gebhart/patrepeval huggingface dataset:
New Cycloartanol Sulfates from the Alga Tydemania expeditionis: Inhibitors of the Protein Tyrosine Kinase pp60v-src (1994)

Bioactivity-directed fractionation of the extracts of the green alga Tydemania expeditionis using the protein tyrosine kinase pp60v-src led to the isolation of three new cycloartanol disulfates, 1-3, which show modest inhibition of this enzyme. The structures were deduced by spectroscopic methods.
Linkage disequilibrium in the region of the autosomal dominant polycystic kidney disease gene (PKD1). (1994)

The gene for autosomal dominant polycystic kidney disease (PKD1) is located on chromosome 16p, between the flanking markers D16S84 and D16S125 (26.6prox). This region is 750 kb long and has been cloned. We have looked at the association of 10 polymorphic markers from the region, with the disease and with each other. This was done in a set of Scottish families that had previously shown association with D16S94, a marker proximal to the PKD1 region. We report significant association between two CA repeat markers and the disease but have not found evidence for a single founder haplotype in these families, indicating the presence of several mutations in this population. Our results favor a location of the PKD1 gene in the proximal part of the candidate region.
A new look at the essence of the imaging photoplethysmography (2015)

Photoplethysmography (PPG) is a noninvasive optical method accepted in the clinical use for measurements of arterial oxygen saturation. It is widely believed that the light intensity after interaction with the biological tissue in vivo is modulated at the heartbeat frequency mainly due to pulsatile variations of the light absorption caused by arterial blood-volume pulsations. Here we report experimental observations, which are not consistent with this model and demonstrate the importance of elastic deformations of the capillary bed in the formation of the PPG waveform. These results provide new insight on light interaction with live tissue. To explain the observations we propose a new model of PPG in which pulse oscillations of the arterial transmural pressure deform the connective-tissue components of the dermis resulting in periodical changes of both the light scattering and absorption. These local changes of the light-interaction parameters are detected as variations of the light intensity returned to a photosensitive camera. Therefore, arterial pulsations can be indirectly monitored even by using the light, which slightly penetrates into the biological tissue.
Activation of the autocrine transforming growth factor alpha pathway in human squamous carcinoma cells. (1991)

Transforming growth factor alpha is an autocrine mitogen for nonneoplastic keratinocytes, which exerts its function by binding to the receptor for epidermal growth factor. In order to determine whether this autocrine pathway is activated in squamous carcinoma cells, we analyzed the production of transforming growth factor alpha as well as the expression and regulation of epidermal growth factor receptors in a panel of human squamous carcinoma cell lines. Immunoreactive transforming growth factor alpha was detectable in squamous carcinoma cells as well as in quiescent nonneoplastic keratinocytes. However, in the absence of exogenous mitogens, only the squamous carcinoma cells secreted the growth factor into the medium, whereas untransformed keratinocytes did not. Each of the squamous carcinoma cell lines expressed significantly greater numbers of cell surface epidermal growth factor receptors than normal keratinocytes. The epidermal growth factor receptor gene was amplified and overexpressed in three of the squamous carcinoma cell lines (A431, CaSki, SqCC/Y1). Two of the squamous carcinoma cell lines (C4-1 and CE-48) displayed a relative inability to down-regulate epidermal growth factor receptors in response to epidermal growth factor. The mechanism of receptor overexpression in the remaining three cell lines (A253, CaLu-1, FaDu) is unexplained. Thus, human squamous carcinoma cell lines frequently exhibit a combination of the constitutive secretion of transforming growth factor alpha and the overexpression of epidermal growth factor receptors. Treatment of these tumor cells with an antibody directed against the ligand-binding domain of the epidermal growth factor receptor inhibited their growth by approximately 50%. These findings suggest that designing strategies to interrupt the transforming growth factor alpha autocrine pathway might lead to new modalities to treat this class of malignant tumors.
N-Acylureido Functionality as Acceptor Substituent in Solvatochromic Fluorescence Probes:  Detection of Carboxylic Acids, Alcohols, and Fluoride Ions (2005)

N,N'-Dicyclohexyl-N-(6'-methoxyanthryl-2-carbonyl)urea (1a) exhibits a strong solvatochromism with respect to its fluorescence properties. The emission maxima of 1a correlate well with the anion-stabilizing properties of the solvent. This feature allows the detection of analytes with high acceptor numbers, such as alcohols and carboxylic acids, and the detection of analytes such as fluoride ions which form strong hydrogen bonds with the amido hydrogen atom.
BRCA1 Ubiquitinates RPB8 in Response to DNA Damage (2007)

