gebhart/patrepeval huggingface dataset:
Senescence Mutants of Saccharomyces cerevisiae With a Defect in Telomere Replication Identify Three Additional EST Genes (1996)

The primary determinant for telomere replication is the enzyme telomerase, responsible for elongating the G-rich strand of the telomere. The only component of this enzyme that has been identified in Saccharomyces cerevisiae is the TLC1 gene, encoding the telomerase RNA subunit. However, a yeast strain defective for the EST1 gene exhibits the same phenotypes (progressively shorter telomeres and a senescence phenotype) as a strain deleted for TLC1, suggesting that EST1 encodes either a component of telomerase or some other factor essential for telomerase function. We designed a multitiered screen that led to the isolation of 22 mutants that display the same phenotypes as est1 and tlc1 mutant strains. These mutations mapped to four complementation groups: the previously identified EST1 gene and three additional genes, called EST2, EST3 and EST4. Cloning of the EST2 gene demonstrated that it encodes a large, extremely basic novel protein with no motifs that provide clues as to function. Epistasis analysis indicated that the four EST genes function in the same pathway for telomere replication as defined by the TLC1 gene, suggesting that the EST genes encode either components of telomerase or factors that positively regulate telomerase activity.
Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension (1998)

We examined whether the serum matrix metalloproteinase-2 (MMP-2) level and MMP-2 density could be predictors of the development and extension of prostate cancer. Serum samples were collected before any clinical treatment from 98 patients with prostate cancer and from 76 patients with benign prostatic hyperplasia (BPH). Control sera were obtained from 70 healthy men. The serum level of MMP-2 was determined by 1-step enzyme immunoassay. A newly defined MMP-2 density parameter was determined by dividing the serum level of MMP-2 by the prostate volume, which was measured by ultrasonography. The mean serum level of MMP-2 in prostate cancer patients was significantly higher than in the control and BPH groups. Furthermore, the serum MMP-2 levels in prostate cancer patients with metastasis were highly elevated compared with those without metastases. The MMP-2 density in pathologically organ-confined prostate cancer was significantly higher than that in BPH. There was a statistically significant difference in the MMP-2 density between pT2N0M0 and pT1N0M0 prostate cancers. Moreover, the serum MMP-2 level correlated well with the clinical course of prostate cancer with bone metastasis. Our results suggest that MMP-2 plays an important role in the development and extension of prostate cancer and that the serum level of MMP-2 and the MMP-2 density indicate prostate cancer extension and are, therefore, useful for the followup of prostate cancer patients.
Stability of proteins. Proteins which do not present a single cooperative system. (1982)

Publisher Summary The chapter discusses the protein stability with emphasis on compact globular proteins representing a single cooperative system. All the small compact globular proteins represent cooperative systems; they exhibit an extreme cooperativity that integrates the whole of their structure into a single structural unit. The large proteins, to which fibrillar proteins are also related, do not present single cooperative systems, but are subdivided into definite cooperative subsystems—structural blocks or domains. The advances in studying the stability of complicated proteins are connected with two methodical achievements: (1) the appearance of the precise scanning microcalorimetric technique, which affords reliable information on the heat capacity function of proteins in a broad temperature range; and (2) realization of the fact that the complicated heat effect of disruption of a complex macromolecular structure can be analyzed thermodynamically. The thermodynamic specificity of collagen has been considered. The volume of globular proteins does not increase at denaturation but decreases, as seen from their ability to denature under high pressure. The results of calorimetric studies are discussed, presenting the specific melting enthalpy of various protein structures—globular proteins, double-stranded coiled coils, and triplestranded coiled coils. The practical importance of thermodynamic studies of protein stability—that is, its importance not only for understanding the principles of organization of these molecules, but just for obtaining structural information on the domain level is emphasized.
Heparin sodium versus 0.9% sodium chloride injection for maintaining patency of indwelling intermittent infusion devices. (1988)

In a double-blind study, heparin sodium was compared with 0.9% sodium chloride injection for use in maintaining patency of indwelling devices for intermittent intravenous infusion. Adult patients who required intermittent intravenous devices were randomly assigned to receive 1 mL of a heparin sodium 100 units/mL flush solution or a 0.9% sodium chloride flush solution. Observations were recorded for each catheter, rather than for each patient. Patients were evaluated daily for the development of phlebitis. In the 160 patients for whom complete data on catheter patency were available, there were 307 observations (170 for the heparin group and 137 for the sodium chloride group). No significant difference in the duration of catheter patency or incidence of phlebitis was observed between the groups. A difference in the incidence of phlebitis could not be excluded with confidence, but inasmuch as there was no effect on duration of catheter patency, the clinical importance of this superficial venous phlebitis is questionable. The duration of patency was significantly greater in men than in women. The use of penicillins, cephalosporins, or clindamycin, alone or in combination, was significantly associated with the development of phlebitis for both treatment groups. No other factors were found to correlate with either the duration of catheter patency or incidence of phlebitis. The results of this study indicate that heparin offers no advantage over 0.9% sodium chloride injection in maintaining the patency of intermittent intravenous devices.
Endogenous electric current is associated with normal development of the vertebrate limb (2001)

