gebhart/patrepeval huggingface dataset:
Targeting the dimerization initiation site of HIV-1 RNA with aminoglycosides: from crystal to cell (2006)

The kissing-loop complex that initiates dimerization of genomic RNA is crucial for Human Immunodeficiency Virus Type 1 (HIV-1) replication. We showed that owing to its strong similitude with the bacterial ribosomal A site it can be targeted by aminoglycosides. Here, we present its crystal structure in complex with neamine, ribostamycin, neomycin and lividomycin. These structures explain the specificity for 4,5-disubstituted 2-deoxystreptamine (DOS) derivatives and for subtype A and subtype F kissing-loop complexes, and provide a strong basis for rational drug design. As a consequence of the different topologies of the kissing-loop complex and the A site, these aminoglycosides establish more contacts with HIV-1 RNA than with 16S RNA. Together with biochemical experiments, they showed that while rings I, II and III confer binding specificity, rings IV and V are important for affinity. Binding of neomycin, paromomycin and lividomycin strongly stabilized the kissing-loop complex by bridging the two HIV-1 RNA molecules. Furthermore, in situ footprinting showed that the dimerization initiation site (DIS) of HIV-1 genomic RNA could be targeted by these aminoglycosides in infected cells and virions, demonstrating its accessibility.
Physical characterization of the cloned protease III gene from Escherichia coli K-12 (1985)

Analysis of the cloned protease III gene (ptr) from Escherichia coli K-12 has demonstrated that in addition to the previously characterized 110,000-Mr protease III protein, a second 50,000-Mr polypeptide (p50) is derived from the amino-terminal end of the coding sequence. The p50 polypeptide is found predominantly in the periplasmic space along with protease III, but does not proteolytically degrade insulin, a substrate for protease III. p50 does not appear to originate from autolysis of the larger protein. Protease III is not essential for normal cell growth since deletion of the structural gene causes no observed alterations in the phenotypic properties of the bacteria. A 30-fold overproduction of protease III does not affect cell viability. A simple new purification method for protease III is described.
Lithium: Event-Driven Network Control (2012)

This paper introduces event-driven network control, a network&#13;\ncontrol framework that makes networks easier to manage&#13;\nby automating many tasks that must currently be performed&#13;\nby manually modifying low-level, distributed, and&#13;\ncomplex device configuration. We identify four policy domains&#13;\nthat inherently capture many events: time, user, history,&#13;\nand traffic flow. We then present Lithium, an event-driven&#13;\nnetwork control framework that can implement policies&#13;\nexpressed using these domains. Lithium can support&#13;\npolicies that automatically react to a wide range of events,&#13;\nfrom fluctuations in traffic volumes to changes in the time of&#13;\nday. Lithium allows network operators to specify networkwide&#13;\npolicies in terms of a high-level, event-driven policy&#13;\nmodel, as opposed to configuring individual network devices&#13;\nwith low-level commands. To show that Lithium is practical,&#13;\ngeneral, and applicable in different types of network scenarios,&#13;\nwe have deployed Lithium in both a campus network and&#13;\na home network and used it to implement more flexible and&#13;\ndynamic network policies. We also perform evaluations to&#13;\nshow that Lithium introduces negligible overhead beyond a&#13;\nconventional OpenFlow-based control framework.
Synthetic Chemistry for Ultrapure, Processable, and High-Mobility Organic Transistor Semiconductors (2001)

An essential aspect of the development of organic-based electronics is the synthetic chemistry devised for the preparation of the semiconductor materials responsible for the activity of organic field-effect transistors. Access to organic semiconductors in sufficient purity and variety has led to breakthroughs in solid-state physics and circuit realization. In this Account, we review the synthetic methods that have been most useful for preparing a range of semiconductors, including thiophene-based oligomers, several kinds of fused rings, and polymers. The tradeoff between process efficiency and target purity is emphasized.
Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death (2001)

