gebhart/patrepeval huggingface dataset:
Spontaneous Regression of Primary Autoreactivity during Chronic Progression of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis (1999)

Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for multiple sclerosis (MS). EAE is typically initiated by CD4(+) T helper cell type 1 (Th1) autoreactivity directed against a single priming immunodominant myelin peptide determinant. Recent studies have shown that clinical progression of EAE involves the accumulation of neo-autoreactivity, commonly referred to as epitope spreading, directed against peptide determinants not involved in the priming process. This study directly addresses the relative roles of primary autoreactivity and secondary epitope spreading in the progression of both EAE and MS. To this end we serially evaluated the development of several epitope-spreading cascades in SWXJ mice primed with distinctly different encephalitogenic determinants of myelin proteolipid protein. In a series of analogous experiments, we examined the development of epitope spreading in patients with isolated monosymptomatic demyelinating syndrome as their disease progressed to clinically definite MS. Our results indicate that in both EAE and MS, primary proliferative autoreactivity associated with onset of clinical disease invariably regresses with time and is often undetectable during periods of disease progression. In contrast, the emergence of sustained secondary autoreactivity to spreading determinants is consistently associated with disease progression in both EAE and MS. Our results indicate that chronic progression of EAE and MS involves a shifting of autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the self-recognition process during disease progression.
Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy (2008)

We cannot determine whether the bias observed resulted from a failure to submit manuscripts on the part of authors and sponsors, from decisions by journal editors and reviewers not to publish, or both. Selective reporting of clinical trial results may have adverse consequences for researchers, study participants, health care professionals, and patients.
Effect of monomer structure on the gelation of a class of metallo-supramolecular polymers (2009)

Gelation of metallo-supramolecular polymers prepared from three ditopic ligand monomers, 1, 2 and 3, derived, respectively, from tetra-, penta-, and hexaethylene glycols, in the presence of the transition metal ion ZnII, as well as the properties of the resulting gels, are investigated and compared. It is found that these slight changes in the core length of the monomer lead to substantial variations in the gel characteristics, which can be attributed to solubility differences between the corresponding metallo-supramolecular polymers. Observations of gelation kinetics indicate 3:Zn has the slowest and 1:Zn the fastest rate. Rheological measurements of the gelation kinetics of 1:Zn indicate unusual behavior in that the modulus exhibits a distinct maximum at a gel time of around 15–30 min. The origin of this phenomenon is suggested to be the transient formation of a metastable colloidal structure which occurs on account of the fast phase separation kinetics of 1:Zn and subsequent particle densificationvia redistribution of solvent. Under equivalent conditions of solvent quality and polymer concentration, the shear modulus of 2:Zn gels is substantially higher than that of 1:Zn and 3:Zn. It appears that the lower modulus of 1:Zn is a consequence of its lower solubility, which results in smaller, more dense colloidal particles and hence a lower particle volume fraction. On the other hand, 3:Zn gels also have a lower modulus than 2:Zn on account of their higher solubility, resulting in a larger sol fraction under the equivalent conditions.
Acute Irreversible Intestinal Failure and Early Intestinal Transplantation: Indications and Survival Outcomes (2004)

O61* Aims: The current established indications for intestinal transplantation are limited to intestinal failure patients who have failed TPN therapy. However, the recently documented compound negative impacts of chronic intestinal and TPN failure on outcomes after transplantation support the notion of modifying the current strict criteria and timing for transplantation. This study was designed to establish the medical indications for early transplantation and validate the assumed therapeutic benefits. Methods: Between July 2000 and March 2004, 15 (20%) out of 74 adult consecutive patients underwent intestinal transplantation within 6 months from the onset of TPN therapy with a median of 3 months (range: 0.5–6). Five patients were male and 10 were female with a mean (SD) age of 37 ± 13 (range: 17–57). The primary causes of intestinal failure were vascular thrombosis (n=6), volvulus (n=5), Crohn’s disease (n=3), and trauma (n=1). The indications for early transplantation were ultra-short gut syndrome/active duodenopancreatic fistulae (n=11), portal/hepatic artery thrombosis (n=2), extra-gastrointestinal autoimmune diseases (n=1) and brutal diabetes (n=1). The blood type was O in 6, A in 7, and AB in 2. The cytomegaloviral serology was negative in 7 and positive in 8 recipients. Thirteen patients underwent an isolated intestinal transplantation and the remaining 2 required an allograft that contained the stomach and/or pancreas en-bloc with the intestine. Results: With a mean (SD) follow-up of 22 ± 14 months, one patient died of cardiac arrest with a fully functioning graft with an overall survival rate of 93%. Of the 14 current survivors, 12 (86%) are off TPN enjoying unrestricted oral diet. The other 2 recipients required allograft enterectomy due to graft thrombosis in a hypercoagulable patient (n=1) and chronic rejection (n=1) and both are currently waiting for retransplantation. As expected, the postoperative course for most patients was uneventful and the initial hospitalization was relatively short with a median of 23 days. With our current tolerogenic immunosuppressive protocol, 10 (83%) of the 12 current survivors with functioning grafts are on spaced doses of tacrolimus and free of steroid therapy. Of particular interest is the full restoration of the nutritional autonomy and normalization of patient lifestyle at an earlier time compared to recipients transplanted after development of TPN failure. Conclusions: This study outlines the medical indications for early consideration of intestinal transplantation before the development of TPN failure. The reported herein successful outcomes and the expected long-term continuation of these therapeutic benefits may justify the need for early referral of patients with irreversible intestinal failure and timing of transplantation.
A New Orthogonal Suppressor tRNA/Aminoacyl-tRNA Synthetase Pair for Evolving an Organism with an Expanded Genetic Code (2000)

