gebhart/patrepeval huggingface dataset:
HPV-18 E6 mediated inhibition of p53 DNA binding activity is independent of E6 induced degradation. (1995)

A key activity of the p53 protein during suppression of cell growth is its ability to stimulate transcription from promoters of cellular genes which contain a p53 responsive element. The E6 proteins from the oncogenic associated Human Papillomaviruses (HPVs) have been shown to inhibit specifically the p53 transcriptional activation and this has been proposed as a mechanism whereby the virus prevents the suppression of cell cycle progression and the induction of apoptosis. However, the mechanism by which E6 exercises this function is unknown, as is the ability of E6 to associate with different oligomeric forms of p53. In this study we demonstrate that E6 induces changes within the p53 protein which result both in inhibition of DNA binding and in dissociation of p53 protein previously bound to the DNA. These activities correlate exactly with the ability of E6 to inhibit p53 transcriptional activation and are independent of the ability of E6 to direct the degradation of the p53 protein. Further, we show that E6 labels wild type tetrameric and dimeric forms of p53 proteins for ubiquitin mediated degradation more readily than monomeric forms of the protein. However, in vivo analyses indicate that E6 is capable of inhibiting the transcriptional activation induced by the tetrameric, dimeric and monomeric forms of p53.
Regulating Myoblast Phenotype Through Controlled Gel Stiffness and Degradation (2007)

Mechanical stiffness and degradability are important material parameters in tissue engineering. The aim of this study was to address the hypothesis that these variables regulate the function of myoblasts cultured in 2-D and 3-D microenvironments. Development of cell-interactive alginate gels with tunable degradation rates and mechanical stiffness was established by a combination of partial oxidation and bimodal molecular weight distribution. Higher gel mechanical properties (13 to 45 kPa) increased myoblast adhesion, proliferation, and differentiation in a 2-D cell culture model. Primary mouse myoblasts were more highly responsive to this cue than the C2C12 myoblast cell line. Myoblasts were then encapsulated in gels varying in degradation rate to simultaneously investigate the effect of degradation and subsequent reduction of mechanical properties on cells in a 3-D environment. C2C12 cells in more rapidly degrading gels exhibited lower proliferation, as they exited the cell cycle to differentiate, compared to those in nondegradable gels. In contrast, mouse primary myoblasts illustrated significantly higher proliferation in degradable gels than in nondegradable gels, and exhibited minimal differentiation in either type of gel. Altogether, these studies suggest that a critical balance between material degradation rate and mechanical properties may be required to regulate formation of engineered skeletal muscle tissue, and that results obtained with the C2C12 cell line may not be predictive of the response of primary myoblasts to environmental cues. The principles delineated in these studies may be useful to tailor smart biomaterials that can be applied to many other polymeric systems and tissue types.
The Carboxyl-terminal Domain of RNA Polymerase II Is Not Sufficient to Enhance the Efficiency of Pre-mRNA Capping or Splicing in the Context of a Different Polymerase (2009)

Eukaryotic messenger RNA precursors (pre-mRNAs) synthesized by RNA polymerase II (RNAP II) are processed co-transcriptionally. The carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II is thought to mediate the coupling of transcription with pre-mRNA processing by coordinating the recruitment of processing factors during synthesis of nascent transcripts. Previous studies have demonstrated that the phosphorylated CTD is required for efficient co-transcriptional processing. In the study presented here we investigated whether the CTD is sufficient to coordinate transcription with pre-mRNA capping and splicing in the context of two other DNA-dependent RNA polymerases, mammalian RNAP III and bacteriophage T7 RNAP. Our results indicate that the CTD fused to the largest subunit of RNAP III (POLR3A) is not sufficient to enhance co-transcriptional pre-mRNA splicing or capping in vivo. Additionally, we analyzed a T7 RNAP-CTD fusion protein and examined its ability to enhance pre-mRNA splicing and capping of both constitutively and alternatively spliced substrates. We observed that the CTD in the context of T7 RNAP was not sufficient to enhance pre-mRNA splicing or capping either in vitro or in vivo. We propose that the efficient coupling of transcription to pre-mRNA processing requires not only the phosphorylated CTD but also other RNAP II specific subunits or associated factors.
Impact of preventing exacerbations on deterioration of health status in COPD (2004)

