gebhart/patrepeval huggingface dataset:
Antibody to gp39, the Ligand for CD40 Significantly Inhibits the Humoral Response from Graves' Thyroid Tissues Xenografted into Severe Combined Immunodeficient (SCID) Mice (1996)

Experimental evidence suggests that interference with gp39-CD40 interactions may have therapeutic potential in prevention of certain autoimmune disorders (i.e., collagen-induced rheumatoid arthritis). The binding between CD40 expressed on mature B cells and CD40 ligand (CD40L, gp39) transiently expressed on activated T helper cells (Th) further stabilizes the interactions (between Th and B cells) and co-ordinates the responses of the interacting cells during antigen presentation, and is essential for thymus-dependent humoral immunity. Graves' disease is the most common form of hyperthyroidism, in which hyperactivity of the thyroid gland is due to an autoantibody directed against the thyrotropin receptor (TSHR). The main objective of our study was to determine the role of interactions between gp39 and CD40 in "an established" human Graves' disease (GD). Severe combined immunodeficient (SCID) mouse served as a vehicle for human Graves' thyroid tissue. This experimental setting allows us to study, observe, and immunomodulate human autoimmune tissue in so called in vivo condition. We studied the effects of ip administration of anti-gp39 mAb on humoral response, thyroid function tests, expression of adhesion molecules, and HLA-DR on human thyrocytes and histopathological changes from human GD thyroid tissue xenografts. GD thyroid tissue from 4 patients was xenografted into 20 SCID mice (0.8 g/mouse). Human immunoglobulin G (IgG) levels became detectable in SCID mice 1 week after xenograftment. Ten SCID mice were sequentially administered anti-gp39 mAb (250 micrograms/mouse/ dose) ip every 4 days until the end of the experiment. Ten control animals were injected with vehicle (PBS) in similar fashion. Blood samples were taken every 2 weeks from the tail veins for measurement of the humoral response [human IgG, thyroid-stimulating antibody (TSAb), antithyroperoxidase (anti-TPO), and antithyroglobulin (anti-Tg), Abs], and thyroid function tests. After 8 weeks, animals were sacrificed and thyroid tissue was examined histologically. The humoral response from the intrathyroidal lymphocytes was measured and the tissue morphology of GD was preserved during the 8-week period in phosphate-buffered saline (PBS)-treated SCID mice xenografted with GD xenografts. However, administration of anti-gp39 mAb completely blocked or significantly decreased the humoral response in all treated animals. On the other hand, no significant histological changes were associated with the administration of anti-gp39 mAb. The degree of lymphocytic infiltration in thyroid tissue xenografts was comparable in both groups. Serum thyroxine values were normal in both groups. In spite of a profound immunosuppressive effect on the humoral response by directly blocking CD40-gp39 interactions in vivo, this did not result in complete deletion of the responding Th in the thyroid specimens.
The Importance of Placebo in Headache Research (2008)

The best way to appreciate the efficacy of drug and behavioural therapy in the acute and prophylactic treatment of headache is to perform placebo-controlled randomized trials. In order to plan and conduct these studies in the most appropriate way, it is desirable to know which factors influence the placebo response. This paper reviews factors which influence the placebo response in clinical trials, such as expectation, blinding, route of application of drugs and age, gender and geographical distribution. Response rates of placebo in the treatment of acute headache episodes are higher than in headache prophylaxis. Invasive procedures such as injections have a higher placebo response compared with oral drugs. Variables known to influence the placebo response have to be taken into consideration to calculate properly the power of planned randomized trials.
The human homologue for the Caenorhabditis elegans cul-4 gene is amplified and overexpressed in primary breast cancers. (1998)

