gebhart/patrepeval huggingface dataset:
Molecular biology of breast cancer metastasis Clinical implications of experimental studies on metastatic inefficiency (2000)

Recent technological advances have led to an increasing ability to detect isolated tumour cells and groups of tumour cells in patients' blood, lymph nodes or bone marrow. However, the clinical significance of these cells is unclear. Should they be considered as evidence of metastasis, necessitating aggressive treatment, or are they in some cases unrelated to clinical outcome? Quantitative experimental studies on the basic biology of metastatic inefficiency are providing clues that may help in understanding the significance of these cells. This understanding will be of use in guiding clinical studies to assess the significance of isolated tumour cells and micrometastases in cancer patients.
Identification of genes encoding components of the swarmer cell flagellar motor and propeller and a sigma factor controlling differentiation of Vibrio parahaemolyticus (1993)

Vibrio parahaemolyticus possesses two distinct motility systems, the polar system used for swimming in liquid environments and the lateral system used for swarming over surfaces. Growth on surfaces induces swarmer cell differentiation and expression of the lateral motility system. Mutants, created by transposon mutagenesis of a clone expressing lateral flagellin and gene disruption in V. parahaemolyticus, were unable to swarm and failed to make lateral flagellin; therefore, unlike the case for the polar system, there is one gene (lafA) encoding lateral flagellin. In addition to lafA, other genes required for swarming but not for swimming were identified by gene replacement mutagenesis. The nucleotide sequence of the clone determined open reading frames (ORFs) and deduced amino acid sequences showed similarities to flagellar components of other bacteria: flagellin, hook-associated protein (HAP2), motor components, and flagellar sigma factor (sigma 28). Many sigma 28 factors have been shown to recognize cognate promoters; however, expression of lafA in Escherichia coli required LafS, and E. coli sigma 28 did not substitute. Also, there were no sequences preceding genes encoding flagellin or HAP2 resembling the sigma 28 consensus promoter. The product of the sigma-like gene seems to be a unique member of the sigma 28 cluster. It appears the result of requiring expression for immunodetection of flagellin clones was that the sigma locus was fortuitously cloned, since the sigma and lafA loci were not contiguous in the chromosome. This work initiates identification and placement of genes in a scheme of control for swarmer cell differentiation; three levels have been identified in the transcriptional hierarchy.
Domain Knowledge and the Design Process (1981)

During the past 10 or 12 years, Artificial Intelligence researchers have explored techniques for bringing large amounts of domain knowledge to bear in solving ill-structured problems. Several programs that make use of these knowledge-based techniques are currently being developed to assist in various design tasks. This paper introduces one technique -- rule-based programming - and illustrates its use with two programs, R1 and XSEL, which are used by Digital Equipment Corporation in the design of computer system configurations.
An Introduction to Optimization (1996)

Preface. MATHEMATICAL REVIEW. Methods of Proof and Some Notation. Vector Spaces and Matrices. Transformations. Concepts from Geometry. Elements of Calculus. UNCONSTRAINED OPTIMIZATION. Basics of Set--Constrained and Unconstrained Optimization. One--Dimensional Search Methods. Gradient Methods. Newton's Method. Conjugate Direction Methods. Quasi--Newton Methods. Solving Ax = b. Unconstrained Optimization and Neural Networks. Genetic Algorithms. LINEAR PROGRAMMING. Introduction to Linear Programming. Simplex Method. Duality. Non--Simplex Methods. NONLINEAR CONSTRAINED OPTIMIZATION. Problems with Equality Constraints. Problems with Inequality Constraints. Convex Optimization Problems. Algorithms for Constrained Optimization. References. Index.
Abstract 266: Antitumor activity of REGN2810, a fully human anti-PD-1 monoclonal antibody, against MC38.Ova tumors grown in immune-competent humanized PD-1 mice (2015)

