gebhart/patrepeval huggingface dataset:
The p53 tumor suppressor gene as a common cellular target in human carcinogenesis. (1993)

The p53 gene is a 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 375-amino acid nuclear phosphoprotein which involves in the regulation of cell proliferation. The p53 gene was originally regarded as a dominant oncogene because its overexpression resulted in the immortalization of rodent cells, and the p53 gene could transform rat embryonic fibroblasts in concert with an activated ras gene. It soon became clear, however, that many of the p53 clones that had been studied were in fact mutated versions of the gene, and the wild-type p53 actually acts as a tumor suppressor. Loss of normal p53 function has been associated with the cell transformation in vitro and the development of neoplasms in vivo. More than one-half of human malignancies derived from the epithelial, mesenchymal, hematopoietic, and lymphoid tissues, as well as the central nervous system, analyzed thus far, were shown to contain an altered p53 gene. Most p53 gene alterations are the missense mutations, giving rise to an altered protein. These mutations are most frequently located in the evolutionally conserved areas. Furthermore, it has been demonstrated that the SV40 large T antigen, the adenovirus E1B protein, and papillomavirus E6 protein can bind to wild-type p53 protein and presumably lead to inactivation of this gene product as well. Therefore, the inactivation of normal (or wild-type) p53 is currently regarded as an important genetic pathway for human carcinogenesis generated by endogenous factors and exogenous carcinogens, as well as several tumor viruses. The current data on the p53 gene and its alterations in human malignancies, particularly those in the gastrointestinal tract, are reviewed.
Antibody-guided localization of intraperitoneal tumors following intraperitoneal or intravenous antibody administration. (1987)

Intraperitoneal tumors from a human cancer cell line (LoVo) were established in nude mice by i.p. inoculation of a single cell suspension. Two preparations of the same monoclonal antibody, radiolabeled with 125I and 131I were injected i.p. and i.v. into the same animals. Localization was assessed by dissection and counting the activity in tumors and normal tissues. Tumor/tissue ratios 1 h after i.p. injection of antibody were approximately 50 times higher than after i.v. administration. This i.p./i.v. advantage fell to around 4 by 8 h and was just greater than 1 by 24 h. This effect was observed with both specific and nonspecific antibody, indicating that it is due to the route of administration. However, the absolute amounts of antibody bound to tumors depended on the specificity of the antibody. Twenty % of the injected dose of specific antibody was bound per gram to tumor 1 to 2 h after i.p. injection, falling to 10%/g by 24 h and remaining at this level up to 5 days after antibody administration. In contrast, less than 10%/g of nonspecific antibody was detected in tumors after 1 h; this fell rapidly to normal organ levels of less than 5%/g by 8 h. This study demonstrates a major advantage when administering radiolabeled monoclonal antibodies i.p. for targeting intraperitoneal tumors.
Targeting the TGFβ pathway for cancer therapy (2014)

The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.
Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 Are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively (1999)

Systemic administration of rIL-18 protein to mice significantly suppresses the growth of murine tumor cell lines. The antitumor effect of IL-18 appears to be primarily mediated by asialo GM1+ cells. Since IL-18 enhances Fas ligand (FasL) expression on NK cell lines, the IL-18 antitumor effects could be mediated by FasL-induced cross-linking of Fas and subsequent tumor apoptosis. To address this question, rIL-18 or rIL-12 was administered to animals bearing the CL8-1 melanoma inoculated intradermally into wild type (wt), lymphoproliferation gene (lpr) (Fas deficient), or generalized lymphoproliferative disease gene (gld) (FasL deficient) mice. Although rIL-12 treatment retained significant antitumor effects in gld and lpr mice, those of rIL-18 administration were completely abrogated in gld but not lpr or wt mice. In vitro cytotoxicity was significantly enhanced against NK-sensitive YAC-1 cells and CL8-1 cells by rIL-18 administration to wt mice, but not to gld mice. Furthermore, rIL-18 administration augmented the cytotoxicity of liver lymphocytes harvested from perforin-deficient mice, whereas rIL-12 administration did not. Consistent with the role of this pathway, rIL-18 administration also up-regulates the expression of FasL mRNA in splenocytes. Lysis of CL8-1 cells induced by anti-Fas agonistic Ab was enhanced about 1.4-fold by IFN-gamma, a cytokine that is induced by IL-18 in vitro and in vivo. We conclude that the antitumor effect of IL-18 is exerted predominantly through a Fas-dependent pathway. The perforin pathway, however, appears to be the predominant cytolytic pathway mediating IL-12 antitumor effects.
Isobaric Labeling-Based Relative Quantification in Shotgun Proteomics (2014)

