gebhart/patrepeval huggingface dataset:
Delineation of two functionally distinct domains of cytosolic phospholipase A2, a regulatory Ca(2+)-dependent lipid-binding domain and a Ca(2+)-independent catalytic domain. (1994)

Cytosolic phospholipase A2 (cPLA2) associates with natural membranes in response to physiological increases in Ca2+, resulting in the selective hydrolysis of arachidonyl phospholipids. The isolation and sequence analysis of cPLA2 cDNA clones from four different species revealed several highly conserved regions. The NH2-terminal conserved region is homologous to several other Ca(2+)-dependent lipid-binding proteins. Here we report that the first 178 residues of cPLA2, containing the homologous Ca(2+)-dependent lipid-binding (CaLB) motif, and another recombinant protein containing the cPLA2(1-178) fragment placed at the COOH terminus of the maltose-binding protein (MBP-CaLB) associate with membranes in a Ca(2+)-dependent manner. cPLA2 and MBP-CaLB also bind to synthetic liposomes at physiological Ca2+ concentrations, demonstrating that accessory proteins are not required. In contrast, delta C2, a truncated cPLA2 lacking the CaLB domain, fails to associate with membranes and fails to hydrolyze liposomal substrates. However, both delta C2 and cPLA2 hydrolyze monomeric 1-palmitoyl-2-lysophosphatidylcholine at identical rates in a Ca(2+)-independent fashion. These results delineate two functionally distinct domains of cPLA2, the Ca(2+)-independent catalytic domain, and the regulatory CaLB domain that presents the catalytic domain to the membrane in response to elevated Ca2+.
Sex Differences in the Abundance of Endothelial Nitric Oxide in a Model of Genetic Hypertension (1997)

A deficiency of nitric oxide may be responsible for the increased vascular resistance associated with human essential hypertension and that seen in animal models of hypertension. Premenopausal females are relatively protected from hypertension and cardiovascular complications. Levels of superoxide can influence the availability of nitric oxide. We hypothesize that there are differences in nitric oxide availability between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at least some of these differences. We studied vascular reactivity in endothelium-intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase activity in endothelial cells removed from aortas and also measured circulating nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174; P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004) and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to 17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI: 1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect on the stroke prone spontaneously hypertensive rats' carbachol response than that of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide may be responsible for strain differences in vascular reactivity, whereas nitric oxide availability may be responsible for sex differences independently of endothelial nitric oxide synthase activity and superoxide.
Expression of two human growth hormone genes in monkey cells infected by simian virus 40 recombinants. (1981)

We have constructed simian virus 40 recombinants carrying two different human growth hormone (hGH) genes. Monkey kidney cells infected with these recombinants synthesize, process, and secrete hGH. The product of gene 1, which has coding sequences identical to those of a cloned hGH complementary DNA, is indistinguishable from pituitary hGH by several criteria. The product of gene 2, which is predicted to encode a variant protein, is less immunoreactive than pituitary hGH but binds efficiently to hGH cell surface receptors. These results show that gene 2 has the potential to be expressed into a previously unidentified form of hGH. They also demonstrate that it is possible to produce a mature hormone by gene transfer in eukaryotic cells and indicate the utility of the simian virus 40-monkey cell system for producing and characterizing secreted animal cell proteins.
Shedding of c-Met is regulated by crosstalk between a G-protein coupled receptor and the EGF receptor and is mediated by a TIMP-3 sensitive metalloproteinase (2001)

ABSTRACT A wide repertoire of transmembrane proteins are proteolytically released from the cell surface by a process known as ‘ectodomain shedding’, under both normal and pathophysiological conditions. Little is known about the physiological mechanisms that regulate this process. As a model system, we have investigated the metalloproteinase-mediated cleavage of the hepatocyte growth factor receptor, Met. We show that epidermal growth factor (EGF) receptor activation, either directly by EGF or indirectly via the G-protein coupled receptor (GPCR) agonist lysophosphatidic acid (LPA), induces cleavage of Met through activation of the Erk MAP kinase signalling cascade. The tyrosine kinase activity of the EGFR was a prerequisite for this stimulation, since treatment of cells with a synthetic inhibitor of this receptor, AG1478, completely abrogated shedding. The metalloproteinase mediating Met cleavage was specifically inhibited by the tissue inhibitor of metalloproteinases (TIMP)-3, but not by TIMP-1 or TIMP-2. Furthermore, the level of Met shedding could be modulated by different cell-matrix interactions. Our results indicate that ectodomain shedding is a highly regulated process that can be stimulated by EGFR signalling pathways and integrin ligation.
The arthroscopic meniscal repair (1988)

