gebhart/patrepeval huggingface dataset:
Endotoxin and cytokine profile in plasma of baboons challenged with lethal and sublethal Escherichia coli. (1991)

This descriptive study compares the inflammatory, coagulant, and hemodynamic responses of the baboon to a 2-hr infusion of lethal and sublethal concentrations of Escherichia coli (40 and 4.0 billion organisms per kilogram, respectively). The response to lethal E. coli challenge occurred in three stages: an inflammatory stage marked by a fall in white blood cell count (0-2 hr), a coagulant stage marked by a fall in fibrinogen concentration (2-6 hr), and a hypoxic cell injury stage marked by a rise in SGPT/BUN and by a gradual cardiovascular collapse, and death (6-24 hr). The inflammatory, or first stage coincided with the appearance in plasma of tumor necrosis factor (TNF) and interleukin-1 beta (IL-1 beta), which peaked at 120 and 240-300 min, respectively; a slow but continuous appearance and rise of interleukin-6 (IL-6); and the appearance of endotoxin reaching a maximum at 120 min. This contrasted markedly with the response to sublethal E. coli, in which only one of the three stages was observed (inflammatory) and only minor amounts of the cytokines or endotoxin appeared in the plasma. This study describes the cytokine and endotoxin profiles and the bacteremia in the primate under experimental conditions. It shows for the first time the extreme qualitative differences in their response to lethal and sublethal concentrations of E. coli. It raises the possibility that lethality is associated with an override of the tissue threshold for processing these mediators, as marked by their appearance in plasma in response to lethal E. coli infusion.
Recombinant adeno-associated virus (rAAV) vectors for somatic gene therapy: recent advances and potential clinical applications. (1996)

Adeno-associated virus (AAV) is a single-stranded DNA dependovirus of the family of Parvoviridae that has promising features as a vector for somatic gene therapy. Different recombinant (r) AAV vectors have been generated that seem to have some advantages compared with other vector systems, such as the transduction of terminally differentiated and non-dividing cells, the lack of any apparent pathogenicity, low immunogenicity, relatively high stability of transgene expression, and the potential of targeted integration. Recent improvements in rAAV packaging should allow the generation of sufficient quantities of rAAV for clinical trials. Preclinical studies with rAAV are currently being performed for the treatment of a variety of inherited monogenic defects, such as beta-thalassemia, sickle cell anemia. Fanconi anemia, chronic granulomatous disease, Gaucher disease, metachromatic leukodystrophy and cystic fibrosis, and of acquired diseases, such as HIV infection and non-Hodgkin lymphoma. The diversity of these studies indicates that rAAV might have a broad range of clinical applications. A first clinical trial with rAAV vectors has been started for cystic fibrosis. While several important issues, including safety, tissue tropism and methods to achieve site-specific integration, need further clarification, rAAV seems to have a sufficient number of advantages to be seriously considered as a future gene therapy vector.
Characterization of a transferrin-diphtheria toxin conjugate. (1985)

We report here the synthesis and properties of a hybrid toxin prepared by covalently coupling diphtheria toxin to transferrin. The purified material contained two major hybrid protein species and was highly cytotoxic to mouse LMTK- cells in culture, reducing protein synthesis by 50% in 24 h at a concentration of 1 ng/ml. Cytotoxic activity was completely abolished in the presence of exogenous transferrin or anti-transferrin or anti-diphtheria toxin, thus demonstrating that the hybrid toxin was intoxicating cells via their transferrin receptors and that both the diphtheria toxin and transferrin components of the conjugate were necessary for activity. NH4Cl, a drug that elevates the pH within acidic intracellular vesicles, also blocked cytotoxic activity, suggesting that a low intravesicular pH was required for activity. The inhibitory effect of NH4Cl could be abolished by exposing toxin-treated cells to acidic culture medium, further implicating an acid-dependent step in the mechanism of the hybrid toxin action. Studies on the kinetics of intoxication also implied that endocytosis and exposure to a low pH within vesicles were necessary for cytotoxicity. Altogether, the results suggest that the transferrin-diphtheria toxin conjugate binds to transferrin receptors and is internalized into acidic endocytic vesicles. The enzymatic moiety of diphtheria toxin then apparently enters the cytosol in response to the low pH and subsequently arrests protein synthesis.
Characterisation of the rat and mouse homologues of gC1qBP, a 33 kDa glycoprotein that binds to the globular `heads' of C1q (1997)

