gebhart/patrepeval huggingface dataset:
Midazolam-fentanyl-isoflurane anaesthesia is suitable for haemodynamic and fluid balance studies in pigs (1998)

The domestic pig is a useful model in certain areas of biomedical research. Effective use of this species is often encumbered by lack of reference values in conscious as well as anaesthetized animals. Anaesthesia itself influences physiological and biological variables; the anaesthetic technique often affects experimental results. The relationship between anaesthesia and haemodynamics is well characterized in man, but less established in pigs. We studied the effect of midazolam-fentanyl-isoflurane anaesthesia in six immature, male, domestic pigs (Norwegian landrace). Haemodynamic variables (heart rate, arterial systolic, mean, diastolic pressures, pulmonary systolic, mean, diastolic pressures, pulmonary capillary wedge pressure), tissue perfusion, lymph flow (thoracic duct) were recorded for 3 h in animals with open chest through midline sternotomy. Variables relevant to fluid balance, e.g. interstitial hydrostatic pressure (Pi), serum-colloid osmotic pressure (s-COP) and serum-albumin (s-albumin) and -protein (s-protein) concentrations were measured. With the chosen anaesthetic technique haemodynamic variables, including lymph flow, and laboratory variables remained constant during the study period. Most variables were similar to conditions in humans. In contrast to adult humans exposed to the same anaesthetic technique, these pigs had lower haemoglobin-, s-albumin- and s-protein concentrations. A finding which may reflect immaturity. Liver and lung perfusion decreased significantly during the study period whereas perfusion of the other organs studied remained constant. Lack of responses to defined noxious stimuli during the study period suggest adequate analgesia. We conclude that midazolam, fentanyl and isoflurane provide cardiovascular stability including normal microvascular fluid exchange, which are essential elements for securing the quality of results obtained during cardiovascular research in anaesthetized pigs.
Solving the Kinematics of Planar Mechanisms by Dixon Determinant and a Complex-Plane Formulation (2000)

Abstract This paper presents a general method for the analysis of any planar mechanism consisting of rigid links connected by revolute and slider joints. The method combines the complex plane formulation of Wampler (1999) with the Dixon determinant procedure of Nielsen and Roth (1999). The result is simple to derive and implement, so in addition to providing numerical solutions, the approach facilitates analytical explorations. The procedure leads to a generalized eigenvalue problem of minimal size. Both input/output problems and the derivation of tracing curve equations are addessed.
Activation of Complement in the Central Nervous System (2003)

The complement system is an essential effector of the humoral and cellular immunity involved in cytolysis and immune/inflammatory responses. Complement participates in host defense against pathogens by triggering the formation of the membrane attack complex. Complement opsonins (C1q, C3b, and iC3b) interact with surface complement receptors to promote phagocytosis, whereas complement anaphylatoxins C3a and C5a initiate local inflammatory responses that ultimately contribute to the protection and healing of the host. However, activation of complement to an inappropriate extent has been proposed to promote tissue injury. There is now compelling evidence that complement activation in the brain is a double-edged sword in that it can exert beneficial or detrimental effects depending on the pathophysiological context. This review focuses on the roles of the complement system in the pathogenesis of acute brain injury (cerebral ischemia and trauma) and chronic neurodegeneration (Alzheimer's disease). Because many effects of the complement appear to promote neuronal survival and tissue remodeling, directing activation of the complement system in the brain may provide a better therapeutic rationale than inhibiting it.
BGP/MPLS IP Virtual Private Networks (VPNs) (2006)

This document describes a method by which a Service Provider may use an IP backbone to provide IP Virtual Private Networks (VPNs) for its customers. This method uses a "peer model", in which the customers' edge routers (CE routers) send their routes to the Service Provider's edge routers (PE routers); there is no "overlay" visible to the customer's routing algorithm, and CE routers at different sites do not peer with each other. Data packets are tunneled through the backbone, so that the core routers do not need to know the VPN routes.
X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor (2013)

