gebhart/patrepeval huggingface dataset:
Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP (2015)

Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Mychigh/TXNIPlow gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Mychigh/TXNIPlow gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Mychigh/TXNIPlow gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Mychigh/TXNIPlow gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Mychigh/TXNIPlow-driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.
Memory overflow protection for embedded systems using run-time checks, reuse and compression (2004)

Out-of-memory errors are a serious source of unreliability in most embedded systems. Applications run out of main memory because of the frequent difficulty of estimating the memory requirement before deployment, either because it depends on input data, or because certain language features prevent estimation. The typical lack of disks and virtual memory in embedded systems has two serious consequences when an out-of-memory error occurs. First, there is no swap space for the application to grow into, and the system crashes. Second, since protection from virtual memory is usually absent, the fact that a segment has exceeded its bounds is not even detected and hence no pre-crash remedial action is possible.This work improves system reliability in two ways. First it proposes a low-overhead system of run-time checks by which the out-of-memory errors are detected just before they will happen, by using carefully optimized compiler-inserted run-time check code. Such error detection enables the designer to incorporate system-specific remedial action, such as transfer to manual control, shutting down of non-critical tasks, or other actions. Second, this work proposes five related techniques that can grow the stack or heap segment after it is out of memory, into previously un-utilized space such as dead variables and space freed by compressed live variables. These techniques can avoid the out-of-memory error if the extra space recovered is enough to complete execution.Results from our benchmarks show that the overheads from the system of run-time checks for detecting memory overflow are extremely low: the run-time and code-size overheads are 1.1% and 0.09% on average. When the reuse functionality is included, the run-time and code-size overheads increase to only 3.2%and 2.33%, but the method is able to grow the stack or heap beyond its overflow by an amount that ranges from 0.7% to 93.5% of the combined stack and heap size.
NOD Mouse Diabetes: The Ubiquitous Mouse Hsp60 is a β-Cell Target Antigen of Autoimmune T Cells (1996)

In the NOD mouse, the onset of beta-cell destruction is associated with spontaneous development of T-lymphocytes reactive to members of the 60 kDa heat shock protein (hsp60) family, including the Mycobacterial (MT) and the human (H) hsp60 molecules. Diabetes in the NOD mouse is a spontaneous tissue-specific autoimmune disease occurring without prior immunization. Therefore, it has been suggested that the anti-hsp60 T cells involved in the autoimmune diabetes of NOD mice might reflect molecular mimicry between MT-hsp60 and a beta-cell tissue specific molecule sharing similar T cell epitopes, the p277 peptide of hsp60 in particular. We cloned and expressed the mouse hsp60 cDNA from a beta-cell tumour. This mouse beta-cell hsp60 cDNA was found to be identical in sequence to the hsp60 of mouse fibroblasts. We further report that NOD spleen cells and an NOD diabetogenic T cell clone C9 responded to the recombinant mouse hsp60 and to its peptide M-p277 to the same extent as to H-hsp60 and H-p277. Splenocytes of mice of other strains did not respond to p277. Moreover, treatment of 3 month old NOD mice with the non-modified self M-p277 peptide was as efficient as H-p277, from which it differs in one amino acid, in halting progression of the disease. Thus, anti-H-p277 T cells modulating diabetes in the NOD mouse are autoreactive, and are targeted at the mouse beta-cell hsp60, which is not tissue specific. These findings raise the question of how a non-tissue specific molecule may be a target of a tissue-specific autoimmune disease.
It takes two to tango: mast cell and Schwann cell interactions in neurofibromas (2003)

Neurofibromas are benign tumors comprised primarily of Schwann cells and fibroblasts. Mast cell infiltration is a well-known phenomenon; however, their role in tumor pathogenesis has been enigmatic. In an elegant set of experiments using cells derived from a murine model of neurofibromatosis 1 (NF1), Yang et al. dissect the molecular pathways involved in mast cell migration to neurofibromin-deficient Schwann cells. These results set the stage for rational development of therapeutics that could influence the multicellular microenvironment of neurofibromas to inhibit the development and/or progression of these tumors in human NF
Characterization of Human Hematopoietic Cells with Short‐Lived in Vivo Repopulating Activity (2001)

