gebhart/patrepeval huggingface dataset:
Manipulating the mouse embryo: A laboratory manual (1986)

Manipulating the Mouse Embryo: A Laboratory Manual by B. Hogan, F. Constantini and E. Lacy, Cold Spring Havi~ Laboratmy, 1986. $60.00 (332 pages) ISBN 0 87969 175 1 These are heady days for developmental biologists. Prob- lems that have puzzled scientists for centuries seem to be moving tom the realm of abstract philosophy towards practical solo ution. The power of recombinant DNA technology fuels this opti- mism; at last genes can be engineered, inserted, located, monitored, neutralized and their impact on development asses- sed. The prospect of interfering positively, rather than randomly, with the genetic basis for development is real. The prac- tical basis for this optimism, as recorded in this manual, is clearly well founded. It is impressive that so much pro- gress in the genetic manipulation of the mouse has been made so rapidly. Here are recorded the tech- niques for preparing, inserting and analysing DNA sequences, for retroviral infection of em- bryos, for production and use of EC and EK cells as vehicles for engineered sequences and for nuclear transplantation - all this against a background of the basic procedures required for pro- ducing and handling the em- bryos. If there is one critidsm, it is that the format and content of manual do reveal a fashionable, but perhaps a rather narrow, belief that it is by gene injection (or variants of it) alone that the problem of development will be solved. One might expect a laboratory manual entitled Manilmlating the Mouse Embryo to inform about more general practical aspects of mouse em- bryology than are contained here
Myeloma Cells Selected for Resistance to CD95-Mediated Apoptosis Are Not Cross-Resistant to Cytotoxic Drugs: Evidence for Independent Mechanisms of Caspase Activation (1999)

We have previously shown that selection for resistance to the anthracenes, doxorubicin or mitoxantrone, results in coselection for resistance to CD95-mediated apoptosis (Landowski et al: Blood 89:1854, 1997). In the present study, we were interested in determining if the converse is also true; that is, does selection for CD95 resistance coselect for resistance to chemotherapeutic drugs. To address this question, we used two isogenic models of CD95-resistant versus CD95-sensitive cell lines: 8226/S myeloma cells selected for resistance to CD95-mediated apoptosis; and K562 cells expressing ectopic CD95. Repeated exposure of the CD95-sensitive human myeloma cell line, 8226/S, to agonistic anti-CD95 antibody resulted in a cell line devoid of CD95 receptor surface expression and completely resistant to CD95-mediated apoptosis. Multiple clonal populations derived from the CD95-resistant cell line showed no difference in sensitivity to doxorubicin, mitoxantrone, Ara-C, or etoposide, demonstrating that cross-resistance between Fas-mediated apoptosis and drug-induced apoptosis occurs only when cytotoxic drugs are used as the selecting agent. Using the inverse approach, we transfected the CD95-negative cell line, K562, with a CD95 expression vector. Clones expressing variable levels of cell-surface CD95 were isolated by limiting dilution, and analyzed for sensitivity to CD95-mediated apoptosis and response to chemotherapeutic drugs. We show that CD95 surface expression confers sensitivity to CD95-mediated apoptosis; however, it does not alter response to chemotherapeutic drugs. Similarly, doxorubicin-induced activation of caspases 3 and 8 was identical in the CD95-sensitive and CD95-resistant cell lines in both isogenic cell systems. In addition, prior treatment with the CD95 receptor-blocking antibody, ZB4, inhibited CD95-activated apoptosis in 8226/S cells, but had no effect on doxorubicin cytotoxicity. These results show that CD95 and chemotherapeutic drugs use common apoptotic effectors, but the point of convergence in these two pathways is downstream of CD95 receptor/ligand interaction.
Induction of collagenase secretion in human fibroblast cultures by growth promoting factors. (1985)