The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as Akt) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine protein kinase that is one of several known substrates of PKB. PKB phosphorylates GSK-3 in response to insulin and growth factors, which inhibits GSK-3 activity and leads to the modulation of multiple GSK-3 regulated cellular processes. We show that the novel potent and selective small-molecule inhibitors of GSK-3; SB-415286 and SB-216763, protect both central and peripheral nervous system neurones in culture from death induced by reduced PI 3-kinase pathway activity. The inhibition of neuronal death mediated by these compounds correlated with inhibition of GSK-3 activity and modulation of GSK-3 substrates tau and beta-catenin. Thus, in addition to the previously assigned roles of GSK-3, our data provide clear pharmacological and biochemical evidence that selective inhibition of the endogenous pool of GSK-3 activity in primary neurones is sufficient to prevent death, implicating GSK-3 as a physiologically relevant principal regulatory target of the PI 3-kinase/PKB neuronal survival pathway.
Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma (2009)

Elevated intraocular pressure (IOP) in glaucoma causes loss of retinal ganglion cells (RGCs) and damage to the optic nerve. Although IOP is controlled pharmacologically, no treatment is available to restore retinal and optic nerve function. We evaluated the effects of NGF eye drops in a rat model of glaucoma. We also treated 3 patients with progressive visual field defects despite IOP control. Glaucoma was induced in rats through injection of hypertonic saline into the episcleral vein. Initially, 2 doses of NGF (100 and 200 mug/mL) were tested on 24 rats, and the higher dose was found to be more effective. Glaucoma was then induced in an additional 36 rats: half untreated and half treated with 200 mug/mL NGF QID for 7 weeks. Apoptosis/survival of RGCs was evaluated by histological, biochemical, and molecular analysis. Three patients with advanced glaucoma underwent psychofunctional and electrofunctional tests at baseline, after 3 months of NGF eye drops, and after 3 months of follow-up. Seven weeks of elevated IOP caused RGC degeneration resulting in 40% cell death. Significantly less RGC loss was observed with NGF treatment (2,530 +/- 121 vs. 1,850 +/- 156 RGCs/mm(2)) associated with inhibition of cell death by apoptosis. Patients treated with NGF demonstrated long lasting improvements in visual field, optic nerve function, contrast sensitivity, and visual acuity. NGF exerted neuroprotective effects, inhibiting apoptosis of RGCs in animals with glaucoma. In 3 patients with advanced glaucoma, treatment with topical NGF improved all parameters of visual function. These results may open therapeutic perspectives for glaucoma and other neurodegenerative diseases.
Genes amplified and overexpressed in human multidrug-resistant cell lines. (1988)

Multidrug resistance (MDR) is associated with overproduction of Mr 170,000 membrane proteins (P-glycoproteins) caused by either gene amplification, transcriptional activation, or both. In rodents the amplified domain comprises genes that encode P-glycoproteins and at least five unrelated genes, one of which encodes the calcium-binding protein sorcin. The amplification and increased expression of these genes always includes one P-glycoprotein-encoding gene (pgp1 in hamsters, homologous to mdr1 in humans). In human MDR cells only elevated mdr1 expression has been shown thusfar, although another P-glycoprotein encoding gene (mdr3, homologous to hamster pgp3) is closely linked. Here we show that the human homolog of the hamster sorcin gene resides on chromosome 7 like the P-glycoprotein-encoding genes. Furthermore, gene classes designated 4, 5, and 6 are coamplified with mdr1 and mdr3 in the human ovarian carcinoma cell line 2780AD, which strongly suggests that the overall structure of the human MDR domain is the same as in rodents. Class 6 was moderately and mdr1 was highly overexpressed in this cell line. Four other human MDR cell lines also have much higher mdr1 overexpression than expected from the relatively low levels (2- to 30-fold) of gene amplification. This contrasts with the results of previous work with rodent MDR cells, in which the increase in P-glycoprotein mRNA levels usually parallels the increase in gene copy number. Although four of the five human MDR cell lines have coamplified mdr3, its expression was undetectable. Our results confirm the central role of the mdr1 (pgp1) gene in MDR and suggest that different cross-resistance patterns are not due to differential expression of different P-glycoprotein genes.
The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer. (2001)

