gebhart/patrepeval huggingface dataset:
Regulatory and Exhausted T Cell Responses to AAV Capsid (2017)

Recombinant adeno-associated viruses (AAVs) are quickly becoming the preferred viral vector for viral gene delivery for the treatment of a wide variety of genetic disorders. However, since their use in a clinical trial targeting hemophilia B patients 10 years ago, immune responses to the AAV capsid appear to have hampered some of the early clinical gene transfer efficacy. Indeed, AAV-based gene transfer has been shown to reactivate capsid-specific memory T cells, which have correlated with a decline in AAV-transduced tissue in some patients. Importantly, clinical trials have also shown that this reactivation can be quelled by administering time-course taper of glucocorticoid steroids before or after dosing. More recently, two clinical studies have shown that AAV gene transfer is not only able to induce a deleterious immune response, but also can result in the initiation of a tolerance to the AAV capsid mediated by regulatory T cells and exhausted T cells. This article reviews clinical trials describing immune responses to AAV, as well as the mechanisms responsible for immune tolerance in chronic infections and how it could apply to AAV-based gene transfer. A better understanding of both cytotoxic and tolerogenic immune responses to recombinant AAV will lead to safer gene transfer protocols in patients.
Left Atrial Appendage Exclusion for Stroke Prevention in Patients With Nonrheumatic Atrial Fibrillation (2007)

The efficacy of oral anticoagulation (OAC) for stroke prevention in patients with nonrheumatic atrial fibrillation (AF) has clearly been established. However, a substantial number of patients with AF who are at high risk for thromboembolic events are not candidates for long-term OAC. The left atrial appendix (LAA) is the most common place of thrombosis in patients with AF, and it can easily be excluded from the systemic circulation at the time of cardiac surgery by excision, ligation, suturing, or stapling. Currently, removal of the LAA at the time of mitral valve surgery is recommended to reduce future stroke risk. The ongoing LAA Occlusion Study (LAAOS) is evaluating the efficacy of the routine LAA occlusion in patients undergoing elective coronary artery bypass graft surgery. Recently, two devices specifically designed for percutaneous transcatheter LAA occlusion have been introduced: the Percutaneous LAA Transcatheter Occlusion (PLAATO; Appriva Medical Inc) and WATCHMAN LAA system (Atritech, Inc). More than 200 PLAATO devices were implanted worldwide in patients with nonrheumatic AF who were at high risk for ischemic stroke and not candidates for long-term OAC. In a follow-up time of 258 patient-years, an estimated 61% reduction in stroke risk was achieved with PLAATO procedure. The WATCHMAN Left Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation (PROTECT AF) study was designed to demonstrate the safety and efficacy of the WATCHMAN device in patients with nonvalvular AF who are eligible for long-term OAC. The trial is assessing whether the treatment arm (WATCHMAN device) is noninferior to the control arm (warfarin). Although present results suggest that LAA occlusion may reduce the long-term stroke risk, available data are still very limited. At present, percutaneous LAA occlusion may be an acceptable option in selected high-risk patients with AF who are not candidates for OAC. The current understanding of LAA exclusion for the prevention of stroke in patients with nonrheumatic AF is the major focus of this review.
American Academy of Pediatrics. Committee on Injury and Poison Prevention. Transporting children with special health care needs. (1999)

Children with special health care needs should have access to proper resources for safe transportation. This statement reviews important considerations for transporting children with special health care needs and provides current guidelines for the protection of children with specific health care needs, including those with a tracheostomy, a spica cast, challenging behaviors, or muscle tone abnormalities as well as those transported in wheelchairs.
From bacteria to humans, chromatin to elongation, and activation to repression: The expanding roles of noncoding RNAs in regulating transcription (2009)

Noncoding RNAs (ncRNAs) have emerged as key regulators of transcription, often functioning as trans-acting factors akin to prototypical protein transcriptional regulators. Inside cells, ncRNAs are now known to control transcription of single genes as well as entire transcriptional programs in response to developmental and environmental cues. In doing so, they target nearly all levels of the transcription process from regulating chromatin structure through controlling transcript elongation. Moreover, trans-acting ncRNA transcriptional regulators have been found in organisms as diverse as bacteria and humans. With the recent discovery that much of the DNA in genomes is transcribed into ncRNAs with yet unknown function, it is likely that future studies will reveal many more ncRNA regulators of transcription.
<i>Response</i> : Zinc and Alzheimer's Disease (1995)

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C<scp>ARBON</scp> D<scp>IOXIDE</scp> E<scp>MISSIONS FROM THE</scp> G<scp>LOBAL</scp> C<scp>EMENT</scp> I<scp>NDUSTRY</scp> (2001)