Amplification is a key mechanism whereby a cancer cell increases the message level of genes that confer a selective advantage when they are overexpressed. In breast cancer, there are many chromosome regions present in multiple copies relative to overall DNA copy number (amplicons), and their target genes are unknown. Using differential display, we have cloned and sequenced the full coding region of a candidate amplicon target gene located on chromosome 13. This candidate is the human homologue of the Caenorhabditis elegans cul-4 gene, cul-4A, a member of the novel cullin gene family, which is involved in cell cycle control of C. elegans. cul-4A was amplified and overexpressed in 3 of 14 breast cancer cell lines analyzed, and it was overexpressed in 8 additional cell lines in which it was not amplified. The latter observation, indicating that its overexpression can occur by mechanisms other than gene amplification, suggests that cul-4A plays a key role in carcinogenesis. Moreover, cul-4A was found to be amplified in 17 of 105 (16%) cases of untreated primary breast cancers, and 14 of 30 cases analyzed (47%) were shown by RNA in situ hybridization to overexpress cul-4A. These results suggest that up-regulation of cul-4A may play an important role in tumor progression.
Transient delivery of modified mRNA encoding TERT rapidly extends telomeres in human cells (2015)

Telomere extension has been proposed as a means to improve cell culture and tissue engineering and to treat disease. However, telomere extension by nonviral, nonintegrating methods remains inefficient. Here we report that delivery of modified mRNA encoding TERT to human fibroblasts and myoblasts increases telomerase activity transiently (24-48 h) and rapidly extends telomeres, after which telomeres resume shortening. Three successive transfections over a 4 d period extended telomeres up to 0.9 kb in a cell type-specific manner in fibroblasts and myoblasts and conferred an additional 28 ± 1.5 and 3.4 ± 0.4 population doublings (PDs), respectively. Proliferative capacity increased in a dose-dependent manner. The second and third transfections had less effect on proliferative capacity than the first, revealing a refractory period. However, the refractory period was transient as a later fourth transfection increased fibroblast proliferative capacity by an additional 15.2 ± 1.1 PDs, similar to the first transfection. Overall, these treatments led to an increase in absolute cell number of more than 10(12)-fold. Notably, unlike immortalized cells, all treated cell populations eventually stopped increasing in number and expressed senescence markers to the same extent as untreated cells. This rapid method of extending telomeres and increasing cell proliferative capacity without risk of insertional mutagenesis should have broad utility in disease modeling, drug screening, and regenerative medicine.
A Parallel Miniature Cylindrical Ion Trap Array (2000)

A small mass spectrometer array is described in which each element is a cylindrical ion trap (CIT). The array contains four CITs, each having an inner radius of 2.5 mm, arranged in parallel and operated using a single electronics system under common conditions for trapping and mass analysis. By using an array of identically sized traps, higher ion capacity can be achieved than with a single miniature CIT, but the advantage of lower power and voltage requirements associated with the smaller ion trap is maintained. Overall signal intensity of the array of four traps is compared with that of a two-element CIT array to demonstrate the increased ion capacity of larger arrays. Resolution for m-dichlorobenzene is shown to be approximately 180 (full width at half-maximum), with no significant loss in resolution as a result of using multiple CITs. The detection of 5 x 10(-9) Torr partial pressure of krypton in argon with a signal-to-noise ratio of approximately 30 for the most abundant isotope is shown, demonstrating the applicability of the device for process gas monitoring. Also, a preliminary spectrum from a 10-CIT array with each element having an inner radius of 1.5 mm is reported.
Reliable, rapid and simple voltammetric detection of urea nitrate explosive (2008)

A highly selective and rapid electrochemical assay of the improvised explosive urea nitrate (UN) is reported. The method involves a short ( approximately 10 s) acid-catalyzed reaction of UN with 4-nitrotoluene (NT) followed by a rapid ( approximately 2 s) square-wave voltammetric (SWV) detection of the 2,4-dinitrotoluene (DNT) product. The new protocol offers great promise for a reliable field detection of UN, with significant advantages of speed, sensitivity, portability, simplicity, and cost.
Post-copy live migration of virtual machines (2009)

