gebhart/patrepeval huggingface dataset:
N-terminal Deletion Mutants of Insulin-like Growth Factor-II (IGF-II) Show Thr7 and Leu8 Important for Binding to Insulin and IGF-I Receptors and Leu8 Critical for All IGF-II Functions (1995)

To define the role of the N-terminal region of insulin-like growth factor-II (IGF-II) in its binding to insulin and IGF receptors, deletion mutants des-(1-5)-, des-(1-7)-, and des-(1-8)-recombinant (r) IGF-II, and the Gly8 for Leu substitution mutant of rIGF-II were prepared by site-directed mutagenesis, expressed in Escherichia coli, and purified. The binding affinity and mitogenic activity of these rIGF-II mutants as well as commercially available des-(1-6)-rIGF-II were analyzed. While the relative affinity of des-(1-5)- and des-(1-6)-rIGF-II for purified human insulin and IGF-I receptors remained at > or = 50% levels of that of rIGF-II, the affinity of des-(1-7)-rIGF-II decreased to approximately 10% and approximately 3%, respectively, of that of rIGF-II. When the octapeptide including Leu8 was removed prior to the Cys9-Cys47 intrachain bond, the relative affinity of this deletion mutant, des-(1-8)-rIGF-II, for these receptors dramatically decreased to < 1% of that of rIGF-II. Substituting Gly8 for Leu in rIGF-II decreased the affinity of this mutant for the IGF-I and insulin receptors to about the same extent. These results suggest that the side chains of Thr7 and Leu8 may play an important role in retaining all of the IGF-II functions. Decreases in the relative affinity for binding of the mutants to these receptors paralleled the decreases in their mitogenic potency for cultured Balb/c 3T3 cells. Although the relative affinity of des-(1-8)- or [Gly8]rIGF-II for rat IGF-II/CIM6-P (cation-independent mannose 6-phosphate) receptors was also < 1% of that of rIGF-II, the relative affinities of des-(1-5)-, des-(1-6)-, and des-(1-7)-rIGF-II for these receptors was significantly greater than that of rIGF-II. These results clearly demonstrate that Thr7 and Leu8 are important for binding to insulin and IGF-I receptors and Leu8 is critical for expression of all IGF-II functions.
A ten-year study of 5-flurouracil in disseminated breast cancer with clinical results and survival times.. (1969)

The clinical results of 676 patients with widely disseminated breast cancer treated with 5-fluorouracil (5-FU) alone or with any additional therapy over the past ten years are presented. One observes a significantly increased survival in the 23.1 percent that improved and the 23.1 percent that were unchanged compared to the 53.8 percent that had progression on 5-FU therapy. To eliminate the beneficial influence on survival as a result of any other treatment, all patients who improved or were unchanged by other therapy were deleted, leaving a “corrected” group which showed a pattern almost identical to the overall total group, correlating increased survival with 5-FU responsiveness.
Crystallization of polymer melts under fast cooling. II. High‐purity iPP (1992)

Abstract Samples of a high‐purity isotactic polypropylene (iPP) were quenched from the melt so as to monitor cooling history. A continuous variation of morphology and crystal structure was obtained with cooling rate. This is discussed in relation to sample thermal history evidencing that cooling history relevant to quenched samples is in the neighborhood of 90°C. In particular the samples are essentially mesomorphic when at this temperature cooling rates larger than 80°C/s were adopted, while below a few tens of °C/s only α‐monocline form is obtained. Densities of quenched samples were compared with predictions of an isokinetic extrapolation of Avrami model of polymer crystallization kinetics.
Magic Lenses for augmented virtual environments (2006)

The authors developed a Magic Lens framework for Scape, an augmented virtual environment (AVE). They generalize the functional characteristics of Magic Lenses in terms of 3D visualization in AVEs and present two tangible Magic Lens-enabled devices with complementary interface capabilities. The authors also demonstrate their Magic Lens devices through testbed applications relevant to urban planning and medical training. This article explores an interface technique that manages viewing complexity and offers a set of versatile visualization capabilities in 3D augmented virtual environments (AVE)
Through a glass darkly: can we improve clarity about mechanism and aims of medications in drug and alcohol treatments? (2012)