Abstract Programmed Cell Death Protein 1 (PD-1), is an inhibitory checkpoint receptor, expressed in an activation-induced manner on T cells. PD-1 signals upon binding to its ligands PD-L1 and PD-L2, expressed on APCs and some types of cancer cells, and delivers inhibitory signals to T cells, promoting T-cells functional exhaustion in a tumor microenvironment. Clinically, antibodies (Abs) that block the interaction between PD-1 and PD-L1 can release the cytotoxic function of tumor-specific T cells, yielding durable objective responses in multiple cancer types. REGN2810 is a fully human hinge-stabilized IgG4P monoclonal Ab that binds to the extracellular domain of human PD-1 with high affinity and specificity. REGN2810 was selected using a combination of binding studies (Surface Plasmon Resonance [SPR]-Biacore), enzyme-linked immunosorbent assays (ELISA), novel engineered cell-based bioassays, and preclinical studies in mouse models. REGN2810 was investigated in PD-1 humanized mice, an approach that allows direct testing of clinical PD-1 Ab that does not cross-react with mouse PD-1. Humanized PD-1 mice were created by Velocigene technology to express a humanized hybrid PD-1 protein comprising the extracellular portion of human PD-1 and the transmembrane and intracellular portion of mouse PD-1. Humanized PD-1 mice were validated for inducible cell surface expression of hybrid PD-1 protein on activated T-cells, intact PD-1/PD-L1 signaling and immune responses. A weakly immunogenic murine colorectal cancer cell line MC38 was engineered to express ovalbumin (MC38.Ova) in order to increase tumor immunogenicity and allow monitoring of T-cell immune responses to well-defined antigenic ovalbumin peptides. Prophylactic treatment with REGN2810 PD-1 Ab significantly suppressed growth of subcutaneous syngeneic MC38.Ova tumors in humanized PD-1 mice in a dose dependent manner, and improved mouse survival. Therapeutic treatment with REGN2810 also promoted dose dependent regression of established MC38.Ova tumors in humanized PD-1 mice. Treatment with REGN2810 induced CD8 T cells proliferation and cytokine production in spleens of tumor bearing huPD-1 mice. The mechanism of action and robust anti-tumor efficacy of REGN2810 support its clinical development for the treatment of human cancers. Citation Format: Elena Burova, Omaira Allbritton, William Poueymirou, Venus Lai, Janelle White, Dimitris Skokos, Nicholas Papadopoulos, Drew Murphy, Israel Lowy, Ella Ioffe, Gavin Thurston. Antitumor activity of REGN2810, a fully human anti-PD-1 monoclonal antibody, against MC38.Ova tumors grown in immune-competent humanized PD-1 mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 266. doi:10.1158/1538-7445.AM2015-266
Probing Site Specificity of DNA Binding Metallointercalators by NMR Spectroscopy and Molecular Modeling (2001)

The molecular recognition of oligonucleotides by chiral ruthenium complexes has been probed by NMR spectroscopy using the template Delta-cis-alpha- and Delta-cis-beta-[Ru(RR-picchxnMe(2)) (bidentate)](2+), where the bidentate ligand is one of phen (1,10-phenanthroline), dpq (dipyrido[3,2-f:2',3'-h]quinoxaline), or phi (9,10-phenanthrenequinone diimine) and picchxnMe(2)() is N,N'-dimethyl-N,N'-di(2-picolyl)-1,2-diaminocyclohexane. By varying only the bidentate ligand in a series of complexes, it was shown that the bidentate alone can alter binding modes. DNA binding studies of the Delta-cis-alpha-[Ru(RR-picchxnMe(2))(phen)](2+) complex indicate fast exchange kinetics on the chemical shift time scale and a "partial intercalation" mode of binding. This complex binds to [d(CGCGATCGCG)](2) and [d(ATATCGATAT)](2) at AT, TA, and GA sites from the minor groove, as well as to the ends of the oligonucleotide at low temperature. Studies of the Delta-cis-beta-[Ru(RR-picchxnMe(2))(phen)](2+) complex with [d(CGCGATCGCG)](2) showed that the complex binds only weakly to the ends of the oligonucleotide. The interaction of Delta-cis-alpha-[Ru(RR-picchxnMe(2))(dpq)](2+) with [d(CGCGATCGCG)](2) showed intermediate exchange kinetics and evidence of minor groove intercalation at the GA base step. In contrast to the phen and dpq complexes, Delta-cis-alpha- and Delta-cis-beta-[Ru(RR-picchxnMe(2))(phi)](2+) showed evidence of major groove binding independent of the metal ion configuration. DNA stabilization induced by complex binding to [d(CGCGATCGCG)](2) (measured as DeltaT(m)) increases in the order phen < dpq and DNA affinity in the order phen < dpq < phi. The groove binding preferences exhibited by the different bidentate ligands is explained with the aid of molecular modeling experiments.
Feedback directed optimization in Compaq's compilation tools for Alpha (1999)

