gebhart/patrepeval huggingface dataset:
In vitro and in vivo antibacterial activities of CS-807, a new oral cephalosporin (1987)

CS-807 is a new oral prodrug of R-3746, a cephalosporin derivative, with potent in vitro and in vivo antibacterial activity against both gram-positive and gram-negative bacteria. The susceptibility of about 1,200 clinical isolates to R-3746 was determined by the agar dilution method. Ninety percent or more of pathogens such as Staphylococcus aureus, streptococci, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, indole-positive and indole-negative Proteus spp., Providencia rettgeri, and Haemophilus influenzae were inhibited at concentrations ranging less than or equal to 0.01 to 1.56 micrograms/ml. Furthermore, at a concentration of 3.13 micrograms/ml, 50% or more of Staphylococcus epidermidis, Morganella morganii, Citrobacter freundii, and Serratia marcescens strains were also inhibited. Pseudomonas aeruginosa and Xanthomonas maltophilia were resistant to R-3746. The activity of R-3746 was scarcely influenced by several growth conditions. R-3746 was highly resistant to hydrolysis by beta-lactamases derived from various species of bacteria. Killing-curve studies demonstrated bactericidal activity of R-3746 at concentrations above the MIC. R-3746 showed high affinity for penicillin-binding proteins 1, 3, and 4 of Staphylococcus aureus and 1A, 1Bs, and 3 of Escherichia coli. Systemic infections in mice caused by various pathogens, including beta-lactamase-producing strains, responded well to therapy with oral doses of CS-807.
IL-12 Is an Effective Adjuvant for Induction of Mucosal Immunity (1999)

We addressed the effects of two cytokines, IL-6 and IL-12, derived from APCs, for the development of mucosal IgA Ab responses following their nasal delivery with the protein vaccine tetanus toxoid (TT). Mice treated nasally with IL-6 and TT showed higher TT-specific serum IgG (mainly IgG1 and IgG2b) Ab responses than did control mice, but exhibited no IgE and negligible secretory IgA (S-IgA) Ab responses. In contrast, IL-12 administered nasally with TT not only induced sharp increases in TT-specific serum IgG (mainly IgG1 and IgG2b) and IgA, but also elevated mucosal S-IgA Ab responses. Coadministration of IL-6 and IL-12 with TT did not enhance the mucosal or serum Ab responses over those seen with IL-12 alone. TT-specific CD4+ T cells from mice given TT with IL-6 or IL-12 produced higher levels of IFN-gamma, IL-6, and IL-10 than did those from control mice, but only negligible levels of IL-4 and IL-5. In summary, both intranasal IL-6 and IL-12 induced serum Abs that protected mice from systemic challenge with TT, whereas only IL-12 induced mucosal S-IgA Ab responses. The significance of IL-12-induced Th1-type responses for regulation of both mucosal and systemic immunity is discussed.
Phosphatidylinositol 3-Kinase Is Required for Insulin-Like Growth Factor-I–Induced Vascular Smooth Muscle Cell Proliferation and Migration (2000)

Insulin-like growth factor-I (IGF-I) plays an important role in regulating vascular smooth muscle cell (VSMC) proliferation and directed migration. The mitogenic and chemotactic actions of IGF-I are mediated through the IGF-I receptor, but how the activation of the IGF-I receptor leads to these biological responses is poorly understood. In this study, we examined the role of phosphatidylinositol 3-kinase (PI3 kinase) in mediating the mitogenic and chemotactic signals of IGF-I. IGF-I treatment resulted in a significant increase in phosphotyrosine-associated PI3 kinase activity in cultured primary VSMCs. To determine whether insulin receptor substrate (IRS)-1, -2, or both are involved in IGF-I signaling in VSMCs, cell lysates were immunoprecipitated with either an anti-IRS-1 or an anti-IRS-2 antibody, and the associated PI3 kinase activity was determined. IGF-I stimulation resulted in a significant increase in IRS-1- but not IRS-2-associated PI3 kinase activity, suggesting that IGF-I primarily utilizes IRS-1 to transmit its signal in VSMCs. The IGF-I-induced increase in IRS-I-associated PI3 kinase activity was concentration dependent. At the maximum concentration (50 ng/mL), IGF-I induced a 60-fold increase. This activation occurred within 5 minutes and was sustained at high levels for at least 6 hours. IGF-I also caused a concentration-dependent and long-lasting activation of protein kinase B (PKB/Akt). Inhibition of PI3 kinase activation by LY294002 or wortmannin abolished IGF-I-stimulated VSMC proliferation and reduced IGF-I-directed VSMC migration by approximately 60%. These results indicate that activation of PI3 kinase is required for both IGF-I-induced VSMC proliferation and migration.
Mechanisms of precise genome editing using oligonucleotide donors (2017)