The treatment of addiction and dependence on, and misuse of, alcohol and other drugs is one of the largest unmet needs in medicine today, so the development of new treatments is a pressing need. However, we have seen the development and use of different terminologies for different drug addictions, which confuses prescribers, users and regulators alike. Here we try to clarify terminology of treatment models based on the pharmacology of treatment agents. This editorial covers all drugs that are used for their pleasurable effects and which therefore can lead to harmful/hazardous use, dependence and addiction. These include nicotine, alcohol and abused prescription drugs such as benzodiazepines, as well as opioids and stimulants.
Ebola Virus Inactivation with Preservation of Antigenic and Structural Integrity by a Photoinducible Alkylating Agent (2007)

Current methods for inactivating filoviruses are limited to high doses of irradiation or formalin treatment, which may cause structural perturbations that are reflected by poor immunogenicity. In this report, we describe a novel inactivation technique for Zaire Ebola virus (ZEBOV) that uses the photoinduced alkylating probe 1,5-iodonaphthylazide (INA). INA is incorporated into lipid bilayers and, when activated by ultraviolet irradiation, alkylates the proteins therein. INA treatment of ZEBOV resulted in the complete loss of infectivity in cells. Results of electron microscopy and virus-capture assays suggested the preservation of conformational surface epitopes. Challenge with 50,000 pfu of INA-inactivated, mouse-adapted ZEBOV did not cause disease or death in mice. A single vaccination with INA-inactivated ZEBOV (equivalent to 5 x 10(4) pfu) protected mice against lethal challenge with 1000 pfu of ZEBOV. INA-inactivated virus induced a protective response in 100% of mice when administered 3 days before challenge. Thus, INA may have significant potential for the development of vaccines and immunotherapeutics for filoviruses and other enveloped viruses.
RECIPROCITY IN THE INTERACTIONS BETWEEN THE POXVIRUSES AND THEIR HOST CELLS (1990)

Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute respiratory syndrome coronavirus (SARS-CoV) and ...Read More
An everted repeat mediates retinoic acid induction of the gamma F-crystallin gene: evidence of a direct role for retinoids in lens development. (1993)

The vertebrate lens is a classical system for examining mechanisms of tissue determination and differentiation, yet little is known about the signaling molecules controlling its development. Here, we report that retinoic acid (RA), a substance known for its teratogenic effects on the eye and as a natural endogenous morphogenetic agent, acts as a regulator of gene expression in the lens. We have identified a novel type of RA response element (RARE) within the lens-specific mouse gamma F-crystallin promoter, consisting of two (A/G)GGTCA motifs in an everted arrangement spaced by 8 nucleotides. This element (gamma F-RARE) mediates activation of the gamma F-crystallin promoter by ligand-activated endogenous lens cell RA receptors (RARs) and confers RA responsiveness when linked to a heterologous promoter. gamma F-RARE is bound in vitro by RAR/RXR heterodimers, and both receptors cooperate in vivo to trans-activate this element. These observations demonstrate a direct effect of RA on lens-specific gene expression and reveal a novel role for retinoids in the development and homeostasis of the mammalian eye.
Mammalian Abasic Site Base Excision Repair (1998)

Base excision repair (BER) is one of the cellular defense mechanisms repairing damage to nucleoside 5'-monophosphate residues in genomic DNA. This repair pathway is initiated by spontaneous or enzymatic N-glycosidic bond cleavage creating an abasic or apurinic-apyrimidinic (AP) site in double-stranded DNA. Class II AP endonuclease, deoxyribonucleotide phosphate (dRP) lyase, DNA synthesis, and DNA ligase activities complete repair of the AP site. In mammalian cell nuclear extract, BER can be mediated by a macromolecular complex containing DNA polymerase beta (beta-pol) and DNA ligase I. These two enzymes are capable of contributing the latter three of the four BER enzymatic activities. In the present study, we found that AP site BER can be reconstituted in vitro using the following purified human proteins: AP endonuclease, beta-pol, and DNA ligase I. Examination of the individual enzymatic steps in BER allowed us to identify an ordered reaction pathway: subsequent to 5' "nicking" of the AP site-containing DNA strand by AP endonuclease, beta-pol performs DNA synthesis prior to removal of the 5'-dRP moiety in the gap. Removal of the dRP flap is strictly required for DNA ligase I to seal the resulting nick. Additionally, the catalytic rate of the reconstituted BER system and the individual enzymatic activities was measured. The reconstituted BER system performs repair of AP site DNA at a rate that is slower than the respective rates of AP endonuclease, DNA synthesis, and ligation, suggesting that these steps are not rate-determining in the overall reconstituted BER system. Instead, the rate-limiting step in the reconstituted system was found to be removal of dRP (i.e. dRP lyase), catalyzed by the amino-terminal domain of beta-pol. This work is the first to measure the rate of BER in an in vitro reaction. The potential significance of the dRP-containing intermediate in the regulation of BER is discussed.
Organogels and Low Molecular Mass Organic Gelators (2000)