▪ Abstract The cement industry contributes about 5% to global anthropogenic CO 2 emissions, making the cement industry an important sector for CO 2 -emission mitigation strategies. CO 2 is emitted from the calcination process of limestone, from combustion of fuels in the kiln, as well as from power generation. In this paper, we review the total CO 2 emissions from cement making, including process and energy-related emissions. Currently, most available data only includes the process emissions. We also discuss CO 2 emission mitigation options for the cement industry. Estimated total carbon emissions from cement production in 1994 were 307 million metric tons of carbon (MtC), 160 MtC from process carbon emissions, and 147 MtC from energy use. Overall, the top 10 cement-producing countries in 1994 accounted for 63% of global carbon emissions from cement production. The average intensity of carbon dioxide emissions from total global cement production is 222 kg of C/t of cement. Emission mitigation options include energy efficiency improvement, new processes, a shift to low carbon fuels, application of waste fuels, increased use of additives in cement making, and, eventually, alternative cements and CO 2 removal from flue gases in clinker kilns.
Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis (1994)

Mechanisms of guanosine triphosphate (GTP) hydrolysis by members of the G protein alpha subunit-p21ras superfamily of guanosine triphosphatases have been studied extensively but have not been well understood. High-resolution x-ray structures of the GTP gamma S and GDP.AlF4- complexes formed by the G protein Gi alpha 1 demonstrate specific roles in transition-state stabilization for two highly conserved residues. Glutamine204 (Gln61 in p21ras) stabilizes and orients the hydrolytic water in the trigonal-bipyramidal transition state. Arginine 178 stabilizes the negative charge at the equatorial oxygen atoms of the pentacoordinate phosphate intermediate. Conserved only in the G alpha family, this residue may account for the higher hydrolytic rate of G alpha proteins relative to those of the p21ras family members. The fold of Gi alpha 1 differs from that of the homologous Gt alpha subunit in the conformation of a helix-loop sequence located in the alpha-helical domain that is characteristic of these proteins; this site may participate in effector binding. The amino-terminal 33 residues are disordered in GTP gamma S-Gi alpha 1, suggesting a mechanism that may promote release of the beta gamma subunit complex when the alpha subunit is activated by GTP.
The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases (2011)

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity.
Binding of a fibrinogen mimetic stabilizes integrin αIIbβ3's open conformation (2001)

The platelet integrin alphaIIbbeta3 is representative of a class of heterodimeric receptors that upon activation bind extracellular macromolecular ligands and form signaling clusters. This study examined how occupancy of alphaIIbbeta3's fibrinogen binding site affected the receptor's solution structure and stability. Eptifibatide, an integrin antagonist developed to treat cardiovascular disease, served as a high-affinity, monovalent model ligand with fibrinogen-like selectivity for alphaIIbbeta3. Eptifibatide binding promptly and reversibly perturbed the conformation of the alphaIIbbeta3 complex. Ligand-specific decreases in its diffusion and sedimentation coefficient were observed at near-stoichiometric eptifibatide concentrations, in contrast to the receptor-perturbing effects of RGD ligands that we previously observed only at a 70-fold molar excess. Eptifibatide promoted alphaIIbbeta3 dimerization 10-fold more effectively than less selective RGD ligands, as determined by sedimentation equilibrium. Eptifibatide-bound integrin receptors displayed an ectodomain separation and enhanced assembly of dimers and larger oligomers linked through their stalk regions, as seen by transmission electron microscopy. Ligation with eptifibatide protected alphaIIbbeta3 from SDS-induced subunit dissociation, an effect on electrophoretic mobility not seen with RGD ligands. Despite its distinct cleft, the open conformer resisted guanidine unfolding as effectively as the ligand-free integrin. Thus, we provide the first demonstration that binding a monovalent ligand to alphaIIbbeta3's extracellular fibrinogen-recognition site stabilizes the receptor's open conformation and enhances self-association through its distant transmembrane and/or cytoplasmic domains. By showing how eptifibatide and RGD peptides, ligands with distinct binding sites, each affects alphaIIbbeta3's conformation, our findings provide new mechanistic insights into ligand-linked integrin activation, clustering and signaling.
Towards a user interface generation approach based on object oriented design and task model (2005)

This paper presents an approach of generating the user interface from the task model. Our work is situated in the course of approaches based on models. This approach called TOOD (Task Object Oriented Design) is based on a formal notation, which gives quantitative results that may be checked by designers and provide the possibility of performing mathematical verifications on the models. The modelling formalism is based on the joint use of the object approach and high level Petri nets. The TOOD method integrates different models (task model, user model, local model of the interface, abstract model of the interface, and model of the implementation) and their relations. An example, extracted from the air traffic control, is presented to illustrate TOOD methodology.
Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells (2014)