In human foreskin fibroblast cultures, two proteins with Mr 60,000 and 55,000 were found to be induced about 3.5-fold by epidermal growth factor (EGF), platelet-derived growth factor, and beta-transforming growth factor. The induced proteins were identified as procollagenases by immunoprecipitation of induced medium with antibodies to purified human fibroblast collagenase. Collagenase enzyme activity in the medium from EGF-treated cultures was also induced at least 3-fold compared to control cultures. Induction of collagenase was dependent upon de novo protein and RNA synthesis and was observed in the medium 10 h after addition of EGF. Although these growth-promoting factors interact with separate membrane receptors, each induced the secretion of a common protein, suggesting that collagenase may be important in some aspect of mitogenesis, cell mobilization, and migration.
Medical and Economic Long-term Effects of B-Type Natriuretic Peptide Testing in Patients with Acute Dyspnea (2007)

Rapid BNP testing in patients with acute dyspnea has no effect on long-term mortality. However, morbidity as quantified by days spent in-hospital and economic outcome are still improved at 360 days.
Transport effects in cesium thermionic converters (1963)

One of the primary reasons for the failure of thermionic converters to attain their ultimate theoretical performance is electron transport effects occurring in the interelectrode spacing. Two major types of transport effects, electron scattering and electron space charge, are discussed and theoretical results compared with experimental data. The uniform plasma theory is reviewed and experimental data show that for a monocrystal emitter this theory is consistent with the energy equation. Space charge neutralization is discussed. Both surface ionization and volume ionization are considered. Experimental results indicate that surface ionization is not as effective as would be expected by theory. This fact is responsible for the discrepancy between theoretically expected and experimentally obtained performance of converters. Under the conditions where surface ionization is inadequate for space charge neutralization, volume ionization can provide the necessary ions. Volume ionization, however, is achieved at the expense of the output power of the converter.
GATHER: a systems approach to interpreting genomic signatures (2006)

GATHER is available at http://gather.genome.duke.edu/
Highly stereoselective [3 + 2] annulations by cyclopropanation of vinyl ethers with rhodium(II)-stabilized vinylcarbenoids followed by a formally forbidden 1,3-sigmatropic rearrangement (1992)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTHighly stereoselective [3 + 2] annulations by cyclopropanation of vinyl ethers with rhodium(II)-stabilized vinylcarbenoids followed by a formally forbidden 1,3-sigmatropic rearrangementHuw M. L. Davies and Baihua HuCite this: J. Org. Chem. 1992, 57, 11, 3186–3190Publication Date (Print):May 1, 1992Publication History Published online1 May 2002Published inissue 1 May 1992https://pubs.acs.org/doi/10.1021/jo00037a041https://doi.org/10.1021/jo00037a041research-articleACS PublicationsRequest reuse permissionsArticle Views855Altmetric-Citations54LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts
Gene Silencing Mediated by siRNA-binding Fusion Proteins Is Attenuated by Double-stranded RNA-binding Domain Structure (2012)

Delivery of small interfering RNA (siRNA) targeted to specific cell types is a significant challenge for the development of RNA interference-based therapeutics. Recently, PTD-DRBD, a double-stranded RNA binding domain (DRBD) fused to the TAT protein transduction domain (PTD), was shown to be effective at delivering siRNA in a non-cell type-specific manner. Here, we evaluated the potential of DRBD as a general protein platform for targeted small interfering RNA (siRNA) delivery. We found that a single DRBD was insufficient to stably complex siRNA when fused to targeting peptides other than PTD, which facilitated nonspecific nucleic acid binding. In contrast to PTD-DRBD, fusion proteins containing two DRBDs (2× DRBD) yielded specific and stable siRNA binding. These proteins could mediate the cellular uptake of siRNA in vitro, though compared with PTD-DRBD gene silencing was attenuated by endosomal entrapment. Our findings suggest that unlike a single DRBD, 2× DRBD inhibits siRNA escape into the cytoplasm and/or induces an internalization pathway distinct from that of PTD-DRBD. Collectively, these data indicate that while 2× DRBD retains siRNA-binding activity when fused to different cell surface-interacting peptides, the utility of 2× DRBD for cell-specific RNA interference is limited without further protein engineering to enhance the bioavailability of the delivered siRNAs.Molecular Therapy - Nucleic Acids (2012) 1, e53; doi:10.1038/mtna.2012.43; published online 13 November 2012.
The NS5A Protein of Hepatitis C Virus Is a Zinc Metalloprotein (2004)