The use of programmable meganucleases is transforming genome editing and functional genomics. CRISPR/Cas9 was developed such that targeted genomic lesions could be introduced in vivo with unprecedented ease. In the presence of homology donors, these lesions facilitate high-efficiency precise genome editing (PGE) via homology-directed repair (HDR) pathways. However, the identity and hierarchy of the HDR (sub)pathways leading to the formation of PGE products remain elusive. Here, we established a green to blue fluorescent protein conversion system to systematically characterize oligodeoxynucleotide (ODN)-mediated PGE using Cas9 and its nickase variants in human cells. We demonstrate that, unlike double-stranded DNA (dsDNA) donors with central heterologies, ODNs generated short conversion tracts with Gaussian-like distributions. Interestingly, single-nick-induced PGE using ODN donors produced conversion tracts biased either mostly uni- or bidirectional depending on the relative strandedness of the ODNs and the nick. Moreover, the ODNs were physically incorporated into the genome only in the bidirectional, but not in the unidirectional, conversion pathway. In the presence of double-stranded genomic lesions, the unidirectional conversion pathway was preferentially utilized even though the knock-in mutation could theoretically have been converted by both pathways. Collectively, our results suggest that ODN-mediated PGE utilizes synthesis-dependent strand annealing and single-stranded DNA incorporation pathways. Both of these pathways generate short conversion tracts with Gaussian-like distributions. Although synthesis-dependent strand annealing is preferentially utilized, our work unequivocally establishes the existence of a single-stranded DNA incorporation pathway in human cells. This work extends the paradigms of HDR-mediated gene conversion and establishes guidelines for PGE in human cells.
A novel cytokine exhibiting megakaryocyte potentiating activity from a human pancreatic tumor cell line HPC-Y5. (1994)

Sixty-four kinds of cell lines were examined for their ability to produce megakaryocyte potentiating activity by means of conditioned media obtained from a protein-free culture system. Six human tumor cell lines were shown to produce this activity, and the cell line HPC-Y5, established from human pancreatic cancer, was shown to have the highest level of activity. The megakaryocyte potentiating factor (MPF) was purified from an HPC-Y5 conditioned medium by a combination of ion-exchange chromatography, gel filtration and reverse-phase HPLC. The purified MPF showed a megakaryocyte potentiating activity almost equal to human interleukin-6 in the presence of murine interleukin-3 in a colony formation assay with mouse bone marrow cells. The apparent molecular weight of MPF is 32,000 when determined by SDS-polyacrylamide gel electrophoresis. Glycopeptidase F digestion, and amino sugar analysis of the factor demonstrated that MPF is a glycoprotein carrying at least one N-linked sugar chain. The N-terminal amino acid sequence of MPF was determined to be Leu-Ala-Gly-Glu-Thr-Gly-Gln-Glu-Ala-Ala-Pro-Leu- Asp-Gly-Val-Leu-Ala-Asn. The same or homologous amino acid sequence has not been found in known proteins, demonstrating that MPF is a novel cytokine that has megakaryocyte potentiating activity in the murine assay system.
Graft-versus-host disease therapy: something else beyond glucocorticoids? (2011)

