gebhart/patrepeval huggingface dataset:
A deletion within the translocation domain of Pseudomonas exotoxin A enhances translocation efficiency and cytotoxicity concomitantly (1999)

Pseudomonas exotoxin A (PE) is a cytotoxin composed of three structural domains. Domain I is responsible for cell binding, domain II for membrane translocation enabling access to the cytosol, and domain III for the catalytic inactivation of protein synthesis, which results in cell death. To investigate the role of the six alpha-helices (A-F) that form the translocation domain, we deleted them successively one at a time. All mutants showed native cell-binding and catalytic activities, indicating that deletions specifically affected translocation activity. This step of the intoxication procedure was examined directly using a cell-free translocation assay, and indirectly by monitoring cytotoxicity. Translocation activity and log(cytotoxicity) were highly correlated, directly indicating that translocation is rate limiting for PE intoxication. Deletion of B, C and D helices resulted in non-toxic and non-translocating molecules, whereas mutants lacking the A or E helix displayed significant cytotoxicity albeit 500-fold lower than native PE. We concluded that B, C and D helices, which make up the core of domain II, are essential, whereas the more peripheral A and E helices are comparatively dispensable. The last helix (F) is inhibitory for translocation because its deletion produced a mutant displaying a translocation activity 60% higher than PE, along with a three- to sixfold increase in cytotoxicity in all tested cell lines. This toxin is the most in vitro active PE mutant obtained until now. Finally, partial duplication of domain II did not give rise to a more actively translocated PE, but rather to a threefold less active molecule.
RNase/Anti-RNase Activities of the BacterialparDToxin-Antitoxin System (2005)

The bacterial parD toxin-antitoxin system of plasmid R1 encodes two proteins, the Kid toxin and its cognate antitoxin, Kis. Kid cleaves RNA and inhibits protein synthesis and cell growth in Escherichia coli. Here, we show that Kid promotes RNA degradation and inhibition of protein synthesis in rabbit reticulocyte lysates. These new activities of the Kid toxin were counteracted by the Kis antitoxin and were not displayed by the KidR85W variant, which is nontoxic in E. coli. Moreover, while Kid cleaved single- and double-stranded RNA with a preference for UAA or UAC triplets, KidR85W maintained this sequence preference but hardly cleaved double-stranded RNA. Kid was formerly shown to inhibit DNA replication of the ColE1 plasmid. Here we provide in vitro evidence that Kid cleaves the ColE1 RNA II primer, which is required for the initiation of ColE1 replication. In contrast, KidR85W did not affect the stability of RNA II, nor did it inhibit the in vitro replication of ColE1. Thus, the endoribonuclease and the cytotoxic and DNA replication-inhibitory activities of Kid seem tightly correlated. We propose that the spectrum of action of this toxin extends beyond the sole inhibition of protein synthesis to control a broad range of RNA-regulated cellular processes.
Strategies and recent technologies in drug discovery. (1995)

In the last years, the paradigms of drug research changed significantly. New technologies were developed, in several different fields. Combinatorial chemistry and high-throughput screening increase our chances to find new lead structures, with less effort than by dedicated syntheses. Gene technology, in addition to providing therapeutically useful proteins, significantly contributes to rational drug design. The primary structure of a protein can be derived from the DNA sequence of the corresponding gene. Its relevance for a certain disease is investigated in transgenic animals. Expression of the protein in bacteria or in cell culture produces material for screening systems and for 3D structure determination by protein crystallography. NMR techniques, or electron cryo-microscopy. Structure-based and computer-aided design methods are applied to optimize lead structures with the least effort. A serious problem in the application of such techniques is their limitation to ligand-protein interactions. For the design of a therapeutically useful drug, also absorption, distribution, metabolism and elimination have to be considered. QSAR methods help in this respect. Scope and limitations of the new technologies are discussed in the context of conventional approaches in drug discovery.
Distinguishing Homologous from Analogous Proteins (1970)