The NS5A protein of hepatitis C virus is believed to be an integral part of the viral replicase. Despite extensive investigation, the role of this protein remains elusive. Only limited biochemical characterization of NS5A has been performed, with most research to date involving the myriad of host proteins and signaling cascades that interact with NS5A. The need for better characterization of NS5A is paramount for elucidating the role of this protein in the virus life cycle. Examination of NS5A using bioinformatics tools suggested the protein consisted of three domains and contained an unconventional zinc binding motif within the N-terminal domain. We have developed a method to produce NS5A and performed limited proteolysis to confirm the domain organization model. The zinc content of purified NS5A and the N-terminal domain of NS5A was determined, and each of these proteins was found to coordinate one zinc atom per protein. The predicted zinc binding motif consists of four cysteine residues, conserved among the Hepacivirus and Pestivirus genera, fitting the formula of CX17CXCX20C. Mutation of any of the four cysteine components of this motif reduced NS5A zinc coordination and led to a lethal phenotype for HCV RNA replication, whereas mutation of other potential metal coordination residues in the N-terminal domain of NS5A, but outside the zinc binding motif, had little effect on zinc binding and, aside from one exception, were tolerated for replication. Collectively, these results indicate that NS5A is a zinc metalloprotein and that zinc coordination is likely required for NS5A function in the hepatitis C replicase.
Sequential Inactivation of rdxA (HP0954) and frxA (HP0642) Nitroreductase Genes Causes Moderate and High-Level Metronidazole Resistance in Helicobacter pylori (2000)

Helicobacter pylori is a human-pathogenic bacterial species that is subdivided geographically, with different genotypes predominating in different parts of the world. Here we test and extend an earlier conclusion that metronidazole (Mtz) resistance is due to mutation in rdxA (HP0954), which encodes a nitroreductase that converts Mtz from prodrug to bactericidal agent. We found that (i) rdxA genes PCR amplified from 50 representative Mtz(r) strains from previously unstudied populations in Asia, South Africa, Europe, and the Americas could, in each case, transform Mtz(s) H. pylori to Mtz(r); (ii) Mtz(r) mutant derivatives of a cultured Mtz(s) strain resulted from mutation in rdxA; and (iii) transformation of Mtz(s) strains with rdxA-null alleles usually resulted in moderate level Mtz resistance (16 microg/ml). However, resistance to higher Mtz levels was common among clinical isolates, a result that implicates at least one additional gene. Expression in Escherichia coli of frxA (HP0642; flavin oxidoreductase), an rdxA paralog, made this normally resistant species Mtz(s), and frxA inactivation enhanced Mtz resistance in rdxA-deficient cells but had little effect on the Mtz susceptibility of rdxA(+) cells. Strains carrying frxA-null and rdxA-null alleles could mutate to even higher resistance, a result implicating one or more additional genes in residual Mtz susceptibility and hyperresistance. We conclude that most Mtz resistance in H. pylori depends on rdxA inactivation, that mutations in frxA can enhance resistance, and that genes that confer Mtz resistance without rdxA inactivation are rare or nonexistent in H. pylori populations.
Changes of p53 protein blood level in esophageal cancer patients and normal subjects from a high incidence area in Henan,China (1998)

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BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation (2001)

During endochondral ossification, two secreted signals, Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP), have been shown to form a negative feedback loop regulating the onset of hypertrophic differentiation of chondrocytes. Bone morphogenetic proteins (BMPs), another family of secreted factors regulating bone formation, have been implicated as potential interactors of the Ihh/PTHrP feedback loop. To analyze the relationship between the two signaling pathways, we used an organ culture system for limb explants of mouse and chick embryos. We manipulated chondrocyte differentiation by supplementing these cultures either with BMP2, PTHrP and Sonic hedgehog as activators or with Noggin and cyclopamine as inhibitors of the BMP and Ihh/PTHrP signaling systems. Overexpression of Ihh in the cartilage elements of transgenic mice results in an upregulation of PTHrP expression and a delayed onset of hypertrophic differentiation. Noggin treatment of limbs from these mice did not antagonize the effects of Ihh overexpression. Conversely, the promotion of chondrocyte maturation induced by cyclopamine, which blocks Ihh signaling, could not be rescued with BMP2. Thus BMP signaling does not act as a secondary signal of Ihh to induce PTHrP expression or to delay the onset of hypertrophic differentiation. Similar results were obtained using cultures of chick limbs. We further investigated the role of BMP signaling in regulating proliferation and hypertrophic differentiation of chondrocytes and identified three functions of BMP signaling in this process. First we found that maintaining a normal proliferation rate requires BMP and Ihh signaling acting in parallel. We further identified a role for BMP signaling in modulating the expression of IHH: Finally, the application of Noggin to mouse limb explants resulted in advanced differentiation of terminally hypertrophic cells, implicating BMP signaling in delaying the process of hypertrophic differentiation itself. This role of BMP signaling is independent of the Ihh/PTHrP pathway.
Metronomic irinotecan and standard FOLFIRI regimen as first-line chemotherapy in metastatic colorectal cancer (MCRC). Final results of phase II study (2007)