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.
161. A search for new trypanocides. Part V. Some derivatives of 10-phenyl-4 : 9-diazaphenanthrene (1958)

M. Davis, J. Chem. Soc., 1958, 828 DOI: 10.1039/JR9580000828
Microprocessor-controlled automatic clutter-cancellation circuits for microwave systems to sense physiological movements remotely through the rubble (2002)

A novel microprocessor-controlled automatic clutter-cancellation subsystem, consisting of a programmable microwave attenuator and a programmable microwave phase shifter controlled by a microprocessor-based control unit, has been developed for a microwave life-detection system (L-band 2 GHz or X-band 10 GHz) which can remotely sense breathing and heartbeat movements of living subjects. This automatic clutter-cancellation subsystem is a drastic improvement over the very slow process of adjusting clutter-cancellation manually in the old microwave system; this is very important for some potential applications, which include locating earthquake- or avalanche-trapped victims through rubble. A series of experiments have been conducted to demonstrate the applicability of this microwave life-detection system. The 2-GHz system performs well for remotely detecting human breathing and heartbeat signals through a pile of rubble of up to about 3 ft. thick. The automatic clutter canceler may also have a potential application in some CW (continuous wave) radars.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Proteolytic Release of the Intramolecular Chaperone Domain Confers Processivity to Endosialidase F (2009)

Endosialidases (endoNs), as identified so far, are tailspike proteins of bacteriophages that specifically bind and degrade the alpha2,8-linked polysialic acid (polySia) capsules of their hosts. The crystal structure solved for the catalytic domain of endoN from coliphage K1F (endoNF) revealed a functional trimer. Folding of the catalytic trimer is mediated by an intramolecular C-terminal chaperone domain. Release of the chaperone from the folded protein confers kinetic stability to endoNF. In mutant c(S), the replacement of serine 911 by alanine prevents proteolysis and generates an enzyme that varies in activity from wild type. Using soluble polySia as substrate a 3-times higher activity was detected while evaluation with immobilized polySia revealed a 190-fold reduced activity. Importantly, activity of c(S) did not differ from wild type with tetrameric sialic acid, the minimal endoNF substrate. Furthermore, we show that the presence of the chaperone domain in c(S) destabilizes binding to polySia in a similar way as did selective disruption of a polySia binding site in the stalk domain. The improved catalytic efficiency toward soluble polySia observed in these mutants can be explained by higher dissociation and association probabilities, whereas inversely, an impaired processivity was found. The fact that endoNF is a processive enzyme introduces a new molecular basis to explain capsule degradation by bacteriophages, which until now has been regarded as a result of cooperative interaction of tailspike proteins. Moreover, knowing that release of the chaperone domain confers kinetic stability and processivity, conservation of the proteolytic process can be explained by its importance in phage evolution.
Amino-terminal processing of proteins by N-myristoylation. Substrate specificity of N-myristoyl transferase. (1987)

Using synthetic octapeptides, we examined the amino-terminal sequence requirements for substrate recognition by myristoyl-CoA:protein N-myristoyl transferase (NMT). NMT is absolutely specific for peptides with amino-terminal Gly residues. Peptides with Asn, Gln, Ser, Val, or Leu penultimate to the amino-terminal Gly were substrates, whereas peptides with Asp, D-Asn, Phe, or Tyr at this position were not myristoylated. Peptides with aromatic residues at this position competitively inhibited myristoylation of substrates, introducing the possibility of developing specific in vivo inhibitors of NMT. Peptides having sequences which correspond to those of known N-myristoyl proteins, including p60src, appear to be recognized by a single enzyme, and yeast and murine NMT have identical substrate specificities. The catalytic selectivity of NMT for myristoyl transfer accounts for the remarkable acyl chain specificity of this enzyme.
A study of twins and stroke. (1992)

This nearly fivefold increase in the prevalence of stroke among the monozygotic compared with the dizygotic twin pairs suggests that genetic factors are involved in the etiology of stroke. The twin study paradigm holds considerable promise for identifying both genetic and environmental influences on stroke.
Botulinum toxin-A injections via electrical motor point stimulation to treat writer's cramp: pilot study. (2006)

Lower dosages of BTX-A, administered using EMPS, offers the advantages of decreased cost and increased accuracy of targeting, while achieving good outcomes.
Mice immunized with a subviral particle containing the japanese encephalitis virus prM/M and E proteins are protected from lethal JEV infection (1992)