This paper describes and evaluates the feedback directed optimizations that are used in the Compaq C compiler tool chain for Alpha. The optimizations include superblock formation, inlining, commando loop optimization, register allocation, code layout, and switch statement optimization. The optimizations either are extensions of classical optimizations or are restructuring transformations that enable classical optimizations. Feedback directed optimization is highly effective, achieving a 17 % speedup over aggressive classical optimization. Inlining contributes the most performance and code layout, superblock formation, and loop restructuring are also important. 1
Precoding for Asymmetric MIMO-OFDM Channels (2006)

We study space-time precoding techniques for asymmetric multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) channels with more transmit than receive antennas which is a typical downlink setup. Under the condition of perfect channel state information (CSI) at the receiver but no CSI at the transmitter, we consider linear dispersion coding (LDC), groupwise space-time block coding (GSTBC), quasi-orthogonal space-time block coding (QSTBC), and spatial spreading (SS) and study their capacity and diversity performances. Our results show that for both ergodic and outage capacities, SS is worse than LDC, GSTBC and QSTBC, while the latter three have very close/same performance. We also show that by adjusting the phase shift values in the SS matrices, its outage capacities can be improved. In terms of diversity, LDC, GSTBC and QSTBC have both transmit and receive spatial diversity, and LDC's diversity order is slightly higher than the latter two. SS, on the other hand, has not only receive spatial diversity, but also introduces additional frequency diversity. This contributes to their very close bit error rate (BER) performance when turbo processing is deployed at the receiver. Considering the implementation flexibility and complexity, we therefore recommend SS and GSTBC as the promising precoding schemes for asymmetric MIMO-OFDM channels.
Calculating the secrets of life: applications of the mathematical sciences in molecular biology (1996)

Molecular biology has emerged from the synthesis of two complementary approaches to the study of life-biochemistry and genetics--to become one of the most exciting and vibrant scientific fields at the end of the twentieth century. This book covers the following topic areas: a brief history of the intellectual foundations of modem molecular biology; mapping heredity; seeing conserved signals: using algorithms to detect similarities between biosequences; hearing distant echoes: using extremal statistics to probe evolutionary origins; calibrating the clock: using stochastic processes to measure the rate of evolution; winding the double helix; using geometry, topology, and mechanics of DNA; unwinding the double helix: using differential mechanics to probe conformational changes in DNA; lifting the curtain: using topology to probe the hidden action of enzymes; folding the sheets: using computational methods to predict the structure of proteins.
Mutation of a Single CTCF Target Site within the <i>H19</i> Imprinting Control Region Leads to Loss of <i>Igf2</i> Imprinting and Complex Patterns of De Novo Methylation upon Maternal Inheritance (2004)

The differentially methylated imprinting control region (ICR) region upstream of the H19 gene regulates allelic Igf2 expression by means of a methylation-sensitive chromatin insulator function. We have previously shown that maternal inheritance of mutated (three of the four) target sites for the 11-zinc finger protein CTCF leads to loss of Igf2 imprinting. Here we show that a mutation in only CTCF site 4 also leads to robust activation of the maternal Igf2 allele despite a noticeably weaker interaction in vitro of site 4 DNA with CTCF compared to other ICR sites, sites 1 and 3. Moreover, maternally inherited sites 1 to 3 become de novo methylated in complex patterns in subpopulations of liver and heart cells with a mutated site 4, suggesting that the methylation privilege status of the maternal H19 ICR allele requires an interdependence between all four CTCF sites. In support of this conclusion, we show that CTCF molecules bind to each other both in vivo and in vitro, and we demonstrate strong interaction between two CTCF-DNA complexes, preassembled in vitro with sites 3 and 4. We propose that the CTCF sites may cooperate to jointly maintain both methylation-free status and insulator properties of the maternal H19 ICR allele. Considering many other CTCF targets, we propose that site-specific interactions between various DNA-bound CTCF molecules may provide general focal points in the organization of looped chromatin domains involved in gene regulation.
Replication, Pathogenicity, Shedding, and Transmission of Zaire ebolavirus in Pigs (2011)