A steady ionic current is driven out of both developing and regenerating amphibian limbs. In the developing limbs of anurans and urodeles, focal outwardly directed current (0.5-2 microA/cm(2)) predicts the location of mesenchyme accumulations producing the early bud. Here, we report measurements of a similar outwardly directed ionic current associated with the development of the limb bud in the mouse and chick embryo by using a noninvasive, self-referencing electrode for the measurement of extracellular current. In both the mouse and chick embryo, flank currents were usually inwardly directed - the direction of Na(+) uptake by ectoderm. Outward currents associated with the mouse limb bud ranged from 0.04-10.8 microA/cm(2). Mouse limb bud and flank currents were similar to those measured in amphibian larvae, because they were reversibly collapsed and/or reversed by application of 30 microM amiloride, a Na(+) channel blocker. Unlike the amphibian embryos, flank ectoderm adjacent to the mouse limb bud in the anterior/posterior axis was usually associated with outwardly directed ionic current. This raises the possibility of a different, or changing, gradient of extracellular voltage experienced by mesenchyme cells in this plane of development than that observed in other regions of the limb bud. In the chick flank caudal to the somites, a striking reversal of the inwardly directed flank currents to very large ( approximately 100 microA/cm(2)) outwardly directed currents occurred three developmental stages before limb bud formation. We tested the relevance of this outwardly directed ionic current to limb formation in the chick embryo by reversing it by using an artificially applied "countercurrent" pulled through a microelectrode inserted just beneath the caudal ectoderm of the embryo. This application was performed for approximately 6 hr 2.5-3 developmental stages before hindlimb bud formation. This method resulted in abnormal limb formation by the tenth day of gestation in some embryos, whereas all control embryos developed normally. These data suggest an early physiological control of limb development.
Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus (2005)

The immune defect that could account for the multisystemic involvement that characterizes systemic lupus erythematosus (SLE) remains unknown. We hypothesized that iterative disease flares correspond to a recurrent defect in the peripheral immune suppression exerted by naturally occurring T regulatory cells (Tregs). Surprisingly, Tregs isolated from lupus patients show the same phenotypic and functional characteristics as corresponding cells found in healthy controls. A decrease in the proportion of circulating Tregs among other CD4+ T cells is nevertheless evidenced in active patients when this group is compared with healthy controls (0.57 +/- 0.24%, n = 45 vs 1.29 +/- 0.38%, n = 82, p < 0.0001) or with inactive patients (1.22 +/- 0.67%, n = 62, p < 0.0001). In contrast, the proportion of Tregs in other systemic autoimmune diseases such as primary Sjögren syndrome and inflammatory myopathy does not significantly differ from controls' values (1.15 +/- 0.46%, n = 21, p = 0.09 and 1.16 +/- 0.44%, n = 16, p = 0.43, respectively). Lupus Tregs do not accumulate in either the lymph nodes or the diseased kidneys and are not killed by a circulating soluble factor, but demonstrate in vitro a heightened sensitivity to Fas-induced apoptosis. Finally, we show that the extent of Treg depletion correlates with the clinical severity of the flare. SLE flares are therefore associated with a global Treg depletion and not with a phenomenon of tissue redistribution. In summary, we suggest that the physiopathology of SLE could be tied to a defect in the homeostatic control of the Treg subpopulation.
Mesoporous Silica Nanoparticles for Intracellular Delivery of Membrane-Impermeable Proteins (2007)

An MCM-41-type mesoporous silica nanoparticle (MSN) material with a large average pore diameter (5.4 nm) is synthesized and characterized. The in vitro uptake and release profiles of cytochrome c by the MSN were investigated. The enzymatic activity of the released protein was quantitatively analyzed and compared with that of the native cytochrome c in physiological buffer solutions. We found that the enzymes released from the MSNs are still functional and highly active in catalyzing the oxidation of 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonate) (ABTS) by hydrogen peroxide. In contrast to the fact that cytochrome c is a cell-membrane-impermeable protein, we discovered that the cytochrome c-encapsulated MSNs could be internalized by live human cervical cancer cells (HeLa) and the protein could be released into the cytoplasm. We envision that these MSNs with large pores could serve as a transmembrane delivery vehicle for controlled release of membrane-impermeable proteins in live cells, which may lead to many important biotechnological applications including therapeutics and metabolic manipulation of cells.
Three dimensional EUV simulations: a new mask near field and imaging simulation system (2005)