14520 Background: Angiogenesis is necessary to sustain the growth of both the primary tumour and the development of metastases in colorectal cancer. Before the clinical use of bevacizumab, metronomic chemotherapy was the only mean to block the growth of tumor microvessel. CPT-11 showed, in preclinical model, to have antiangiogenetic properties using low doses and weekly administration. We carried out this study in order to evaluate the activity and toxicity of mixed metronomic and standard FOLFIRI regimen in MCRC. Methods: From 10/03 to 9/05 we treated 46 pts (24M 22F), median age 66 years (range 41–79), ECOG PS 0–2 with this schedule: CPT- 11 10 mg/mq days 1, 7, 10 and CPT-11 150 mg/mq day 2, l-Folinic Acid 100 mg/mq days 2 and 3, 5-FU 400 mg/mq bolus days 2 and 3 and 5- FU 600 mg/mq 44 hours c.i. days 2 and 3 every two weeks for a maximum of 12 cycles. Results: All pts have been evaluable activity and toxicity. We obtained 9 CR (20%), 12 PR (26%) with an ORR of 46% (CI 95%: ±13%) and 17 SD. After a median follow-up of 24 months we registered a median TTP of 10 months and a median OS of 22 months. As regard toxicity, the chemotherapy has been well tolerated; no toxic deaths occurred and no therapy ended for toxicity. 6 pts had 25% dose reduction (standard schedule) for diarrhea G4 after the first cycle. The main toxicities recorded on a total of 440 cycles (cy) delivered were: diarrhea G4 1.7% and G3 2.3% of the cy. Neutropenia G3 5.8% and vomiting G3 0.5% of the cy. Anemia G2 was recorded in 14 pts. All pts suffered from partial alopecia and half of the pts from mild oral mucositis. Conclusions: This mixed schedule seems to be active and well tolerated, ORR, TTP and OS are similar to Hurwitz results (NEJM 2004; 350: 2335–42) but with less adverse events. The combination of this schedule with bevacizumab deserves further studies. No significant financial relationships to disclose.
Regulation of volume-sensitive outwardly rectifying anion channels in pulmonary arterial smooth muscle cells by PKC (2002)

We tested the possible role of endogenous protein kinase C (PKC) in the regulation of native volume-sensitive organic osmolyte and anion channels (VSOACs) in acutely dispersed canine pulmonary artery smooth muscle cells (PASMC). Hypotonic cell swelling activated native volume-regulated Cl(-) currents (I(Cl.vol)) which could be reversed by exposure to phorbol 12,13-dibutyrate (0.1 microM) or by hypertonic cell shrinkage. Under isotonic conditions, calphostin C (0.1 microM) or Ro-31-8425 (0.1 microM), inhibitors of both conventional and novel PKC isozymes, significantly activated I(Cl.vol) and prevented further modulation by subsequent hypotonic cell swelling. Bisindolylmaleimide (0.1 microM), a selective conventional PKC inhibitor, was without effect. Dialyzing acutely dispersed and cultured PASMC with epsilon V1-2 (10 microM), a translocation inhibitory peptide derived from the V1 region of epsilon PKC, activated I(Cl.vol) under isotonic conditions and prevented further modulation by cell volume changes. Dialyzing PASMC with beta C2-2 (10 microM), a translocation inhibitory peptide derived from the C2 region of beta PKC, had no detectable effect. Immunohistochemistry in cultured canine PASMC verified that hypotonic cell swelling is accompanied by translocation of epsilon PKC from the vicinity of the membrane to cytoplasmic and perinuclear locations. These data suggest that membrane-bound epsilon PKC controls the activation state of native VSOACs in canine PASMC under isotonic and anisotonic conditions.
Pyruvate Administered After Severe Hypoglycemia Reduces Neuronal Death and Cognitive Impairment (2005)