The protein kinase ERK5 (MAPK7) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role mediating cell proliferation, survival, epithelial-mesenchymal transition, and angiogenesis. To date, no three-dimensional structure has been published that would allow rational design of inhibitors. To address this, we determined the X-ray crystal structure of the human ERK5 kinase domain in complex with a highly specific benzo[e]pyrimido[5,4-b]diazepine-6(11H)-one inhibitor. The structure reveals that specific residue differences in the ATP-binding site, compared to the related ERKs p38s and JNKs, allow for the development of ERK5-specific inhibitors. The selectivity of previously observed ERK5 inhibitors can also be rationalized using this structure, which provides a template for future development of inhibitors with potential for treatment of disease.
Isolation of a novel histone deacetylase reveals that class I and class II deacetylases promote SMRT-mediated repression (2000)

The transcriptional corepressor SMRT functions by mediating the repressive effect of transcription factors involved in diverse signaling pathways. The mechanism by which SMRT represses basal transcription has been proposed to involve the indirect recruitment of histone deacetylase HDAC1 via the adaptor mSin3A. In contrast to this model, a two-hybrid screen on SMRT-interacting proteins resulted in the isolation of the recently described HDAC5 and a new family member termed HDAC7. Molecular and biochemical results indicate that this interaction is direct and in vivo evidence colocalizes SMRT, mHDAC5, and mHDAC7 to a distinct nuclear compartment. Surprisingly, HDAC7 can interact with mSin3A in yeast and in mammalian cells, suggesting association of multiple repression complexes. Taken together, our results provide the first evidence that SMRT-mediated repression is promoted by class I and class II histone deacetylases and that SMRT can recruit class II histone deacetylases in a mSin3A-independent fashion.
ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats (2002)

Expansion of CAG trinucleotide repeats that encode polyglutamine is the underlying cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease and spinocerebellar ataxias. PolyQ fragments accumulate as aggregates in the cytoplasm and/or in the nucleus, and induce neuronal cell death. However, the molecular mechanism of polyQ-induced cell death is controversial. Here, we show the following: (1) polyQ with pathogenic repeat length triggers ER stress through proteasomal dysfunction; (2) ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex; and (3) ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death. These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.
T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. (1992)

Organ graft rejection is a T-cell-dependent process. The activation of alloreactive T cells requires stimulation of the T-cell receptor/CD3 complex by foreign major histocompatibility complex (MHC)-encoded gene products. However, accumulating evidence suggests that, in addition to T-cell receptor occupancy, other costimulatory signals are required to induce T-cell activation. Previously, the CD28 receptor expressed on T cells has been shown to serve as a surface component of a signal transduction pathway that can provide costimulation. In vitro, interaction of CD28 with its natural ligand B7 expressed on the surface of activated B cells or macrophages can act as a costimulus to induce proliferation and lymphokine production in antigen receptor-activated T cells. We now report evidence that stimulation of T cells by the CD28 ligand B7 is a required costimulatory event for the rejection of a MHC-incompatible cardiac allograft in vivo. These results demonstrate that the B7/CD28 activation pathway plays an important role in regulating in vivo T-cell responses.
Crystal Structures of Human Factor Xa Complexed with Potent Inhibitors (2000)

Involved in the coagulation cascade, factor Xa (FXa) is a serine protease which has received great interest as a potential target for the development of new antithrombotics. Although there is a great wealth of structural data on thrombin complexes, few structures of ligand/FXa complexes have been reported, presumably because of the difficulty in growing crystals. Reproducible crystallization conditions for human des-Gla1-45 coagulation FXa have been found. This has led to an improvement in the diffraction quality of the crystals (about 2.1 A) when compared to the previously reported forms (2.3-2.8 A) thus providing a suitable platform for a structure-based drug design approach. A series of crystal structures of noncovalent inhibitors complexed with FXa have been determined, three of which are presented herein. These include compounds containing the benzamidine moiety and surrogates of the basic group. The benzamidine-containing compound binds in a canonical fashion typical of synthetic serine protease inhibitors. On the contrary, molecules that contain surrogates of the benzamidine group do not make direct hydrogen-bonding interactions with the carboxylate of Asp189 at the bottom of the S1 pocket. The structural data provide a likely explanation for the specificity of these inhibitors and a great aid in the design of bioavailable potent FXa inhibitors.
A Comprehensive Clinical and Biochemical Functional Study of a NovelRPE65Hypomorphic Mutation (2008)