These results shed light on the susceptibility of pigs to ZEBOV infection and identify an unexpected site of virus amplification and shedding linked to transmission of infectious virus.
Isolation and structural characterization of the <i>Leishmania donovani</i> kinetoplastid membrane protein-11, a major immunoreactive membrane glycoprotein (1995)

A novel membrane molecule, previously observed to be co-isolated with lipophosphoglycan and called lipophosphoglycan-associated protein, has been detected in Leishmania donovani promastigotes and amastigotes. This kinetoplastid membrane protein (KMP-11) has been purified by preparative SDS/PAGE after organic solvent extraction of promastigote membranes. Isoelectric-focusing experiments indicated that this was an acidic protein with an isoelectric point of 4.8. Immunoblot analysis of subcellular fractions, together with 125I-labelling experiments, showed this molecule to be associated with the promastigote cell surface membrane. KMP-11 was expressed at a copy number similar to that of lipophosphoglycan (1 x 10(6)-2 x 10(6) molecules per cell), making this glycoprotein one of the major features on the parasite cell surface. The primary structure, less a blocked N-terminal region, was determined by automated Edman degradation of peptides derived from CNBr or enzymic fragmentation. Several post-translational modifications were also found during these studies, including an O-linked oligosaccharide and an NG-monomethylarginine functionality which was verified by m.s. Finally, a set of sequential synthetic peptides was made based on the established partial sequence allowing structural determination of two distinct antibody-binding sites for the monoclonal antibodies L98 and L157.
Transmission of Multiplexed PAM Signals Over Multiple Channel and Diversity Systems (1970)

It is well known that the optimum receiver for pulse-amplitude-modulated (PAM) signals, transmitted over a single channel, consists of a cascade of continuous and transversal filters. It is shown that an extended structure of this type is also optimum for the completely general case of <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">M</tex> multiplexed PAM signals transmitted over random-time and frequency-dispersive multichannel systems with <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">I</tex> inputs and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">N</tex> outputs, where each output is subjected to arbitrarily correlated additive noise. The random channels may also be arbitrarily correlated. In general, the receiver consists of <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">MN</tex> continuous filters and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">M</tex> tapped delay lines with M <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> sets of taps. An adaptive version is also described. The results include, as special cases, the situations considered by Gonsalves and Tufts [8], Shnidman [5], and Kaye [3]. Also, included as special cases are new results for diversity systems, multi-input systems such as multipair cables, and multiple-terminal systems such as multiple access repeaters in which cochannel interference occurs.
Fundamental Elements of the Quality of Care: A Simple Framework (1990)

This article argues for attention to a neglected dimension of family planning services--their quality. A framework for assessing quality from the client's perspective is offered, consisting of six parts (choice of methods, information given to clients, technical competence, interpersonal relations, follow-up and continuity mechanisms, and the appropriate constellation of services). The literature is reviewed regarding evidence that improvements in these various dimensions of care result in gains at the individual level; an even scarcer body of literature is reviewed for evidence of gains at the level of program efficiency and impact. A concluding section discusses how to make practical use of the framework and distinguishes three vantage points from which to view quality: the structure of the program, the service-giving process itself, and the outcome of care, particularly with respect to individual knowledge, behavior, and satisfaction with services.
Multiple mechanisms of peripheral T cell tolerance to the fetal "allograft". (1998)

The fetus represents a foreign entity to the maternal immune system, yet this "natural" allograft is not normally rejected. This unique situation provides a physiologic system to evaluate peripheral tolerance in which the maternal immune system is challenged with relatively rare Ags not previously encountered in the thymus. Using H-Y-specific TCR transgenic mice, we demonstrate that T cells specific for fetal Ags decrease in an Ag-specific manner during pregnancy and remain low postpartum, the result of an encounter with fetal cells expressing the appropriate MHC/peptide complexes. The finding that placental trophoblasts can induce Fas-mediated death of T cells is consistent with peripheral clonal deletion as one mechanism of tolerance. The remaining clonotypic T cells are unresponsive to antigenic stimulation, although neither TCR nor coreceptor is down-regulated. Our study demonstrates that specific recognition of fetal allogeneic Ags by maternal T cells results in tolerance induction of reactive T cells via multiple mechanisms.
Immunocytochemical Localization of Gonadotropins, Growth Hormone, and Prolactin in Equine Pituitary. (1996)