raft-versus-host disease (GVHD) remains the main complication and limitation to successful allogeneic hematopoietic stem cell transplantation (alloSCT). Although a decreased incidence of severe GVHD has been reported throughout the last 20 years, acute and chronic GVHD events still have a great impact on early and late non-relapsed mortality and on the quality of life of long-term survivors. In spite of significant advances in the understanding of the pathophysiology of GVHD and the development of more targeted immunosuppressive therapies, glucocorticoids remain the gold standard for therapy for acute and chronic GVHD. However, the results of glucocorticoid treatment are clearly suboptimal, with continuing complete response rates of only 20-40% in acute and chronic GVHD. 2-3 Moreover, the administration of high doses and/or prolonged use of glucocorticoids is associated with severe side effects, such as opportunistic infections, diabetes, myopathy, and osteonecrosis, that are significant factors for morbidity and mortality. It still remains a matter of debate whether there is an alternative therapy to glucocorticoids that can overcome these problems. In this issue of Haematologica, Pidala et al. report results of sirolimus as an alternative to glucocorticoids in the first-line treatment of acute GVHD. Their main action is in switching off multiple activated inflammatory genes that encode for cytokines such as IL-2, TNF-, chemokines, adhesion molecules, inflammatory enzymes and receptors. In addition, glucocorticoids increase transcription of several antiinflammatory or inhibitory cytokine genes such as IL-10, IL-12 or IL-1 receptor antagonists. Most of these cytokines have been involved in the pathophysiology of GVHD.
The isolation of differentially expressed genes in fibroblast growth factor stimulated BC3H1 cells by subtractive hybridization. (1994)

We have developed a subtractive hybridization procedure based on the hybridization of a single-stranded phagemid cDNA library (target) to biotinylated RNA (driver). We have applied this method to fibroblast growth factor (FGF) induced-uninduced mouse brain tumor-derived muscle-like cell. BC3Hl cDNA libraries. After hybridization to a C(o)t value of 1000, cDNAs common to the target and driver populations were subtracted up to 231-fold, whereas several highly induced genes were enriched from 2-15-fold. Interestingly, moderately induced genes (e.g., the 12-fold-induced nur/77 gene) were subtracted even at a low C(o)t value of 50. Therefore, at every C(o)t tested, subtractive hybridization tended to equalize the uninduced and moderately induced common sequences within target populations regardless of the abundance of the gene species. These observations suggest that subtractive hybridization should only be used for identifying target genes that are either uniquely expressed or highly induced.
Buffer‐free therapeutic antibody preparations provide a viable alternative to conventionally buffered solutions: From protein buffer capacity prediction to bioprocess applications (2015)

Protein therapeutics, including monoclonal antibodies (mAbs), have significant buffering capacity, particularly at concentrations>50 mg/mL. This report addresses pH-related issues critical to adoption of self-buffered monoclonal antibody formulations. We evaluated solution conditions with protein concentrations ranging from 50 to 250 mg/mL. Samples were both buffer-free and conventionally buffered with citrate. Samples were non-isotonic or adjusted for isotonicity with NaCl or trehalose. Studies included accelerated temperature stability tests, shaking stability studies, and pH changes in infusion media as protein concentrate is added. We present averaged buffering slopes of capacity that can be applied to any mAb and present a general method for calculating buffering capacity of buffer-free, highly concentrated antibody liquid formulations. In temperature stability tests, neither buffer-free nor conventionally buffered solution conditions showed significant pH changes. Conventionally buffered solutions showed significantly higher opalescence than buffer-free ones. In general, buffer-free solution conditions showed less aggregation than conventionally buffered solutions. Shaking stability tests showed no differences between buffer-free and conventionally buffered solutions. "In-use" preparation experiments showed that pH in infusion bag medium can rapidly approximate that of self-buffered protein concentrate as concentrate is added. In summary, the buffer capacity of proteins can be predicted and buffer-free therapeutic antibody preparations provide a viable alternative to conventionally buffered solutions.
Controlling the Electronic Structure of Bilayer Graphene (2006)

We describe the synthesis of bilayer graphene thin films deposited on insulating silicon carbide and report the characterization of their electronic band structure using angle-resolved photoemission. By selectively adjusting the carrier concentration in each layer, changes in the Coulomb potential led to control of the gap between valence and conduction bands. This control over the band structure suggests the potential application of bilayer graphene to switching functions in atomic-scale electronic devices.
Ultrasonographic Correlates of Carotid Atherosclerosis in Transient Ischemic Attack and Stroke (1995)

