event handling is implemented in the MIT's MAP (Multi-ALU Processor) chip.
Interaction and outeraction (2000)

We discuss findings from an ethnographic study of instant messaging (IM) in the workplace and its implications for media theory. We describe how instant messaging supports a variety of informal communication tasks. We document the affordances of IM that support flexible, expressive communication. We describe some unexpected uses of IM that highlight aspects of communication which are not part of current media theorizing. They pertain to communicative processes people use to connect with each other and to manage communication, rather than to information exchange. We call these processes "outeraction". We discuss how outeractional aspects of communication affect media choice and patterns of media use.
In Vitro and in Vivo Inactivation of Transcobalamin II Receptor by Its Antiserum (1996)

Rabbits injected with pure human placental transcobalamin II-receptor (TC II-R) failed to thrive with no apparent tissue or organ damage, but a 2-fold elevation of the metabolites, homocysteine, methylmalonic acid, and the ligand, transcobalamin II, in their plasma. Exogenously added transcobalamin II-[57Co]cyanocobalamin bound very poorly (2-5%) to the affected rabbit liver, kidney, and intestinal total or intestinal basolateral membrane extracts relative to the binding by membrane extracts from normal rabbit tissues. The activity was restored to normal values following a wash of affected rabbit tissue membranes with pH 3 buffer containing 200 mM potassium thiocyanate. Immunoblot analysis of normal and affected rabbit kidney and liver total membranes revealed similar amounts of 124-kDa TC II-R dimer protein. The neutralized and dialyzed extract from the affected rabbit membranes inhibited the binding of the ligand to pure TC II-R and the harvested affected rabbit serum inhibited the uptake of TC II-[57Co]cobalamin (Cbl) from the basolateral side of human intestinal epithelial (Caco-2) cells and decreased the utilization of [57Co]Cbl as coenzymes by the Cbl-dependent enzymes. The loss of exogenously added ligand binding or the binding of 125I-protein A occurred with the intestinal basolateral, but not the apical membranes. Based on these results, we suggest that circulatory antibodies to TC II-R cause its in vivo functional inactivation, suppress Cbl uptake by multiple tissues, and thus cause severe Cbl deficiency and the noted failure to thrive.
New paper enzyme-linked immunosorbent technique compared with microimmunofluorescence for detection of human serum antibodies to Rickettsia tsutsugamushi (1980)

A new paper enzyme-linked immunosorbent assay was developed for the screening and titration of human serum antibodies against the scrub typhus rickettsia, Rickettsia tsutsugamushi. The objective [corrected] was to provide a relatively simple method for antibody screening which required neither sophisticated laboratory equipment nor a high degree of technological skill. The technique develops an enzyme product from filter paper saturated with a 5-aminosalicylic acid substrate and enzymatically reacted with a commerically available anti-human immunoglobulin G peroxidase conjugate. The product of the enzymatic reaction can be interpreted visually. Comparison of 351 human sera tested by the immunofluorescent and paper enzyme-linked immunosorbent assays against a three-antigen pool of the Karp, Kato, and Gilliam strains of R. tsutsugamushi demonstrated an agreement of 96%. The sensitivity of the paper enzyme-linked immunosorbent assay as compared to immunofluorescence was 98.2%, and the specificity was 94.4%.
Twisted gastrulation (Tsg) is regulated by Tob and enhances TGF-β signaling in activated T lymphocytes (2006)

Quiescent T cells express Tob, an APRO gene family member, which functions as a transcriptional regulator. Subtractive hybridization identified Twisted gastrulation (Tsg) as one of the genes suppressed by Tob. Tsg is a secreted protein that interacts with Drosophila decapentaplegic (Dpp) and its vertebrate orthologs BMP2/4 and regulates morphogenetic effects in embryos. Here, we report the expression and function of Tsg in human T cells. Tsg mRNA was almost undetectable in unstimulated T cells and was up-regulated after activation by TCR/CD3 and either CD28, IL-2, or PMA. Tsg protein had no effect on responses of primary T cells to TCR/CD3 stimulation but had a potent inhibitory effect on proliferation and cytokine production of primed alloreactive CD4+ cells. Surprisingly, Tsg did not affect phosphorylation of the BMP-specific Smad1 but induced phosphorylation of the TGF-beta-specific Smad2 and mediated DNA binding on Smad3/4 consensus-binding sites, suggesting that it acted downstream of TGF-beta. In vitro association assays revealed a direct interaction of Tsg and TGF-beta proteins. Thus, Tsg functions as an agonist synergizing with TGF-beta to inhibit T-cell activation. Modulation of Tsg signaling may represent a novel target for molecular intervention toward control of aberrant T-cell responses during ongoing graft-versus-host disease (GVHD) and autoimmune diseases.
ChemInform Abstract: THREE NEW SESTERTERPENOID ANTIBIOTICS FROM THE MARINE SPONGE LUFFARIELLA VARIABILIS (POLEJAFF) (1981)

Abstract (Ic) werden isoliert und identifiziert.
ERdj5 Sensitizes Neuroblastoma Cells to Endoplasmic Reticulum Stress-induced Apoptosis (2009)

Down-regulation of the unfolded protein response (UPR) can be therapeutically valuable in cancer treatment, and endoplasmic reticulum (ER)-resident chaperone proteins may thus be targets for developing novel chemotherapeutic strategies. ERdj5 is a novel ER chaperone that regulates the ER-associated degradation of misfolded proteins through its associations with EDEM and the ER stress sensor BiP. To investigate whether ERdj5 can regulate ER stress signaling pathways, we exposed neuroblastoma cells overexpressing ERdj5 to ER stress inducers. ERdj5 promoted apoptosis in tunicamycin, thapsigargin, and bortezomib-treated cells. To provide further evidence that ERdj5 induces ER stress-regulated apoptosis, we targeted Bcl-2 to ER of ERdj5-overexpressing cells. Targeting the Bcl-2 to ER prevented the apoptosis induced by ER stress inducers but not by non-ER stress apoptotic stimuli, suggesting induction of ER stress-regulated apoptosis by ERdj5. ERdj5 enhanced apoptosis by abolishing the ER stress-induced phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) and the subsequent translational repression. ERdj5 was found to inhibit the eIF2alpha phosphorylation under ER stress through inactivating the pancreatic endoplasmic reticulum kinase. The compromised integrated stress response observed in ERdj5-overexpressing ER-stressed cells due to repressed eIF2alpha phosphorylation correlated with impaired neuroblastoma cell resistance under ER stress. These results demonstrate that ERdj5 decreases neuroblastoma cell survival by down-regulating the UPR, raising the possibility that this protein could be a target for anti-tumor approaches.