gebhart/patrepeval huggingface dataset:
Vibrational imaging of newly synthesized proteins in live cells by stimulated Raman scattering microscopy (2013)

Synthesis of new proteins, a key step in the central dogma of molecular biology, has been a major biological process by which cells respond rapidly to environmental cues in both physiological and pathological conditions. However, the selective visualization of a newly synthesized proteome in living systems with subcellular resolution has proven to be rather challenging, despite the extensive efforts along the lines of fluorescence staining, autoradiography, and mass spectrometry. Herein, we report an imaging technique to visualize nascent proteins by harnessing the emerging stimulated Raman scattering (SRS) microscopy coupled with metabolic incorporation of deuterium-labeled amino acids. As a first demonstration, we imaged newly synthesized proteins in live mammalian cells with high spatial-temporal resolution without fixation or staining. Subcellular compartments with fast protein turnover in HeLa and HEK293T cells, and newly grown neurites in differentiating neuron-like N2A cells, are clearly identified via this imaging technique. Technically, incorporation of deuterium-labeled amino acids is minimally perturbative to live cells, whereas SRS imaging of exogenous carbon-deuterium bonds (C-D) in the cell-silent Raman region is highly sensitive, specific, and compatible with living systems. Moreover, coupled with label-free SRS imaging of the total proteome, our method can readily generate spatial maps of the quantitative ratio between new and total proteomes. Thus, this technique of nonlinear vibrational imaging of stable isotope incorporation will be a valuable tool to advance our understanding of the complex spatial and temporal dynamics of newly synthesized proteome in vivo.
Toll Pathway-Dependent Blockade of CD4 + CD25 + T Cell-Mediated Suppression by Dendritic Cells (2003)

Toll-like receptors (TLRs) control activation of adaptive immune responses by antigen-presenting cells (APCs). However, initiation of adaptive immune responses is also controlled by regulatory T cells (TR cells), which act to prevent activation of autoreactive T cells. Here we describe a second mechanism of immune induction by TLRs, which is independent of effects on costimulation. Microbial induction of the Toll pathway blocked the suppressive effect of CD4+CD25+ TR cells, allowing activation of pathogen-specific adaptive immune responses. This block of suppressor activity was dependent in part on interleukin-6, which was induced by TLRs upon recognition of microbial products.
Bortezomib for multiple myeloma (2006)

The ubquitin-proteasome pathway is a key regulator of homeostasis within cells, degrading misfolded or redundant proteins, and also those involved in mediating transcription, cell-cycle progression and apoptosis. Inhibition of the 26S proteasome results in accumulation of such proteins and ultimately leads to cell death. Malignant cells are more susceptible to proteasome inhibition due to their higher proliferation rates, protein production and their dependence on anti-apoptotic molecules for cell survival. Bortezomib has recently gained European Commission approval for the treatment of relapsed multiple myeloma on the basis of clinical trials demonstrating its efficacy, tolerability and superiority to high-dose dexamethasone. Preclinical data demonstrates the ability to synergise with other chemotherapeutic agents and overcome drug resistance, and hence combination studies are underway. This review describes the pharmacology, toxicity, preclinical and clinical activity of bortezomib, predominantly in the setting of multiple myeloma.
Antioxidant Activities of Bile Pigments (2004)

Biliverdin and bilirubin are reducing species and hence potential antioxidants formed by the action of heme oxygenase and biliverdin reductase. Indeed, there is increasing evidence for the suggestion that a beneficial role of the potentially toxic bilirubin may be to act as a powerful chain-breaking antioxidant in biological systems, and that bilirubin may contribute to the cellular and tissue protection seen with increased heme oxygenase. This article reviews the in vitro antioxidant activities of the two bile pigments with emphasis on the different physiological forms of bilirubin and types of oxidants, and discusses these properties in light of the presence and reactivity other nonproteinaceous antioxidants.
Is there a role for Chlamydia pneumoniae infection in systemic lupus erythematosus and in the associated atherosclerotic cardiovascular disease? (2004)