gC1qBP is a 33 kDa glycoprotein that binds to the globular 'heads' of C1q. We have cloned cDNAs encoding the rat and mouse homologues of gC1qBP. Comparison of the cDNA-derived amino acid sequences of gC1qBP reveals that either of the rodent sequences is 89.9% identical to the reported human sequence. Recombinant rat gC1qBP binds avidly to human C1q. gC1qBP mRNA is abundantly expressed in every rat and mouse tissue analysed. Rat mesangial cells synthesise gC1qBP, but do not express gC1qBP on the cell surface. In rat serum, gC1qBP is present at low levels.
Highly Efficient Targeted Mutagenesis of Drosophila with the CRISPR/Cas9 System (2013)

Here, we present a simple and highly efficient method for generating and detecting mutations of any gene in Drosophila melanogaster through the use of the CRISPR/Cas9 system (clustered regularly interspaced palindromic repeats/CRISPR-associated). We show that injection of RNA into the Drosophila embryo can induce highly efficient mutagenesis of desired target genes in up to 88% of injected flies. These mutations can be transmitted through the germline to make stable lines. Our system provides at least a 10-fold improvement in efficiency over previously published reports, enabling wider application of this technique. We also describe a simple and highly sensitive method of detecting mutations in the target gene by high-resolution melt analysis and discuss how the new technology enables the study of gene function.
Improving the resolution of cryopreserved X- and Y-sperm during DNA flow cytometric analysis with the addition of Percoll to quench the fluorescence of dead sperm. (1998)

The most effective method to control the sex of offspring is by separating X- from Y-bearing sperm on the basis of their DNA content. Sperm can be stained with Hoechst 33342 and efficiently sexed using a flow cytometer/cell sorter. However, applying this established assay to cryopreserved bovine sperm presents specific problems, such as broad fluorescence distributions without a distinct X- and Y-peak. Our results indicate that these problems are mainly caused by the large amount of dead sperm normally present in a thawed sperm population. We showed that Percoll quenches the fluorescence of chromatin stained with Hoechst 33342 and that this quenching can be applied to reduce the fluorescence of dead sperm. We used this finding to exclude the dead sperm from the sorting window and thus obtained narrower fluorescence distributions and sorted X- and Y-bearing sperm populations containing up to 85 to 92% viable sperm. The viability of the sorted sperm was monitored by propidium iodide exclusion.
Structure-activity relationships of dihydrofolated reductase inhibitors (1984)

ADVERTISEMENT RETURN TO ISSUEPREVArticleStructure-activity relationships of dihydrofolated reductase inhibitorsJeffrey M. Blaney, Corwin Hansch, Carlo Silipo, and Antonio VittoriaCite this: Chem. Rev. 1984, 84, 4, 333–407Publication Date (Print):August 1, 1984Publication History Published online1 May 2002Published inissue 1 August 1984https://doi.org/10.1021/cr00062a002RIGHTS & PERMISSIONSArticle Views980Altmetric-Citations139LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (10 MB) Get e-Alertsclose Get e-Alerts
Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors (2006)

Combining transcriptional targeting by the CMV(enh)/MLC1.5 promoter and AAV vectors devoid of binding the AAV-2 primary receptor results in an efficient cardiac gene transfer with a significantly reduced hepatic transduction.
Multimode video coding for noisy channels (2002)