Exacerbations of chronic obstuctive pulmonary disease (COPD) are associated with worse health status. The Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study showed that treatment with fluticasone propionate (FP) reduced exacerbation frequency and the rate of deterioration in health status as compared with placebo. The present study analysed these data to test whether the effect of FP on health status was attributable to its effect on exacerbations. Rates of deterioration in St George's Respiratory Questionnaire (SGRQ) total score were obtained for 613 patients with moderate to severe COPD followed for a maximum of 3 yrs. Exacerbation rates were skewed and could not be normalised, therefore, patients were stratified into three exacerbation groups: none, infrequent (<1.65 exacerbations x yr(-1)) and frequent (>1.65 exacerbations x yr(-1)). There were 91 patients with no exacerbations, 285 with infrequent exacerbations and 235 with frequent exacerbations. Frequent exacerbations were independently associated with a worse baseline SGRQ score (p<0.0001) and a more rapid rate of deterioration in health status (p=0.0003). Exacerbation frequency and rate of decline in forced expiratory volume in one second were independently related to the rate of deterioration in SGRQ score. Statistical modelling showed the beneficial effect of fluticasone propionate on deterioration in health status to be largely due to its effect on exacerbation frequency.
Dynamics of a two-level system strongly coupled to a high-frequency quantum oscillator (2005)

Recent experiments on quantum behavior in microfabricated solid-state systems suggest tantalizing connections to quantum optics. Several of these experiments address the prototypical problem of cavity quantum electrodynamics: a two-level system coupled to a quantum harmonic oscillator. Such devices may allow the exploration of parameter regimes outside the near-resonance and weak-coupling assumptions of the ubiquitous rotating-wave approximation (RWA), necessitating other theoretical approaches. One such approach is an adiabatic approximation in the limit that the oscillator frequency is much larger than the characteristic frequency of the two-level system. A derivation of the approximation is presented, together with a discussion of its applicability in a system consisting of a Cooper-pair box coupled to a nanomechanical resonator. Within this approximation the time evolution of the two-level-system occupation probability is calculated using both thermal- and coherent-state initial conditions for the oscillator, focusing particularly on collapse and revival phenomena. For thermal-state initial conditions parameter regimes are found in which collapse and revival regions may be clearly distinguished, unlike the erratic evolution of the thermal-state RWA model. Coherent-state initial conditions lead to complex behavior, which exhibits sensitive dependence on the coupling strength and the initial amplitude of the oscillator state. One feature of the regime considered here is that closed-form evaluation of the time evolution may be carried out in the weak-coupling limit, which provides insight into the differences between the thermal- and coherent-state models. Finally, potential experimental observations in solid-state systems, particularly the Cooper-pair box---nanomechanical resonator system, are discussed and found to be promising.
Structural Basis for Potency and Promiscuity in Poly(ADP-ribose) Polymerase (PARP) and Tankyrase Inhibitors (2016)

Selective inhibitors could help unveil the mechanisms by which inhibition of poly(ADP-ribose) polymerases (PARPs) elicits clinical benefits in cancer therapy. We profiled 10 clinical PARP inhibitors and commonly used research tools for their inhibition of multiple PARP enzymes. We also determined crystal structures of these compounds bound to PARP1 or PARP2. Veliparib and niraparib are selective inhibitors of PARP1 and PARP2; olaparib, rucaparib, and talazoparib are more potent inhibitors of PARP1 but are less selective. PJ34 and UPF1069 are broad PARP inhibitors; PJ34 inserts a flexible moiety into hydrophobic subpockets in various ADP-ribosyltransferases. XAV939 is a promiscuous tankyrase inhibitor and a potent inhibitor of PARP1 in vitro and in cells, whereas IWR1 and AZ-6102 are tankyrase selective. Our biochemical and structural analysis of PARP inhibitor potencies establishes a molecular basis for either selectivity or promiscuity and provides a benchmark for experimental design in assessment of PARP inhibitor effects.
FcγRIIIa and FcγRIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia (2003)

