gebhart/patrepeval huggingface dataset:
Use of Substrate Analogs and Mutagenesis to Study Substrate Binding and Catalysis in the Sir2 Family of NAD-dependent Protein Deacetylases (2006)

The Sir2 family of enzymes is highly conserved throughout evolution and functions in silencing, control of life span, apoptosis, and many other cellular processes. Since the discovery of the NAD-dependent deacetylase activity of Sir2 proteins, there has been a flurry of activity aiming to uncover the mode of substrate binding and catalysis. Structural and biochemical studies have led to several proposed reaction mechanisms, yet the exact catalytic steps remain unclear. Here we present in vitro studies of yeast homolog Hst2 that shed light on the mechanism of Sir2 proteins. Using acetyl-lysine substrate analogs, we demonstrate that the Hst2 reaction proceeds via an initial SN2-type mechanism with the direct formation of an ADP-ribose-acetyl-lysine intermediate. Kinetic studies further suggest that ADP-ribose inhibits the Hst2 reaction in a biologically relevant manner. Through biochemical and kinetic analyses of point mutants, we also clarify the role of several conserved core domain residues in substrate binding, stabilization of the ADP-ribose-acetyl-lysine intermediate, and catalysis. These findings bring us a few steps closer to understanding Sir2 activity and may provide a useful platform for the design of Sir2-specific inhibitors for analysis of Sir2 function and possibly therapeutic applications.
Uptake of [3H] dihydroartemisinine by erythrocytes infected with Plasmodium falciparum in vitro (1984)

Artemisinine ( qinghaosu ) was reduced and radio-labelled using tritiated borohydride. The tritiated dihydroartemisinine produced was differentially accumulated from low concentrations in culture medium into erythrocytes infected with Plasmodium falciparum. Uninfected erythrocytes concentrated the drug less than two-fold whereas infected erythrocytes achieved more than 300 times the medium concentration. The uptake process is reversible and saturable, with a dissociation constant (Kd) at the hypothetical receptor of 10.5 nmol.l-1. Competition studies indicate that the receptor is the same as that for artemether , another quinghaosu derivative. Chloroquine showed an interesting partial inhibition of uptake but was unable to release the bound radio-labelled drug from infected cells.
How αβ T cells deal with induced TCRα ablation (2001)

On deletion of the gene encoding the constant region of the T cell antigen receptor (TCR)alpha chain in mature T cells by induced Cre-mediated recombination, the cells lose most of their TCR from the cell surface within 7--10 days, but minute amounts of surface-bound TCR beta chains are retained for long periods of time. In a situation in which cellular influx from the thymus is blocked, TCR-deficient naive T cells decay over time, the decay rates being faster for CD8(+) cells (t(1/2) approximately 16 days) than for CD4(+) cells (t(1/2) approximately 46 days). TCR(+) naïve cells are either maintained (CD8(+)) or decay more slowly (CD4(+); t(1/2) approximately 78 days.) Numbers of TCR-deficient memory T cells decline very slowly (CD8(+) cells; t(1/2) approximately 52 days) or not at all (CD4(+) cells), but at the population level, these cells fail to expand as their TCR(+) counterparts do. Together with earlier data on T cell maintenance in environments lacking appropriate major histocompatibility complex antigens, these data argue against the possibility that spontaneous ligand-independent signaling by the alpha beta TCR contributes significantly to T-cell homeostasis.
Defocused orientation and position imaging (DOPI) of myosin V (2006)

The centroid of a fluorophore can be determined within approximately 1.5-nm accuracy from its focused image through fluorescence imaging with one-nanometer accuracy (FIONA). If, instead, the sample is moved away from the focus, the point-spread-function depends on both the position and 3D orientation of the fluorophore, which can be calculated by defocused orientation and position imaging (DOPI). DOPI does not always yield position accurately, but it is possible to switch back and forth between focused and defocused imaging, thereby getting the centroid and the orientation with precision. We have measured the 3D orientation and stepping behavior of single bifunctional rhodamine probes attached to one of the calmodulins of the light-chain domain (LCD) of myosin V as myosin V moves along actin. Concomitant with large and small steps, the LCD rotates and then dwells in the leading and trailing position, respectively. The probe angle relative to the barbed end of the actin (beta) averaged 128 degrees while the LCD was in the leading state and 57 degrees in the trailing state. The angular difference of 71 degrees represents rotation of LCD around the bound motor domain and is consistent with a 37-nm forward step size of myosin V. When beta changes, the probe rotates +/-27 degrees azimuthally around actin and then rotates back again on the next step. Our results remove degeneracy in angles and the appearance of nontilting lever arms that were reported.
Successful Virtual Screening of a Chemical Database for Farnesyltransferase Inhibitor Leads (2000)

