gebhart/patrepeval huggingface dataset:
Confidence estimation for speculation control (1998)

Modern processors improve instruction level parallelism by speculation. The outcome of data and control decisions is predicted, and the operations are speculatively executed and only committed if the original predictions were correct. There are a number of other ways that processor resources could be used, such as threading or eager execution. As the use of speculation increases, we believe more processors will need some form of speculation control to balance the benefits of speculation against other possible activities.Confidence estimation is one technique that can be exploited by architects for speculation control. In this paper, we introduce performance metrics to compare confidence estimation mechanisms, and argue that these metrics are appropriate for speculation control. We compare a number of confidence estimation mechanisms, focusing on mechanisms that have a small implementation cost and gain benefit by exploiting characteristics of branch predictors, such as clustering of mispredicted branches.We compare the performance of the different confidence estimation methods using detailed pipeline simulations. Using these simulations, we show how to improve some confidence estimators, providing better insight for future investigations comparing and applying confidence estimators.
Histone synthesis in Leishmania infantum is tightly linked to DNA replication by a translational control (2000)

We have analysed the regulation of histone synthesis in Leishmania infantum following inhibition of DNA replication. Run-on experiments indicated that transcription rates of the genes coding for the four core histones (H2A, H2B, H3 and H4) were not affected by the inhibition with hydroxyurea of DNA synthesis. However, a dramatic decrease was observed in the newly synthesized histones after inhibition of DNA synthesis. Furthermore, the synthesis of both the histones and DNA resumed in promastigotes after removal of hydroxyurea, indicating that inhibition was reversible. Unlike most eukaryotes, in which the replication-dependent histone transcripts decrease upon a replication blockade, the levels of L. infantum histone mRNAs do not change under similar conditions. Thus the present data indicate that histone synthesis in Leishmania is tightly coupled to DNA replication by a mechanism operating at the translational level.
A comparison of application sharing mechanisms in real-time desktop conferencing systems (1990)

Desktop conferencing is a term used to describe real-time, computer-based conferences in which users may share data through their personal computers. In these conferences, the participants may access user-level programs, called application programs, which produce common displays (screens or windows) on their computers. Because each participant may give input to the application program and sees its resulting output as though the program were executing on his or her local computer, these applications retain their own look and feel as they form a shared environment for the conference. We compare some methods of sharing application programs during real-time, computer-based conferencing. In particular, we have explored different methods in three versions of Rapport, a multimedia conferencing system. We examine the qualitative and quantitative differences of these implementations using some typical shared applications and find that one method possesses good semantic characteristics as well as good performance in several network environments.
AMINOALUMINUM HYDRIDE AS NEW REDUCING AGENTS. I. SELECTIVE REDUCTION OF CARBOXYLIC ACIDS TO ALDEHYDES (1974)

Abstract A new method for the preparation of aldehydes from carboxylic acids by use of diaminoaluminum hydride is described. Reducing agents, diaminoaluminum hydrides, were prepared from aluminum hydride and two moles of various secondary amines. It was found that bis(4-methylpiperazinyl)aluminum hydride is the most suitable reducing agent, which reduces carboxylic acids to the corresponding aldehydes at room temperature or under reflux in good yields.
Evaluation of combination treatment benefits of nab-paclitaxel in experimental pancreatic cancer. (2012)