This pilot study demonstrates for the first time that C. pneumoniae DNA can be identified in the PBMC of some SLE subjects and there may be an association with CAC. Smoking may be an additional risk factor for infection in this population. Determination of pathogenicity of this organism in atherosclerotic coronary vascular disease in SLE will require further study.
The Sequential Organ Failure Assessment score for predicting outcome in patients with severe sepsis and evidence of hypoperfusion at the time of emergency department presentation* (2009)

The SOFA score provides potentially valuable prognostic information on in-hospital survival when applied to patients with severe sepsis with evidence of hypoperfusion at the time of ED presentation.
Cytogenetics and oncogenes. (1992)

There is abundant evidence that leukemia arise through somatically acquired genetic changes. Familial or congenital predisposition is rarely involved. These genetic changes are often visible as chromosomal aberrations. Molecular analyses of the DNA sequences rearranged in leukemia has demonstrated the presence of cellular oncogenes which are modified (fused, mutated, truncated) by the specific translocations. This results in a disturbance of the delicate balance between proliferation and differentiation and constitute a major step towards cell transformation. Some of these genetic rearrangements have been analyzed in depth, but the exact defect that causes leukemia is often not yet understood. Meanwhile these studies have increased our knowledge of normal cell proliferation and differentiation and provided us with new tools for diagnosis and for developing more specifically targeted treatment. An example would be the production of antibodies that recognize specifically the new chimeric proteins. Oncogenesis is a complex and multiple step process that proceeds by acquisition of successive genetic insults. The different steps do not necessarily occurs following a predetermined order, although some secondary changes are preferentially induced by a given first mutation. In leukemia, sequential changes in karyotype are well documented but molecular makers for tumor progression have not yet been systematically investigated. This is one of our many challenges for the future.
Cannabinoid CB2 receptors in human brain inflammation (2007)

The presence of functional cannabinoid CB2 receptors in the CNS has provoked considerable controversy over the past few years. Formerly considered as an exclusively peripheral receptor, it is now accepted that it is also present in limited amounts and distinct locations in the brain of several animal species, including humans. Furthermore, the inducible nature of these receptors under neuroinflammatory conditions, in contrast to CB1, makes them attractive targets for the development of novel therapeutic approaches. In fact, the undesired psychoactive effects caused by CB1 activation have largely limited the clinical use of cannabinoid-related compounds that act on these receptors. In this review some recent findings on the antiinflammatory properties of CB2 receptors are presented, as well as new perspectives that have been obtained based on studies of human postmortem brain samples. In addition, various working hypotheses are also proposed and discussed.
Arthroscopy under local anaesthesia using controlled pressure-irrigation with prilocaine (1982)

One hundred and seventy-four consecutive patients with symptoms of derangement of the knee were examined with an arthroscope under local anaesthesia using a continuous pressure-irrigation system. A 0.2 per cent prilocaine-saline solution was used as irrigation fluid. In the first 19 patients the serum level of prilocaine was monitored for six hours after the start of irrigation. Eighteen of the 174 patients had a transcutaneous partial meniscectomy at the same time as the examination. All the patients tolerated the examination well. The distension of the knee produced by the pressure-irrigation system provided a high degree of diagnostic accuracy. The serum levels of prilocaine were low throughout the monitoring period reaching a mean peak value of 0.28 micrograms per millilitre after one hour. There were no adverse side-effects. This technique provides a safe and efficient method to meet the increasing demands of arthroscopic procedures of the knee.
Molecular characterization of the 50-kD subunit of dynactin reveals function for the complex in chromosome alignment and spindle organization during mitosis. (1996)