Virtual screening of chemical databases is an emerging approach in drug discovery that uses computers to dock chemicals into the active site of a drug target to identify leads through evaluation of binding affinities of the chemicals. However, there are concerns about the validity and scope of the reported virtual screens due to lack of studies to show that randomly selected chemicals are not equally active and due to the fact that metalloproteins were rarely used as drug targets. We have performed a virtual screening of a chemical database to identify prototypic inhibitors of farnesyltransferase (FT) with zinc present in the active site. Among the 21 compounds identified by computers, four inhibited FT in vitro with IC(50) values in the range from 25 to 100 microM. The most potent inhibitor also inhibited FT in human lung cancer cells. In contrast, none of 21 randomly selected compounds have an IC(50) lower than 100 microM. The results demonstrate the validity of virtual screening and the feasibility of applications of this approach to metalloprotein drug targets, such as matrix metalloproteinases, farnesyltransferase, and HIV-1 integrase, for the treatments of cardiovascular diseases, cancers, and AIDS.
Thiazolidinediones: effects on the development and progression of type 2 diabetes and associated vascular complications (2009)

In addition to reducing hyperglycaemia, the metabolic actions of TZDs (pioglitazone and rosiglitazone) in theory might improve the prognosis of patients with type 2 diabetes. However, it appears from recent data that pioglitazone and rosiglitazone have different cardiovascular risk profiles. The scope of this paper is to examine the benefits and risks of pioglitazone and rosiglitazone. Three large clinical studies (DREAM, and ADOPT with rosiglitazone; PROactive with pioglitazone) have recently been reported. A lower annual rate of decline of ss-cell function observed with rosiglitazone in the ADOPT study, compared with metformin and glyburide (glibenclamide), along with a reduced progression to insulin use seen with pioglitazone in the PROactive study, provides evidence that TZDs are effective in treating progressive hyperglycaemia. In PROactive, although the primary endpoint was not met, pioglitazone was associated with a reduction in a secondary composite endpoint of clinical cardiovascular events in high-risk patients with existing macrovascular disease who were already receiving other glycaemic and cardiovascular medications. Further evidence supporting an anti-atherogenic effect of pioglitazone was gained from the PERISCOPE study of carotid intima-media thickness. Recent controversy concerning a possible increased risk of myocardial infarction associated with rosiglitazone has fuelled uncertainty about the risk-benefit profile of this agent. In 2008, an update of an American Diabetes Association-European Association for the Study of Diabetes consensus statement on initiation and adjustment of therapy in patients with type 2 diabetes advised clinicians against using rosiglitazone. Skeletal fractures have recently emerged as a side effect of both TZDs. Available data suggest that cardiovascular benefits observed with pioglitazone might not be a class effect of TZDs.
Majority-Minority Influence: Identifying Argumentative Patterns and Predicting Argument-Outcome Links (2000)

In this paper, the authors investigate the argument activities of majority and minority factions in small group decision-making situations. We begin by identifying patterns of argument that characterize majority and minority communication in 34 discussions and then test several subgroup-outcome and argument-outcome links. Results indicate that winning and losing subgroups argue differently (as do minority and majority subgroups overall) and that consistency in argument is a strong predictor of subgroup success. Both theoretical and practical implications for subgroup influence in group decision making accrue from these findings.
Validation of the Archimedes Diabetes Model (2003)

The Archimedes diabetes model is a realistic representation of the anatomy, pathophysiology, treatments, and outcomes pertinent to diabetes and its complications for applications that involve the populations, treatments, outcomes, and health care settings spanned by the trials.
Physiology and Cell Biology of the Endothelium: A Dynamic Interface for Cell Communication (1997)