The mild clinical phenotype observed is consistent with the residual activity of a severely hypomorphic mutant RPE65. Reduction to <10% of wild-type RPE65 activity by homozygous P25L correlates with almost complete rod function loss and cone amplitude reduction. Functional survival of cones is possible in patients with residual RPE65 isomerase activity. This patient should profit most from gene therapy.
Considerations on Antibody-Phage Display Methodology (2005)

For almost 15 years phage display is being used for the selection of specific antigen-binders from artificial libraries of single chain antibodies. Filamentous phages have been developed in a way to express foreign proteins on the surface and at the same time carrying the genetic information of the surface expressed molecule within the phage capsid. This property guarantees the coupling of phenotype and genotype during phage amplification and affinity selection. The possibility to generate large antibody libraries and the simplified antibody-backbone of a single chain antibody has made antibody-phage display to a powerful tool for the development of new therapeutics against various human diseases. In this review we discuss the general principles and latest developments and applications in antibody phage display technology.
Standing-wave Fourier transform spectrometer based on integrated MEMS mirror and thin-film photodetector (2002)

We report a novel, miniature Fourier transform spectrometer with a linear architecture that works by sampling a standing wave. The spectrometer consists of an electrostatically actuated microelectromechanical mirror with on-resonance displacement of up to 65 /spl mu/m, a thin-film photodetector, and an electrical back plane for actuating the mirror. The integrated device offers mirror stability and fixed relative alignment of the three components. The spectrometer has better than 32-nm resolution at 633 nm.
Transmission of Chronic Nociception by Spinal Neurons Expressing the Substance P Receptor (1999)

Substance P receptor (SPR)-expressing spinal neurons were ablated with the selective cytotoxin substance P-saporin. Loss of these neurons resulted in a reduction of thermal hyperalgesia and mechanical allodynia associated with persistent neuropathic and inflammatory pain states. This loss appeared to be permanent. Responses to mildly painful stimuli and morphine analgesia were unaffected by this treatment. These results identify a target for treating persistent pain and suggest that the small population of SPR-expressing neurons in the dorsal horn of the spinal cord plays a pivotal role in the generation and maintenance of chronic neuropathic and inflammatory pain.
Role of PI3K/Akt signaling in memory CD8 T cell differentiation (2013)

The clonal expansion, differentiation into effectors and establishing an immunological memory are crucial components of the adaptive immune response. Following the initial encounter with a pathogen, clonal CD8 T cell expansion yields at least two distinct populations of effector cells, short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). SLECs are the terminally differentiated cells, which play an active role in pathogen clearance and undergo apoptosis once the pathogen is eliminated. In contrast, MPECs persist and give rise to self-renewing memory cells. These memory CD8 T cells maintain a state of heightened alertness and are poised to rapidly respond and swiftly clear the pathogen upon antigen re-encounter. As one of the goals of vaccination is to induce the development of these memory CD8 T cells, understanding the cellular and molecular basis of memory cell differentiation is critical to rational vaccine design. It is clear that memory differentiation is complex and involves multiple interrelated signaling pathways. It is influenced by factors such as the strength and duration of antigen receptor signaling and concurrent exposure to cytokines. Several signaling pathways that influence T cell fate have been recently described, and many culminate in the differential expression of specific transcription factors. Unfortunately, the mechanisms underlying the coordination and confluence of these signaling pathways remain largely unknown. In this review, we will discuss the role of the phosphatidylinositol 3-kinase signaling pathway as a central signaling node, and the function of Akt as a rheostat in orchestrating the differentiation of memory CD8 T cells.
CHILD: a new tool for detecting low-abundance insertions and deletions in standard sequence traces (2011)