Nanostructured materials have many forms. One that has been somewhat neglected until recently is organogels, especially those whose three-dimensional structural networks are based on the self-assembly of low molecular-mass organic gelators (LMOGs). These thermoreversible materials consist of a small amount of LMOG and an organic liquid. Because of the wide diversity of structures of molecules known to function as LMOGs and the dearth of direct information concerning how they pack in their gel assemblies, it has been difficult to decipher the salient features that constitute an LMOG. The stepwise simplification of LMOG structures and the development of methods to determine their packing in organogels at the micrometer-to-angstrom distance regimes are discussed for the simplest known LMOGs to the more complex, such as CEP (see Figure), which is known to form molecular wires when gelling chloroform. Work from the laboratory of the authors is emphasized. In addition, an overview of current and potential applications for these materials is presented.
Investigating the Thin-Film Versus Bulk Material Properties of Structural Adhesives (2011)

A combined experimental and computational investigation was performed to determine whether the material properties of structural adhesives differ between their thin-film “in-situ” and bulk forms. Shear testing focused on the use of the V-notched Iosipescu shear specimen whereas tensile testing focused on adhesively bonded butt-joint specimens as well as bulk adhesive bar specimens. The apparent shear strength was found to be independent of bondline thickness. Further, shear strengths obtained from bulk adhesive testing were comparable with those from in-situ testing. Results from butt-tensile testing and analysis suggest that the apparent variation in tensile strength as a function of bondline thickness is a result of variations in the adhesive stress state, rather than the actual tensile strength of the adhesive. These results suggest that the adhesive properties obtained from bulk adhesive specimens are valid for use in structural analysis of in-situ thin-film adhesives.
Toll-Like Receptor Agonists: Current Status and Future Perspective on their Utility as Adjuvants in Improving Antic Ancer Vaccination Strategies (2013)

Toll-like receptor (TLR) agonists possess remarkable properties, particularly with regard to dendritic cell activation, promoting Th1-type cytokine production and optimizing cytotoxic T-cell responses. Preclinical and clinical studies conducted to date show that TLR agonists can improve currently applied anticancer vaccination protocols. Although these have resulted in the US FDA approval of three TLR agonists for use in humans, their abundant application encounters limitations, principally due to dose-limiting toxicity evoking from systemic cytokine production. Here, using selected examples of clinical studies, we provide a concise review regarding the knowledge acquired thus far on the adjuvant use of TLR agonists as cancer vaccine components. We also provide evidence on the exploitation of a novel TLR agonist, prothymosin-α, which enhances the efficacy of tumor-reactive effectors without causing severe adverse effects.
Green fluorescent protein expression in germ‐line transmitted transgenic zebrafish under a stratified epithelial promoter from Keratin8 (2001)

A zebrafish cDNA encoding a novel keratin protein was characterized and named keratin8, or krt8. krt8 expression was initiated at 4.5 hr postfertilization, immediately after the time of zygotic genome activation. The expression is limited to a single layer of envelope cells on the surface of embryos and, in later stages, it also appears in the innermost epithelial layer of the anterior- and posteriormost portions of the digestive tract. In adult, its expression was limited to the surface layer of stratified epithelial tissues, including skin epidermis and epithelia of mouth, pharynx, esophagus, and rectum but not in the gastral and intestinal epithelia. By using a 2.2-kb promoter from krt8, several stable green fluorescent protein (gfp) transgenic zebrafish lines were established. All of these transgenic lines displayed GFP expression in tissues mentioned above except for the rectum; therefore, the pattern of transgenic GFP expression is essentially identical to that of the endogenous krt8 mRNAs. krt8-GFP fusion protein was also expressed in zebrafish embryos under a ubiquitous promoter, and the fusion protein was capable of assembling into intermediate filaments only in the epithelia that normally expressed krt8 mRNAs, indicating the specificity of keratin assembly in vivo.
The AES-XCBC-MAC-96 Algorithm and Its Use With IPsec (2003)

