gebhart/patrepeval huggingface dataset:
Tetanus toxin. The effect of chemical modifications on toxicity, immunogenicity, and conformation. (1975)

Tetanus toxin has been isolated from the extract of Clostridium tetani and analyzed for purity using various methods, e.g. sedimentation velocity, gel filtration, polyacrylamide gel electrophoresis, immunoelectrophoresis, and immunodiffusion. The homogeneous toxin, characterized by a minimum lethal dose of 10 pg (18- to 20-g mouse), was judged to be of high purity. The amino acid composition was determined and found to be in good agreement with reported values for both filtrate and extract toxin. The corrected sedimentation coefficient, so20,w, was found to be 7.5, and the molecular weight was estimated to be 150,000. These values agree closely with those reported by others. The toxin was modified using the conventional formaldehyde reaction to produce toxoid and both reductive methylation and carbamylation, which are highly specific for lysyl residues. Under certain reaction conditions, carbamylation of the toxin completely eliminated toxicity. Whereas reductive methylation yielded a high degree of conversion of lysine to dimethyllysine and monomethyllysine, the toxicity, albeit greatly reduced, was never completely eliminated. The circular dichroic spectrum of each chemically modified toxin was obtained, resolved into Gaussian components, and compared with that of native toxin, which is estimated to contain about 20% alpha helix and 23% beta structure. The far ultraviolet circular dichroic spectra of toxin and toxoid were characterized by negative extrema at 208 nm and 217 nm attributable to ordered secondary structure, and toxin also exhibited a distinct shoulder at 223 nm. Carbamylated toxin and methylated toxin were characterized by negative extrema at 210 nm and 206 nm, respectively, and both exhibited shoulders at 216 to 217 nm and 223 nm. The toxin and derivatives exhibited multiple negative extrema above 250 nm which were assigned to the various aromatic residues. There were differences in the spectra of the toxin and derivatives over the entire wavelength region, thus suggesting changes in the local environment of various chromophores. In particular, the rotational strengths of many of the bands assigned to tryptophan, tyrosine, and phenylalanine were altered in the derivatives. Also, in the far ultraviolet region of the circular dichroic spectrum, the data were suggestive of some reduction in the amount of both alpha helix and beta structure in the derivatives. However, there was no evidence of extensive conformational changes, e.g. unfolding, in the modified toxins. Presently, it is not known if the small conformational differences between toxin and toxoid are important in the loss of toxicity with the retention of immunogenicity in the derivative. The modification data are consistent with the hypothesis that separate amino acid residues are involved in toxicity and immunogenicity.
Virtual Integration Environment as an Advanced Prosthetic Limb Training Platform (2018)

<b>Background:</b> Despite advances in prosthetic development and neurorehabilitation, individuals with upper extremity (UE) loss continue to face functional and psychosocial challenges following amputation. Recent advanced myoelectric prostheses offer intuitive control over multiple, simultaneous degrees of motion and promise sensory feedback integration, but require complex training to effectively manipulate. We explored whether a virtual reality simulator could be used to teach dexterous prosthetic control paradigms to individuals with UE loss. <b>Methods:</b> Thirteen active-duty military personnel with UE loss (14 limbs) completed twenty, 30-min passive motor training sessions over 1-2 months. Participants were asked to follow the motions of a virtual avatar using residual and phantom limbs, and electrical activity from the residual limb was recorded using surface electromyography. Eight participants (nine limbs), also completed twenty, 30-min active motor training sessions. Participants controlled a virtual avatar through three motion sets of increasing complexity (Basic, Advanced, and Digit) and were scored on how accurately they performed requested motions. Score trajectory was assessed as a function of time using longitudinal mixed effects linear regression. <b>Results:</b> Mean classification accuracy for passive motor training was 43.8 ± 10.7% (14 limbs, 277 passive sessions). In active motor sessions, >95% classification accuracy (which we used as the threshold for prosthetic acceptance) was achieved by all participants for Basic sets and by 50% of participants in Advanced and Digit sets. Significant improvement in active motor scores over time was observed in Basic and Advanced sets (per additional session: β-coefficient 0.125, <i>p</i> = 0.022; β-coefficient 0.45, <i>p</i> = 0.001, respectively), and trended toward significance for Digit sets (β-coefficient 0.594, <i>p</i> = 0.077). <b>Conclusions:</b> These results offer robust evidence that a virtual reality training platform can be used to quickly and efficiently train individuals with UE loss to operate advanced prosthetic control paradigms. Participants can be trained to generate muscle contraction patterns in residual limbs that are interpreted with high accuracy by computer software as distinct active motion commands. These results support the potential viability of advanced myoelectric prostheses relying on pattern recognition feedback or similar controls systems.
DNA sequence mapping by fluorescence in situ hybridization (1991)

Various types of DNA probes, such as total genomic DNA, repetitive sequences, unique sequences, and composites of chromosome-specific DNA probes, can be used with fluorescence in situ hybridization (FISH) techniques to address research questions having to do with localization, mapping, and distribution of DNA in situ. FISH involves the formation of a heteroduplex between such DNA probes and chromatin targets on a microscope slide, which can be visualized with fluorescent reporter molecules. Three chromatin targets--metaphase chromosomes, somatic interphases, and zygote interphases--offer increasingly extended states of chromatin which can be strategically selected, individually or in combination, to address specific research questions of interest.
Cellular mechanisms involved in brain ischemia (1995)