Extracellular subviral particles produced by HeLa cells infected with a recombinant vaccinia virus encoding the prM and E genes of Japanese encephalitis virus (JEV) were purified and characterized. These particles contained the JEV prM/M and E proteins embedded in a lipid bilayer, and RNA was not detected in particles using the polymerase chain reaction and primers recognizing a part of the JEV E gene. The particles were uniformly spherical with a 20-nm diameter and had 5-nm projections on their surface. Mice that received a single inoculation of the purified extracellular particles emulsified with Freund's complete adjuvant were fully protected against 4.9 x 10(5) LD50 of JEV. Comparison of the neutralizing and hemagglutination-inhibiting antibody titers and radioimmunoprecipitation data showed that immunization with the particles induced an immune response similar to that following inoculation with the recombinant vaccinia virus.
Mobilization of the genes for photosynthesis from Rhodopseudomonas capsulata by a promiscuous plasmid (1981)

Plasmid pBLM2, a derivative of RP1 with enhanced chromosome mobilization activity in Rhodopseudomonas capsulata, was isolated by screening rare exconjugant clones for sex factor activity. pBLM2 mobilized all known genes affecting photosynthesis as well as chromosomal genes for streptomycin and rifampin resistance and tryptophan and cytochrome biosynthesis. Tight linkage was exhibited among the genes affecting photosynthesis. The frequency of successful transfer of chromosomal markers reached 6 X 10(-4) per donor cell. R-primes were occasionally formed during conjugation, and a number of R-primes bearing the genes for photosynthesis were isolated by screening R. capsulata exconjugants with complementation phenotypes for the ability to transmit plasmid-borne R. capsulata genes to Escherichia coli cells. These R-primes were unstable in R. capsulata, but stable in E. coli or Pseudomonas fluorescens. Complementation and recombination events that occurred upon introduction of R-primes into R. capsulata mutants with altered photosynthetic apparatuses could be visualized as variations in colony pigmentation. Each R-prime studied complemented all known types of mutation affecting the differentiation of the photosynthetic apparatus, and no other R. capsulata gene was identified on those plasmids. The R. capsulata genes borne on the R-primes were not functional in E. coli or P. fluorescens.
Indirect immunotargeting of CIS‐PT to human epidermoid carcinoma KB using the avidin‐biotin system (1991)

Cis-diamminedichloroplatinum (II) (cis-Pt) complexed to a carboxymethyl dextran-avidin conjugate was targeted to biotin-monoclonal antibody 108 (b-MAb 108). This MAb recognizes the extracellular domain of the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma (KB) cells over-expressing EGF-R. Cis-Pt-carboxymethyl-dextran-avidin (Pt-dex-Av) containing 60-90 M cis-Pt/M avidin was administered 24 hr following b-MAb108 containing 3-5 M biotin/M MAb. This treatment was potentially more effective in suppressing the growth of established KB tumor xenografts, or in inhibiting the development of lung metastases in nude mice, than free MAb 108, free drug or MAb 108 followed by drug. Replacing b-MAb 108 by unbiotinylated antibody or by b-MAb of a different specificity also yielded lower suppressive effects. The sequential administration of Pt-dex-Av following b-MAb was more effective than introduction of the Pt-dex-Av when already complexed to b-MAb 108. The results presented in this preliminary investigation suggest that Pt-dex-Av is specifically removed from the circulation by b-MAb 108 concentrated at the tumor site.
DNA sequencing by capillary electrophoresis using copolymers of acrylamide andN,N-dimethyl-acrylamide (2001)

Copolymers of acrylamide (AM) and N,N-dimethylacrylamide (DMA) with AM to DMA molar ratios of 3:1, 2:1 and 1:1 and molecular weights of about 2.2 MDa were synthesized. The polymers were tested as separation media in DNA sequencing analysis by capillary electrophoresis (CE). The dynamic coating ability of polydimethylacrylamide (PDMA) and the hydrophilicity of polyacrylamide (PAM) have been successfully combined in these random copolymers. A separation efficiency of over 10 million theoretical plates per meter has been reached by using the bare capillaries without the additional polymer coating step. Under optimized separation conditions for longer read length DNA sequencing, the separation ability of the copolymers decreased with decreasing AM to DMA molar ratio from 3:1, 2:1 and 1:1. In comparison with PAM, the copolymer with a 3:1 AM:DMA ratio showed a higher separation efficiency. By using a 2.5% w/v copolymer with 3:1 AM:DMA ratio, one base resolution of 0.55 up to 699 bases and 0.30 up to 963 bases have been achieved in about 80 min at ambient temperatures.
Use of Chlorophyllin in the Care of Geriatric Patients (1980)

In a test group of 62 geriatric nursing home patients, the administration of chlorophyllin tablets was found to be helpful in controlling body and fecal odors. It aided also in easing chronic constipation, served at times as a useful and morale-building placebo, and assisted in abating excessive flatus. No toxic or other ill effects were observed. Bacteriologic studies failed to confirm reports in the literature of antibacterial properties for chlorophyllin. Further investigation of this possibility is recommended.