These data demonstrate significant relationships between carotid artery ultrasound plaque characteristics and ischemic cerebrovascular events. These findings encourage further prospective studies in asymptomatic subjects focused on echographic carotid plaque characteristics as predictors of subsequent TIA or stroke.
Ductal Carcinoma In Situ of the Breast (2000)

Ductal carcinoma in situ of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup in the breast cancer family; it is projected that more than 39,000 new cases will be diagnosed in the United States during 1999. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Genetic changes routinely precede morphologic evidence of malignant transformation. Medicine must learn how to recognize these genetic changes, exploit them, and in the future, prevent them.
Role of surface coating on cathode materials for lithium-ion batteries (2010)

Surface coating of cathode materials has been widely investigated to enhance the life and rate capability of lithium-ion batteries. The surface coating discussed here was divided into three different configurations which are rough coating, core shell structure coating and ultra thin film coating. The mechanism of surface coating in achieving improved cathode performance and strategies to carry out this surface modification is discussed. An outlook on atomic layer deposition for lithium ion battery is also presented.
Point of View: Spread-Spectrum Television Broadcasting (1992)

The terrestrial broadcast channel, plagued with ghosts, noise, interference, and frequency distortion, is the most difficult of all transmission media, but is nevertheless attractive because of its existing infrastructure, its low cost, and the fact that it is the means by which free and universal television service is made available to the public. To attain the maximum image quality, reliability, and spectrum efficiency in this medium, combined source and channel coding is proposed. Progressive or “multiresolution” source coding, together with a new form of spread-spectrum code-division multiplex (SS-CDM) channel coding, is used. The coded image information is divided into a large number of parallel data streams, each of which is spread to full channel bandwidth and becomes a component in the CDM multiplexing scheme. Each has a different priority and therefore a different carrier-to-noise ratio (CNR). In this article, CNR is reserved for channel conditions and SNR for signal-to-noise ratio of recovered signal The resulting signal occupies one standard 6-MHz channel and is expected to have excellent interference performance. (The opinions expressed herein are solely those of the author.)
The Asialoglycoprotein Receptor Regulates Levels of Plasma Glycoproteins Terminating with Sialic Acid α2,6-Galactose (2008)

The asialoglycoprotein receptor (ASGP-R) is an abundant, carbohydrate-specific, endocytic receptor expressed by parenchymal cells of the liver. We recently demonstrated that the ASGP-R mediates the clearance of glycoproteins bearing Siaalpha2,6GalNAc as well as those bearing terminal Gal or GalNAc. We now report that glycoproteins such as haptoglobin, serum amyloid protein (SAP), and carboxylesterase that bear oligosaccharides with terminal Siaalpha2,6Gal are elevated in the plasma of ASGP-R-deficient mice. Because of their abundance in plasma, glycoproteins bearing terminal Siaalpha2,6Gal will saturate the ASGP-R and compete with each other on the basis of their relative affinities for the ASGP-R and their relative abundance. We propose that the ASGP-R mediates the clearance of glycoproteins that bear oligosaccharides terminating with Siaalpha2,6Gal and thereby helps maintain the relative concentrations of these glycoproteins in the blood.
Variability and Prognostic Values of Virologic and CD4 Cell Measures in Human Immunodeficiency Virus Type 1‐Infected Patients with 200–500 CD4 Cells/mm3(ACTG 175) (1998)

Virologic measurements are increasingly used to evaluate prognosis and treatment responses in human immunodeficiency virus (HIV) type 1 infection. Markers of HIV-1 replication, including infectious HIV-1 titer from peripheral blood mononuclear cells, serum HIV-1 p24 antigen, plasma HIV-1 RNA, CD4 cell numbers, and viral syncytium-inducing (SI) phenotype, were determined in 391 virology substudy participants in AIDS Clinical Trials Group study 175. The subjects had 200-500 CD4 cells/mm3. All markers of viral replication significantly correlated with one another and were inversely related to CD4 cell number. Disease progression to an AIDS-defining event or death or loss of >50% of CD4 cells was associated with infectious HIV-1 titer (P < .001), HIV-1 RNA (P < .001), and HIV-1 p24 antigen (P = .007). In multivariate proportional hazards models, p24 antigen was never significant when HIV-1 RNA level was included. In a model containing infectious HIV-1 titer (P = .038), HIV-1 RNA (P < .001), SI phenotype (P < .001), and CD4 cell number (P = .18), only the virologic parameters remained significantly associated with progression.
Is diabetic retinopathy an inflammatory disease? (2002)