The breast and ovarian tumor suppressor BRCA1 catalyzes untraditional polyubiquitin chains that could be a signal for processes other than proteolysis. However, despite intense investigations, the mechanisms regulated by the enzyme activity remain only partially understood. Here, we report that BRCA1-BARD1 mediates polyubiquitination of RPB8, a common subunit of RNA polymerases, in response to DNA damage. A proteomics screen identified RPB8 as a protein modified after epirubicin treatment in BRCA1-dependent manner. RPB8 interacted with BRCA1-BARD1 and was polyubiquitinated by BRCA1-BARD1 in vivo and in vitro. BRCA1-BARD1 did not destabilize RPB8 in vivo but rather caused an increase in the amount of soluble RPB8. Importantly, RPB8 was polyubiquitinated immediately after UV irradiation in a manner sensitive to BRCA1 knockdown by RNA interference. Substitution of five lysine residues of RPB8 with arginine residues abolished its ability to be ubiquitinated while preserving its polymerase activity. HeLa cell lines stably expressing this ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity. Our findings suggest that ubiquitination of a common subunit of RNA polymerases is a mechanism underlying BRCA1-dependent cell survival after DNA damage.
Structural Nanocomposites (2008)

Materials scientists predict that composites made with nanoscale reinforcing materials such as nanotubes, platelets, and nanofibers will have exceptional mechanical properties. However, the results obtained so far are disappointing, particularly when compared to advanced composites reinforced with high-performance continuous fibers (1–4). The reasons include inadequate dispersion and alignment of the nanoreinforcement, low nanoreinforcement volume fraction, and poor bonding and load transfer at interfaces. Intensive work is under way, but the prospect of bulk structural supernanocomposites appears more remote now than it did just a few years ago. However, recent work shows that some applications in reinforcement of small structures may have a near-term payoff that can foster longer-term work on nanocomposites. Most of the work on structural nanocomposites has relied on ultrastrong nanoreinforcement such as single- walled carbon nanotubes (SWCNTs) (1–3). However, the high SWCNT strength has not yet translated into bulk strength, and it is not even clear whether such translation is possible: Any attempt to create strong interfacial bonds will introduce defects into the SWCNTs that reduce their intrinsic strength. Still, multifunctional applications not relying solely on the mechanical superproperties will benefit (4, 5). Tailorability and controlled anisotropy are other useful special features of nanocomposites. Multiscale modeling (6) will help us achieve the desired balance between various functions.
Secretion of biologically active human proapolipoprotein A-I in a baculovirus-insect cell system: protection from degradation by protease inhibitors (1995)

Studies of the structure and function of apolipoprotein A-I (apoA-I) often require its purification by delipidation of high density lipoprotein isolated from large quantities of human plasma and separation of apoA-I from other plasma apolipoproteins. To reduce the need for extensive purification procedures, we have developed an insect cell/baculovirus expression system for the production and secretion of human proapoA-I. The recombinant baculovirus containing full-length human apoA-I cDNA, when introduced into Spodoptera frugiperda, directs the synthesis of preproapoA-I, which is subsequently secreted into the growth medium as proapoA-I, indicating correct processing of the signal peptide during secretion. To prevent the extensive degradation of secreted proapoA-I, leupeptin and pepstatin A were added to the serum free cell culture medium. The protein was simply purified by filtration of the medium, which contained up to 80 mg/l proapoA-I, followed by chromatography on phenyl-sepharose CL-4B. The resultant proapoA-I was found to bind lipid and to activate lecithin:cholesterol acyltransferase as effectively as apoA-I from human plasma. The advantage of this expression system is the ease of purification of intact, biologically active apoA-I in high yield.
NAD+ Metabolism in Aging and Cancer (2018)

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD + is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD + decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD + precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.
Monitoring networks using ntop (2002)

Today's networks present several management challenges due to the variety of network types and the integration of different network media. Network administrators need automated tools to support human effort, gathering information about the status and behaviour of network elements. Network monitoring is probably the most fundamental aspect of automated network management. The goal of this paper is to describe the design and implementation of ntop a simple, open-source, portable traffic measurement and monitoring tool, which supports various management activities, including network optimisation and planning, and detection of network security violations. In addition, it describes some scenarios where ntop can be effectively used for identifying common network problems as well as detecting intruders and security violations.
Cloning, purification and characterisation of the lipase from Staphylococcus epidermidis (1998)