170 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers and is characterized by early tissue invasion, metastasis and high resistance to systemic therapies. Gemcitabine, a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated combination treatment benefits of nab-paclitaxel with gemcitabine in experimental pancreatic cancer. Methods: In vitro cell proliferation was evaluated by WST-1 assay in human PDAC cells. Animal survival studies were performed in murine xenografts. Results: Nab-paclitaxel inhibited in vitro proliferation of PDAC cell lines with IC50 levels of 7.6 mM, 208 nM, 519 nM and 526 nM for AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells. Nab-paclitaxel combination with gemcitabine had significant additive effect on inhibition of PDAC cell proliferation; 72-hour incubation demonstrated that nab-paclitaxel addition caused a 2.5, 2.5, 8.9 and 2.2-fold decrease in IC50 of gemcitabine in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. In an intraperitoneal murine xenograft model, 2-week therapy demonstrated that compared to controls (median survival: 23 days), animal survival increased after gemcitabine (27 days, p=0.05) and nab-paclitaxel monotherapy (35 days, p=0.0005). In a separate 3-week therapy experiment, animal survival was significantly longer in the nab-paclitaxel treated group (41 days, p&lt;0.002 versus control and Gem) compared with gemcitabine (32 days, p=0.005 versus control), docetaxel (32 days, p=0.005) and controls (20 days). Animal survival in nab-paclitaxel / gemcitabine and docetaxel / gemcitabine sequential treatment group was 43 and 40 days, respectively. Conclusions: Nab-paclitaxel has significant antitumor activity as a single agent in experimental pancreatic cancer and can also enhance gemcitabine effects in combination. These findings provide a strong rationale for testing nab-paclitaxel in patients with pancreatic cancer.
Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor (2005)

Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170ANPS173. P172 was the most critical for rituximab binding, since its replacement with S172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161WPXWLE156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is suggested.
Is the Perceived Association between Chlamydia pneumoniae and Vascular Diseases Biased by Methodology? (2004)

Inter- and intralaboratory inconsistencies in detection rates of Chlamydia pneumoniae in vascular specimens have been demonstrated. In this study, 66 vascular tissue specimens from 66 patients with vascular disease were tested by three PCR assays: a 16S PCR-based reverse line blot (RLB) assay, a single-step PCR, and a nested PCR. Also, we explored the impacts of different DNA polymerase enzymes on the results based on gel electrophoresis and hybridization. The PCR results by gel electrophoresis in the single-step PCR depended on which DNA polymerase was used. All samples were negative with AmpliTaq Gold DNA polymerase, and 54.5% (36 of 66) were positive with the conventional Taq DNA polymerase. All samples were negative after hybridization with a C. pneumoniae-specific probe. In the nested PCR, all specimens were negative by gel electrophoresis and after hybridization. The RLB assay failed to detect C. pneumoniae in any specimen; however, 20 specimens were Chlamydia sp. positive. The sequence analysis of six of these samples demonstrated Chlamydia-like organisms. RLB detected Chlamydia sp. DNA in water and in the elution buffer after passage of the Qiagen columns (11 of 40). This study identified factors that may influence the detection of C. pneumoniae DNA in vascular tissues and consequently bias the perception of a link between C. pneumoniae and vascular diseases. The following are strongly recommended: to use DNA polymerases that have to be activated, to decontaminate with dUTP-uracil-DNA glycosylase, to hybridize with specific probes, to include sufficient controls, and to use molecular grade water.
The Role of Endothelium in the Responses of Vascular Smooth Muscle to Drugs (1984)

Due to the massive data sets available for drug candidates, modern drug discovery has advanced to the big data era. Central to this shift is the development of artificial intelligence approaches to implementing innovative modeling based on the dynamic, ...Read More
Difference in the Binding Mode of Two Mannose-Binding Proteins:  Demonstration of a Selective Minicluster Effect† (1997)

Serum-type and liver-type mannose-binding proteins (MBP) are both present in higher animals and both are composed of a carbohydrate-recognition domain (CRD) and a collagenous domain. Although known as mannose-binding proteins, these proteins bind N-acetylglucosamine and other related sugars quite well. An earlier specificity study using cloned CRD portions of both types of MBP from rat [Childs, R. A., Feizi, T., Yuen, C.-T., Drickamer, K., & Quesenberry, M. (1990) J. Biol. Chem. 265, 20770-20777] revealed that the liver MBP CRD binds the trimannosyl core structure of N-glycosides, whereas the serum MBP CRD does not. We studied the substrate preferences of these CRDs using both solid and solution phase assays, testing monosaccharides, glycoproteins, and synthetic cluster ligands. While there was no significant difference in the monosaccharide binding specificities of the two CRDs, they displayed very different affinities for natural glycoproteins and mannose-containing cluster glycosides. Most interestingly, synthetic cluster ligands with two terminal GlcNAc moieties have affinity equal to monovalent GlcNAc ligands toward both CRDs, whereas a series of structurally similar Man-terminated divalent ligand displays about 20-fold enhanced affinity toward liver CRD only. A plausible explanation is that the liver MBP CRD has two sugar binding sites per subunit, one of which binds only mannose, and the other, both mannose and N-acetylglucosamine. In contrast, the serum MBP CRD has only one site of the latter type. Results of isothermal titration calorimetry support this hypothesis.
Spliceosome-Associated microRNAs Signify Breast Cancer Cells and Portray Potential Novel Nuclear Targets (2020)