We present the design, implementation, and evaluation of post-copy based live migration for virtual machines (VMs) across a Gigabit LAN. Post-copy migration defers the transfer of a VM's memory contents until after its processor state has been sent to the target host. This deferral is in contrast to the traditional pre-copy approach, which first copies the memory state over multiple iterations followed by a final transfer of the processor state. The post-copy strategy can provide a "win-win" by reducing total migration time while maintaining the liveness of the VM during migration. We compare post-copy extensively against the traditional pre-copy approach on the Xen Hypervisor. Using a range of VM workloads we show that post-copy improves several metrics including pages transferred, total migration time, and network overhead. We facilitate the use of post-copy with adaptive prepaging techniques to minimize the number of page faults across the network. We propose different prepaging strategies and quantitatively compare their effectiveness in reducing network-bound page faults. Finally, we eliminate the transfer of free memory pages in both pre-copy and post-copy through a dynamic self-ballooning (DSB) mechanism. DSB periodically reclaims free pages from a VM and significantly speeds up migration with negligible performance impact on VM workload.
Realtime and Robust Hand Tracking from Depth (2014)

We present a realtime hand tracking system using a depth sensor. It tracks a fully articulated hand under large viewpoints in realtime (25 FPS on a desktop without using a GPU) and with high accuracy (error below 10 mm). To our knowledge, it is the first system that achieves such robustness, accuracy, and speed simultaneously, as verified on challenging real data. Our system is made of several novel techniques. We model a hand simply using a number of spheres and define a fast cost function. Those are critical for realtime performance. We propose a hybrid method that combines gradient based and stochastic optimization methods to achieve fast convergence and good accuracy. We present new finger detection and hand initialization methods that greatly enhance the robustness of tracking.
A case for tracking and exploiting inter-node and intra-node memory content sharing in virtualized large-scale parallel systems (2012)

In virtualized large-scale parallel systems scientific workloads consist of numerous processes running across many virtual nodes. Their memory footprint is massive, and this has consequences for services that enhance performance, reliability, or power. We argue that a service that dynamically tracks the sharing of memory content, both within individual nodes, and across nodes, can simplify and enhance the implementation of such services. For example, leveraging content sharing could significantly reduce the size of a checkpoint of a group of nodes. As another example, it could speed VM migration by allowing the reconstruction of a VM's memory from multiple source VMs. Finally, a service that improves reliability by introducing memory redundancy could leverage existing content sharing to minimize the memory costs of any particular level of redundancy. We argue that both intra- and inter-node memory content sharing is common in parallel applications, supporting this claim by a detailed study of both kinds of sharing, at different scales, different granularities, and different times for a range of applications and application benchmarks. We then describe the high level approach we are taking to design and implement a distributed, VMM-based system that can efficiently and scalably identify and track such sharing with low overhead.
4,6-Dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile (2007)

In the crystal structure of the title compound, C8H8N2S, the mol­ecules form centrosymmetric dimers via N—H⋯S hydrogen bonds.
The Metastasis Suppressor Gene KiSS-1 Encodes Kisspeptins, the Natural Ligands of the Orphan G Protein-coupled Receptor GPR54 (2001)

Natural peptides displaying agonist activity on the orphan G protein-coupled receptor GPR54 were isolated from human placenta. These 54-, 14,- and 13-amino acid peptides, with a common RF-amide C terminus, derive from the product of KiSS-1, a metastasis suppressor gene for melanoma cells, and were therefore designated kisspeptins. They bound with low nanomolar affinities to rat and human GPR54 expressed in Chinese hamster ovary K1 cells and stimulated PIP<sub>2</sub> hydrolysis, Ca<sup>2+</sup> mobilization, arachidonic acid release, ERK1/2 and p38 MAP kinase phosphorylation, and stress fiber formation but inhibited cell proliferation. Human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function. Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis.
The Human let-7a-3 Locus Contains an Epigenetically Regulated MicroRNA Gene with Oncogenic Function (2007)