We focus on the design of robust video compression schemes for transmission over noisy channels. A multimode video coding framework is introduced, which enables optimizing the tradeoff between the conflicting objectives of high compression efficiency and error resilience. The starting point is a simple block-based predictive coder, with no motion compensation, for which we develop the robust multimode video compression scheme. The proposed iterative design algorithm for multimode video coders directly minimizes the overall rate-distortion cost. We show that several conventional joint source-channel coding mechanisms can be incorporated within a multimode scheme to further enhance the video coder performance. Simulation results of compressing benchmark video sequences for transmission over noisy channel conditions are presented. They demonstrate that multimode coders outperform conventional fixed length approaches and can achieve substantial gains of more than 6 dB in PSNR of the reconstructed picture.
Successful Treatment of Ebola Virus–Infected Cynomolgus Macaques with Monoclonal Antibodies (2012)

Ebola virus (EBOV) is considered one of the most aggressive infectious agents and is capable of causing death in humans and nonhuman primates (NHPs) within days of exposure. Recent strategies have succeeded in preventing acquisition of infection in NHPs after treatment; however, these strategies are only successful when administered before or minutes after infection. The present work shows that a combination of three neutralizing monoclonal antibodies (mAbs) directed against the Ebola envelope glycoprotein (GP) resulted in complete survival (four of four cynomolgus macaques) with no apparent side effects when three doses were administered 3 days apart beginning at 24 hours after a lethal challenge with EBOV. The same treatment initiated 48 hours after lethal challenge with EBOV resulted in two of four cynomolgus macaques fully recovering. The survivors demonstrated an EBOV-GP-specific humoral and cell-mediated immune response. These data highlight the important role of antibodies to control EBOV replication in vivo, and support the use of mAbs against a severe filovirus infection.
Central hypomyelination associated with congenital hypomyelinating polyneuropathy: report of an autopsied case. (1989)

The central nervous system (CNS) findings associated with congenital hypomyelinating polyneuropathy (CHN) are not established due to a paucity of reported post-mortem examinations. In this report we describe the pathologic changes found in the peripheral nervous system and CNS in a 2 1/2-week-old infant with a clinical diagnosis of CHN who died of respiratory failure clinically attributed to phrenic nerve dysfunction. Macroscopic findings included striking hypoplasia of the corpus callosum and anterior commissure, cerebellum, crus cerebri, ventral pons and pyramids. Histologic and immunohistochemical findings included complete absence of myelin staining and myelin basic protein immunoreactivity (MBP-IR) in the cerebral hemispheres, cerebellum, brainstem, cranial nerves and spinal cord despite little or no detectable reduction in numbers of oligodendrocytes. A severe fibrillary astrocytosis was seen at each of these sites. A slight reduction in neurons was identified in the cerebellum and spinal cord but nowhere else in the brain. These findings raise the possibility that deficient or markedly delayed CNS myelination accompanies peripheral hypomyelination in some cases of CHN.
Src-mediated Cortactin Phosphorylation Regulates Actin Localization and Injurious Blebbing in Acinar Cells (2008)

Suprastimulation of pancreatic acini is a well-known model for pancreatitis, and it is characterized by actin reorganization and cell blebbing. Currently, however, the mechanisms underlying regulation of these aberrant cytoskeletal and membrane dynamics and how they contribute to cell injury are unclear. We observed that suprastimulation results in a rapid activation of Src and relocalization of the actin-binding protein cortactin from the apical to the basolateral domain at the necks of membrane blebs. Furthermore, Src-mediated cortactin tyrosine phosphorylation was markedly increased after suprastimulation. Pretreatment of acini with Src inhibitors or expression of a cortactin tyrosine phospho-inhibitory mutant reduced actin redistribution and bleb formation induced by suprastimulation in vitro. Importantly, inhibition of Src activity in rat models of suprastimulation-induced pancreatitis substantially reduced disease severity, as indicated by a reduction in serum amylase and pancreatic edema and a striking improvement in tissue histology. These findings indicate a novel, disease-relevant role for Src-mediated cortactin phosphorylation in aberrant reorganization of the actin cytoskeleton, a mechanism that is likely to have implications in other types of cell injury. In addition, they suggest a potential use for Src inhibitors as an approach to reduce cell injury.
U.S. Pharmaceutical Markets: Expenditures, Health Insurance, New Products and Generic Prescribing from 1960 to 2016 (2019)