MicroRNAs (miRNAs) act as negative regulators of gene expression in the cytoplasm. Previous studies have identified the presence of miRNAs in the nucleus. Here we study human breast cancer-derived cell-lines (MCF-7 and MDA-MB-231) and a non-tumorigenic cell-line (MCF-10A) and compare their miRNA sequences at the spliceosome fraction (SF). We report that the levels of miRNAs found in the spliceosome, their identity, and pre-miRNA segmental composition are cell-line specific. One such miRNA is miR-7704 whose genomic position overlaps HAGLR, a cancer-related lncRNA. We detected an inverse expression of miR-7704 and HAGLR in the tested cell lines. Specifically, inhibition of miR-7704 caused an increase in HAGLR expression. Furthermore, elevated levels of miR-7704 slightly altered the cell-cycle in MDA-MB-231. Altogether, we show that SF-miR-7704 acts as a tumor-suppressor gene with HAGLR being its nuclear target. The relative levels of miRNAs found in the spliceosome fractions (e.g., miR-100, miR-30a, and let-7 family) in non-tumorigenic relative to cancer-derived cell-lines was monitored. We found that the expression trend of the abundant miRNAs in SF was different from that reported in the literature and from the observation of large cohorts of breast cancer patients, suggesting that many SF-miRNAs act on targets that are different from the cytoplasmic ones. Altogether, we report on the potential of SF-miRNAs as an unexplored route for cancerous cell state.
Resolution of Three Nonproliferative Immature Splenic B Cell Subsets Reveals Multiple Selection Points During Peripheral B Cell Maturation (2001)

Although immature/transitional peripheral B cells may remain susceptible to selection pressures before full maturation, the nature and timing of these selection events remain unclear. We show that correlated expression of surface (s) IgM (sIgM), CD23, and AA4 defines three nonproliferative subpopulations of immature/transitional peripheral B cells. We designate these populations transitional (T) 1 (AA4(+)CD23(-)sIgM(high)), T2 (AA4(+)CD23(+)sIgM(high)), and T3 (AA4(+)CD23(+)sIgM(low)). Cells within all three subsets are functionally immature as judged by their failure to proliferate following sIgM cross-linking in vitro, and their rapid rate of turnover in vivo as assessed by 5-bromo-2'-deoxyuridine labeling. These labeling studies also reveal measurable cell loss at both the T1-T2 and T2-T3 transitions, suggesting the existence of multiple selection points within the peripheral immature B cell pool. Furthermore, we find that Btk-deficient (xid) mice exhibit an incomplete developmental block at the T2-T3 transition within the immature B cell pool. This contrasts markedly with lyn(-/-) mice, which exhibit depressed numbers but normal ratios of each immature peripheral B cell subset and severely reduced numbers of mature B cells. Together, these data provide evidence for multiple selection points among immature peripheral B cells, suggesting that the B cell repertoire is shaped by multiple unique selection events that occur within the immature/transitional peripheral B cell pool.
Suppression of Immunoglobulin-Secreting Cells from Human Peripheral Blood by Toxic-Shock—Syndrome Toxin-1 (1986)