Fitch, W. M. (Dept. Physiological Chetn., U. Wisconsin, Madison 53706) 1970. Distinguishing homologous from analogous proteins. Syst. Zool., 19:99–113.—This work provides a means by which it is possible to determine whether two groups of related proteins have a common ancestor or are of independent origin. A set of 16 random amino acid sequences were shown to be unrelated by this method. A set of 16 real but presumably unrelated proteins gave a similar result. A set of 24 model proteins which was composed of two independently evolving groups, converging toward the same chemical goal, was correctly shown to be convergently related, with the probability that the result was due to chance being <10−21. A set of 24 cytochromes composed of 5 fungi and 19 metazoans was shown to be divergently related, with the probability that the result was due to chance being < 10−9. A process was described which leads to the absolute minimum of nucleotide replacements required to account for the divergent descent of a set of genes given a particular topology for the tree depicting their ancestral relations. It was also shown that the convergent processes could realistically lead to amino acid sequences which would produce positive tests for relatedness, not only by a chemical criterion, but by a genetic (nucleotide sequence) criterion as well. Finally, a realistic case is indicated where truly homologous traits, behaving in a perfectly expectable way, may nevertheless lead to a ludicrous phylogeny.
TESTICULAR LIPIDS (1971)

Summary. Scrotal testes from control and unilaterally cryptorchid rats and rabbits and abdominal testes from animals unilaterally or bilaterally cryptorchid for 6 days were used in this study. Total cholesterol rose (P&amp;lt;0·05) in all abdominal testes as a result of increased (P&amp;lt;0·05) levels of esterified cholesterol. Fatty acids of the scrotal testes from unilaterally cryptorchid animals were only slightly changed by treatment. Changes in fatty acid esters in abdominal testes of unilaterally cryptorchid animals of both species were similar. These changes consisted of increases in most fatty acids with a chain length of 14, 16 and 18, both saturated and unsaturated. Abdominal testes of bilaterally cryptorchid rabbits differed from those of unilateral cryptorchids in that proportions of long chain fatty acids were more consistently increased in the former. Abdominal testes of the bilaterally cryptorchid rats also differed from the unilateral cryptorchids but less than in the rabbit. Differences in hormonal levels in the unilateral and bilateral cryptorchids are suggested as the most probable cause of difference in the abdominal testes of these groups.
Epilepsy, cognition, and behavior: The clinical picture (2011)

Although epilepsy is defined by the occurrence of spontaneous epileptic seizures, a large body of evidence indicates that epilepsy is linked to a spectrum of behavioral, psychiatric, and cognitive disorders as well as to sudden death. Explanations for these associations include the following: (1) The effects of structural lesions that may impair the functions subserved by the regions of the brain involved in the lesion. (2) The effects of seizure activity that may begin well before a clinical seizure occurs and may persist long after it is over, raising questions about what truly constitutes "interictal." In addition, encephalopathic effects of epilepsy in infancy during critical periods in development may be particularly severe and potentially irreversible. (3) Shared mechanisms underlying seizures as well as these other disorders in the absence of structural lesions or separate diseases of the central nervous system (CNS). Epidemiologic and clinical studies demonstrate the elevated risk of cognitive, psychiatric, and behavioral disorders not just during but also prior to the onset of epilepsy (seizures) itself. These may outlast the active phase of epilepsy as well. The mounting evidence argues strongly for the recognition of epilepsy as part of a spectrum of disorders and against the notion that even uncomplicated epilepsy can a priori be considered benign.
The design and synthesis of 5- and 6-isoxazolylbenzimidazoles as selective inhibitors of the BET bromodomains (2012)

Simple 1-substituted 5- and 6-isoxazolyl-benzimidazoles have been shown to be potent inhibitors of the BET bromodomains with selectivity over the related bromodomain of CBP. The reported inhibitors were prepared from simple starting materials in two steps followed by separation of the regioisomers or regioselectively in three steps.
Second virial coefficient determination of a therapeutic peptide by self‐interaction chromatography (2006)