On the chromosome of Staphylococcus epidermidis RP62A the lipase gene (gehSE1) is immediately flanked by the icaAA'BC operon, which is involved in biofilm formation. Since lipase production might play a role in staphylococcal skin colonisation as well, we studied the biochemical properties of the staphylococcal lipases more closely. The DNA sequence and the deduced protein sequence revealed that gehSE1 is very similar to the lipase sequence of S. epidermidis strain 9. Like other staphylococcal lipases, gehSE1 is organised as a preproenzyme. The part of gehSE1 coding for the mature lipase was cloned and overexpressed as a fusion protein with an N-terminal histidine tag in Escherichia coli. The lipase was purified to homogeneity using a combination of precipitation techniques, metal-affinity chromatography and gel filtration. Biochemical characterisation showed that this lipase is closely related to the lipase from Staphylococcus aurelis NCTC8530. Both enzymes have a pH optimum around 6, are very stable at low pH, and need calcium as a cofactor for catalytic activity. The preferred substrates are small triacylglycerols, with a maximum activity toward tributyrylglycerol. Comparison of the substrate selectivity with those of other microbial lipases showed that phospholipids are generally poor substrates for lipases. An exception is the lipase from Staphylococcus hyicus, which prefers phospholipids as a substrate, distinguishing this staphylococcal lipase from other microbial lipases. These results are discussed in view of the structure/function relationships of staphylococcal lipases, and the possible involvement of these enzymes in biological processes such as skin colonisation and pathogenesis.
Identification and Characterization of T-Cell Epitopes Deduced from RGS5, a Novel Broadly Expressed Tumor Antigen (2007)

These results indicate that the RGS5 peptides represent interesting candidates for the development of cancer vaccines designed to target malignant cells and tumor vessels.
Neutralizing Toxic RNA (2009)

Oligonucleotides that target aggregates of RNA and protein show potential for treating myotonic dystrophy.
Studies on Scutellariae Radix (1981)

Ogon, an important Chinese crude drug (the dried roots of Scutellaria baicalensis GEORGI), is listed in ancient Chinese herbals and is used in the treatment of a number of diseases. Ether extract of this crude drug showed a relatively marked antibacterial activity against Gram-positive bacteria. Fractionation of the extract accompanied by the bioassay led to the isolation of active principles. The structure of one of these was elucidated as 2(S), 2′, 5, 6′, 7-tetrahydroxyflavanone.
Alkynyl Phosphonate DNA: A Versatile “Click”able Backbone for DNA-Based Biological Applications (2012)

Major hurdles associated with DNA-based biological applications include, among others, targeted cell delivery, undesirable nonspecific effects, toxicity associated with various analogues or the reagents used to deliver oligonucleotides to cells, and stability toward intracellular enzymes. Although a plethora of diverse analogues have been investigated, a versatile methodology that can systematically address these challenges has not been developed. In this contribution, we present a new, Clickable, and versatile chemistry that can be used to rapidly introduce diverse functionality for studying these various problems. As a demonstration of the approach, we synthesized the core analogue, which is useful for introducing additional functionality, the triazolylphosphonate, and present preliminary data on its biological properties. We have developed a new phosphoramidite synthon--the alkynyl phosphinoamidite, which is compatible with conventional solid-phase oligonucleotide synthesis. Postsynthesis, the alkynylphosphonate can be functionalized via "Click" chemistry to generate the 1,2,3-triazolyl or substituted 1,2,3-triazolyl phosphonate-2'-deoxyribonucleotide internucleotide linkage. This manuscript describes the automated, solid-phase synthesis of mixed backbone oligodeoxyribonucleotides (ODNs) having 1,2,3-triazolylphosphonate (TP) as well as phosphate or thiophosphate internucleotide linkages and also 2'-OMe ribonucleotides and locked nucleic acids (LNAs) at selected sites. Nuclease stability assays demonstrate that the TP linkage is highly resistant toward 5'- and 3'-exonucleases, whereas melting studies indicate a slight destabilization when a TP-modified ODN is hybridized to its complementary RNA. A fluorescently labeled 16-mer ODN modified with two TP linkages shows efficient cellular uptake during passive transfection. Of particular interest, the subcellular distribution of TP-modified ODNs is highly dependent on cell type; a significant nuclear uptake is observed in HeLa cells, whereas diffuse cytoplasmic fluorescence is found in the WM-239A cell line. Cytoplasmic distribution is also present in human neuroblastoma cells (SK-N-F1), but Jurkat cells show both diffuse and punctate cytoplasmic uptake. Our results demonstrate that triazolylphosphonate ODNs are versatile additions to the oligonucleotide chemist's toolbox relative to designing new biological research reagents.
Merkel Polyomavirus-Specific T Cells Fluctuate with Merkel Cell Carcinoma Burden and Express Therapeutically Targetable PD-1 and Tim-3 Exhaustion Markers (2013)