MicroRNAs (miRNAs) are small noncoding RNAs that repress their target mRNAs by complementary base pairing and induction of the RNA interference pathway. It has been shown that miRNA expression can be regulated by DNA methylation and it has been suggested that altered miRNA gene methylation might contribute to human tumorigenesis. In this study, we show that the human let-7a-3 gene on chromosome 22q13.31 is associated with a CpG island. Let-7a-3 belongs to the archetypal let-7 miRNA gene family and was found to be methylated by the DNA methyltransferases DNMT1 and DNMT3B. The gene was heavily methylated in normal human tissues but hypomethylated in some lung adenocarcinomas. Let-7a-3 hypomethylation facilitated epigenetic reactivation of the gene and elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes and oncogenic changes in transcription profiles. Our results thus identify let-7a-3 as an epigenetically regulated miRNA gene with oncogenic function and suggest that aberrant miRNA gene methylation might contribute to the human cancer epigenome.
Proposal of 3-Dimensional Independent Triple-Gate MOS Transistor with Dynamic Current Control (2007)

A three-dimensional nMOSFET with independent parallel triple gates on an SOI beam is successfully developed. Since this FET can provide independent biasing to each gate, both subthreshold behavior and drivability can be flexibly controlled in response to performance requirement. Furthermore, its self-aligned structure provides planar area shrinkage to certain extent.
A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia (1998)

Ras proteins, key regulators of growth, differentiation, and malignant transformation, recently have been implicated in synaptic function and region-specific learning and memory functions in the brain. Rap proteins, members of the Ras small G protein superfamily, can inhibit Ras signaling through the Ras/Raf-1/mitogen-activated protein (MAP) kinase pathway or, through B-Raf, can activate MAP kinase. Rap and Ras proteins both can be activated through guanine nucleotide exchange factors (GEFs). Many Ras GEFs, but to date only one Rap GEF, have been identified. We now report the cloning of a brain-enriched gene, CalDAG-GEFI, which has substrate specificity for Rap1A, dual binding domains for calcium (Ca2+) and diacylglycerol (DAG), and enriched expression in brain basal ganglia pathways and their axon-terminal regions. Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells. Ca2+ ionophore and phorbol ester strongly and additively enhance this Rap1A activation. By contrast, CalDAG-GEFII, a second CalDAG-GEF family member that we cloned and found identical to RasGRP [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L., Dunn, R. J. & Stone, J. C. (1998) Science 280, 1082-1088], exhibits a different brain expression pattern and fails to activate Rap1A, but activates H-Ras, R-Ras, and the Erk/MAP kinase cascade under Ca2+ and DAG modulation. We propose that CalDAG-GEF proteins have a critical neuronal function in determining the relative activation of Ras and Rap1 signaling induced by Ca2+ and DAG mobilization. The expression of CalDAG-GEFI and CalDAG-GEFII in hematopoietic organs suggests that such control may have broad significance in Ras/Rap regulation of normal and malignant states.
Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases (2013)

Protein kinases mediate protein phosphorylation, which is a fundamental component of cell signalling, with crucial roles in most signal transduction cascades: from controlling cell growth and proliferation to the initiation and regulation of immunological responses. Aberrant kinase activity is implicated in an increasing number of diseases, with more than 400 human diseases now linked either directly or indirectly to protein kinases. Protein kinases are therefore regarded as highly important drug targets, and are the subject of intensive research activity. The success of small molecule kinase inhibitors in the treatment of cancer, coupled with a greater understanding of inflammatory signalling cascades, has led to kinase inhibitors taking centre stage in the pursuit for new anti-inflammatory agents for the treatment of immune-mediated diseases. Herein we discuss the main classes of kinase inhibitors; namely Janus kinase (JAK), mitogen-activated protein kinase (MAPK) and spleen tyrosine kinase (Syk) inhibitors. We provide a mechanistic insight into how these inhibitors interfere with kinase signalling pathways and discuss the clinical successes and failures in the implementation of kinase-directed therapeutics in the context of inflammatory and autoimmune disorders.
Implications of climate change for agricultural productivity in the early twenty-first century (2010)