Conservative meniscal repair should limit resection to only pathologic portions of the meniscus. The periphery of the meniscus is well vascularized, enabling healing of longitudinal tears. Sutures that perforate the meniscus vertically usually lead to stable healing. In arthroscopic meniscal surgery, isolated tears are sutured from within the joint, usually using techniques related to specially developed instrumentation. Our system uses three curved cannulas of various radii and a specific needle of 1.2 mm thickness, and can be operated by one hand while the joint is distracted with an AO/ASIF femoral distractor. In our series of 54 arthroscopic meniscal repairs, 42 (78%) healed without reinjury. Retears occurred in 12 patients, and were refixed again using the same techniques. Our experience has led us to conclude that the type of meniscal tear most suitable for arthroscopic repair is a vertical longitudinal lesion that involves the vascularized zone; abrading the synovial surfaces is helpful, as is positioning the sutures tightly together; the repair should be checked at 4 months by arthroscopy or by arthrogram; and a combination of nonabsorbable and resorbable sutures is most satisfactory. We believe that with experience arthroscopic meniscal repair becomes a less involved procedure than open repair, and that in the future such repair will be successfully extended to the more centrally located lesions.
Isolation of a Drosophila genomic sequence homologous to the kinase domain of the human insulin receptor and detection of the phosphorylated Drosophila receptor with an anti-peptide antibody. (1986)

A Drosophila genomic fragment has been isolated with a deduced amino acid sequence that is strikingly homologous to that of the kinase domain of the human insulin receptor. The Drosophila DNA hybridizes with an 11-kilobase mRNA that is most prominent in 8- to 12-hr embryos. An anti-peptide antibody prepared to a sequence in the human insulin receptor kinase domain that is conserved in the Drosophila sequence immunoprecipitates a single 95-kDa Drosophila protein whose phosphorylation on tyrosine residues is dependent on insulin. We conclude that the DNA sequence is that of the kinase domain of the Drosophila insulin receptor and that the 95-kDa phosphoprotein is the autophosphorylated beta subunit of that receptor. The results are compatible with our previous reports demonstrating a specific insulin-binding Drosophila glycoprotein and an insulin-dependent tyrosine protein kinase whose activity is greatest during embryogenesis. The observations suggest a role for insulin-dependent protein tyrosine phosphorylation during embryogenesis.
The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in Alu Exons (2003)

Alu repetitive elements can be inserted into mature messenger RNAs via a splicing-mediated process termed exonization. To understand the molecular basis and the regulation of the process of turning intronic Alus into new exons, we compiled and analyzed a data set of human exonized Alus. We revealed a mechanism that governs 3' splice-site selection in these exons during alternative splicing. On the basis of these findings, we identified mutations that activated the exonization of a silent intronic Alu.
IP switching-ATM under IP (1998)

Internet protocol (IP) traffic on the Internet and private enterprise networks has been growing exponentially for some time. This growth is beginning to stress the traditional processor-based design of current-day routers. Switching technology offers much higher aggregate bandwidth, but presently only offers a layer-2 bridging solution. Various proposals are under way to support IP routing over an asynchronous transfer mode (ATM) network. However, these proposals hide the real network topology from the IP layer by treating the data-link layer as a large opaque network cloud. We argue that this leads to complexity, inefficiency, and duplication of functionality in the resulting network. We propose an alternative in which we discard the end-to-end ATM connection and integrate fast ATM hardware directly with IP, preserving the connectionless nature of IP. We use the soft-state in the ATM hardware to cache the IP forwarding decision. This enables further traffic on the same IP flow to be switched by the ATM hardware rather than forwarded by IP software. We claim that this approach combines the simplicity, scalability, and robustness of IP, with the speed, capacity, and multiservice traffic capabilities of ATM.
c-Jun Induces Mammary Epithelial Cellular Invasion and Breast Cancer Stem Cell Expansion (2010)