More work remains to prove this hypothesis

L ast year an ARVO symposium organised by Tim Kern was titled “Is diabetic retinopathy an inflammatory disease?” It is a timely question. chronic subclinical inflammation may underlie much of the vascular pathology of diabetic retinopathy. Nomenclature is critical to this discussion, so the definition of inflammation bears repeating here. Macroscopic inflammation comprises the classic signs of pain ( dolor ), heat ( calor ), redness ( rubor ), swelling ( tumor ), and loss of function ( functio laesa ).1 None of these signs, except for swelling and loss of function, clearly applies to diabetic retina. However, at a microscopic level, inflammation consists of vessel dilatation, altered flow, exudation of fluids, including plasma proteins, and leucocyte accumulation and migration.1 Given the recent data that have been generated in relevant models of diabetic retinopathy, the latter definition appears to fit. A brief overview of the evidence illustrates this point.

Within one week of experimental diabetes, leucocytes adhere to and accumulate within the vasculature of the retina.2,3 A subset of these leucocytes exit the vasculature and transmigrate into the neural retina.2,4 The leucocyte increases are moderate in nature and precede any overt clinical evidence of retinopathy. However, they progress with time.2 Monocytes and neutrophils predominate,4 although preliminary data suggest that lymphocytes may be involved as well (Ahmed, Ishida, Adamis, et al , unpublished observation). The leucocytes actively tether themselves to the endothelial cell lining via classic adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) on the vasculature2 and β2 integrins on the leucocytes.3 The expression levels for these adhesion molecules increase in early diabetes and correlate with the leucocyte increases.2,3 Additional adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and VLA-4 may also be involved, but here the …
High-affinity neuropeptide Y receptor antagonists. (1995)

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.
The Mouse p44 Mitogen-activated Protein Kinase (Extracellular Signal-regulated Kinase 1) Gene (1995)

Mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase are ubiquitous kinases conserved from fungi to mammals. Their activity is regulated by phosphorylation on both threonine and tyrosine, and they play a crucial role in the regulation of proliferation and differentiation. We report here the cloning of the murine p44 MAP kinase (extracellular signal-regulated kinase 1) gene, the determination of its intron/exon boundaries, and the characterization of its promoter. The gene spans approximately eight kilobases (kb) and can be divided into nine exons and eight introns, each coding region exon containing from one to three of the highly conserved protein kinase domains. Primer extension analysis reveals the existence of two major start sites of transcription located at -183 and -186 base pairs (bp) as well as four discrete start sites for transcription located at -178, -192, -273, and -292 bp of the initiation of translation. However, the start site region lacks TATA-like sequences but does contain initiator-like sequences proximal to the major start sites obtained by primer extension. 1 kb of the promoter region has been sequenced. It contains three putative TATA boxes far upstream of the main start sites region, one AP-1 box, one AP-2 box, one Malt box, one GAGA box, one half serum-responsive element, and putative binding sites for Sp1 (five), GC-rich binding factor (five), CTF-NF1 (one), Myb (one), p53 (two), Ets-1 (one), NF-IL6 (two), MyoD (two), Zeste (one), and hepatocyte nuclear factor-5 (one). To determine the sites critical for the function of the p44 MAPK promoter, we constructed a series of chimeric genes containing variable regions of the 5'-flanking sequence of p44 MAPK gene and the coding region for luciferase. Activity of the promoter, measured by its capacity to direct expression of a luciferase reporter gene, is strong, being comparable with the activity of the Rous sarcoma virus promoter. Progressive deletions of the approximately 1 kb (-1200/-78) promoter region allowed us to define a minimal region of 186 bp (-284/-78) that has maximal promoter activity. Within this context, deletion of the AP-2 binding site reduces by 30-40% the activity of the promoter. Further deletion of this minimal promoter that removes the major start sites (-167/-78) surprisingly preserves promoter activity. This result implicates a major role of this region that contains the Sp1 sites.(ABSTRACT TRUNCATED AT 400 WORDS)