The integrated European research project "More Moore" is designed to push the limits of lithography to enable and exceed the requirements for the 22 nm node. Within the project the lithography group of Fraunhofer IISB is responsible for the development and evaluation of different simulation approaches for a predictive modeling of EUV (extreme ultraviolet) imaging technology for sub 22 nm features. During the first project year two new three dimensional EUV mask simulation models and a new EUV imaging model were developed. For the three dimensional mask near field simulation the modal method by Fourier expansion, developed by the project partner from Centre National de la Recherche Scientifique (CNRS) France, and the waveguide method (WG), developed by Fraunhofer IISB, are available. Both methods are rigorous electromagnetic field solver operating in the frequency domain. A good agreement with the established finite-difference time-domain (FDTD) method and a significantly higher performance compared to FDTD in case of periodic mask structures with rectangular elements can be observed. Additionally the WG method is able to simulate rigorously EUV masks with defective multilayers and with a full consideration of the defect geometry. The imaging model is characterized by a Jones pupil based representation of the imaging system and by a completely vectorial description of the light propagation, taking into account important polarization dependent effects like source polarization effects, mask topography polarization effects and effects resulting from light propagation in multilayer systems. This paper will present the new three dimensional WG method for the EUV mask near field simulation in combination with the vectorial imaging system and in comparison to our FDTD reference method. Typical 2D and 3D mask structures and new EUV mask concepts like phase shift masks with etched multilayers in combination with defect free and defective multilayers stacks are simulated exemplarily. Additionally aerial images and image CDs resulting from the two different simulation approaches (WG and FDTD) are compared as well as the mask near fields, the computation time, and the convergence.
Evaluation of Ketone-Oxime Method for Developing Therapeutic On-Demand Cleavable Immunoconjugates (2008)

The use of antibody molecules in immunoassay, molecular targeting, or detection techniques encompasses a broad variety of applications affecting nearly every field of medical science. In cancer therapy, monoclonal antibodies (mAb) have been used as vehicles to deliver radionuclides, toxins, or drugs to the target cancer cells. New conjugation methods are most needed to conjugate a wide variety of targeting small molecules and peptidomimatic compounds. Here, we exploited a keto-oxime method for conjugation of protease susceptible linkers to an antibody. This modified method involves two steps: (i) introduction of methyl ketone linkers (referred to as linker moiety) to the primary amines present in the antibody and (ii) conjugation of ketone linkers to aminoxy functional group present in the conjugated moiety (referred to as functional moiety). We have optimized this conjugation method and shown that approximately 10 functional moieties can be conjugated to antibody. Conjugation was verified by MALDI-TOF MS and Western blot analysis. The acidic pH conditions used in this method did not change the immune reactivity of the Ab. In addition, in vitro protease susceptibility assay was performed to validate this method for prodrug release assay as well as to remove excess radioimmune conjugates from circulation. This orthogonal method is compatible with peptides containing a thiol, amino, or carboxyl groups in the conjugation moiety.
Preparation and properties of an alpha‐1‐protease inhibitor concentrate with high specific activity (2001)

The high specific activity of the A1PI preparation achieved with this process should allow a reduction of the A1PI total protein load necessary to achieve clinically relevant effects.
Case 19-1991 (1991)

Case Records of the Massachusetts General Hospital from The New England Journal of Medicine — Case 19-1991 — An 80-Year-Old Woman with Increasing Dyspnea and Extensive Pulmonary Opacities While Receiving a Decreasing Prednisone Dose for Polymyalgia Rheumatica
Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts (2011)

The balance between the pro-apoptotic lipids ceramide and sphingosine and the pro-survival lipid sphingosine 1-phosphate (S1P) is termed the "sphingosine rheostat". Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor, ABC294640, alone or in combination with the multikinase inhibitor sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here we evaluated the combined antitumor effects of the aforementioned drug combination in two mouse models of hepatocellular carcinoma. Although combining the SK2 inhibitor, ABC294640, and sorafenib in vitro only afforded additive drug-drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells, indicating that the antitumor effect of this drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was not affected by co-administration of sorafenib. Taken together, these data support combining ABC294640 and sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of ABC294640 activity.
Relative degree of polymerization of sorghum tannin during seed development and maturation (1982)