Self-interaction of macromolecules has been shown to play an important role in a number of physical processes, including crystallization, solubility, viscosity, and aggregation. Peptide self-interaction is not as well studied as for larger proteins, but should play an equally important role. The osmotic second virial coefficient, B, can be used to quantify peptide and protein self-interaction. B values are typically measured using static light scattering (SLS). Peptides, however, do not scatter enough light to allow such measurements. This study describes the first use of self-interaction chromatography (SIC) for the measurement of peptide B values because SIC does not have the molecular size limitations of SLS. In the present work, SIC was used to measure B for enfuvirtide, a 36-amino acid therapeutic peptide, as a function of salt concentration, salt type, and pH. B was found to correlate strongly with solubility and apparent molecular weight. In general, the solubility of enfuvirtide increases with pH from 6 to 10 and decreases as the salt concentration increases from 0 to 0.5M for three different salts. The effect of peptide concentration on B was also investigated and shown to have a significant effect, but only at high concentrations (>80 mg/mL).
The Pathophysiology of Ocular Allergy: Current Thinking (1995)

Seasonal allergic conjunctivitis is the only ocular disease to involve solely Type-1 hypersensitivity, the other main forms of ocular allergy--perennial allergic conjunctivitis, vernal and atopic keratoconjunctivitis and giant papillary conjunctivitis--each having a more complex immunological basis and a chronic inflammatory component. Involvement of secondary inflammatory cells, particularly eosinophils, in addition to the mast cells resident in the conjunctival substantia propria, can lead to more serious corneal damage with vision-threatening potential. Thoughtful management of allergic conjunctivitis is needed in order to control the ocular inflammation without incurring steroid-induced side-effects, and patient education is also an important factor in maintaining optimal allergen avoidance, especially in the more severe and chronic cases. Laboratory models can be helpful in assessing the potential of new drugs, and SWR mice (topically sensitised and challenged with short ragweed) show clinical signs of allergic conjunctivitis, together with mast cell and eosinophil involvement, remarkably similar to the human pathophysiology. The antiinflammatory activity of both steroids and nedocromil sodium observed in this animal model supports therapeutic evidence of the usefulness of second-generation mast cell stabilising drugs in the treatment of ocular allergy.
Detection of mammalian microRNA expression by in situ hybridization with RNA oligonucleotides (2006)

We have developed an in situ hybridization procedure for the detection of microRNAs (miRNAs) in tissue sections from mouse embryos and adult organs. The method uses highly specific washing conditions for RNA oligonucleotide probes conjugated to a fluorescein hapten. We show that this method detects predominantly mature miRNAs rather than the miRNA precursors or primary transcripts. We have determined expression patterns for several miRNAs expressed in the developing and adult nervous system, including miR-124a, miR-9, miR-92, and miR-204. Whereas miR-124a is expressed in neurons, miR-9 is expressed in neural progenitors and some neurons, and miR-204 is expressed in the choroid plexus, retinal pigment epithelium, and ciliary body. miR-204 is located in an intron of the TRPM3 gene, and the TRPM3 mRNA is coexpressed with miR-204 in the choroid plexus. We also find that primary transcripts for miR-124a and miR-9 genes are expressed in patterns similar to their respective mature miRNAs. The ability to visualize expression of specific miRNAs in embryos and tissues should aid studies on miRNA function.
Role of nanoparticles in the drug delivery system (2010)

Over Recent years advancement in nanoparticles drug delivery is widely expected to change the landscape of pharmaceutical industries for the foreseeable future. Nanotechnologies have become a significant priority worldwide. Several manufactured nanoparticles- particles with one dimension less than 100 nm – are increasingly used in consumer products. At nanosize range, the properties of materials differ substantially from bulk materials of the same composition, mostly due to the increased specific surface area and reactivity, which may lead to increased bioavailability and toxicity. Thus, for the assessment of sustainability of nanotechnologies, methods of manufacturing Nanoparticles, properties have to be studied. Despite all the above mentioned, the data on the potential environmental effects of nanoparticles are rare. The pipelines of pharmaceutical companies are believed to be drying up in many cases, and a number of blockbuster drugs will come off patent in the near-term. Using nanoparticles, it may be possible to achieve improved delivery of poorly water-soluble drugs by delivering drug in small particle size increase the total surface area of the drugs allowing faster dissolution in blood stream. Faster the dissolution translates in to faster absorption by human body targeted delivery of drugs in a cell- or tissue-specific manner. A nanoparticle has emerged as a promising strategy for the efficient delivery of drugs used for the treatment of some diseases by specific targeting. These
Rapid Elongation of Arteries and Veins in Rats with a Tissue Expander (1987)