Toxic-shock syndrome toxin-1 (TSST-1), a nonspecific T lymphocyte mitogen, was shown to cause the suppression of immunoglobulin-secreting cells (ISCs) generated in pokeweed mitogen (PWM)-stimulated cultures of human peripheral blood mononuclear cells (PBMs). Greater than 90% suppression of the PWM-stimulated ISC response was achieved when 2 X 10(6) PBMs were cultured in the presence of 1 microgram of TSST-1. The nonspecific suppression induced by the toxin was dose related; amounts of TSST-1 as low as 1.0 ng/2 X 10(6) cultured cells caused significant suppression of the ISC response. TSST-1-induced suppression was due to the activation of a population of cells that secreted a soluble factor that mediated the resulting suppression. PBMs were activated by a 24-hr preincubation of 2 X 10(6) cells in the presence of 1 microgram of TSST-1 followed by repeated washing to remove residual toxin. These cells, when co-cultured with unstimulated PBMs and PWM, suppressed the normal ISC response. The supernatant factor, active at volumes of 10 microliters/2 X 10(6) PBMs, was generated by harvesting the supernatant fluid of TSST-1-activated cells. The results of these in vitro experiments confirm that TSST-1 is an immunosuppressing agent that affects human lymphocyte function and, in such a capacity, may play a role in the development of toxic shock syndrome in humans.
Stress and the General Adaptation Syndrome (1950)

With the concept of the general adaptation syndrome we have attempted to integrate a number of seemingly quite unrelated observations into a single unified biologic system. I would draw attention briefly to the work of Claude Bernard, who showed how important it is to maintain the constancy of the "milieu interieur" ; Cannon's concept of " homoeostasis "; Frank Hartmann's " general tissue hor- mone" theory of the corticoids; Dustin's observations on the " caryoclastic poisons," the " post-operative disease," the curative action of fever, foreign proteins, and of other " non-specific therapeutic agents "; the " nephrotoxic sera " of Masugi; and to the " Goldblatt clamp" for the production of experimental renal hypertension.
Predictable αβ T-Cell Receptor Selection toward an HLA-B*3501-Restricted Human Cytomegalovirus Epitope (2007)

Human cytomegalovirus (HCMV) elicits a very large burden on the immune system, with approximately one in ten T cells being reserved solely to manage this infection. However, information on the clonotypic composition of these vast T-cell populations is limited. In this study, we sequenced 116 T-cell receptor (TcR) alpha/beta-chains specific for the highly immunogenic HLA-B*3501-resticted epitope IPSINVHHY from the pp65 antigen. Interestingly, T cells recovered from all donors bore an identical or near-identical TRBV28/TRBJ1-4/TRAV17/TRAJ33 TcR. The ability to predict the responding alphabeta TcR repertoire before viral infection should prove a powerful tool for basic and clinical immunology.
The type 1 repeats of thrombospondin 1 activate latent transforming growth factor-beta. (1994)

Thrombospondin (TSP) is complexed with transforming growth factor-beta (TGF-beta) in the alpha-granules of stimulated platelets. TSP stripped of associated TGF-beta activity (sTSP) activates latent TGF-beta secreted by bovine aortic endothelial cells (BAE) in culture. To better understand the interactions of TSP with TGF-beta, we investigated which region of sTSP interacts with TGF-beta. The chymotrypsin-resistant core of TSP, which contains the procollagen-like region and the properdin-like type 1 repeats, activated both latent TGF-beta secreted by BAE and a recombinant form of the small latent TGF-beta complex at levels similar to or better than sTSP. The core fragment bound 125I-TGF-beta in solution and shifted the elution profile of 125I-TGF-beta in gel permeation chromatography. Fusion constructs of the type 1, 2, and 3 repeats and the COOH terminus of TSP1 were tested for their ability to activate latent TGF-beta. Only the type 1 construct, containing the three properdin-like repeats of TSP found in the 50-kDa fragment, activated latent TGF-beta. In addition, a polyclonal antibody against the type 1 construct inhibits activation of latent TGF-beta by intact TSP, suggesting that this region is exposed in the intact molecule. These results show that the type 1 properdin-like repeats of TSP are responsible for activating recombinant and endothelial cell-derived latent TGF-beta and that this site is exposed in intact TSP.
Molecular cloning of the major cell surface heparan sulfate proteoglycan from rat liver. (1992)