Between 1960 and 2016 per capita expenditures on retail pharmaceuticals increased from $85.12 to $922.50 in 2009 prices, while the share of spending covered by insurance programs grew to 86%. The introduction of new molecular entities followed only a weak upward trend. Following passage of the Hatch Waxman Act in 1984, the share of retail prescriptions dispensed as generics has expanded from 19% to almost 90%. By employing a three-equation Vector Auto-Regressive (VAR) model and Granger causality, this paper assesses empirically the interdependence among these variables. Our most important finding is that increases in insurance coverage on pharmaceuticals contributed significantly to the spending growth, which in turn led to further insurance expansion. In addition, introduction of new drugs also has contributed to enhanced insurance coverage. While the expansion of generic prescribing has had a strong negative effect on spending, this effect has been largely offset by rapid increases in coverage.
Continuous arbitrary strain profile measurements with fiber Bragg gratings (1998)

A new distributed strain sensing technique using a fiber optic Bragg grating has been developed and tested. This is the first `true' distributed strain sensor, to the authors' knowledge, with a high spatial resolution of about 1 mm. Since gratings can be made with a length of tens of centimeters, this new fiber optic measurement technique could have broad applications to smart materials and structures where monitoring of a continuous strain profile over a length of millimeters to tens of centimeters is needed. In this paper three different demodulation approaches are reviewed indicating a trade-off between a relatively simple measurement process for selected types of strain profile and a more complete measurement process that is suitable for any strain profile. Experimental results with different approaches are presented.
Orexin-1 receptor antagonist SB-334867 reduces the acquisition and expression of cocaine-conditioned reinforcement and the expression of amphetamine-conditioned reward (2011)

Preclinical evidence suggests an important role of the brain orexin system in behaviours related to drug addiction. This study aimed at assessing the effect of the orexin-1 receptor antagonist SB-334867 on aspects of psychostimulant-conditioned behaviours that are thought to contribute to the maintenance of and relapse to psychostimulant drug use. Rats were first allowed to nose poke for cocaine infusions associated with a cue light presentation (conditioned stimulus; CS) over five daily sessions. Subsequently, drug-free rats were tested for the acquisition of a new response in which presses on a novel active lever led to the presentation of the previously paired CS. We tested SB-334867 in two conditions, SB-334867 was given either before each cocaine self-administration or before the initial four sessions of acquisition for a novel instrumental responding paired with the CS (conditioned reinforcement). The effect of SB-334867 was also tested on the expression of conditioned place preference to d-amphetamine. The rats treated with SB-334867 before each cocaine self-administration session subsequently showed reduced active lever pressing compared with controls in the initial days of the conditioned reinforcement. In the second study, untreated rats showed normal acquisition of discriminated responding preferential for the lever providing the cocaine cue. In contrast, SB-334867 decreased the number of active lever pressing (compared with the control) with significant effects in all sessions. Finally, SB-334867 blocked the expression of d-amphetamine-induced conditioned place preference. These results suggest that orexin-1 receptor antagonism could offer therapeutic potential in reducing the impact of psychostimulant-predictive stimuli that contribute to compulsive drug seeking in human drug users.
A novel ultra-wideband pulse design algorithm (2003)

We present a new algorithm to numerically generate pulses that not only have a short time duration for multiple access, but also meet the power spectral constraint of Federal Communications Commission (FCC) ultra-wideband (UWB) mask. In fact, applying our algorithm to the FCC spectral mask for UWB systems can lead to the design of multiple orthogonal pulses that are compliant. Our algorithm presents a flexible and systematic method for generating UWB pulses that have many advantages over the Gaussian monocycle pulse.
Wireless in-house data communication via diffuse infrared radiation (1979)

A novel wireless broadcast/multi-access channel is described for flexibly interconnecting a cluster of data terminals located within the same room. The transmission medium is diffusively scattered infrared radiation at 950-nm wavelength. Transmission is low-to-medium speed and the range up to 50 m. Theoretical analysis indicates that the time dispersion limits the transmission bandwidth of the system to 260 Mbit ċ m/s, but background noise produced by ambient daylight reduces the transmission speed below 1 Mbit/s. The transmission properties of the diffuse optical channel are analyzed, and experimental digital links for baseband PCM at 125 kbit/s and PSK 64 kbit/s are demonstrated.
A novel homocysteine‐responsive gene, smap8, modulates mitogenesis in rat vascular smooth muscle cells (2003)