Several methods have been proposed for detecting insertion/deletions (indels) from chromatograms generated by Sanger sequencing. However, most such methods are unsuitable when the mutated and normal variants occur at unequal ratios, such as is expected to be the case in cancer, with organellar DNA or with alternatively spliced RNAs. In addition, the current methods do not provide robust estimates of the statistical confidence of their results, and the sensitivity of this approach has not been rigorously evaluated. Here, we present CHILD, a tool specifically designed for indel detection in mixtures where one variant is rare. CHILD makes use of standard sequence alignment statistics to evaluate the significance of the results. The sensitivity of CHILD was tested by sequencing controlled mixtures of deleted and undeleted plasmids at various ratios. Our results indicate that CHILD can identify deleted molecules present as just 5% of the mixture. Notably, the results were plasmid/primer-specific; for some primers and/or plasmids, the deleted molecule was only detected when it comprised 10% or more of the mixture. The false positive rate was estimated to be lower than 0.4%. CHILD was implemented as a user-oriented web site, providing a sensitive and experimentally validated method for the detection of rare indel-carrying molecules in common Sanger sequence reads.
Do lipid rafts mediate virus assembly and pseudotyping? (2003)

Co-infection of a host cell by two unrelated enveloped viruses can lead to the production of pseudotypes: virions containing the genome of one virus but the envelope proteins of both viruses. The selection of components during virus assembly must therefore be flexible enough to allow the incorporation of unrelated viral membrane proteins, yet specific enough to exclude the bulk of host proteins. This apparent contradiction has been termed the pseudotypic paradox. There is mounting evidence that lipid rafts play a role in the assembly pathway of non-icosahedral, enveloped viruses. Viral components are concentrated initially in localized regions of the plasma membrane via their interaction with lipid raft domains. Lateral interactions of viral structural proteins amplify the changes in local lipid composition which in turn enhance the concentration of viral proteins in the rafts. An affinity for lipid rafts may be the common feature of enveloped virus proteins that leads to the formation of pseudotypes.
A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta (1988)

On the basis of the complete nucleotide sequence of the single-stranded, covalently closed circular hepatitis delta virus RNA genome (K.-S. Wang, Q.-L. Choo, A. J. Weiner, J.-H. Ou, R. C. Najarian, R. M. Thayer, G. T. Mullenbach, K. J. Denniston, J. L. Gerin, and M. Houghton, Nature [London] 323:508-514, 1986 [Author's correction, 328:456, 1987]), five long open reading frames (ORFs) encoding polypeptides containing a methionine proximal to the amino terminus were expressed in bacteria. Only polypeptides encoded by the antigenomic ORF5 cross-reacted with antisera obtained from patients with hepatitis delta virus infections. Immunological analysis of viral extracts and the recombinant ORF5 polypeptides synthesized in bacteria and yeast cells revealed that ORF5 encodes the immunogenic epitope(s) shared by both hepatitis delta viral polypeptides p27 delta and p24 delta and probably represents the complete structural gene for p27 delta and p24 delta. We also present evidence that ORF5 encodes the hepatitis delta antigen, an antigen originally found in the nuclei of hepatocytes of infected individuals (M. Rizzetto, M. G. Canese, S. Arico, O. Crivelli, F. Bonino, C. G. Trepo, and G. Verme, Gut 18:997-1003, 1977). A comparison of the primary structure of the predicted hepatitis delta antigen polypeptides with that of the core antigen of the hepatitis B virus shows that these polypeptides are very dissimilar.
A novel, small endoglucanase gene, egl5, from Trichoderma reesei isolated by expression in yeast (1994)