A Message Authentication Code (MAC) is a key-dependent one way hash function. One popular way to construct a MAC algorithm is to use a block cipher in conjunction with the Cipher-Block-Chaining (CBC) mode of operation. The classic CBC-MAC algorithm, while secure for messages of a pre-selected fixed length, has been shown to be insecure across messages of varying lengths such as the type found in typical IP datagrams. This memo specifies the use of AES in CBC mode with a set of extensions to overcome this limitation. This new algorithm is named AES-XCBC-MAC-96.
A protein molecular weight map of ES2 clear cell ovarian carcinoma cells using a two-dimensional liquid separations/mass mapping technique (2002)

A molecular weight map of the protein content of ES2 human clear cell ovarian carcinoma cells has been produced using a two-dimensional (2-D) liquid separations/mass mapping technique. This method uses a 2-D liquid separation of proteins from whole cell lysates coupled on-line to an electrospray ionization-time of flight (ESI-TOF) mass spectrometer to map the accurate intact molecular weight (M(r)) of the protein content of the cells. The two separation dimensions involve the use of liquid isoelectric focusing as the first phase and nonporous silica reversed-phase high-performance liquid chromatography (HPLC) as the second phase of separation. The detection by ESI-TOF-MS provides an image of pI versus M(r) analogous to 2-D gel electrophoresis. Each protein is then identified based upon matrix-assisted laser desorption/ionization (MALDI)-TOF-MS peptide mapping and intact M(r) so that a standard map is produced against which other ovarian carcinoma cell lines can be compared. The accurate intact M(r) together with the pI fraction, and peptide map serve to tag the protein for future interlysate comparisons. An internal standard is also used to provide a means for quantitation for future interlysate studies. In the ES2 cell line under study it is shown that nearly 900 M(r) bands are detected over 17 pI fractions from pH 4 to 12 and a M(r) range up to 85 kDa and that around 290 of these bands can be identified using mass spectrometric based techniques. The protein M(r) is detected within an accuracy of 150 ppm and it is shown that many of the proteins in this human cancer sample are modified compared to the database. The protein M(r) map may serve as a highly reproducible standard Web-based method for comparing proteins from related human cell lines.
Site-Specific Conjugation of Monomethyl Auristatin E to Anti-CD30 Antibodies Improves Their Pharmacokinetics and Therapeutic Index in Rodent Models (2015)

Antibody-drug conjugates (ADCs) have demonstrated clinical benefits that have led to the recent FDA approval of KADCYLA and ADCETRIS. Most ADCs that are currently in clinical use or development, including ADCETRIS, are produced by chemical conjugation of a toxin via either lysine or cysteine residues, inevitably leading to heterogeneous products with variable drug-to-antibody ratios (DARs). Here, we describe the in vitro and in vivo characterization of four novel ADCs that are based on the anti-CD30 antibody cAC10, which has the same polypeptide backbone as ADCETRIS, and compare the results with the latter. Bacterial transglutaminase (BTG) was exploited to site-specifically conjugate derivatives of monomethyl auristatin E (all comprising a cleavable linker) to the glutamine at positions 295 and 297 of cAC10, thereby yielding homogeneous ADCs with a DAR of 4. In vitro cell toxicity experiments using two different CD30-positive cell lines (Karpas 299 and Raji-CD30(+)) revealed comparable EC50 values for ADCETRIS (1.8 ± 0.4 and 3.6 ± 0.6 ng/mL, respectively) and the four cAC10-based ADCs (2.0 ± 0.4 to 4.9 ± 1.0 ng/mL). Quantitative time-dependent in vivo biodistribution studies (3-96 h p.i.) in normal and xenografted (Karpas 299 cells) SCID mice were performed with a selected (125)I-radioiodinated cAC10 ADC and compared with that of (125)I-ADCETRIS. The chemo-enzymatically conjugated, radioiodinated ADC showed higher tumor uptake (17.84 ± 2.2% ID/g 24 h p.i.) than (125)I-ADCETRIS (10.5 ± 1.8% ID/g 24 h p.i.). Moreover, (125)I-ADCETRIS exhibited higher nontargeted liver and spleen uptake. In line with these results, the maximum tolerated dose of the BTG-coupled ADC (>60 mg/kg) was significantly higher than that of ADCETRIS (18 mg/kg) in rats. These results suggest that homogeneous ADCs display improved pharmacokinetics and better therapeutic indexes compared to those of chemically modified ADCs with variable DARs.
Sequencing of Breast Cancer Genomes. (2009)