The type I receptor tyrosine kinases constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. The best characterized of these proteins are the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2/neu). We have developed potent quinazoline and pyrido-[3,4-d]-pyrimidine small molecules that are dual inhibitors of ErbB-2 and EGFR. The compounds demonstrate potent in vitro inhibition of the ErbB-2 and EGFR kinase domains with IC(50)s <80 nM. Growth of ErbB-2- and EGFR-expressing tumor cell lines is inhibited at concentrations <0.5 microM. Selectivity for tumor cell growth inhibition versus normal human fibroblast growth inhibition ranges from 10- to >75-fold. Tumor growth in mouse s.c. xenograft models of the BT474 and HN5 cell lines is inhibited in a dose-responsive manner using oral doses of 10 and 30 mg/kg twice per day. In addition, the tested compounds caused a reduction of ErbB-2 and EGFR autophosphorylation in tumor fragments from these xenograft models. These data indicate that these compounds have potential use as therapy in the broad population of cancer patients overexpressing ErbB-2 and/or EGFR.
Cloud computing, REST and Mashups to simplify RFID application development and deployment (2011)

While of increasing importance for the real-time enterprise, deployments of Internet of Things infrastructures such as RFID remain complex and expensive. In this paper, we illustrate these challenges by studying the applications of the EPC Network which is an RFID standards framework that aims to facilitate interoperability and application development. We show how the use of blueprints that were successful on the Web can help to make the adoption of these standards less complex. We discuss in particular how Cloud Computing, RESTful interfaces, Real-time Web (Websockets and Comet) and Web 2.0 Mashups can simplify application development, deployments and maintenance in a common RFID application. Our analysis also illustrates that RFID/EPC Network applications are an excellent playground for Web of Things technologies and that further research in this field can significantly contribute to making real-world applications less complex and cost-intensive.
Induction and Extinction of Mammary Cancer (1962)

This article describes the induction the induction and suppression of breast cancer in albino rats; the study was conducted to permit the analysis of the mechanisms of the causes and extinction of cancer 2 of the central problems in cancer research. A single feeding of 20 mg of 712 dimethylbenz(a)anthracene (712-DMBA) dissolved in sesame oil developed mammary cancer in all of over 700 healthy female rats of the Sprague-Dawley strain. The mammary cancer evoked by the aromatic hydrocarbons were all rather similar in cytologic appearance and all had the cellular pattern of papillary adenocarcinoma. Experiments also showed that while 712-DMBA and 2-aminophenanthrene were strong carcinogens benz(a)anthracene and phenanthrene did not evoke mammary cancer. It appears that the methyl and amnio groups convert the otherwise inactive parent molecular species to powerful carcinogens. 3 factors seem to determine mammary carcinogenicity in polynuclear aromatic hydrocarbons: 1) the electron transfer 2) the geometric factor and 3) the molecular thickness. Regression of mammary cancer has been induced by 2 types of alteration of the endocrine status the withdrawal of the hormones essential for the life and growth of the cancer usually done through ovariectomy on the administration of appropriate hormones. In an experiment female rats previously induced with mammary cancer through administration of 712-DMBA were given for 30 days 20 mcg of estradiol-17 and 4 mg of progesterone. In a group of 100 rats treated this way 52 were free from cancer at necropsy whereas their control companions succumbed to cancer. This experiment was repeated under more rigorous conditions with rats with large mammary cancers; the results were equally successful.
Rheumatoid arthritis: the predictable effect of small immune complexes in which antibody is also antigen (1998)