Several steps have been completed toward the development of a method for the site-specific incorporation of unnatural amino acids into proteins in vivo. Our approach consists of the generation of amber suppressor tRNA/aminoacyl-tRNA synthetase pairs that are orthogonal to all Escherichia coli endogenous tRNA/synthetase pairs, followed by directed evolution of the orthogonal aminoacyl-tRNA synthetases to alter their amino-acid specificities. A new orthogonal suppressor tRNA/aminoacyl-tRNA synthetase pair in E. coli has been derived from the Saccharomyces cerevisiae tRNAAsp and aspartyl-tRNA synthetase, and the in vitro and in vivo characteristics of this pair were determined. Two different antibiotic resistance selections were compared using this novel pair in an effort to develop a tunable positive selection for a mutant synthetase capable of charging its cognate suppressor tRNA with an unnatural amino acid.
Investigating cyberbullying :Emerging research and e-safety strategies within families and communities (2012)

As new technologies and ways of communicating become increasingly central to daily life, new forms of social aggression using digital tools are emerging globally. Social networking technologies have brought about opportunities to engage in cyberbullying and place considerable pressures on families, schools and communities to remain informed and vigilant to this developing phenomenon. While research findings suggest that up to one in four children report being cyberbullied, the impact of this negative behaviour is often hidden from parents, carers, teachers and the broader community. This paper aims to provide an overview of the forms and effects of cyberbullying by reviewing the research literature, the incidence of, and factors contributing to cyberbullying. The paper also explores emerging approaches to developing e-safety strategies across Australia.
Soluble forms of tau are toxic in Alzheimer’s disease (2012)

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer's disease and other tauopathies.
Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies. (1993)

A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.
1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. (1984)

Activated B and T lymphocytes from normal human subjects are known to have the specific high-affinity receptor for 1,25-dihydroxyvitamin D3 (1,25-(OH)2-D3). In an attempt to determine a functional role for the sterol in such cells, we studied the effect of 1,25-(OH)2-D3 on DNA synthesis and Ig production by normal human peripheral blood mononuclear (PBM) cells activated in vitro by the polyclonal lymphocyte activators pokeweed mitogen and phytohemagglutinin, and the specific antigen dermatophyton O. A dose-dependent inhibition of [3H]thymidine incorporation was observed in cells incubated with 1,25-(OH)2-D3 in concentrations ranging from 10(-10) to 10(-7) M. Production of IgG and IgM, determined by enzyme-linked immunosorbent assay, was similarly inhibited by increasing concentrations of 1,25-(OH)2-D3. Half-maximal inhibition of DNA and Ig synthesis was found at 10(-10) to 10(-9) M 1,25-(OH)2-D3. This suppressive effect was specific for 1,25-(OH)2-D3; of the other vitamin D metabolites examined, only 10(-7) M 24R,25 dihydroxyvitamin D3 (24,25-(OH)2-D3) had a similar inhibitory effect. 1,25-(OH)2-D3 was not cytotoxic and did not affect unactivated PBMs. These data demonstrate that 1,25-(OH)2-D3 is a potent inhibitor of human PBM Ig production in vitro and suggest that this action is mediated through the hormone's antiproliferative effect on Ig-producing B cells and/or helper T cells.
Human leukocytes kill varicella-zoster virus-infected fibroblasts in the presence of murine monoclonal antibodies to virus-specific glycoproteins (1985)