The present research was performed to characterize immunoreactive (ir) pituitary cells in the equine species. Two experiments were performed to measure the prevalence of single- and double-hormone labeled gonadotropes, lactotropes, somatotropes, and mammosomatotropes. In Experiments 1 and 2, pituitaries from three intact pony mares were processed for ultrastructural evaluation of cells stained for luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), and growth hormone (GH). Primary antibodies and gold-conjugated antibodies were used to double-stain ir-cells. The percentages of pituitary cells stained for each hormone in intact mares were: total gonadotropes, 15 to 32%; LH-only, 2 to 16%; FSH-only, 1 to 5%; LH/FSH, 6 to 24%; GH-only, 11 to 26%; PRL-only, 5 to 16%; and GH/PRL, 7 to 17%. In Experiments 3 and 4, long-term ovariectomized (OVX) mares (n = 4/group) were injected with vehicle, estradiol (35 $\mu$g/kg), or dihydrotestosterone (DHT; 150 $\mu$g/kg) for 21 days. Immunoreactive-cells were identified immunocytochemically and pituitary content of LH, FSH, GH, and PRL and plasma concentrations of LH, FSH, and PRL were measured. DHT reduced (P $$.1) on plasma PRL. Estradiol reduced (P $$.1) on plasma LH. The percentages of pituitary cells which stained for each hormone in control OVX mares were: total gonadotropes, 12%; LH/FSH, 9%; LH- or FSH-only, 2%; total lactotropes, somatotropes, and mammosomatotropes, 50%; GH-only, 22%; PRL-only, 23%; and GH/PRL, 6%. Estradiol treatment increased (P $<$.05) pituitary concentrations of LH, FSH and PRL. Estradiol also reduced (P $<$.05) the number of cells stained for LH/FSH and increased (P $<$.05) the number of lactotropes and mammosomatotropes. DHT reduced (P $<$.05) pituitary concentrations of LH and FSH but did not significantly affect tissue concentrations of PRL or GH. DHT reduced (P $<$.05) the number of cells that stained for LH/FSH and it increased (P $<$.05) the number of FSH-only cells. It is concluded that equine pituitary gonadotropes are subdivided into cells which contain one or both gonadotropins; and PRL and GH also, can be found in separate cells or in same secretory granules within one cell. Furthermore, OVX and steroid treatment preferentially regulate hormone secretion from gonadotropes that produce both LH and FSH as well as the number of ir-lactotropes and mammosomatotropes.
Bone morphogenetic protein-4 promotes induction of cardiomyocytes from human embryonic stem cells in serum-based embryoid body development (2009)

Cardiomyocytes derived from human embryonic stem (ES) cells are a potential source for cell-based therapy for heart diseases. We studied the effect of bone morphogenetic protein (BMP)-4 in the presence of fetal bovine serum (FBS) on cardiac induction from human H1 ES cells during embryoid body (EB) development. Suspension culture for 4 days with 20% FBS produced the best results for the differentiation of early mesoderm and cardiomyocytes. The addition of Noggin reduced the incidence of beating EBs from 23.6% to 5.3%, which indicated the involvement of BMP signaling in the spontaneous cardiac differentiation. In this condition, treatment with 12.5-25 ng/ml BMP-4 during the 4-day suspension optimally promoted the cardiomyocyte differentiation. The incidence of beating EBs at 25 ng/ml BMP-4 reached 95.8% on day 6 of expansion and then plateaued until day 20. In real-time PCR analysis, the cardiac development-related genes MESP1 and Nkx2.5 were upregulated in the EB outgrowths by 25 ng/ml BMP-4. The activation of BMP signaling in EBs was confirmed by the increase in the phosphorylation of Smad1/5/8 and by the nuclear localization of phospho-Smad1/5/8 and Smad4. The addition of 150 ng/ml Noggin considerably decreased the incidence of beating EBs and Nkx2.5 expression, and Noggin alone increased Nestin expression and neural differentiation in EB outgrowths. The cardiomyocytes induced by 25 ng/ml BMP-4 showed proper cell biological characteristics and a course of differentiation as judged from isoproterenol administration, gene expression, protein assay, immunoreactivity, and subcellular structures. No remarkable change in the extent of apoptosis and proliferation in the cardiomyocytes was observed by BMP-4 treatment. These findings showed that BMP-4 in combination with FBS at the appropriate time and concentrations significantly promotes cardiomyocyte induction from human ES cells.