produce joint disease. Secondly, the relationship between RF and disease is not one to one. Thirdly, ing complement activation. the putative pathogenic eVects of immune complexes Perhaps the most important aspect of this hypothesis were considered chiefly in terms of complement is that it refocuses attention on the possibility that activation. By 1990, cytokines such as tumour necrosis permanent interruption of autoantibody production factor alpha ( TNF-a) had come to be considered the might eVectively cure the disease. We propose that this more important mediators in the joint, and therapeutic might be possible. trials using cytokine blockade have reinforced that Much of the hypothesis is based on conventional view [7]. immunological dogma. Although large IgM-based As early as 1983, it had been shown that immune immune complexes may form in the circulation of RA, complexes, including those derived from RF, could these should bind complement and be cleared via stimulate macrophages to produce soluble factors (i.e. complement receptors. As reviewed by Davies [14], cytokines) capable of inducing extracellular matrix large complexes may cause problems in systemic lupus degradation [8]. It seemed likely that the complexes primarily because the complement system is defective. were binding to IgG Fc receptors ( FccR), but not Kunkel and colleagues identified smaller complexes in until 10 yr later had work by Fanger, Lydyard, the circulation in RA, chiefly in the form of IgG RF Huizinga, van de Winkel and others led to a clear self-associating dimers [4]. These small complexes fix understanding of the structure and function of these complement very poorly [15]. IgG dimers are also receptors [9‐11]. Moreover, only recently has it been small enough to be expected to gain significant access established that synovial intima is a highly specialized to the extravascular space and allow interaction with immunological microenvironment which includes an tissue macrophages. unusual pattern of FccR expression [12, 13].
Lysophospholipid Growth Factors and Their G Protein-Coupled Receptors in Immunity, Coronary Artery Disease, and Cancer (2002)

The physiological lysophospholipids (LPLs), exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are omnific mediators of normal cellular proliferation, survival, and functions. Although both LPA and S1P attain micromolar concentrations in many biological fluids, numerous aspects of their biosynthesis, transport, and metabolic degradation are unknown. Eight members of a new subfamily of G protein-coupled LPA/S1P receptors, originally termed Edg Rs, bind either LPA or S1P with high affinity and transduce a series of growth-related and/or cytoskeleton-based functional responses. The most critical areas of LPL biology and pathobiology are neural development and neurodegeneration, immunity, atherosclerosis and myocardial injury, and cancer. Data from analyses of T cells established two basic points: (1) the plasticity and adaptability of expression of LPA/S1P Rs by some cells as a function of activation, and (2) the role of opposing signals from two different receptors for the same ligand as a mechanism for fine control of effects of LPLs. In the heart, LPLs may promote coronary atherosclerosis, but are effectively cytoprotective for hypoxic cardiac myocytes and those exposed to oxygen free radicals. The findings of production of LPA by some types of tumor cells, overexpression of selected sets of LPA receptors by the same tumor cells, and augmentation of the effects of protein growth factors by LPA have suggested pathogenetic roles for the LPLs in cancer. The breadth of physiologic and pathologic activities of LPLs emphasizes the importance of developing bioavailable nonlipid agonists and antagonists of the LPA/S1P receptors for diverse therapeutic applications.
Photodynamic Therapy in Dermatology – an Update 2008 (2008)

Photodynamic therapy (PDT) is used for the prevention and treatment of non-melanoma skin cancer. Until recently, clinically approved indications have been restricted to actinic keratoses, nodular and superficial basal cell carcinoma, and--since 2006--Bowen disease. However, the range of indications has been expanding continuously. PDT is also used for the treatment of non-malignant conditions such as acne vulgaris and leishmaniasis, as well as for treating premature skin aging due to sun exposure. Here, PDT is used for the stimulation of immunomodulatory effects in contrast to the induction of necrosis and apoptosis as produced in the treatment of skin tumors. The porphyrin precursor 5-aminolevulinic acid (ALA) or its methyl ester (MAL, so far the only approved formulation in Europe) is applied topically as photosensitizer to exclude systemic reactions. Possible light sources include lasers as well as incoherent light sources; irradiation with incoherent light sources is cheaper and more appropriate for large treatment areas. The main advantages of PDT in comparison to other treatment modalities are its excellent cosmetic results and its high remission rates despite low invasiveness.This article provides up-to-date information about PDT with focus on recently published studies.
DnaJ Dramatically Stimulates ATP Hydrolysis by DnaK:  Insight into Targeting of Hsp70 Proteins to Polypeptide Substrates (1999)