The molecular mechanisms governing breast tumor cellular self-renewal contribute to breast cancer progression and therapeutic resistance. The ErbB2 oncogene is overexpressed in approximately 30% of human breast cancers. c-Jun, the first cellular proto-oncogene, is overexpressed in human breast cancer. However, the role of endogenous c-Jun in mammary tumor progression is unknown. Herein, transgenic mice expressing the mammary gland-targeted ErbB2 oncogene were crossed with c-jun(f/f) transgenic mice to determine the role of endogenous c-Jun in mammary tumor invasion and stem cell function. The excision of c-jun by Cre recombinase reduced cellular migration, invasion, and mammosphere formation of ErbB2-induced mammary tumors. Proteomic analysis identified a subset of secreted proteins (stem cell factor (SCF) and CCL5) induced by ErbB2 expression that were dependent upon endogenous c-Jun expression. SCF and CCL5 were identified as transcriptionally induced by c-Jun. CCL5 rescued the c-Jun-deficient breast tumor cellular invasion phenotype. SCF rescued the c-Jun-deficient mammosphere production. Endogenous c-Jun thus contributes to ErbB2-induced mammary tumor cell invasion and self-renewal.
Zinc-sensitive genes as potential new target genes of the metal transcription factor-1 (MTF-1) (2005)

Zinc is an essential trace element that serves as a structural constituent of a large number of transcription factors, which explains its pivotal role in the control of gene expression. Previous studies investigating the effect of zinc deficiency and zinc supplementation on gene expression in the human adenocarcinoma cell line HT-29 led to the identification of a considerable number of genes responding to alterations in cellular zinc status with changes in steady state mRNA levels. For 9 of 20 genes from these previous screenings that were studied in more detail, mRNA steady state levels responded to both high and low media zinc concentrations. As they are primarily zinc-dependent, we assessed whether these genes are controlled by the zinc-finger metal transcription factor MTF-1. To test this hypothesis we generated a doxycyline-inducible Tet-On HT-29 cell line overexpressing MTF-1. Using this conditional expression system, we present evidence that Kruppel-like factor 4 (klf4), hepatitis A virus cellular receptor 1 (hhav), and complement factor B (cfbp) are 3 potential new target genes of MTF-1. To support this, we used in silico analysis to screen for metal-responsive elements (MREs) within promotors of zinc-sensitive genes. We conclude that zinc responsiveness of klf4, hhav, and cfbp in HT-29 cells is mediated at least in part by MTF-1.
PlanetLab (2003)

PlanetLab is a global overlay network for developing and accessing broad-coverage network services. Our goal is to grow to 1000 geographically distributed nodes, connected by a disverse collection of links. PlanetLab allows multiple service to run concurrently and continuously, each in its own slice of PlanetLab. This paper discribes our initial implementation of PlanetLab, including the mechanisms used to impelment virtualization, and the collection of core services used to manage PlanetLab.
Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: Identification of specific tumor marker and potential targets for immunotherapy (2011)

Cancer-testis antigens (CTAs) are often specifically expressed in cancer cells and under normal conditions are only considered to be expressed in the germ line cells and the placenta. CTAs are potential targets for cancer immunotherapy and therefore necessitates their expression profiling. The expression profile of LAGE1, MAGE-A4 and NY-ESO1, their possible correlations and interaction, and the clinicopathological associations of each marker were studied. RNA was extracted from fresh esophagectomy tissues of 41 esophageal squamous cell carcinoma (ESCC) patients prior to any other therapeutic intervention. The relative mRNA expression of LAGE1, MAGE-A4 and NY-ESO1 was assessed with the real-time reverse transcription-polymerase chain reaction (RT-PCR) 5' nuclease assay. The overexpression of LAGE1, MAGE-A4 and NY-ESO1 was found in 39, 90.2 and 41.4% of ESCC samples respectively. Of the patients, 97.5% showed an overexpression of at least one CTA. The relative expression of MAGE-A4 was directly associated with lymph node metastasis and the stage of the tumor (p < 0.05). A significant direct correlation was also detected between the MAGE-A4/LAGE1 and MAGE-A4/NY-ESO1 levels of gene expression. MAGE-A4 is identified as a specific biomarker of ESCC with a possible oncogenic role contributing to tumor progression. Interactions between MAGE-A4, LAGE1 and NY-ESO1 and their significant clinical consequences introduce these CTAs as appropriate targets for a polyvalent cancer vaccine.
Learning the k in k-means (2003)