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRelative degree of polymerization of sorghum tannin during seed development and maturationLarry G. ButlerCite this: J. Agric. Food Chem. 1982, 30, 6, 1090–1094Publication Date (Print):November 1, 1982Publication History Published online1 May 2002Published inissue 1 November 1982https://pubs.acs.org/doi/10.1021/jf00114a021https://doi.org/10.1021/jf00114a021research-articleACS PublicationsRequest reuse permissionsArticle Views381Altmetric-Citations69LEARN 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-Alertsclose Get e-Alerts
HUMIRA®Pen: a novel autoinjection device for subcutaneous injection of the fully human monoclonal antibody adalimumab (2007)

The HUMIRA (adalimumab) Pen is a novel, integrated, disposable autoinjection delivery system for the subcutaneous injection of adalimumab. Adalimumab is a biological disease modifier for the treatment of rheumatoid arthritis and other chronic debilitating diseases mediated by tumor necrosis factor. Sustaining long-term efficacy with a biological therapy is influenced by patient adherence to the therapeutic regimen, which is often affected by the route of drug administration. Self-administered injectables offer several advantages over intravenous injections (i.e., portability, convenience and flexible scheduling). In particular, patients with chronic, debilitating diseases may need a self-administered medication available in an easy-to-use and convenient delivery device that minimizes pain and facilitates adherence to therapy. The adalimumab Pen offers these benefits and recent evidence indicates that patients overwhelmingly prefer the adalimumab Pen to the prefilled syringe.
[Familial amytrophic lateral sclerosis. A study of a family suffering from this disease for three generations]. (1976)

The authors describe nine cases of amytrophic lateral sclerosis running through the same family for three successive generations. The transmission is autosomal dominant with complete penetrance. The clinical picture comprises specific characteristics, amongst which the age of onset and the absence of Achilles reflexes. The course of the disease is fatal before long.
Efficient Endocytosis of the Cystic Fibrosis Transmembrane Conductance Regulator Requires a Tyrosine-based Signal (1999)

We previously demonstrated that the cystic fibrosis transmembrane conductance regulator (CFTR) is rapidly endocytosed in epithelial cells (Prince, L. S., Workman, R. B., Jr., and Marchase, R. B. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 5192-5196). To determine the structural features of CFTR required for endocytosis, we prepared chimeric molecules consisting of the amino-terminal (residues 2-78) and carboxyl-terminal tail regions (residues 1391-1476) of CFTR, each fused to the transmembrane and extracellular domains of the transferrin receptor. Functional analysis of the CFTR-(2-78) and CFTR-(1391-1476) indicated that both chimeras were rapidly internalized. Deletion of residues 1440-1476 had no effect on chimera internalization. Mutations of potential internalization signals in both cytoplasmic domains reveal that only one mutation inhibits internalization, Y1424A. Using a surface biotinylation reaction, we also examined internalization rates of wild type and mutant CFTRs expressed in COS-7 cells. We found that both wild type and A1440X CFTR were rapidly internalized, whereas the Y1424A CFTR mutant, like the chimeric protein, had approximately 40% reduced internalization activity. Deletions in the amino-terminal tail region of CFTR resulted in defective trafficking of CFTR out of the endoplasmic reticulum to the cell surface, suggesting that an intact amino terminus is critical for biosynthesis. In summary, our results suggest that both tail regions of CFTR are sufficient to promote rapid internalization of a reporter molecule and that tyrosine 1424 is required for efficient CFTR endocytosis.
FRET analysis reveals distinct conformations of IN tetramers in the presence of viral DNA or LEDGF/p75 (2011)

A tetramer of HIV-1 integrase (IN) stably associates with the viral DNA ends to form a fully functional concerted integration intermediate. LEDGF/p75, a key cellular binding partner of the lentiviral enzyme, also stabilizes a tetrameric form of IN. However, functional assays have indicated the importance of the order of viral DNA and LEDGF/p75 addition to IN for productive concerted integration. Here, we employed Förster Resonance Energy Transfer (FRET) to monitor assembly of individual IN subunits into tetramers in the presence of viral DNA and LEDGF/p75. The IN-viral DNA and IN-LEDGF/p75 complexes yielded significantly different FRET values suggesting two distinct IN conformations in these complexes. Furthermore, the order of addition experiments indicated that FRET for the preformed IN-viral DNA complex remained unchanged upon its subsequent binding to LEDGF/p75, whereas pre-incubation of LEDGF/p75 and IN followed by addition of viral DNA yielded FRET very similar to the IN-LEDGF/p75 complex. These findings provide new insights into the structural organization of IN subunits in functional concerted integration intermediates and suggest that differential multimerization of IN in the presence of various ligands could be exploited as a plausible therapeutic target for development of allosteric inhibitors.