In follicular lymphoma (FL), genomic polymorphisms corresponding to the expression of valine (V) or phenylalanine (F) at amino acid 158 of Fc gamma RIIIa alter the binding affinity of immunoglobulin G1 (IgG1) to the receptor and have been associated with varied responses to rituximab. We examined Fc gamma RIIIa polymorphisms of 30 CLL patients with the phenotypes V/V (n = 6), V/F (n = 12), and F/F (n = 12) treated with thrice-weekly rituximab (375 mg/m(2)) for 4 weeks to correlate polymorphism type with infusion toxicity and response. Infusion toxicity (grade 3 or greater or hypoxia/hypotension requiring transient cessation of therapy) was observed equally among the groups (V/V, 50%; V/F, 33%; F/F, 41.6%; P =.78). The response to rituximab was also similar among the different polymorphism phenotypes (V/V, 33%; V/F, 41.6%; F/F, 50%). These data suggest that Fc gamma RIIIa polymorphisms are not predictive of response in CLL and that, unlike the case with FL, mechanisms of tumor clearance other than antibody-dependent cellular cytotoxicity may be more important.
Relevance based language models (2001)

We explore the relation between classical probabilistic models of information retrieval and the emerging language modeling approaches. It has long been recognized that the primary obstacle to effective performance of classical models is the need to estimate arelevance model: probabilities of words in the relevant class. We propose a novel technique for estimating these probabilities using the query alone. We demonstrate that our technique can produce highly accurate relevance models, addressing important notions of synonymy and polysemy. Our experiments show relevance models outperforming baseline language modeling systems on TREC retrieval and TDT tracking tasks. The main contribution of this work is an effective formal method for estimating a relevance model with no training data.
Synthesis of novel proteins (1997)

De novo and rational protein design are progressing towards the chemical synthesis of proteins with pre-selected structure and function. The data illustrate diverse experimental and computational approaches which test our comprehension of protein structure, hydrophobic core packing and global stability, especially of coiled-coil proteins. The incorporation of biological cofactors, including hemes, as well as active sites, such as that of iron superoxide dismutase, into designed proteins provides an exciting next step towards the synthesis of proteins with enzymatic function.
Heart Disease and Rehabilitation (1995)

Epidemiology of Heart Disease The Heart Disease Patient: Pathophysiology, Diagnosis, and Treatment Risk Factor Modification Rehabilitation of the Cardiac Patient Special Considerations in Cardiac Rehabilitation Cardiac Rehabilitation in Perspective Index.
Phosphorus Retention by Bioretention Mesocosms Using Media Formulated for Phosphorus Sorption: Response to Accelerated Loads (2010)