When clustering a dataset, the right number $k$ of clusters to use\nis often not obvious, and choosing k automatically is a hard algorithmic\nproblem. In this paper we present a new algorithm for choosing k that is based\non a new statistical test for the hypothesis that a subset of data follows a\nGaussian distribution. The algorithm runs k-means with increasing k until the\ntest fails to reject the hypothesis that the data assigned to each k-means\ncenter are Gaussian. We present results from experiments on synthetic and\nreal-world data showing that the algorithm works well, and better than a recent\nmethod based on the BIC penalty for model complexity.Pre-2018 CSE ID: CS2002-0716
Deletion mapping of DNA regions required for SV40 early region promoter function in vivo. (1982)

The SV40 early region promoter, previously localized to the DNA segment bounded by the HpaII and HindIII restriction sites (nucleotides 346 and 5171), was further defined by construction of an extensive set of deletions within this region and measurement of their effects on (a) viral DNA replication, (b) virus multiplication and the ability to complement early and late mutations, (c) transformation of rat cells, (d) large T antigen formation, and (e) the location of the 5' ends of early mRNAs. One set of mutations is represented by deletions that begin at the HpaII site and extend unidirectionally for varying lengths toward the BglI site at ori. A second set of mutants contains deletions that start at ori and extend unidirectionally for varying lengths towards the HpaII site. A third set of mutants, with deletions or duplications of various lengths and boundaries, lie between the HpaII and BglI sites. Our studies indicate the following. (a) Ori, the sequence needed for initiating SV40 DNA replication, extends from the sequences needed for initiating SV40 DNA replication, extends from the sequences needed to bind T antigen to the palindrome in site II to nucleotide 34, the late region edge of the AT block. Flanking sequences adjacent to the AT block facilitate DNA replication. (b) The SV40 early region promoter comprises two functionally distinct nucleotide sequence elements. One is flanked by nucleotides 5231 and 107, and contains the RNA initiation sites at nucleotides 5231-5237, a positioning element resembling the TATAAATA consensus sequence about 20-25 nucleotides upstream, and an RNA polymerase II recognition sequence contributed by short GC-rich sequences clustered between nucleotides 35 and 107; we refer to this as the RNA polymerase II interaction site. The second distinct sequence element is contained within each of two 72-bp segments located between nucleotides 107 and 250; the behavior of this element suggests that it may influence the accessibility of RNA polymerase II for the interaction site or the efficiency of RNA chain initiation. Large T antigen binding sites I, II, and III overlap with the putative RNA polymerase II interaction site; since large T antigen does not prevent elongation of RNA transcripts initiated upstream, T antigen probably represses early region expression by preventing RNA polymerase II binding to the promoter.
Safety and tolerability of increasing doses of CB-839, a first-in-class, orally administered small molecule inhibitor of glutaminase, in solid tumors. (2015)