Hypoglycemia-induced brain injury is a significant obstacle to optimal blood glucose control in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may culminate in cell death even after glucose normalization. A key event in this cascade is the activation of poly(ADP-ribose) polymerase-1 (PARP-1). Activated PARP-1 consumes cytosolic NAD, and because NAD is required for glycolysis, hypoglycemia-induced PARP-1 activation may render cells unable to use glucose even when glucose availability is restored. Pyruvate, however, can be metabolized in the absence of cytosolic NAD. Here we tested whether pyruvate could improve the outcome in rats subjected to insulin-induced hypoglycemia by terminating hypoglycemia with either glucose alone or glucose plus pyruvate. In the four brain regions studied--CA1, subiculum, dentate gyrus of the hippocampus, and piriform cortex--the addition of pyruvate reduced neuron death by 70-90%. Improved neuron survival was also observed when pyruvate delivery was delayed for up to 3 h. The improved neuron survival was accompanied by a sustained improvement in cognitive function as assessed by the Morris water maze. These results suggest that pyruvate may significantly improve the outcome after severe hypoglycemia by circumventing a sustained impairment in neuronal glucose utilization resulting from PARP-1 activation.
Biomarker Discovery in Urine by Proteomics (2002)

A hypothesis was formed that it would be possible to isolate an adequate amount of protein from a patient, having normal renal function, to identify biological markers of a particular disease state using a variety of proteomics techniques. To support this hypothesis, three samples of urine were collected from a volunteer: first when healthy, later when experiencing acute inflammation due to a pilonidal abcess, and again later still after successful recovery from the condition. The urine from these samples was processed by solid-phase extraction to concentrate and desalt the endogenous proteins and peptides. The proteins and peptides from these urine samples were analyzed in three different experiments: (1) traditional two-dimensional gel electrophoresis followed by proteolysis and mass spectrometric identification of various protein spots, (2) whole mixture proteolysis followed by one-dimensional packed capillary liquid chromatography and tandem mass spectrometry, (3) whole mixture proteolysis followed by two-dimensional capillary liquid chromatography and tandem mass spectrometry. In all three cases, a set of proteins was identified representing putative biomarkers. Each of these proteins was then found to have been previously linked in the scientific literature to inflammation. One acute phase reactant in particular, orosomucoid, was readily observed in all three experiments to dramatically increase in abundance, thereby supporting the hypothesis.
Airway Smooth Muscle as a Target for Asthma Therapy (2007)

The precise role of airway smooth muscle in the pathogenesis of asthma remains uncertain. The contraction of airway smooth muscle certainly causes acute narrowing of the airway and airflow obstruction in asthma, and smooth-muscle mass is increased in asthmatic airways. However, whether airway smooth muscle generates sufficient force in vivo to account for the excessive airway obstruction that characterizes asthma is unknown. Abnormalities in the dynamics of contraction,1 in the capacity of smooth muscle to maintain shortening in the face of load fluctuations imposed by tidal breathing,2 or in the capacity to relax3 represent other important mechanisms by which airway . . .
Gene Expression Profiling of Embryonic Stem Cells Leads to Greater Understanding of Pluripotency and Early Developmental Events1 (2004)

Embryonic stem cells are characterized by their ability to propagate indefinitely in culture, maintaining a normal karyotype and their undifferentiated state. They have the potential of differentiating into any specialized cell type in the body. An understanding of the transcriptional profile related to pluripotency and early development is necessary to better tap their developmental potential and also maintain their undifferentiated phenotype. Currently, several techniques are in use to ascertain the gene expression profile of embryonic stem cells. This review summarizes the information generated using microarray and other approaches on the gene expression analyses of stem cells in both mouse and human cell lines. We also discuss specific approaches useful in future studies aimed at further deciphering the pluripotent nature of human embryonic stem cells.