Recent studies with purified hematopoietic stem cells in vitro support a model of stem cell self-renewal control that involves distinct mechanisms regulating permissiveness to and execution of lineage restriction. Such a model predicts the existence of phenotypically separable populations of hematopoietic cells that are pluripotent and either capable or incapable of extensive self-renewal. Such populations have been previously described in the mouse. We describe here the first evidence that such cells can now be identified in humans using different types of immunodeficient mice as hosts.
Arrangement of disulfide bridges and positions of sulfhydryl groups in tetanus toxin (1990)

Tetanus toxin is a 151-kDa protein. The complete amino acid sequence is known. The mature toxin is made up of two peptide chains and contains 10 half-cystine residues. Treatment with 4-vinylpyridine in the presence of 6 M guanidine converted six of them into S-pyridylethyl cysteine residues as determined by amino acid analysis. When alkylation was preceded by mercaptolysis, all 10 half-cystine residues were recovered in the S-pyridylethylated form. It was therefore concluded that the toxin contains six sulfhydryl groups and two disulfide bonds. The positions of the residues carrying sulfhydryl groups and of those involved in disulfide bridges were determined by labelling of the toxin alternatively with 4-vinylpyridine or with 4-dimethylaminoazobenzene-4'-iodoacetamide (DABIA), directly or after mercaptolysis. The toxin derivatives were cleaved with cyanogen bromide and the elution patterns in reversed-phase HPLC compared. The chromatography components were identified by N-terminal amino acid sequence and amino acid composition. In the chromatography of the non-mercaptolysed, DABIA-treated sample four chromophore-carrying components were detected which could be demonstrated by N-terminal sequence analysis to correspond to six half-cystine-containing cyanogen bromide fragments. In the mercaptolysed, DABIA-treated sample three additional chromophore-carrying components were present, corresponding to two previously disulfide-linked cyanogen bromide fragments and one fragment which had contained an internal disulfide bridge. The HPLC patterns showed characteristic differences as the DABIA-labelled fragments were considerably more hydrophobic than the corresponding vinylpyridine-labelled fragments. It was established that the half-cystine residues in positions 26, 185, 198, 311, 868, and 1300 are present in the sulfhydryl form, that those in positions 438 and 466 are disulfide-bridged, thereby connecting the light and heavy chains of the toxin, and that those in positions 1076 and 1092 are disulfide-bridged, thereby giving rise to a loop in the heavy chain. During the progress of the investigations about 20% of the amino acid sequence previously predicted from DNA analysis was confirmed by protein-chemical methods.
Development and biological applications of chloride-sensitive fluorescent indicators (1990)

Chloride movement across cell plasma and internal membranes, is of central importance for regulation of cell volume and pH, vectorial salt movement in epithelia, and, probably, intracellular traffic. Quinolinium-based chloride-sensitive fluorescent indicators provide a new approach to study chloride transport mechanisms and regulation that is complementary to 36Cl tracer methods, intracellular microelectrodes, and patch clamp. Indicator fluorescence is quenched by chloride by a collisional mechanism with Stern-Volmer constants of up to 220 M-1. Fluorescence is quenched selectively by chloride in physiological systems and responds to changes in chloride concentration in under 1 ms. The indicators are nontoxic and can be loaded into living cells for continuous measurement of intracellular chloride concentration by single-cell fluorescence microscopy. In this review, the structure-activity relationships for chloride-sensitive fluorescent indicators are described. Methodology for measurement of chloride transport in isolated vesicle and liposome systems and in intact cells is evaluated critically by use of examples from epithelial cell physiology. Future directions for synthesis of tailored chloride-sensitive indicators and new applications of indicators for studies of transport regulation and intracellular ion gradients are proposed.
The Proinflammatory Cytokines Interleukin-l and Tumor Necrosis Factor and Treatment of the Septic Shock Syndrome (1991)

Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a, platelet-activating factor antagonists, and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the proinflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover, blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or to IL-1 receptors have reduced the consequences of infection and inflammation, including lethal outcomes in animal models. The IL-1 receptor antagonist, a natural-occurring cytokine, blocks shock and death due to Escherichia coli and ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors, which bind their respective cytokines, also ameliorate disease processes. Current clinical trials are evaluating the safety and efficacy of these anticytokine therapies either alone or together.
New Anticoagulants for Treatment of Venous Thromboembolism (2008)