This manuscript presents a brief overview of the physiology and cell biology of the endothelium, which is the basis for understanding the role of endothelial cells in pathological processes as diverse as atherosclerosis, tumour intravasation and multiple organ failure. Following consideration of general aspects of endothelial function in regulating haemostasis, vascular tone and growth, special emphasis will be placed on endothelial regulation of the inflammatory response, which centres on the microcirculation. A particular role in inflammation is played by cell adhesion molecules (CAM), expressed both on endothelial and blood cells. Cell and molecular biological methods to investigate the expression of CAM in endothelial cells in vitro will be presented, as well as novel data, indicating that cytokine-induced up-regulation of CAM in the endothelium may involve signal transduction pathways other than those culminating in the activation of NF-kappa B. Finally, the phenomenon of angiogenesis will be briefly reviewed as a characteristic of endothelial cell activity of central importance to both physiology and pathology and new experimental data presented from an in vitro model to study the ability of individual endothelial cells to form vessel-like structures. In comparative studies to investigate the roles of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, the dominant role of VEGF in the formation of capillary networks could be unequivocally demonstrated.
The design of a new type of micro robot for the intestinal inspection (2003)

In the last few years, we have observed a fast development of modern science and technology. In the field of medical engineering, the same evolution is observed, and the minimally invasive surgery (MIS) has became one of the most important research area. Medical endoscope is one typical medical instrument that complies with the requirement of MIS. This paper deals with the design of a new type of micro-robot for intestinal inspection. Because of the injuries caused by the colonoscope during the operation, and the long time spent at the hospital by the patient, we focus on a new type of intelligent colonoscope. The main purpose of this medical tool is to be in accordance with MIS by minimizing the contact between the colonoscope and the interior boundary of the colon, and to make the progression of the colonoscope easier for the surgeon. Our current prototype, which is twice the size of the final tool, is electro pneumatically driven. It is constituted by three metal bellows disposed 120/spl deg/ apart, and its position in the intestine is driven by three sensors positioned on the superior plate. Some experimental results are presented.
Improving GaN‐on‐silicon properties for GaN device epitaxy (2011)

Abstract GaN growth on silicon has recently found its way into products as transistor devices for high frequencies and high‐voltage applications as well as for light emitting diodes (LEDs). Here, we present the importance of high quality GaN layers for growing LED structures and high‐voltage transistors on silicon. The major difference is that LED growth on silicon substrates suffers from edge type dislocations during silicon doping while FETs suffer from a lowered breakdown field. We will show that the latter is most likely originating in screw type dislocations. By optimizing GaN material quality the breakdown field strength can be doubled from less than 0.7x10 6 V/cm up to ∼ 1.5x10 6 V/cm. (© 2011 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)
Photovoltaic effect in a gated two-dimensional electron gas in magnetic field (2009)

The photovoltaic effect induced by terahertz radiation in a gated two-dimensional electron gas in magnetic field is considered theoretically. It is assumed that the incoming radiation creates an ac voltage between the source and the gate and that the gate length is long compared to the damping length of plasma waves. In the presence of pronounced Shubnikov-de Haas (SdH) oscillations, an important source of nonlinearity is the oscillating dependence of the mobility on the ac gate voltage. This results in a photoresponse oscillating as a function of magnetic field, which is enhanced in the vicinity of the cyclotron resonance, in accordance with recent experiments. Another smooth component of the photovoltage, unrelated to SdH oscillations, has a maximum at cyclotron resonance.
Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. (1981)

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.
Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease (2016)

Oral ER calcifediol is safe and effective in treating SHPT and vitamin D insufficiency in CKD.
Self-Assembly of Fluorescent Inclusion Complexes in Competitive Media Including the Interior of Living Cells (2007)

Anthracene-containing tetralactam macrocycles are prepared and found to have an extremely high affinity for squaraine dyes in chloroform (log Ka = 5.2). Simply mixing the two components produces highly fluorescent, near-infrared inclusion complexes in quantitative yield. An X-ray crystal structure shows the expected hydrogen bonding between the squaraine oxygens and the macrocycle amide NH residues, and a high degree of cofacial aromatic stacking. The kinetics and thermodynamics of the assembly process are very sensitive to small structural changes in the binding partners. For example, a macrocycle containing two isophthalamide units associates with the squaraine dye in chloroform 400,000 times faster than an analogous macrocycle containing two 2,6-dicarboxamidopyridine units. Squaraine encapsulation also occurs in highly competitive media such as mixed aqueous/organic solutions, vesicle membranes, and the organelles within living cells. The highly fluorescent inclusion complexes possess emergent properties; that is, as compared to the building blocks, the complexes have improved chemical stabilities, red-shifted absorption/emission maxima, and different cell localization propensities. These are useful properties for new classes of near-infrared fluorescent imaging probes.
FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors. (1998)