Dynactin is a multi-subunit complex which has been implicated in cytoplasmic dynein function, though its mechanism of action is unknown. In this study, we have characterized the 50-kD subunit of dynactin, and analyzed the effects of its overexpression on mitosis in living cells. Rat and human cDNA clones revealed p50 to be novel and highly conserved, containing three predicted coiled-coil domains. Immunofluorescence staining of dynactin and cytoplasmic dynein components in cultured vertebrate cells showed that both complexes are recruited to kinetochores during prometaphase, and concentrate near spindle poles thereafter. Overexpression of p50 in COS-7 cells disrupted mitosis, causing cells to accumulate in a prometaphase-like state. Chromosomes were condensed but unaligned, and spindles, while still bipolar, were dramatically distorted. Sedimentation analysis revealed the dynactin complex to be dissociated in the transfected cultures. Furthermore, both dynactin and cytoplasmic dynein staining at prometaphase kinetochores was markedly diminished in cells expressing high levels of p50. These findings represent clear evidence for dynactin and cytoplasmic dynein codistribution within cells, and for the presence of dynactin at kinetochores. The data also provide direct in vivo evidence for a role for vertebrate dynactin in modulating cytoplasmic dynein binding to an organelle, and implicate both dynactin and dynein in chromosome alignment and spindle organization.
Nanoparticle halos: A new colloid stabilization mechanism (2001)

A new mechanism for regulating the stability of colloidal particles has been discovered. Negligibly charged colloidal microspheres, which flocculate when suspended alone in aqueous solution, undergo a remarkable stabilizing transition upon the addition of a critical volume fraction of highly charged nanoparticle species. Zeta potential analysis revealed that these microspheres exhibited an effective charge buildup in the presence of such species. Scanning angle reflectometry measurements indicated, however, that these nanoparticle species did not adsorb on the microspheres under the experimental conditions of interest. It is therefore proposed that highly charged nanoparticles segregate to regions near negligibly charged microspheres because of their repulsive Coulombic interactions in solution. This type of nanoparticle haloing provides a previously unreported method for tailoring the behavior of complex fluids.
The therapeutic potential of a kallikrein inhibitor for treating hereditary angioedema (2006)

Hereditary angioedema (HAE) manifests as intermittent, painful attacks of submucosal oedema affecting the larynx, gastrointestinal tract or limbs. Currently, acute treatment is available in Europe but not USA, and requires intravenous administration of a pooled blood product. HAE is most likely caused by dysinhibition of the contact cascade, resulting in overproduction of bradykinin. DX-88 (ecallantide, Dyax Corp.) is a highly specific recombinant plasma kallikrein inhibitor that halts the production of bradykinin and can be dosed subcutaneously. In a placebo-controlled Phase II trial in patients with HAE, DX-88 resulted in significant improvement in symptoms compared with placebo. A Phase III trial is ongoing. This review explains the pathophysiology of HAE and the mechanism by which DX-88, a non-intravenous, nonplasma-derived therapy, might improve the disease, and discusses the clinical course of HAE and available treatments. Finally, it explores the potential value and efficacy of DX-88 in treating HAE.
Inhibition of A2A Adenosine Receptor Signaling in Cancer Cells Proliferation by the Novel Antagonist TP455 (2017)