Mass spectrometry plays a key role in relative quantitative comparisons of proteins in order to understand their functional role in biological systems upon perturbation. In this review, we review studies that examine different aspects of isobaric labeling-based relative quantification for shotgun proteomic analysis. In particular, we focus on different types of isobaric reagents and their reaction chemistry (e.g., amine-, carbonyl-, and sulfhydryl-reactive). Various factors, such as ratio compression, reporter ion dynamic range, and others, cause an underestimation of changes in relative abundance of proteins across samples, undermining the ability of the isobaric labeling approach to be truly quantitative. These factors that affect quantification and the suggested combinations of experimental design and optimal data acquisition methods to increase the precision and accuracy of the measurements will be discussed. Finally, the extended application of isobaric labeling-based approach in hyperplexing strategy, targeted quantification, and phosphopeptide analysis are also examined.
Kangaroo Island paradise lost (2020)

I saw a koala in the wild for the first time last year, on a visit to Kangaroo Island. It was a thrilling moment, captured in frames by my fast shutter-speed eyes and tucked like treasure into my memory. The creature had climbed down from one towering eucalypt and was ambling over to another; catching sight of us humans, it raced - in that awkward, shambling way - to the opposite trunk, wrapped its squat little arms around it and pulled itself up into the safety of the canopy.
Recording Techniques for Clinical Electrophysiology (2005)

The precise techniques employed in the electrophysiology laboratory influence the nature of the electrograms that are recorded during mapping procedures. Unipolar recordings that are minimally filtered can be useful for mapping focal arrhythmia sources, but have substantial far-field signal that can obscure low-amplitude signals of interest in abnormal regions. Bipolar recordings are standard in most laboratories because rejection of far-field signal facilitates identification of local potentials in abnormal areas, but the signal of interest can be beneath either recording electrode and far-field signals do occur. Simultaneously obtained unipolar recordings are a useful adjunct to bipolar recordings in some situations. High pass filtering and digital sampling also influence electrogram characteristics. High pass filtering of unipolar recordings can be useful to reduce far-field components, but limits inferences from electrogram morphology.
Maturation of fetal responses to music (2004)

Maturation of fetal response to music was characterized over the last trimester of pregnancy using a 5-minute piano recording of Brahms' Lullaby, played at an average of 95, 100, 105 or 110 dB (A). Within 30 seconds of the onset of the music, the youngest fetuses (28-32 weeks GA) showed a heart rate increase limited to the two highest dB levels; over gestation, the threshold level decreased and a response shift from acceleration to deceleration was observed for the lower dB levels, indicating attention to the stimulus. Over 5 minutes of music, fetuses older than 33 weeks GA showed a sustained increase in heart rate; body movement changes occurred at 35 weeks GA. These findings suggest a change in processing of complex sounds at around 33 weeks GA, with responding limited to the acoustic properties of the signal in younger fetuses but attention playing a role in older fetuses.
Exploring gesture-based interaction techniques in multi-display environments with mobile phones and a multi-touch table (2010)

In this paper, we explore the potential of combining shared and interactive displays (e.g. a multi-touch table) with personal devices (e.g. mobile phones) as an important class of heterogeneous multi-display environments. Within six case studies applications and interactions were invented and implemented that utilize the potential of such heterogeneous multi-display environments. We were in particular interested how to design systems that include interaction across different displays and how to manage public and private information in a group setting. One case study, a digital card game, highlights these design challenges. We explore different natural ways of interaction, including touching the table as well as motion gestures with mobile phones. With this application we provide a use case to discuss gestures combining mobile phones with tabletop surfaces, as well as to explore a private-public display setting. First results showed that combining tables and mobile phones provide a suitable and understandable way for interaction in these settings.
Human thermoregulatory system state estimation using non-invasive physiological sensors (2011)

Small teams of emergency workers/military can often find themselves engaged in critical, high exertion work conducted under challenging environmental conditions. These types of conditions present thermal work strain challenges which unmitigated can lead to collapse (heat exhaustion) or even death from heat stroke. Physiological measurement of these teams provides a mechanism that could be an effective tool in preventing thermal injury. While indices of thermal work strain have been proposed they suffer from ignoring thermoregulatory context and rely on measuring internal temperature (IT). Measurement of IT in free ranging ambulatory environments is problematic. In this paper we propose a physiology based Dynamic Bayesian Network (DBN) model that estimates internal temperature, heat production and heat transfer from observations of heart rate, accelerometry, and skin heat flux. We learn the model's conditional probability distributions from seven volunteers engaged in a 48 hour military field training exercise. We demonstrate that sum of our minute to minute heat production estimates correlate well with total daily energy expenditure (TDEE) measured using the doubly labeled water technique (r(2) = 0.73). We also demonstrate that the DBN is able to infer IT in new datasets to within ±0.5 °C over 85% of the time. Importantly, the additional thermoregulatory context allows critical high IT temperature to be estimated better than previous approaches. We conclude that the DBN approach shows promise in enabling practical real time thermal work strain monitoring applications from physiological monitoring systems that exist today.
Platelet Factor 4, β-Thromboglobulin and Thrombospondin Levels in Type I Diabetes Mellitus Patients (1994)