These data indicate that GLUT-1 expression plays an essential role in higher FDG accumulation in pancreatic tumor FDG PET, and the cellularity has a significant influence on SUVs only in the condition of GLUT-1 strong positive expression.
Contribution of the complement control protein modules of C2 in C4b binding assessed by analysis of C2/factor B chimeras (1997)

To identify the complement control protein (CCP) module(s) of C2 that are required for C4b recognition, we constructed a panel of C2/factor B chimeras by substituting intact or partial factor B CCP modules for the corresponding ones of C2. Epitope mapping indicated that the anti-C2b mAb 3A3.3, which inhibits binding of C2 to C4b, reacts with the second CCP of C2 and similarly the anti-Ba mAb HA4-1A, which inhibits binding of factor B to C3b, reacts with the second CCP of factor B. The hemolytic activity of the chimeras CP1, CP2, and CP3a containing CCP1, CCP2, and a fragment of CCP3 of factor B, respectively, was substantially decreased compared with that of wild-type C2. The CP3 and CP1-3 chimeras, in which CCP3 and all three CCP modules of factor B, respectively, were substituted, had no hemolytic activity. Loss of activity could be attributed to the resistance of these two chimeras to C1s cleavage, which was probably due to conformational changes of the cleavage site. The combined results indicate that all three CCP modules of C2 contribute structural elements to the C4b-binding site of C2b. This site has been shown previously to be necessary for the initial binding of C2 to C4b which leads to the formation of the classical pathway C3 convertase.
Insulin resistance, impaired glucose tolerance and non-insulin-dependent diabetes, pathologic mechanisms and treatment: Current status and therapeutic possibilities (1998)

Impaired glucose tolerance and non-insulin-dependent diabetes (NIDDM) are the pathologic consequence of two co-incident and interacting conditions, namely insulin resistance and relative insulin deficiency. Recognised by the World Health Authority as a global health problem there are at 1995 estimates at least 110 million diagnosed diabetics world wide with at least the same number undiagnosed. Diabetes is the 4th leading cause of death in developed countries and its management exerts a vast economic and social burden. Insulin resistance is established as the characteristic pathologic feature of patients with glucose intolerance and NIDDM describing a state in which insulin stimulated glucose uptake and utilisation in liver, skeletal muscle and adipose tissue is impaired and coupled to impaired suppression of hepatic glucose output. Although the biochemical mechanisms underpinning both defects are becoming better understood, the genetic and molecular causes remain elusive; and whether insulin resistance or relative insulin deficiency represents the primary defect in patients with NIDDM is the matter of some debate. In this article we review the biochemical and molecular nature of the defects in insulin sensitivity and glucose uptake, and discuss some of the potential causative mechanisms. The genetic and environmental basis of insulin resistance is reviewed and presented, and potential therapeutic targets including thiazolidinediones are discussed.
Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors (2007)

Guiding multipotent cells into distinct lineages and controlling their expansion remain fundamental challenges in developmental and stem cell biology. Members of the Wnt pathway control many pivotal embryonic events, often promoting self-renewal or expansion of progenitor cells. In contrast, canonical Wnt ligands are thought to negatively regulate cardiomyogenesis in several species. However, the cell-autonomous role of canonical Wnt signaling within precardiac mesoderm, through its obligatory transcriptional mediator, beta-catenin, is unknown. Using tissue-specific in vivo genetic manipulation, we found that beta-catenin is required for development of cardiac progenitors and is a positive regulator of proliferative expansion of such progenitor cells. At discrete windows of development in embryonic stem cells, activation of canonical Wnt signaling promoted expansion of cardiac progenitors after initial commitment and was required for cardiac differentiation. Together, these data provide in vivo and in vitro evidence that canonical Wnt signaling promotes the expansion of cardiac progenitors and differentiation of cardiomyocytes.
Changing the Receptor Specificity of Anthrax Toxin (2012)

Bacterial toxins that act within mammalian cells have receptor-dependent mechanisms to transport their enzymatic components to the cytoplasmic compartment. By inactivating or otherwise modifying their respective intracellular targets, these intracellular effectors disrupt metabolic pathways and in some cases cause death of the cell. Our results show that the receptor specificity of the transport protein of anthrax toxin may be readily changed, raising the possibility that receptor-redirected forms of protective antigen (PA) and PA homologs may be useful for research and medical applications requiring modification or ablation of designated populations of cells.