Several evidences indicate that the ubiquitous nucleoside adenosine, acting through A<sub>1</sub>, A<sub>2A</sub>, A<sub>2B</sub>, and A<sub>3</sub> receptor (AR) subtypes, plays crucial roles in tumor development. Adenosine has contrasting effects on cell proliferation depending on the engagement of different receptor subtypes in various tumors. The involvement of A<sub>2A</sub>ARs in human A375 melanoma, as well as in human A549 lung and rat MRMT1 breast carcinoma proliferation has been evaluated in view of the availability of a novel A<sub>2A</sub>AR antagonist, with high affinity and selectivity, named as 2-(2-furanyl)-N<sup>5</sup>-(2-methoxybenzyl)[1,3]thiazolo[5,4-d]pyrimidine-5,7-diammine (TP455). Specifically, the signaling pathways triggered in the cancer cells of different origin and the antagonist effect of TP455 were investigated. The A<sub>2A</sub>AR protein expression was evaluated through receptor binding assays. Furthermore, the effect of A<sub>2A</sub>AR activation on cell proliferation at 24, 48 and 72 hours was studied. The selective A<sub>2A</sub>AR agonist 2-<i>p</i>-(2-carboxyethyl)phenethylamino-5'-<i>N</i>-ethylcarboxamidoadenosine hydrochloride (CGS21680), concentration-dependently induced cell proliferation in A375, A549, and MRMT1 cancer cells and the effect was potently antagonized by the A<sub>2A</sub>AR antagonist TP455, as well as by the reference A<sub>2A</sub>AR blocker 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). As for the signaling pathway recruited in this response we demonstrated that, by using the specific inhibitors of signal transduction pathways, the effect of A<sub>2A</sub>AR stimulation was induced through phospholipase C (PLC) and protein kinase C-delta (PKC-δ). In addition, we evaluated, through the AlphaScreen SureFire phospho(p) protein assay, the kinases enrolled by A<sub>2A</sub>AR to stimulate cell proliferation and we found the involvement of protein kinase B (AKT), extracellular regulated kinases (ERK1/2), and c-Jun N-terminal kinases (JNKs). Indeed, we demonstrated that the CGS21680 stimulatory effect on kinases was strongly reduced in the presence of the new potent compound TP455, as well as by ZM241385, confirming the role of the A<sub>2A</sub>AR. In conclusion, the A<sub>2A</sub>AR activation stimulates proliferation of A375, A549, and MRMT1 cancer cells and importantly TP455 reveals its capability to counteract this effect, suggesting selective A<sub>2A</sub>AR antagonists as potential new therapeutics.
An efficient screen for peroxisome-deficient mutants of Pichia pastoris (1992)

We describe a rapid and efficient screen for peroxisome-deficient (per) mutants in the yeast Pichia pastoris. The screen relies on the unusual ability of P. pastoris to grow on two carbon sources, methanol and oleic acid, both of which absolutely require peroxisomes to be metabolized. A collection of 280 methanol utilization-defective (Mut-) P. pastoris mutants was isolated, organized into 46 complementation groups, and tested for those that were also oleate-utilization defective (Out-) but still capable of growth on ethanol and glucose. Mutants in 10 groups met this phenotypic description, and 8 of these were observed by electron microscopy to be peroxisome deficient (Per-). In each per mutant, Mut-, Out-, and Per- phenotypes were tightly linked and therefore were most likely due to a mutation at a single locus. Subcellular fractionation experiments indicated that the peroxisomal marker enzyme catalase was mislocalized to the cytosol in both methanol- and oleate-induced cultures of the mutants. In contrast, alcohol oxidase, a peroxisomal methanol utilization pathway enzyme, was virtually absent from per mutant cells. The relative ease of per mutant isolation in P. pastoris, in conjunction with well-developed procedures for its molecular and genetic manipulation, makes this organism an attractive system for studies on peroxisome biogenesis.
Network information flow (2000)

We introduce a new class of problems called network information flow which is inspired by computer network applications. Consider a point-to-point communication network on which a number of information sources are to be multicast to certain sets of destinations. We assume that the information sources are mutually independent. The problem is to characterize the admissible coding rate region. This model subsumes all previously studied models along the same line. We study the problem with one information source, and we have obtained a simple characterization of the admissible coding rate region. Our result can be regarded as the max-flow min-cut theorem for network information flow. Contrary to one's intuition, our work reveals that it is in general not optimal to regard the information to be multicast as a "fluid" which can simply be routed or replicated. Rather, by employing coding at the nodes, which we refer to as network coding, bandwidth can in general be saved. This finding may have significant impact on future design of switching systems.
Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice (2003)