Most, if not all, of the cellular functions of Hsp70 proteins require the assistance of a DnaJ homologue, which accelerates the weak intrinsic ATPase activity of Hsp70 and serves as a specificity factor by binding and targeting specific polypeptide substrates for Hsp70 action. We have used pre-steady-state kinetics to investigate the interaction of the Escherichia coli DnaJ and DnaK proteins, and the effects of DnaJ on the ATPase reaction of DnaK. DnaJ accelerates hydrolysis of ATP by DnaK to such an extent that ATP binding by DnaK becomes rate-limiting for hydrolysis. At high concentrations of DnaK under single-turnover conditions, the rate-limiting step is a first-order process, apparently a change of DnaK conformation, that accompanies ATP binding and proceeds at 12-15 min-1 at 25 degrees C and 1-1.5 min-1 at 5 degrees C. By prebinding ATP to DnaK and subsequently adding DnaJ, the effects of this slow step may be bypassed, and the maximal rate-enhancement of DnaJ on the hydrolysis step is approximately 15 000-fold at 5 degrees C. The interaction of DnaJ with DnaK.ATP is likely a rapid equilibrium relative to ATP hydrolysis, and is relatively weak, with a KD of approximately 20 microM at 5 degrees C, and weaker still at 25 degrees C. In the presence of saturating DnaJ, the maximal rate of ATP hydrolysis by DnaK is similar to previously reported rates for peptide release from DnaK.ATP. This suggests that when DnaK encounters a DnaJ-bound polypeptide or protein complex, a significant fraction of such events result in ATP hydrolysis by DnaK and concomitant capture of the polypeptide substrate in a tight complex with DnaK.ADP. Furthermore, a broadly applicable kinetic mechanism for DnaJ-mediated specificity of Hsp70 action arises from these observations, in which the specificity arises largely from the acceleration of the hydrolysis step itself, rather than by DnaJ-dependent modulation of the affinity of Hsp70 for substrate polypeptides.
Metabolic Stability of [18F]Fluoroalkylbiphenyls (2004)

The stability of fluoroalkyl groups as a pendent on the phenyl ring was measured in vitro using rat hepatic microsomes and human serum to predict their in vivo stabilities. We have prepared three [<TEX>$^{18}F$</TEX>]fluoroalkyl-biphenyls as the model compounds of fluoroalkyl aromatic compounds to compare the in vitro stabilities. In addition, in vitro stabilities were measured separately using rat hepatic microsomes and human serum at <TEX>$37^{\circ}C$</TEX>. Fluoroethylbiphenyl had similar or slightly superior stability to fluoropropylbiphenyl and these two compounds were much more stable than fluoromethylbiphenyl in vitro.
Understanding RNA modifications: the promises and technological bottlenecks of the ‘epitranscriptome’ (2017)

The discovery of mechanisms that alter genetic information via RNA editing or introducing covalent RNA modifications points towards a complexity in gene expression that challenges long-standing concepts. Understanding the biology of RNA modifications represents one of the next frontiers in molecular biology. To this date, over 130 different RNA modifications have been identified, and improved mass spectrometry approaches are still adding to this list. However, only recently has it been possible to map selected RNA modifications at single-nucleotide resolution, which has created a number of exciting hypotheses about the biological function of RNA modifications, culminating in the proposition of the 'epitranscriptome'. Here, we review some of the technological advances in this rapidly developing field, identify the conceptual challenges and discuss approaches that are needed to rigorously test the biological function of specific RNA modifications.
Posttranscription Initiation Control of Tryptophan Metabolism in Bacillus subtilis by the trp RNA-Binding Attenuation Protein (TRAP), anti-TRAP, and RNA Structure (2001)

Organisms utilize a wide range of regulatory mechanisms to control gene expression. While regulation of transcription initiation is a common regulatory strategy, it is now apparent that this is only the starting point. Bacteria have developed several sophisticated regulatory mechanisms that allow