The proteins beta-thromboglobulin, platelet factor 4 and thrombospondin are stored in platelet alpha-granules and released from the platelet by the release reaction. The assays of these proteins were studied in patients with type I diabetes mellitus (n = 30) and a healthy control group (n = 15). Platelet factor 4 and beta-thromboglobulin levels were not significantly different in both groups but thrombospondin concentrations in diabetic patients were significantly higher than those of the control group (136.6 +/- 14.2 ng/ml vs 91.2 +/- 14.3 ng/ml, P < 0.05). When the diabetic patients were divided into those with or without complications, the diabetic patients with complications (n = 11) had significantly elevated plasma thrombospondin concentrations compared with the control group (150.4 +/- 23.7 ng/ml vs 91.2 +/- 14.3 ng/ml, P < 0.05), while thrombospondin concentrations in the control group were not statistically different from the diabetic patients without complications. Plasma beta-thromboglobulin and platelet factor 4 levels were not significantly different between the diabetic and the control group. It is suggested that thrombospondin may be a convenient marker of in vivo platelet release reaction.
Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of I Kr Inhibition on Ventricular Repolarization (2011)

Endogenous late I(Na) contributes to the RRD of I(Kr) inhibitor-induced increases in APD and BVR and to bradycardia-related ventricular arrhythmias.
In Search of the Ideal Bone Morphogenetic Protein Delivery System: In Vitro Studies on Demineralized Bone Matrix, Purified, and Recombinant Bone Morphogenetic Protein (2003)

The clinical use of recombinant bone morphogenetic protein (rBMP) is limited by the lack of a suitable delivery system. The bone morphogenetic protein (BMP) delivery system provided by nature is highly effective, and by studying purified BMP (BMP/NCP) and demineralized bone matrix (DBM), it may be possible to learn how to emulate nature's success. The current study used an in vitro muscle cell model to study the activity of BMP/NCP and DBM and the effects of extracellular matrix on BMP activity. C2C12 cells transiently exposed to recombinant human BMP-4 (rhBMP-4) rapidly increased their alkaline phosphatase (AP) activity to day 5, after which it steadily declined. Cells exposed to BMP/NCP or DBM continued to increase their AP activity over the 14-day culture. If BMP/NCP was treated to remove a 22-kd protein, it became water-soluble and exhibited a similar activity pattern to rhBMP-4. Cells cultured on collagen type I, fibronectin, and hyaluronic-coated surfaces demonstrated increased AP activity when exposed to rhBMP-4 or BMP/NCP compared with cells cultured on bovine serum albumin or poly-l-lysine. These results suggest that the natural BMP delivery system operates both by binding to the BMP molecule and slowly releasing it into the extracellular milieu and by interacting with the responding cells through cell-matrix receptors to enhance the cellular response to BMP.
Processive Incorporation of Deoxynucleoside Triphosphate Analogs by Single-Molecule DNA Polymerase I (Klenow Fragment) Nanocircuits (2015)

DNA polymerases exhibit a surprising tolerance for analogs of deoxyribonucleoside triphosphates (dNTPs), despite the enzymes' highly evolved mechanisms for the specific recognition and discrimination of native dNTPs. Here, individual DNA polymerase I Klenow fragment (KF) molecules were tethered to a single-walled carbon nanotube field-effect transistor (SWCNT-FET) to investigate accommodation of dNTP analogs with single-molecule resolution. Each base incorporation accompanied a change in current with its duration defined by τclosed. Under Vmax conditions, the average time of τclosed was similar for all analog and native dNTPs (0.2 to 0.4 ms), indicating no kinetic impact on this step due to analog structure. Accordingly, the average rates of dNTP analog incorporation were largely determined by durations with no change in current defined by τopen, which includes molecular recognition of the incoming dNTP. All α-thio-dNTPs were incorporated more slowly, at 40 to 65% of the rate for the corresponding native dNTPs. During polymerization with 6-Cl-2APTP, 2-thio-dTTP, or 2-thio-dCTP, the nanocircuit uncovered an alternative conformation represented by positive current excursions that does not occur with native dNTPs. A model consistent with these results invokes rotations by the enzyme's O-helix; this motion can test the stability of nascent base pairs using nonhydrophilic interactions and is allosterically coupled to charged residues near the site of SWCNT attachment. This model with two opposing O-helix motions differs from the previous report in which all current excursions were solely attributed to global enzyme closure and covalent-bond formation. The results suggest the enzyme applies a dynamic stability-checking mechanism for each nascent base pair.
Google Vizier (2017)