Abstract All cancer genomes carry somatic mutations. The recent advent of second generation sequencing technologies has brought closer the prospect of sequencing large numbers of cancer genomes. Early studies in breast cancer have investigated the prevalence and nature of rearrangements. These studies have shown that there are many more rearrangements in breast cancer than have previously been appreciated, some of which have distinctive patterns suggesting underlying DNA repair defects. These studies are now leading into the sequencing of complete breast cancer genomes which aim to generate comprehensive catalogues of somatic mutations. These will include point mutations, rearrangements and copy number changes and most of the driver and passenger mutations operative in individual cancers. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr ES3-2.
Natural killer T cell‐mediated antitumor immune responses and their clinical applications (2006)

A unique lymphocyte population, CD1d-restricted NKT cells, has been revealed to be a key player in both the innate and acquired immune responses, including antitumor effects. Recent studies revealed that at least two subsets of CD1d-restricted NKT cells exist: type I, having invariant Valpha14 receptor; and type II, having heterogeneous non-Valpha14 receptor. The specific glycolipid ligand, alpha-GalCer, effectively stimulates mouse and human type I NKT cells. The activation of type I NKT cells substantially influences function of other various cell types, particularly DC, NK cells, CD4 Th1 cells, and CD8 cytotoxic T cells, all contributing to the antitumor immune responses. Recent studies also indicated that, unlike type I NKT cells, type II NKT cells have a potential to repress antitumor immune responses. In this review, we summarize the characteristics of the antitumor immune responses mediated by both mouse and human CD1d-restricted NKT cells and discuss their potential in clinical applications against cancer.
The persistence of papovavirus BK DNA sequences in normal human renal tissue (1981)

Evidence has accumulated indicating that BK virus, following an inapparent primary infection, persists in the renal organs of normal healthy individuals and reactivates upon immunosuppression. Data to support this hypothesis are presented and suggest that BK virus DNA sequences are present at very low levels in the kidneys of more than 50% of the population and that this persistence is localized in several foci within these organs.
Metabolic engineering of Escherichia coli for the production of fumaric acid (2013)

Fumaric acid is a naturally occurring organic acid that is an intermediate of the tricarboxylic acid cycle. Fungal species belonging to Rhizopus have traditionally been employed for the production of fumaric acid. In this study, Escherichia coli was metabolically engineered for the production of fumaric acid under aerobic condition. For the aerobic production of fumaric acid, the iclR gene was deleted to redirect the carbon flux through the glyoxylate shunt. In addition, the fumA, fumB, and fumC genes were also deleted to enhance fumaric acid formation. The resulting strain was able to produce 1.45 g/L of fumaric acid from 15 g/L of glucose in flask culture. Based on in silico flux response analysis, this base strain was further engineered by plasmid-based overexpression of the native ppc gene, encoding phosphoenolpyruvate carboxylase (PPC), from the strong tac promoter, which resulted in the production of 4.09 g/L of fumaric acid. Additionally, the arcA and ptsG genes were deleted to reinforce the oxidative TCA cycle flux, and the aspA gene was deleted to block the conversion of fumaric acid into L-aspartic acid. Since it is desirable to avoid the use of inducer, the lacI gene was also deleted. To increase glucose uptake rate and fumaric acid productivity, the native promoter of the galP gene was replaced with the strong trc promoter. Fed-batch culture of the final strain CWF812 allowed production of 28.2 g/L fumaric acid in 63 h with the overall yield and productivity of 0.389 g fumaric acid/g glucose and 0.448 g/L/h, respectively. This study demonstrates the possibility for the efficient production of fumaric acid by metabolically engineered E. coli.