Anticoagulant therapy is the cornerstone of treatment of venous thromboembolism (VTE). Such treatment is divided into 2 stages: Rapid initial anticoagulation is given to minimize the risk of thrombus extension and fatal pulmonary embolism, whereas extended anticoagulation is aimed at preventing recurrent VTE, thereby reducing the risk of postphlebitic syndrome. With currently available drugs, immediate anticoagulation can only be achieved with parenteral agents, such as heparin, low-molecular-weight heparin, or fondaparinux. Extended treatment usually involves the administration of vitamin K antagonists, such as warfarin. Emerging anticoagulants have the potential to streamline VTE treatment. These agents include idraparinux, a long-acting synthetic pentasaccharide that is given subcutaneously on a once-weekly basis, and new oral anticoagulants that target thrombin or factor Xa. This article (1) reviews the pharmacology of these agents, (2) outlines their potential strengths and weaknesses, (3) describes the results of clinical trials with these new drugs, and (4) identifies the evolving role of new anticoagulants in the management of VTE.
Fiberoptic System for Recording Dendritic Calcium Signals in Layer 5 Neocortical Pyramidal Cells in Freely Moving Rats (2007)

Calcium influx into the dendritic tufts of layer 5 neocortical pyramidal neurons modifies a number of important cellular mechanisms. It can trigger local synaptic plasticity and switch the firing properties from regular to burst firing. Due to methodological limitations, our knowledge about Ca2+ spikes in the dendritic tuft stems mostly from in vitro experiments. However, it has been speculated that regenerative Ca2+ events in the distal dendrites correlate with distinct behavioral states. Therefore it would be most desirable to be able to record these Ca2+ events in vivo, preferably in the behaving animal. Here, we present a novel approach for recording Ca2+ signals in the dendrites of populations of layer 5 pyramidal neurons in vivo, which ensures that all recorded fluorescence changes are due to intracellular Ca2+ signals in the apical dendrites. The method has two main features: 1) bolus loading of layer 5 with a membrane-permeant Ca2+ dye resulting in specific loading of pyramidal cell dendrites in the upper layers and 2) a fiberoptic cable attached to a gradient index lens and a prism reflecting light horizontally at 90 degrees to the angle of the apical dendrites. We demonstrate that the in vivo signal-to-noise ratio recorded with this relatively inexpensive and easy-to-implement fiberoptic-based device is comparable to conventional camera-based imaging systems used in vitro. In addition, the device is flexible and lightweight and can be used for recording Ca2+ signals in the distal dendritic tuft of freely behaving animals.
CpG Oligodeoxynucleotides as a Future Vaccine for Allergic Diseases (2005)

An astounding feature of the DNA sequences termed CpG motifs is the induction of immune and inflammatory responses in a senseless manner. CpG motifs exist abundantly in microbes and evoke innate immunity that constitutes the first line of defense against microbial infections in vertebrates. CpG motifs that essentially work in an antigen-nonspecific fashion, however, turn into novel immunomodulators that can manipulate acquired immunity in an antigen-specific manner if oligodeoxynucleotides containing CpG motifs (CpG ODNs) are directly conjugated to the antigen. CpG ODNs with potent polyclonal Th1-inducing ability show promise for application in immunotherapy whereby neutralization of dominant allergy-prone Th2 cells is achieved by inducing allergen-specific Th1 cells. The underlying mechanisms include an unexpected enhancement of dendritic cell function as a linker between innate and acquired immunity. In the foreseeable future the mainstream therapeutic role of corticosteroids in anti-inflammatory therapy for allergic diseases could possibly be replaced by immunotherapy using CpG ODN-conjugated antigens.
Structure of ricin A‐chain at 2.5 Å (1991)

Ricin has been refined in a crystallographic sense to 2.5 A resolution and the model for the A-chain (RTA) is described in detail. Because RTA is the first member of the class of plant toxins to be analyzed, this model probably defines the major structural characteristics of the entire family of these medically important proteins. Explanations are provided to rationalize amino acids that are conserved between RTA and a number of homologous plant and bacterial toxins. Eight invariant residues appear to be involved in creating or stabilizing the active site. In the active site Arg180 and Glu177 are hydrogen bonded to each other and also coordinate a water molecule; each of these groups may be important in the N-glycosidation reaction. Several other polar residues may play lesser roles in the mechanism, including tyrosines 80 and 123 and asparagines 78 and 209. A number of conserved hydrophobic residues are seen to cluster within several patches and probably drive the overall folding of the toxin molecule.
GAD1 mRNA Expression and DNA Methylation in Prefrontal Cortex of Subjects with Schizophrenia (2007)

Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia.
Intracellular Leucine Zipper Interactions Suggest c-Myc Hetero-Oligomerization (1991)

The physiological significance of in vitro leucine zipper interactions was studied by the use of two strategies which detect specific protein-protein interactions in mammalian cells. Fusion genes were constructed which produce chimeric proteins containing leucine zipper domains from several proteins fused either to the DNA-binding domain of the Saccharomyces cerevisiae GAL4 protein or to the transcriptional activation domain of the herpes simplex virus VP16 protein. Previous studies in mammalian cells have demonstrated that a single chimeric polypeptide containing these two domains will activate transcription of a reporter gene present downstream of the GAL4 DNA-binding site. Similarly, if the GAL4 DNA-binding domain of a chimeric protein could be complexed through leucine zipper interactions with the VP16 activation domain of another chimeric protein, then transcriptional activation of the reporter gene would be detected. Using this strategy for detecting leucine zipper interactions, we observed homo-oligomerization between leucine zipper domains of the yeast protein GCN4 and hetero-oligomerization between leucine zipper regions from the mammalian transcriptional regulating proteins c-Jun and c-Fos. In contrast, homo-oligomerization of the leucine zipper domain from c-Myc was not detectable in cells. The inability of the c-Myc leucine zipper to homo-oligomerize strongly in cells was confirmed independently. The second strategy to detect leucine zipper interactions takes advantage of the observation that the addition of nuclear localization sequences to a cytoplasmic protein will allow the cytoplasmic protein to be transported to and retained in the nucleus. Chimeric genes encoding proteins with sequences from a cytoplasmic protein fused either to the GCN4 or c-Myc leucine zipper domains were constructed. Experiments with the c-Myc chimeric protein failed to demonstrate transport of the cytoplasmic marker protein to the nucleus in cells expressing the wild-type c-Myc protein. In contrast, the cytoplasmic marker was translocated into the nucleus when the GCN4 leucine zippers were present on both the cytoplasmic marker and a nuclear protein, presumably as a result of leucine zipper interaction. These results suggest that c-Myc function requires hetero-oligomerization to an as yet undefined factor.
4.2: TFT AMOLED Pixel Circuits and Driving Methods (2003)

Abstract Active matrix organic light emitting diode AMOLED displays are now entering the market place. TFT active matrix allow OLED displays to be larger in size, higher in resolution and lower in power dissipation than is possible using a passive matrix. A number of TFT active matrix pixel circuits have been developed for luminance control while correcting for TFT parameter variations. The circuits and driving methods are reviewed. A new driving method is presented
Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials (2013)

HF-rTMS seems to be associated with clinically relevant antidepressant effects and with a benign tolerability profile.
4′-Phosphopantetheine and Coenzyme A Biosynthesis in Plants (2003)

Coenzyme A is required for many synthetic and degradative reactions in intermediary metabolism and is the principal acyl carrier in prokaryotic and eukaryotic cells. Coenzyme A is synthesized in five steps from pantothenate, and recently the CoaA biosynthetic genes in bacteria and human have all been identified and characterized. Coenzyme A biosynthesis in plants is not fully understood, and to date only the AtHAL3a (AtCoaC) gene of Arabidopsis thaliana has been cloned and identified as 4'-phosphopantothenoylcysteine (PPC) decarboxylase (Kupke, T., Hernández-Acosta, P., Steinbacher, S., and Culiáñez-Macià, F. A. (2001) J. Biol. Chem. 276, 19190-19196). Here, we demonstrate the cloning of the four missing genes, purification of the enzymes, and identification of their functions. In contrast to bacterial PPC synthetases, the plant synthetase is not CTP-but ATP-dependent. The complete biosynthetic pathway from pantothenate to coenzyme A was reconstituted in vitro by adding the enzymes pantothenate kinase (AtCoaA), 4'-phosphopantothenoylcysteine synthetase (AtCoaB), 4'-phosphopantothenoylcysteine decarboxylase (AtCoaC), 4'-phosphopantetheine adenylyltransferase (AtCoaD), and dephospho-coenzyme A kinase (AtCoaE) to a mixture containing pantothenate, cysteine, ATP, dithiothreitol, and Mg2+.