The saphenous arteries and veins of 40 rats were elongated with 20-cc tissue expanders underlying the leg adductor muscles. The mean rate of successful elongation of the vessels was 84 +/- 47 percent SD, with a maximum gain of 140 percent. The fastest mean elongation velocity reached 45 percent per day. Thrombosis occurred only with stretching velocities of more than 10 percent per day, which seemed to be a safe margin. Distribution of the volume into many intervals was safer than infrequent high-volume injections. Histology showed no reduction in vessel wall diameter or loss intimal integrity. Subendothelial cellular proliferation was an indicator of this rapid regeneration. Microvascular anastomoses performed in elongated arteries and veins had the same patency rate (90 percent) as in controls.
Chemiluminescence and oxygen radical generation by Walker carcinosarcoma cells following chemotactic stimulation. (1987)

The peptide N-formyl-Met-Leu-Phe stimulates chemotaxis and metastasis in rat Walker carcinosarcoma cells by a receptor-mediated pathway. Since oxygen radical generation follows chemotactic stimulation in leukocytes, we looked for similar responses in the Walker tumor. Upon incubation with 10(-6) M N-formyl-Met-Leu-Phe, Walker cells elicited chemiluminescence in the presence of 5 X 10(-5) M luminol. The response peaked within 2 min and was maintained for greater than 20 min; it was dose dependent with a 50% maximal effective dose (ED50) value of 4.5 X 10(-8) comparable to the 50% maximal effective dose value for chemotaxis. The responses were significantly reduced but not abolished in the absence of calcium in the external medium and were elicited by the ionophore A23187. The lipoxygenase inhibitor nordihydroguaiaretic acid had almost no effect in decreasing the response, while flurbiprofen, a cyclooxygenase inhibitor was very effective at 10(-6) M. Evidence for the generation of oxygen radicals included: (a) marked inhibition of light emission in the absence of oxygen; (b) inhibition in the presence of superoxide dismutase, catalase, and mannitol; and (c) dose-dependent reduction of acetylated cytochrome c. We postulate that activation of circulating tumor cells may facilitate metastasis by the release of toxic oxygen species.
Absence of memory dysfunction after bilateral mammillary body and mammillothalamic tract electrode implantation: preliminary experience in three patients. (2005)

The anatomic bases for memory disorders have been widely debated. Lesions of the medial dorsal (MD) and anterior nuclei (AN) of the thalami and lesions of the mammillary bodies (MB) are most commonly involved in amnesic syndromes in humans ([1][1], [2][2]).

In a monkey model, Mishkin ([3][3])
Adipose stem cells on a biodegradable polymer for spinal fusion: pre-clinical studies (2014)

promotiedatum: 19-12-2014 � prom-id: 10574
An open-source framework for testing tracking devices using Lego Mindstorms (2009)

In this paper, we present an open-source framework for testing tracking devices in surgical navigation applications. At the core of image-guided intervention systems is the tracking interface that handles communication with the tracking device and gathers tracking information. Given that the correctness of tracking information is critical for protecting patient safety and for ensuring the successful execution of an intervention, the tracking software component needs to be thoroughly tested on a regular basis. Furthermore, with widespread use of extreme programming methodology that emphasizes continuous and incremental testing of application components, testing design becomes critical. While it is easy to automate most of the testing process, it is often more difficult to test components that require manual intervention such as tracking device. Our framework consists of a robotic arm built from a set of Lego Mindstorms and an open-source toolkit written in C++ to control the robot movements and assess the accuracy of the tracking devices. The application program interface (API) is cross-platform and runs on Windows, Linux and MacOS. We applied this framework for the continuous testing of the Image-Guided Surgery Toolkit (IGSTK), an open-source toolkit for image-guided surgery and shown that regression testing on tracking devices can be performed at low cost and improve significantly the quality of the software.
IL-12 Responsiveness and Expression of IL-12 Receptor in Human Peripheral Blood Monocyte-Derived Dendritic Cells (2000)