2512 Background: Glutamine is required for the growth and survival of multiple tumor types. CB-839 is a highly selective, reversible, allosteric inhibitor of glutaminase, a choke point in the utilization of glutamine. CB-839 has broad in vitro and in vivo anti-tumor activity in solid and heme malignancies. Methods: CX-839-001 is an ongoing Phase 1 study of escalating doses of CB-839 in advanced and/or treatment-refractory solid tumor patients (pts) to evaluate safety and tolerability, and to identify the recommended Phase 2 dose (R2PD). CB-839 was administered orally continuously in 21-day cycles. Pharmacokinetics (PK) was monitored on Days 1, 15, and 22; pharmacodynamic (PD) assessment of glutaminase activity was measured ex vivo in platelets and tumor biopsies. Additional pts will be enrolled at the RP2D with triple negative breast cancer (TNBC), non-small cell lung adenocarcinoma (NSCLC), renal cell carcinoma (RCC), mesothelioma, and tumors with mutations in enzymes of the TCA cycle. Results: 35 pts were enrolled in dose escalation receiving CB-839 doses from 100 to 800 mg TID and 600 mg BID. Exposure increased less than dose proportionally but there was a clear PK/PD relationship with > 90% glutaminase inhibition in platelets when CB-839 exceeded 450 nM; target inhibition was confirmed in tumors. Radiographic stable disease (SD) was observed in 7 (28%) of 25 efficacy-evaluable pts (average duration 107 days; range 59-209) across all diseases and dose levels including TNBC (2/9 evaluable pts), NSCLC (2/4), mesothelioma (2/4) and RCC (1/3). Grade ≥ 3 treatment-related AEs occurred in 7 (20%) of pts, including ALT/AST (4 pts), creatinine, alkaline phosphatase, and GGT increases, lymphopenia, and hypoglycemia (1 pt each). A Grade 3 increase in creatinine considered unlikely related to CB-839 was a DLT at 250 mg TID. CB-839 was absorbed rapidly (Tmax 1-2 hr fasted and 2-4 hr fed) and cleared with a half-life of about 4 hr. Plasma Cminwas > 450 nM at steady state at the RP2D of 600 mg BID. Conclusions: Continuous CB-839 administration showed an acceptable safety profile, significant glutaminase inhibition and preliminary signs of clinical activity in multiple tumor types. Clinical trial information: NCT02071862.
IL-8 production by human polymorphonuclear leukocytes. The chemoattractant formyl-methionyl-leucyl-phenylalanine induces the gene expression and release of IL-8 through a pertussis toxin-sensitive pathway (1992)

IL-8 is a novel chemotactic cytokine, produced by a variety of blood and tissue cells, that has marked activating effects on polymorphonuclear leukocytes (PMN). We report that IL-8 is produced and released by human PMN after stimulation with the chemotactic agonist FMLP. Release of IL-8 in response to FMLP was transient and not influenced by PMN adherence or by the absence of serum in the medium. Maximum yields were usually obtained with 10 nM FMLP within 2 h of stimulation (0.5-3.5 ng/ml/7 x 10(6) cells, range of 17 different donors). IL-8 release was dependent on FMLP-induced de novo protein synthesis because it was inhibited by cycloheximide, was paralleled by enhanced expression of IL-8 mRNA and was potentiated from two- to sixfold after preincubation of PMN with cytochalasin B. The FMLP effect was direct and not dependent on LPS or on contaminating monocytes, which showed only low responsiveness to FMLP. Pretreatment of PMN with pertussis toxin prevented FMLP-dependent IL-8 production, the effect being evident both at the level of mRNA expression and protein secretion. In addition, two other chemoattractans, platelet-activating factor and C5a, were found capable to induce release of IL-8 by PMN. The results of this study suggest that chemotactically stimulated PMN may be able to amplify the recruitment process of PMN to the inflammatory site by releasing IL-8. As a long-lived cytokine, IL-8 could markedly prolong the attractant effect.
Guidelines for Diagnosis, Treatment, and Prevention of Clostridium difficile Infections (2013)

Clostridium difficile infection (CDI) is a leading cause of hospital-associated gastrointestinal illness and places a high burden on our health-care system. Patients with CDI typically have extended lengths-of-stay in hospitals, and CDI is a frequent cause of large hospital outbreaks of disease. This guideline provides recommendations for the diagnosis and management of patients with CDI as well as for the prevention and control of outbreaks while supplementing previously published guidelines. New molecular diagnostic stool tests will likely replace current enzyme immunoassay tests. We suggest treatment of patients be stratified depending on whether they have mild-to-moderate, severe, or complicated disease. Therapy with metronidazole remains the choice for mild-to-moderate disease but may not be adequate for patients with severe or complicated disease. We propose a classification of disease severity to guide therapy that is useful for clinicians. We review current treatment options for patients with recurrent CDI and recommendations for the control and prevention of outbreaks of CDI.