Any sufficiently complex system acts as a black box when it becomes easier to experiment with than to understand. Hence, black-box optimization has become increasingly important as systems have become more complex. In this paper we describe Google Vizier, a Google-internal service for performing black-box optimization that has become the de facto parameter tuning engine at Google. Google Vizier is used to optimize many of our machine learning models and other systems, and also provides core capabilities to Google's Cloud Machine Learning HyperTune subsystem. We discuss our requirements, infrastructure design, underlying algorithms, and advanced features such as transfer learning and automated early stopping that the service provides.
3-Draw: a tool for designing 3D shapes (1991)

A fundamentally new type of CAD system for designing shape that is intuitive, easy to use, and powerful is presented. It is based on a paradigm that can be described as designing directly in 3-D. By virtue of two hand-held sensors, designers using 3-Draw to sketch their ideas in the air feel as if they're actually holding and working on objects. Current design practice and related work are reviewed, and current work on 3-Draw is summarized. To capture the flavor of 3-Draw, construction of a sample model of a 12-m yacht is described. 3-Draw's features and data structures are discussed.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Genetic relationship of two highly studied Synechococcus strains designated Anacystis nidulans (1989)

The cyanobacteria Synechococcus sp. strain PCC 7942 and Synechococcus sp. strain PCC 6301 are very closely related and both have been designated by the binomial Anacystis nidulans. The only established difference between the two strains is the superior transformation properties of strain PCC 7942. Significant homology between the rRNA genes of these strains was demonstrated by the ability of an rRNA operon from strain PCC 6301, interrupted by a spectinomycin and streptomycin resistance marker, to transform strain PCC 7942 by recombining with and replacing an endogenous rRNA operon. Restriction fragment length polymorphism data indicated that the chromosomes of the two strains were conserved around the three psbA loci, the two rRNA operons, and the psbDI locus. However, multiple polymorphisms were detected downstream of the psbDII locus, identifying a DNA rearrangement such as an inversion, insertion, or deletion within the chromosome. Analysis of genome structure by pulsed-field gel electrophoresis of large NotI restriction fragments showed only two bands that were visibly shifted between the chromosomes of the two strains. These data support their very close genetic relationship and the feasibility of studying genes derived from strain PCC 6301 in the highly transformable PCC 7942 strain.
c-Myc Accelerates S-Phase and Requires WRN to Avoid Replication Stress (2009)

c-Myc interacts with components of the pre-replication complex and directly regulates DNA replication [1]. However the consequences of this novel c-Myc function on cell cycle dynamics and replication-associated damage are unknown. Here, we show that c-Myc overexpression in primary human fibroblasts markedly accelerates S-phase while c-Myc deficient fibroblasts exhibit a prolonged S-phase. We also show that the Werner DNA helicase protein (WRN) plays a critical role in supporting c-Myc-driven S-phase, as depletion of WRN in c-Myc overexpressing cells increases DNA damage specifically at sites of DNA synthesis. This excess DNA damage activates a "replication stress" pathway involving ATR, CHK1, CHK2, and p53, leading to rapid senescence of WRN deficient c-Myc overexpressing cells. Indeed, depletion of p53 rescues this senescence response. We propose that WRN functions to repair abnormal replication structures caused by the acceleration of DNA replication by c-Myc. This work provides an additional mechanistic explanation for c-Myc-induced DNA damage and senescence, and reveals a vulnerability of c-Myc overexpressing cells that could potentially be exploited in cancer therapy.
Graph construction and b -matching for semi-supervised learning (2009)

Graph based semi-supervised learning (SSL) methods play an increasingly important role in practical machine learning systems. A crucial step in graph based SSL methods is the conversion of data into a weighted graph. However, most of the SSL literature focuses on developing label inference algorithms without extensively studying the graph building method and its effect on performance. This article provides an empirical study of leading semi-supervised methods under a wide range of graph construction algorithms. These SSL inference algorithms include the Local and Global Consistency (LGC) method, the Gaussian Random Field (GRF) method, the Graph Transduction via Alternating Minimization (GTAM) method as well as other techniques. Several approaches for graph construction, sparsification and weighting are explored including the popular k-nearest neighbors method (kNN) and the b-matching method. As opposed to the greedily constructed kNN graph, the b-matched graph ensures each node in the graph has the same number of edges and produces a balanced or regular graph. Experimental results on both artificial data and real benchmark datasets indicate that b-matching produces more robust graphs and therefore provides significantly better prediction accuracy without any significant change in computation time.