We analyzed the expression of IL-12Rbeta1 and IL-12Rbeta2 and the role of IL-12 in the activation of monocyte-derived dendritic cells (DCs) via IL-12Rbeta1-mediated signaling events. Flow cytometric analysis revealed that IL-12Rbeta1 was expressed in T cells, Con A blasts, and monocyte-derived DCs, but not in monocytes, while its transcript was detected in all of these cell types. Transcriptional expression of IL-12Rbeta2 was observed in T cells, Con A blasts, and monocyte-derived DCs, but not monocytes. The ligation of DCs as well as Con A blasts by IL-12 induced the production of GM-CSF, IL-1beta, IL-6, TNF-alpha, and IFN-gamma at the transcription levels. Furthermore, stimulation of DCs with IL-12 induced IL-12p40 transcript, but not IL-12p35 transcript, whereas this stimulation caused the expressions of both transcripts in Con A blasts. Stimulation of DCs with IL-12 caused a tyrosine phosphorylation of several intracellular proteins, and the pattern of these events were distinct from those of IL-12-stimulated Con A blasts. IL-12 also induced tyrosine phosphorylation of IL-12Rbeta1 as well as recruitment of several tyrosine-phosphorylated proteins to IL-12Rbeta1 in DCs and Con A blasts. Receptor engagement of DCs as well as Con A blasts by IL-12 resulted in activation of Janus kinase 2 and Tyk2 kinases and Stat3 and Stat4 transcription factors and the association of these proteins to IL-12Rbeta1. Stimulation with IL-12 caused a tyrosine phosphorylation and enzymatic activity of a family of mitogen-activated protein kinases, p38mapk. These results suggest that IL-12 acts directly on DCs to induce their functional activation via IL-12Rbeta1-mediated signaling events.
Destabilizing Domains Derived from the Human Estrogen Receptor (2012)

Methods to rapidly and reversibly perturb the functions of specific proteins are desirable tools for studies of complex biological processes. We have demonstrated an experimental strategy to regulate the intracellular concentration of any protein of interest by using an engineered destabilizing protein domain and a cell-permeable small molecule. Destabilizing domains have general utility to confer instability to a wide range of proteins including integral transmembrane proteins. This study reports a destabilizing domain system based on the ligand binding domain of the estrogen receptor that can be regulated by one of two synthetic ligands, CMP8 or 4-hydroxytamoxifen.
Where will the Standards for Intelligent Computer-Assisted Language Learning Come from? (2002)

Intelligent computer-assisted language learning—Intelligent CALL, or ICALL—can be defined in a number of ways, but one understanding of the term is that of CALL incorporating language technology (LT) for e.g. analyzing language learners’ language production, in order to provide the learners with more fle xible—indeed, more ‘intelligent’—feedback and guidance in their language learning process. However, CALL, ICALL and LT have been three largely unrelated research areas, at least until recently. In the world of education, ‘e-learning’ and ‘ICT-based learning’ are the new buzzwords. Generally, what is meant is some kind of web-based setup, where course materials are delivered via the Internet or/and learners are collaborating using computer-mediated communication (CMC). An important trend in ICT-based learning is that of standardization for reusability. Standard formats for all aspects of so-called ‘instructional management systems’ are rapidly gaining acceptance in the e-learning industry. Thus, learning applications will need to support them in order to be commercially viable. This in turn means that the proposed standards should be general enough to support all conceivable kinds of educational content and learning systems. In this paper, we will discuss how ICALL applications can be related to the various standards proposals, basing our discussion on concrete experiences from a number of (I)CALL projects, where these standards are used or where their use has been contemplated.
A 3.33gb/s (1200,720) low-density parity check code decoder (2005)

In this paper, a (1200,720) LDPC decoder based on an irregular parity check matrix is presented. For achieving higher chip density and less critical path delay, the proposed architecture features a data reordering such that only one specific data bus exists between message memories and computational units. Moreover, the LDPC decoder can also process two different codewords concurrently to increase throughput and datapath efficiency. After chip implementation, a 3.33Gb/s data rate is achieved with 8 decoding iterations in the 21.23mm/sup 2/ 0.18/spl mu/m silicon area. The other 0.13/spl mu/m chip with the 10.24mm/sup 2/ core can further reach a 5.92Gb/s data rate under 1.02V supply.