A method is presented for the isolation of genes encoding hydrolytic enzymes without any knowledge of the corresponding proteins. cDNA made from the organism of interest is cloned into a yeast vector to construct an expression library in the yeast Saccharomyces cerevisiae. Colonies producing hydrolytic enzymes are screened by activity plate assays. In this work, we constructed a yeast expression library from the filamentous fungus Trichoderma reesei and isolated a new beta-1,4-endoglucanase gene on plates containing beta-glucan. This gene, egl5, codes for a previously unknown small protein of 242 amino acids. Despite its small size, the protein contains two conservative domains found in Trichoderma cellulases, namely the cellulose-binding domain (CBD) and the linker region that connects the CBD to the catalytic core domain. Molecular modelling of the EGV CBD revealed some interesting structural differences compared to the CBD of the major cellulase CBHI from T. reesei. The catalytic core of EGV is unusually small for a cellulase and represents a new family of cellulases (Family K) and of glycosyl hydrolases (Family 45) together with the endoglucanase B of Pseudomonas fluorescens and the endoglucanase V of Humicola insolens on the basis of hydrophobic cluster analysis.
The Tmp Gene, Encoding a Membrane Protein, Is a c-Myc Target with a Tumorigenic Activity (1999)

The c-Myc oncoprotein induces cell proliferation and transformation through its activity as a transcription factor. Uncovering the genes regulated by c-Myc is an essential step for understanding these processes. We recently isolated the tumor-associated membrane protein gene, Tmp, from a c-myc-induced mouse brain tumor. Here we show that Tmp is specifically highly expressed in mammary tumors and T-cell lymphomas which develop in c-myc transgenic mice, suggesting that Tmp expression is a general characteristic of c-Myc-induced tumors. In addition, Tmp expression is induced upon serum stimulation of fibroblasts as shown in a time course closely correlated with c-myc expression. We have isolated the Tmp promoter region and identified a putative c-Myc binding element, CACGTG, located in the first intron of the gene. We show here that constructs containing the Tmp regulatory region fused to a reporter gene are activated by c-Myc through this CACGTG element and that the c-Myc-Max protein complex can bind to this element. Moreover, an inducible form of c-Myc, the MycER fusion protein, can activate the endogenous Tmp gene. We also show that Tmp-overexpressing fibroblasts induce rapidly growing tumors when injected into nude mice, suggesting that Tmp may possess a tumorigenic activity. Thus, TMP, a member of a novel family of membrane glycoproteins with a suggested role in cellular contact, is a c-Myc target and is possibly involved in c-Myc-induced transformation.
Factors Affecting Selectivity of Brilliant Green-Phenol Red Agar for Salmonellae (1974)

Commercial brilliant green (BG)-sulfa agar was found to be nonselective toward a test series of Enterobacteriaceae. Various formulations of BG were prepared by using Trypticase soy agar (BBL) as a base. Results were more reproducible when BG dye was added after sterilization than before. Sulfonamides improved selectivity as compared with brilliant green alone. Sulfanilamide (SN) was slightly more selective for salmonellae than other sulfonamides tested. Bile salts and sodium dodecyl sulfate markedly reduced the toxicity of BG to all the test bacteria. Enterobacter strains were most difficult to inhibit. A combination of 5 mg of BG and 1 g of SN/liter prevented growth of Proteus mirabilis and Escherichia coli and retarded growth of Enterobacter strains. The BG-SN agars were superior in selectivity to a series of commercial agars tested, and numbers of salmonellae recovered on BG-SN agar and Trypticase soy agar (BBL) were the same. Brilliant green agars with various degrees of selectivity are described.
Colic and Crying Syndromes in Infants (1998)

Colic or excessive crying is one of the most frequent problems presented to pediatricians by new parents. Organic disease accounts for <5% of infants presenting with colic syndrome. Colic may be best viewed as a clinical manifestation of normal emotional development, in which an infant has diminished capacity to regulate crying duration.