The glial glutamate transporter EAAT2 is primarily responsible for clearance of glutamate from the synaptic cleft and loss of EAAT2 has been previously reported in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The loss of functional EAAT2 could lead to the accumulation of extracellular glutamate, resulting in cell death known as excitotoxicity. However, it is still unknown whether it is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. The goals of this study were to generate transgenic mice overexpressing EAAT2 and then to cross these mice with the ALS-associated mutant SOD1(G93A) mice to investigate whether supplementation of the loss of EAAT2 would delay or rescue the disease progression. We show that the amount of EAAT2 protein and the associated Na+-dependent glutamate uptake was increased about 2-fold in our EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protects neurons from L-glutamate induced cytotoxicity and cell death in vitro. Furthermore, our EAAT2/G93A double transgenic mice showed a statistically significant (14 days) delay in grip strength decline but not in the onset of paralysis, body weight decline or life span when compared with G93A littermates. Moreover, a delay in the loss of motor neurons and their axonal morphologies as well as other events including caspase-3 activation and SOD1 aggregation were also observed. These results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
The molecular response of mammalian cells to hypoxia and the potential for exploitation in cancer therapy. (1996)

In this review, reports of the increased expression of selected genes in response to hypoxia have been summarised. The best studied mammalian hypoxia response systems are those of the erythropoietin (Epo) and the vascular endothelial growth factor (VEGF) genes, which will be described in some detail. Other genes discussed here include those encoding growth factors, cytokines, transcription factors, metabolic enzymes and DNA repair enzymes. Short DNA sequences (hypoxia response elements) governing the increased gene expression in response to hypoxia have been discovered in the vicinity of most of these genes. The review will end by analysing the possibility of exploiting tumour hypoxia via the use of hypoxia response elements for gene therapy of cancer.
A Drosophila protein related to the human zinc finger transcription factor PRDII/MBPI/HIV-EP1 is required for dpp signaling (1995)

Little is known about the signal transduction pathways by which cells respond to mammalian TGF-beta s or to decapentaplegic (dpp), a Drosophila TGF-beta-related factor. Here we describe the genetic and molecular characterization of Drosophila schnurri (shn), a putative transcription factor implicated in dpp signaling. The shn protein has eight zinc fingers and is related to a human transcription factor, PRDII/MBPI/HIV-EP1, that binds to nuclear factor-kappa B-binding sites and activates transcription from the HIV long terminal repeat (LTR). shn mRNA is expressed in a dynamic pattern in the embryo that includes most of the known target tissues of dpp, including the dorsal blastoderm, the mesodermal germlayer and parasegments 4 and 7 of the midgut. Mutations in shn affect several developmental processes regulated by dpp including induction of visceral mesoderm cell fate, dorsal/ventral patterning of the lateral ectoderm and wing vein formation. Absence of shn function blocks the expanded expression of the homeodomain protein bagpipe in the embryonic mesoderm caused by ectopic dpp expression, illustrating a requirement for shn function downstream of dpp action. We conclude that shn function is critical for cells to respond properly to dpp and propose that shn protein is the first identified downstream component of the signal transduction pathway used by dpp and its receptors.
B-raf and a B-raf pseudogene are located on 7q in man. (1992)

The B-raf gene was localized to human chromosome region 7p11-7qter by Southern blot analysis of its segregation in a panel of rodent-human hybrids, using a B-raf cDNA clone. Chromosomal in situ hybridization refined the localization to 7q33-36. Analysis of genomic B-raf clones identified a B-raf pseudogene in addition to the active gene. Based on the chromosomal mapping data we conclude that the pseudogene is located near the active gene.
Genomic Characterization of Brain Metastases Reveals Branched Evolution and Potential Therapeutic Targets (2015)

Decisions for individualized therapies in patients with brain metastasis are often made from primary-tumor biopsies. We demonstrate that clinically actionable alterations present in brain metastases are frequently not detected in primary biopsies, suggesting that sequencing of primary biopsies alone may miss a substantial number of opportunities for targeted therapy.