Seven murine monoclonal antibodies reacting with major glycoproteins of varicella-zoster virus were tested for functional activity in assays for antibody-dependent cellular cytotoxicity (ADCC) and antibody-plus-complement-mediated lysis. Human peripheral blood mononuclear cells killed varicella-zoster virus-infected fibroblasts in the presence of three of four monoclonal antibodies directed against gp98/62 and a single monoclonal antibody directed against gp118. Neither of two monoclonal antibodies directed against gp66 was able to mediate ADCC. In 18-h assays, adherent effector cells were more active than nonadherent effector cells in mediating ADCC. Adherent cells treated with anti-Leu-11b and complement retained their cytotoxic activity, suggesting that monocytes are responsible for most of the adherent-cell-mediated cytotoxicity. Both immunoglobulin G1 and G2a murine monoclonal antibodies were able to participate in ADCC. Of the two immunoglobulin G2a monoclonal antibodies tested, both of which reacted with gp98/62, only one mediated lysis in the presence of complement. These results indicate that some murine monoclonal antibodies against major glycoproteins of varicella-zoster virus have functional activity in cytotoxicity assays.
Vector-Free and Transgene-Free Human iPS Cells Differentiate into Functional Neurons and Enhance Functional Recovery after Ischemic Stroke in Mice (2013)

Stroke is a leading cause of human death and disability in the adult population in the United States and around the world. While stroke treatment is limited, stem cell transplantation has emerged as a promising regenerative therapy to replace or repair damaged tissues and enhance functional recovery after stroke. Recently, the creation of induced pluripotent stem (iPS) cells through reprogramming of somatic cells has revolutionized cell therapy by providing an unlimited source of autologous cells for transplantation. In addition, the creation of vector-free and transgene-free human iPS (hiPS) cells provides a new generation of stem cells with a reduced risk of tumor formation that was associated with the random integration of viral vectors seen with previous techniques. However, the potential use of these cells in the treatment of ischemic stroke has not been explored. In the present investigation, we examined the neuronal differentiation of vector-free and transgene-free hiPS cells and the transplantation of hiPS cell-derived neural progenitor cells (hiPS-NPCs) in an ischemic stroke model in mice. Vector-free hiPS cells were maintained in feeder-free and serum-free conditions and differentiated into functional neurons in vitro using a newly developed differentiation protocol. Twenty eight days after transplantation in stroke mice, hiPS-NPCs showed mature neuronal markers in vivo. No tumor formation was seen up to 12 months after transplantation. Transplantation of hiPS-NPCs restored neurovascular coupling, increased trophic support and promoted behavioral recovery after stroke. These data suggest that using vector-free and transgene-free hiPS cells in stem cell therapy are safe and efficacious in enhancing recovery after focal ischemic stroke in mice.
Control-flow integrity principles, implementations, and applications (2009)

Current software attacks often build on exploits that subvert machine-code execution. The enforcement of a basic safety property, control-flow integrity (CFI), can prevent such attacks from arbitrarily controlling program behavior. CFI enforcement is simple and its guarantees can be established formally, even with respect to powerful adversaries. Moreover, CFI enforcement is practical: It is compatible with existing software and can be done efficiently using software rewriting in commodity systems. Finally, CFI provides a useful foundation for enforcing further security policies, as we demonstrate with efficient software implementations of a protected shadow call stack and of access control for memory regions.
Molecular cloning of a human apoC-III variant: Thr 74----Ala 74 mutation prevents O-glycosylation. (1987)

Apolipoprotein C-III (apoC-III) is a major protein of very low density lipoprotein (VLDL). The apoC-III polypeptide contains a carbohydrate chain containing galactosamine, galactose, and sialic acid attached in O-linkage to a threonine residue at position 74. We have cloned the apoC-III gene from a subject whose serum contained unusually high amounts of apoC-III lacking the carbohydrate moiety (C-III-0). DNA sequence analysis of the cloned gene revealed a single nucleotide substitution (A----G) that encodes an alanine at position 74 instead of the normal threonine. As a result of this amino acid replacement, the mutant apoC-III polypeptide is not glycosylated. The mutation in the apoC-III gene creates a novel AluI site that permits diagnosis of the change by Southern blotting of genomic DNA.
Sertraline: a new antidepressant. (1988)

The authors review preclinical data; clinical pharmacology data; and efficacy data of sertraline, a novel serotonin uptake inhibitor. Both in vitro and in vivo, sertraline is a potent and specific serotonin uptake inhibitor (possessing up to 10 times the activity of similar agents). Chronic dosing produces down-regulation of beta-adrenergic receptors. In man, sertraline inhibits platelet serotonin uptake and is devoid of obvious cardiac effects. The plasma half-life of sertraline is 25 hours. Studies on psychomotor performance show little or no effect at doses up to 100 mg, whereas 200 and 400 mg appear to possess some sedating action. Sertraline exhibits acute antidepressant effects in the dose range 50 to 200 mg/day; in addition, in the same dose range it prevents recurrence of depression. Its side-effect profile is similar to that of drugs of the same class (dry mouth, nausea, and diarrhea being the most prominent); it lacks the obvious anticholinergic and sedating effects of amitriptyline.
Domain swapping in a COOH-terminal fragment of platelet factor 4 generates potent angiogenesis inhibitors. (2002)