This paper reviews recent literature concerning a wide range of processes through which climate change could potentially impact global-scale agricultural productivity, and presents projections of changes in relevant meteorological, hydrological and plant physiological quantities from a climate model ensemble to illustrate key areas of uncertainty. Few global-scale assessments have been carried out, and these are limited in their ability to capture the uncertainty in climate projections, and omit potentially important aspects such as extreme events and changes in pests and diseases. There is a lack of clarity on how climate change impacts on drought are best quantified from an agricultural perspective, with different metrics giving very different impressions of future risk. The dependence of some regional agriculture on remote rainfall, snowmelt and glaciers adds to the complexity. Indirect impacts via sea-level rise, storms and diseases have not been quantified. Perhaps most seriously, there is high uncertainty in the extent to which the direct effects of CO(2) rise on plant physiology will interact with climate change in affecting productivity. At present, the aggregate impacts of climate change on global-scale agricultural productivity cannot be reliably quantified.
Viable Viruses with Deletions in the Left Inverted Terminal Repeat Define the Adenovirus Origin of DNA Replication (1986)

A series of human adenovirus type 2 genomes with deletions in the left inverted terminal repeat (ITR) have been constructed. Viral genomes that contained a minimum of 45 base pairs (bp) from the terminus of the genome were fully infectious and gave rise to progeny virus which maintained the deletion. In contrast, genomes containing 36 bp or less from the termini of the genome were not infectious. The boundary of a cis-acting element required for viral replication is therefore between 36 and 45 bp from the adenovirus termini and corresponds to the previously identified viral origin of replication, defined using a transfection assay to measure ori activity in vivo. The growth parameters of viruses with deletions in the left ITR were examined. These deletions had no measurable effect on plaque formation or morphology, viral DNA synthesis or early viral mRNA synthesis. Thus, it appears that DNA sequences in the left ITR, outside the replication origin, are completely dispensable for lytic viral growth in tissue culture cells.
Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains (1996)

The role of target cell autoantigens and their repertoire vs those of foreign Ags, superantigens, or non-Ag-specific stimuli in the activation and recruitment of effector T cells in most spontaneous models of autoimmune diseases remains elusive. Here we report on the use of single TCR-beta transgenic mice to study the mechanisms that drive the accumulation of pathogenic T cells in the pancreatic islets of nonobese diabetic (NOD) mice, a model for insulin-dependent diabetes mellitus. Expression of the V(beta)8.1+ TCR-beta rearrangement of a diabetogenic H-2Kd-restricted beta cell cytotoxic CD8+ T cell (beta-CTL) clone in NOD mice caused a 10-fold increase in the peripheral precursor frequency of beta-CTL and a selective acceleration of the recruitment of CD8+ T cells to the pancreatic islets of prediabetic animals. This resulted in an earlier onset and a faster progression of beta cell depletion, and led to a dramatic acceleration of the onset of diabetes. Most islet-derived beta-CTL from diabetic transgenic NOD mice expressed an endogenously-derived TCR-alpha sequence identical to that of the clonotype donating the TCR-beta transgene, and a TCR-alpha-CDR3 sequence homologous to those expressed by most islet-derived beta-CTL from nontransgenic NOD mice. TCR-beta transgene expression did not change the peripheral frequency of beta cell-specific CD4+ T cells, the rate at which these cells accumulated in the pancreatic islets, or the incidence of diabetes. Taken together, our data indicate that retention of CD8+ and CD4+ T cells in the pancreatic islets of NOD mice is driven by beta cell autoantigens, rather than by local superantigens or non-Ag-specific stimuli, and that beta-CTL are major effectors of beta cell damage in spontaneous insulin-dependent diabetes mellitus.