Recent research indicates that phosphorus (P) retention by bioretention systems comprising sandy media may not be effective for even a decade of urban runoff loads. To improve P retention for longer durations, this paper present findings from bioretention mesocosms using media amended with red mud (RM), a by-product of bauxite processing; water treatment residuals (WTRs), a by-product of water treatment; or Krasnozem soil (K), a highly aggregated clay soil. All treatments were vegetated except for one (K20nv). All treatments had outlets to restrict outflows except for one (WTR-Knr). To simulate the effect of long-term nutrient loads, the mesocosms were loaded weekly with secondary treated effluent with P concentrations averaging 3.3 mg-L-1. Over 80 weeks, this comprised hydraulic loads from 24.5 to 29.3 m-year-1 at a flow-weighted average between 2.8 and 3.2 mg-L-1 PO4-P, or mass loads from 1,115 to 1,284 kg-ha-1 PO4-P. These cumulative P loads represent the equivalent of over three decades of runoff loads. After 80 weeks, cumulative PO4-P retention in the K and RM soil treatments ranged from 79% to 95%, whereas PO4-P retention in the WTR treatments ranged from 95% to 99% of the input load. At 6-month intervals, the treatments were dosed with at least four sequential dosing runs of synthetic storm water with concentrations less than 0.8 mg-L-1 PO4-P. After 56 weeks of effluent loading, removal of PO4-P from storm water was negative 109% in the unvegetated K20nv treatment, compared with 33% retention in the corresponding vegetated K20 treatment. The K40 treatment with the most K retained 69% PO4-P, while the RM10 treatment with the most RM retained 78% PO4-P. After 80 weeks of effluent loading, removal of PO4-P from storm water was negative in both the K20nv and vegetated K20 treatments. The K40 treatment retained 76% PO4-P, and the RM10 treatment retained 55% PO4-P, while the total dissolved P (TDP) retention was 72% and 52%, respectively. After 110 weeks of effluent loading comprising 1,598 kg-ha-1 PO4-P, equivalent to 48 years of bioretention loads, PO4-P retention from storm water by the K40 treatment increased to 85%, and retention by the RM10 treatment increased to 91%. TDP retention also increased to 78% and 75%, respectively. These observations of P retention increasing after exposure to additional loads are uncharacteristic of typical sorption responses. After 80 weeks of effluent loading equivalent to 32 years of bioretention loads, the flow-restricted WTR-K treatment removed 99% of the storm-water PO4-P load while the corresponding free-discharge WTR-Knr treatment retained 94%. The WTR-K treatment was less effective than the WTR-Knr treatment in the earlier storm-water runs. The restricted outlet WTR30 treatment, which contained the most WTRs, retained 99% of the storm-water PO4-P load. These high rates of P retention from storm water after accelerated P loads indicate that these amendments can provide effective P retention for the expected lifetime of bioretention facilities.
Sample deposition onto cryo-EM grids: from sprays to jets and back (2020)

Despite the great strides made in the field of single-particle cryogenic electron microscopy (cryo-EM) in microscope design, direct electron detectors and new processing suites, the area of sample preparation is still far from ideal. Traditionally, sample preparation involves blotting, which has been used to achieve high resolution, particularly for well behaved samples such as apoferritin. However, this approach is flawed since the blotting process can have adverse effects on some proteins and protein complexes, and the long blot time increases exposure to the damaging air-water interface. To overcome these problems, new blotless approaches have been designed for the direct deposition of the sample on the grid. Here, different methods of producing droplets for sample deposition are compared. Using gas dynamic virtual nozzles, small and high-velocity droplets were deposited on cryo-EM grids, which spread sufficiently for high-resolution cryo-EM imaging. For those wishing to pursue a similar approach, an overview is given of the current use of spray technology for cryo-EM grid preparation and areas for enhancement are pointed out. It is further shown how the broad aspects of sprayer design and operation conditions can be utilized to improve grid quality reproducibly.
The hopkins verbal learning test: Development of a new memory test with six equivalent forms (1991)

Abstract A new test of verbal learning and memory, the Hopkins Verbal Learning Test, was developed. The test consists of three trials of free-recall of a 12-item, semantically categorized list, followed by yes/no recognition. Six parallel forms yielded equivalent results in normals. The performance of patients with Alzheimer's disease and chronic amnesia is described. The test is likely to be useful in patients too impaired for more comprehensive memory assessments and where repeated testing is necessary.
The Long March: A Sample Preparation Technique that Enhances Contig Length and Coverage by High-Throughput Short-Read Sequencing (2008)

High-throughput short-read technologies have revolutionized DNA sequencing by drastically reducing the cost per base of sequencing information. Despite producing gigabases of sequence per run, these technologies still present obstacles in resequencing and de novo assembly applications due to biased or insufficient target sequence coverage. We present here a simple sample preparation method termed the "long march" that increases both contig lengths and target sequence coverage using high-throughput short-read technologies. By incorporating a Type IIS restriction enzyme recognition motif into the sequencing primer adapter, successive rounds of restriction enzyme cleavage and adapter ligation produce a set of nested sub-libraries from the initial amplicon library. Sequence reads from these sub-libraries are offset from each other with enough overlap to aid assembly and contig extension. We demonstrate the utility of the long march in resequencing of the Plasmodium falciparum transcriptome, where the number of genomic bases covered was increased by 39%, as well as in metagenomic analysis of a serum sample from a patient with hepatitis B virus (HBV)-related acute liver failure, where the number of HBV bases covered was increased by 42%. We also offer a theoretical optimization of the long march for de novo sequence assembly.
Static and low-frequency magnetic field effects: health risks and therapies (2000)