We have used an antiserum raised against a purified heparan sulfate proteoglycan (HSPG) preparation isolated from rat liver to screen a lambda gt11 expression library and have obtained overlapping cDNA clones that contain the full-length coding sequence of an HSPG core protein capable of spanning the plasma membrane. The open reading frame of the rat cDNA encodes a protein of 211 amino acids. The predicted protein sequence (23 kDa) has a high degree of homology with the published partial sequence of the human lung fibroblast HSPG, fibroglycan. The deduced protein sequence contains a 24-amino acid transmembrane domain and a 33-amino acid cytoplasmic domain, both of which are identical with the corresponding regions of human fibroglycan and are highly homologous to the human, hamster, and mouse epithelial HSPG, syndecan. The putative ectodomain, which has 85% homology to fibroglycan, contains three possible glycosaminoglycan attachment sites that may be occupied by heparan sulfate chains. The major 49-kDa core protein in the liver HSPG preparation was found to be reactive to an antibody that specifically recognizes the cytoplasmic domain of fibroglycan. We have used the full-length cDNA clone to analyze the expression of this transmembrane core protein gene in whole tissues and several epithelial and fibroblastoid cell lines. It hybridizes to three mRNA species in all cell and tissue types examined, but in liver, isolated hepatocytes, and kidney, an additional 0.8-kilobase mRNA was detected. The three common messages arise from differential use of alternative polyadenylation sites, whereas the fourth tissue-restricted RNA species represents a related gene transcript. The rat equivalent of human fibroglycan therefore appears to be the major transmembrane proteoglycan in liver, and its widespread expression in many diverse tissues and cells suggests that it plays an important role in cellular interactions.
Trans ‐sialidase: a unique enzyme activity discovered in the protozoan Trypanosoma cruzi (1993)

Trypanosoma cruzi, the agent of Chagas' disease, an ailment characterized by a progressive chronic fibrotic myocarditis and degeneration of tissues that are innervated by the autonomic nervous system, is a voracious sialic acid eater from glycoconjugates of the surrounding medium. This is accomplished through an active trans-sialidase residing on the surface membrane of the trypomastigote stage, which is the parasite form that invades vertebrate cells. The existence of the enzyme was proposed and established only 7 years ago and yet a flood of information on the subject is already available. Trans-sialidase is able to reversibly transfer sialic acid alpha(2-->3)-linked to an external Gal beta from the host cell surface sialoglycoconjugates to a terminal Gal beta of an appropriate acceptor on the parasite surface. In the absence of an acceptor, the enzyme acts as a hydrolase transferring sialic acid to water. Trans-sialidase belongs to a highly heterogeneous gene family of surface molecules sharing with each other and with bacterial neuraminidases variable degrees of nucleotide sequence homology and common motifs. It has been proposed that sialylation of the parasite surface catalyzed by trans-sialidase is necessary for successful invasion of the host cell, but the evidence available is still indirect. Another function could be a protection from lysis by the alternative pathway of complement while the parasite is circulating in the acute phase of the disease.
Further Studies on the Inactivation of the Scrapie Agent by Ultraviolet Light (1969)

We have exposed suspensions containing the infective agent of scrapie to doses of ultraviolet light (u.v.) up to 12 times greater than those used in the experiments reported by Alper et al. (1967). Suspensions were prepared and assayed by the methods described by those authors and by Alper, Haig &amp; Clarke (1966). Two different suspensions were irradiated on 2 days separated by a week and were exposed to nearly monochromatic u.v. at 254 nm. from a 15 w ‘germicidal’ lamp. All of the samples were assayed in duplicate and about the same level of activity remained after similar doses in both experiments (Fig. 1). Ultraviolet absorption spectra taken on several preparations made at various times, were constant within fairly narrow limits. Transmittances of the total samples (thickness 2 mm.) irradiated were 0.93. Samples were stirred during irradiation.