A few peptide residues in structurally important locations often determine biological functions of proteins implicated in the regulation of angiogenesis. We have shown recently that the short COOH-terminal segment PF-4(47-70) derived from platelet factor 4 (PF-4) is the smallest sequence that conserves potent antiangiogenic activity in vitro and in vivo. Here we show that modified COOH-terminal PF-4 peptides containing the sequence ELR (or related DLR), a critical domain present in proangiogenic chemokines, surprisingly elicit several times greater antiangiogenic potential than the original peptide. The modified peptides inhibit binding of iodinated vascular endothelial growth factor and fibroblast growth factor 2 to endothelial cell receptors, endothelial cell proliferation, migration, and microvessel assembly in the rat aortic ring model at lower doses than PF-4(47-70). On the differentiated chick chorioallantoic membrane, topical application of 40 micro g of modified peptides potently reduces capillary angiogenesis induced by vascular endothelial growth factor(165), a dose where peptide PF-4(47-70) was inactive. Established intracranial glioma in nude mice decreased significantly in size when treated locally with a total dose of 250 micro g of peptide PF-4(47-70)DLR (n = 10) compared with the same dose of the original PF-4(47-70) peptide (n = 10) or controls (n = 30). Tailored PF-4 peptides represent a new class of antiangiogenic agents with a defined mode of action and a strong in vivo activity.
Update on Pharmacologic Approaches to Prevent Thromboembolism in Atrial Fibrillation: Are Thrombin and Factor Xa Inhibitors the Ultimate Answer? (2011)

Atrial fibrillation (AF) is the most common clinically relevant cardiac arrhythmia. Prevalence and incidence rates are rising with the advancing population age. A severe complication of untreated AF is thrombus formation in the left atrial appendage with consecutive peripheral thromboembolism. Thus, AF is a major contributor to thromboembolic events, especially in the elderly. Depending on the CHADS2 score for thromboembolic events that takes into account congestive heart failure, hypertension, age, diabetes mellitus and stroke as risk factors, oral anticoagulation therapy with vitamin K antagonists is currently the treatment of choice for the prevention of thromboembolism. However, due to drawbacks of current anticoagulation therapy new substances for oral therapy are currently evaluated in various clinical studies. This article provides an up to date overview of orally active compounds for the future treatment of AF. Emphasis lies on comparison of direct thrombin inhibitors with factor Xa inhibitors that are currently investigated in clinical phase III studies for the treatment of non-valvular AF. The direct thrombin inhibitor dabigatran will be compared with factor Xa inhibitors like rivaroxaban and apixaban. Other promising agents currently investigated in phase II trials such as direct factor Xa inhibitors DU-176b (edoxaban) and YM150, will also be discussed.
Computational Studies of the Thermochemistry for Conversion of Glucose to Levulinic Acid (2010)

The thermochemistry of the conversion of glucose to levulinic acid through fructofuranosyl intermediates is investigated using the high-level ab initio methods G4 and G4MP2. The calculated gas phase reaction enthalpies indicate that the first two steps involving water molecule elimination are highly endothermic, while the other steps, including additional water elimination and rehydration to form levulinic acid, are exothermic. The calculated gas phase free energies indicate that inclusion of entropic effects makes the dehydration steps more favorable, although the elimination of the first water is still endothermic. Elevated temperatures and aqueous reaction environments are also predicted to make the dehydration reaction steps thermodynamically more favorable. On the basis of these enthalpy and free energy calculations, the first dehydration step in conversion of glucose to levulinic acid is likely a key step in controlling the overall progress of the reaction. An assessment of density functional theories and other theoretical methods for the calculation of the dehydration and hydration reactions in the decomposition of glucose is also presented.
Using learning objects to support introductory computer architecture education (2006)

Teaching the internal operation of computer systems (at any level) is not a simple task. The material covered on such introductory computer architecture modules can often be found to be dull and complex by students. One of the main reasons for the complexity and lack of interest relates to coverage of material that students find difficult to visualise and/or interact with. When module material includes coverage of low level electronics, boolean logic and data representation then students can quickly start to lose interest or perceive higher levels of complexity presenting significant barriers to their learning. This paper describes the creation and integration of a range of multimedia based learning objects into an introductory computer and Internet Architectures module. The learning objects were designed with the aim of enabling enhanced student learning through a focus on experience, interaction and repetition. The application of multimedia learning objects on this module is evaluated through collection of pre and post module student feedback.
Improved Vancomycin Dosing in Children Using Area Under the Curve Exposure (2013)

: Targeted exposure using vancomycin AUC/MIC, compared with trough concentrations, is a more realistic target in children. Depending on age, serum creatinine and MIC distribution, vancomycin in a dosage of 60 to 70 mg/kg/day was necessary to achieve AUC/MIC ≥ 400 in 75% of patients.