Many biological processes are affected by electromagnetic fields. Hence incremental internal fields generated by external magnetic fields can be expected to affect that biology. With some exceptions, most of the present interest in the effects of exogenous static and low-frequency magnetic fields centres on three intensity regions. (1) There are concerns that 50-60 Hz power distribution fields as small as 0.2 µT, may affect the health of populations. (2) ac fields that are larger than 1 mT (and usually smaller than 100 mT) with frequencies of a few kHz or less may have therapeutic value with respect to the healing of bone fractures and soft-tissue injuries. (3) The very large slowly varying fields of the order of 2 T used in magnetic resonance imaging might affect the physiology of the patients.
Native-like in vivo folding of a circularly permuted jellyroll protein shown by crystal structure analysis. (1994)

A jellyroll beta-sandwich protein, the Bacillus beta-glucanase H(A16-M), is used to probe the role of N-terminal peptide regions in protein folding in vivo. A gene encoding H(A16-M) is rearranged to place residues 1-58 of the protein behind a signal peptide and residues 59-214. The rearranged gene is expressed in Escherichia coli. The resultant circularly permuted protein, cpA16M-59, is secreted into the periplasm, correctly processed, and folded into a stable and active enzyme. Crystal structure analysis at 2.0-A resolution, R = 15.3%, shows cpA16M-59 to have a three-dimensional structure nearly identical with that of the parent beta-glucanase. An analogous experiment based on the wild-type Bacillus macerans beta-glucanase, giving rise to the circularly permuted variant cpMAC-57, yields the same results. Folding of these proteins, therefore, is not a vectorial process depending on the conformation adopted by their native N-terminal oligopeptides after ribosomal synthesis and translocation through the cytoplasmic membrane.
Prototype of Instrument for Minimally Invasive Surgery with 6-Axis Force Sensing Capability (2006)

Minimally invasive surgery (MIS) challenges the surgeon’s skills due to his separation from the operation area which can only be reached with long instruments. To overcome these drawbacks, minimally invasive robotic surgery (MIRS) plays an important role. This paper describes the development of actuated and sensorized instruments for minimally invasive robotic surgery which help to increase the surgeon’s immersion and dexterity.
Novel Approach for 3-D Reconstruction of Coronary Arteries From Two Uncalibrated Angiographic Images (2009)

Three-dimensional reconstruction of vessels from digital X-ray angiographic images is a powerful technique that compensates for limitations in angiography. It can provide physicians with the ability to accurately inspect the complex arterial network and to quantitatively assess disease induced vascular alterations in three dimensions. In this paper, both the projection principle of single view angiography and mathematical modeling of two view angiographies are studied in detail. The movement of the table, which commonly occurs during clinical practice, complicates the reconstruction process. On the basis of the pinhole camera model and existing optimization methods, an algorithm is developed for 3-D reconstruction of coronary arteries from two uncalibrated monoplane angiographic images. A simple and effective perspective projection model is proposed for the 3-D reconstruction of coronary arteries. A nonlinear optimization method is employed for refinement of the 3-D structure of the vessel skeletons, which takes the influence of table movement into consideration. An accurate model is suggested for the calculation of contour points of the vascular surface, which fully utilizes the information in the two projections. In our experiments with phantom and patient angiograms, the vessel centerlines are reconstructed in 3-D space with a mean positional accuracy of 0.665 mm and with a mean back projection error of 0.259 mm. This shows that the algorithm put forward in this paper is very effective and robust.