Abstract Purpose: The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status. Experimental Design: Multiparameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n = 7) and blood (n = 18) of patients with MCC and control subjects (n = 10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n = 35) and immunohistochemistry (n = 13). Results: MCPyV-specific CD8 T cells were detected directly ex vivo from the blood samples of 7 out of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (P &amp;lt; 0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared with T cells specific to other human viruses (P &amp;lt; 0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8-lymphocyte infiltration. Conclusions: MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer. Clin Cancer Res; 19(19); 5351–60. ©2013 AACR.
Engineered Protein Protease Inhibitors (2009)

Proteases are a class of proteins that degrade other proteins. There are several classes of proteases and these are defined by the chemical nature of the catalytic sites. The process of proteolysis is a vital function that is exquisitely regulated. Many diseases involve deregulation of proteolysis due to over-expression of one or more proteases or endogenous protease inhibitors being faulty or missing. Engineered protease inhibitors that control proteolysis are a well recognized class of therapeutics. For certain classes of proteases, small molecule inhibitors have been very successful (Threonine, Cysteine, and Aspartate proteases). For Serine and Zinc proteases, there has been little success with small molecules. Kunitz domains are natural inhibitors of Serine proteases. Using phage display, Kunitz domains can be engineered rapidly to have very high affinity and specificity for a particular serine protease. One of these, DX-88, is a potent, specific inhibitor of human plasma kallikrein and has successfully completed two phase 3 trials for hereditary angioedema, for which a BLA has been filed to the FDA, and is currently in phase 2 for reduction of blood loss in thoracic surgery. For metalloproteases, potent, specific inhibitory antibodies against several MMPs have been discovered also by phage display.
Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation (2013)

Primordial germ cells (PGCs) and somatic cells originate from postimplantation epiblast cells in mice. As pluripotency is lost upon differentiation of somatic lineages, a naive epigenome and the pluripotency network are re-established during PGC development. Here we demonstrate that Prdm14 contributes not only to PGC specification, but also to naive pluripotency in embryonic stem (ES) cells by repressing the DNA methylation machinery and fibroblast growth factor (FGF) signalling. This indicates a critical role for Prdm14 in programming PGCs and promoting pluripotency in ES cells.
Prevention of Lens Protein-Induced Ocular Inflammation with Cyclooxygenase and Lipoxygenase Inhibitors (1989)

By the use of fluorophotometry, ocular inflammation induced by lens proteins can be objectively quantified. This method of measuring inflammation was applied to studying the effectiveness of a cyclooxygenase inhibitor, indomethacin, and a lipoxygenase inhibitor, REV 5901, in reducing ocular inflammation induced by lens proteins. Pretreatment with indomethacin prevented the leakage of fluorescein into the anterior chamber up to 2 hrs after intracameral injection of lens proteins. After the first 2 hrs, fluorescein concentration in the pretreated eye rapidly increased to equal the control eye by 4 hrs. When REV 5901 was used to pretreat the eye, there was an increase in fluorescein leakage up to 3 hrs after lens protein injection. However, when a combination of indomethacin and REV 5901 was used to pretreat the eye, there was a significant reduction in fluorescein leakage up to 5 hrs after the injection of lens proteins. The reduction of fluorescein leakage with a combination of indomethacin and REV 5901 was greater than that obtained with prednisolone alone. These results indicate that prostaglandins are the primary mediators of inflammation in the early phase (less than 3 hr) of lens protein induced ocular inflammation and leukotrienes are the primary mediators in the late phase (greater than 3 hr) of lens protein induced ocular inflammation. Also the use of a nonsteroidal antiinflammatory drug which blocks only one arm of the arachidonic acid cascade may potentiate the production of metabolites in the other arm of the cascade. By using a combination of a cyclooxygenase inhibitor and a lipoxygenase inhibitor, metabolites from both arms of arachidonic acid cascade are reduced, hence reducing inflammation in both the early phase and late phase of lens protein induced ocular inflammation.
Nuclear Cloning, Stem Cells, and Genomic Reprogramming (2002)

The generation of adult animals by nuclear cloning from adult donor cells is extremely inefficient, with most clones dying soon after implantation. In contrast, cloning from embryonic stem cell donor nuclei is significanty more efficient than from adult donor cells. However, regardless of donor cell type, all clones that survive to birth and beyond suffer serious phenotypic and gene expression abnormalities. All available evidence is consistent with the notion that the anomalous phenotypes of cloned animals are caused by faulty epigenetic reprogramming of the donor nucleus. Faulty reprogramming appears to be caused by the cloning process itself as well as by the epigenetic state of the donor nucleus. In contrast to reproductive cloning, faulty reprogramming of the donor nucleus does not tend to interfere with the application of nuclear transfer technology for therapeutic purposes (therapeutic cloning).