We isolated the cDNA of a gene, designated smooth muscle-associated protein 8 (smap8), during a search for new genes expressed in human aortic smooth muscle cells. The full-length smap8 cDNA is 3241 bp long and contains an open reading frame of 1113 bp encoding an approximately 45 kDa soluble protein identical to NDRG4 protein. Smap8 mRNA was expressed predominantly in the brain and heart, and moderately in vascular smooth muscle cells. Expression of smap8 mRNA was induced within 3-12 h by treatment with 10 mm homocysteine in rat aortic smooth muscle cells (A10 cells). Expression of exogenous smap8 markedly reduced both the proliferation and migration rates of rat A10 cells, however, PDGF-induced proliferation was significantly enhanced in smap8-expressed cells compared with mock-transfected cells. To ascertain the involvement of smap8 in mitogenesis, we tested the effects of stimulation of smap8, MEK1/2 or ERK1/2, which is known as a proliferation relating intermediate, by various growth factors and cytokines. PDGF was the most prominent in promoting phosphorylation of the smap8 protein. PDGF-dependent phosphorylation of smap8 was induced prior to ERK1/2 activation, and was repressed by staurosporine, a general inhibitor of serine/threonine kinases. Furthermore, activation of both MEK1/2 and ERK1/2 was markedly enhanced in these cells. Smap8 might therefore regulate the potentiation of ERK1/2 signalling induced by PDGF treatment. Our results imply that smap8 is involved in the regulation of mitogenic signalling in vascular smooth muscle cells, possibly in response to a homocysteine-induced injury.
Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. (1987)

CD28 (Tp44) is a human T-cell-specific homodimer surface protein that may participate in T-cell activation. We have isolated a cDNA clone encoding CD28 by a simple and highly efficient cloning strategy based on transient expression in COS cells. Central to this strategy is the use of an efficient method to prepare large plasmid cDNA libraries. The libraries are introduced into COS cells, where transient expression of surface antigen allows the isolation of cDNAs by way of monoclonal antibody binding. The CD28 cDNA encodes a highly glycosylated membrane protein with homology to the immunoglobulin superfamily and directs the production of a homodimer in transfected COS cells.
Effect of oligosaccharide chain length, exposed terminal group, and hapten loading on the antibody response of human adults and infants to vaccines consisting of Haemophilus influenzae type b capsular antigen unterminally coupled to the diphtheria protein CRM197. (1989)

Vaccines consisting of oligosaccharide (OS) derived from Haemophilus influenzae type b capsular polysaccharide and conjugated to carrier proteins had been shown capable of eliciting memory-type capsular polysaccharide of H. influenza type b antibody responses in human infants, but the structural variables governing immunogenicity were not defined. Here a series of conjugates were made with the diphtheria protein CRM197 and with uniterminally coupled OS haptens that varied in chain length, exposed terminal residue, or multiplicity of loading as defined by ribose/protein ratio. Adults were given a single injection, 1-yr-old infants were given a two-injection sequence, and capsular polysaccharide of H. influenzae type b antibody responses were assessed by radioantigen binding. Vaccines C-4r, C-6r, and C-12r, in which ribitol-ended OS of mean length 4, 6, or 12 repeat units were coupled at low hapten loading, were about equally immunogenic (geometric means 2 to 5 micrograms/ml in infants, 5 to 9 micrograms/ml in adults). Vaccine C7p was made with a higher loading of OS having mean length 7 repeat units and having mainly phosphate monoester at the exposed termini Vaccine C-7R was made from a portion of C-7p by enzymatic removal of most of the terminal phosphates. Compared to the C-4r, C-6r, and C-12r series, vaccines C-7p and C-7R induced geometric means about 10-fold higher in adults and 20-fold higher in infants. Thus OS chain length (in the range studied) and exposed terminus are less critical variables in this system than the extent of hapten loading.