Cellular mechanisms, both destructive and protective, that are associated with cerebral ischemia are reviewed in this paper. Central to understanding the evolution of stroke are the concepts of ischemic core and surrounding penumbral region damage, delayed neuronal death, and neuronal rescue. The role of spreading depression in the evolution of subsequent ATP depletion, ion shifts, glutamate release, activation of glutamate receptors, intracellular Ca2+ changes, and generation of reactive oxygen species in the penumbra in relationship to neuronal and glial cell damage are discussed. We conclude that the most fruitful areas for future stroke research include traditional approaches as well as novel approaches. Traditional approaches include stroke prevention and examination of the effects of combinations of proven and promising effective therapeutic interventions. Novel approaches include delineating mechanisms whereby growth factors and compounds such as deprenyl and staurosporine afford neuroprotection, ultimately leading to direct manipulation of the signal transduction pathways that lead to neuronal dysfunction and death. This includes determining which genes are activated and repressed in specific response to hypoxia-ischemia and determining how such alterations in gene expression affect survival and function of neurons. We also suggest that advantage be taken of the blood-brain barrier compromise during stroke in designing neuroprotective therapies.
Stem cell repair of central nervous system injury (2002)

Neural stem cells (NSCs) have great potential as a therapeutic tool for the repair of a number of CNS disorders. NSCs can either be isolated from embryonic and adult brain tissue or be induced from both mouse and human ES cells. These cells proliferate in vitro through many passages without losing their multipotentiality. Following engraftment into the adult CNS, NSCs differentiate mainly into glia, except in neurogenic areas. After engraftment into the injured and diseased CNS, their differentiation is further retarded. In vitro manipulation of NSC fate prior to transplantation and/or modification of the host environment may be necessary to control the terminal lineage of the transplanted cells to obtain functionally significant numbers of neurons. NSCs and a few types of glial precursors have shown the capability to differentiate into oligodendrocytes and to remyeliate the demyelinated axons in the CNS, but the functional extent of remyelination achieved by these transplants is limited. Manipulation of endogenous neural precursors may be an alternative therapy or a complimentary therapy to stem cell transplantation for neurodegenerative disease and CNS injury. However, this at present is challenging and so far has been unsuccessful. Understanding mechanisms of NSC differentiation in the context of the injured CNS will be critical to achieving these therapeutic strategies.
Synthesis and reactions of 1-aryl-3-formyl-4,6-dinitro-1H-indazoles (2002)

The title compounds were prepared by the reactions of picrylacetaldehyde with aryldiazonium salts followed by the intramolecular cyclization of the resulting picrylglyoxal monoarylhydrazones, and the regiospecific substitution for the nitro group at the 4-position under the action of anionic N-, O- and S-nucleophiles was found.
Considerations for animal models of blast-related traumatic brain injury and chronic traumatic encephalopathy (2014)

The association of military blast exposure and brain injury was first appreciated in World War I as commotio cerebri, and later as shell shock. Similar injuries sustained in modern military conflicts are now classified as mild traumatic brain injury (TBI). Recent research has yielded new insights into the mechanisms by which blast exposure leads to acute brain injury and chronic sequelae, including postconcussive syndrome, post-traumatic stress disorder, post-traumatic headache, and chronic traumatic encephalopathy, a tau protein neurodegenerative disease. Impediments to delivery of effective medical care for individuals affected by blast-related TBI include: poor insight into the heterogeneity of neurological insults induced by blast exposure; limited understanding of the mechanisms by which blast exposure injures the brain and triggers sequelae; failure to appreciate interactive injuries that affect frontal lobe function, pituitary regulation, and neurovegetative homeostasis; unknown influence of genetic risk factors, prior trauma, and comorbidities; absence of validated diagnostic criteria and clinical nosology that differentiate clinical endophenotypes; and lack of empirical evidence to guide medical management and therapeutic intervention. While clinicopathological analysis can provide evidence of correlative association, experimental use of animal models remains the primary tool for establishing causal mechanisms of disease. However, the TBI field is confronted by a welter of animal models with varying clinical relevance, thereby impeding scientific coherence and hindering translational progress. Animal models of blast TBI will be far more translationally useful if experimental emphasis focuses on accurate reproduction of clinically relevant endpoints (output) rather than scaled replication of idealized blast shockwaves (input). The utility of an animal model is dependent on the degree to which the model recapitulates pathophysiological mechanisms, neuropathological features, and neurological sequelae observed in the corresponding human disorder. Understanding the purpose of an animal model and the criteria by which experimental results derived from the model are validated are critical components for useful animal modeling. Animal models that reliably demonstrate clinically relevant endpoints will expedite development of new treatments, diagnostics, preventive measures, and rehabilitative strategies for individuals affected by blast TBI and its aftermath.
Expression of chemokines, CXC chemokine ligand 10 (CXCL10) and CXCR3 in the inflamed islets of patients with recent-onset autoimmune type 1 diabetes (2010)

The aim of this study is to present direct evidence for the involvement of CXC chemokine ligand 10 (CXCL10) and CXCR3 in human autoimmune type 1 diabetes. We examined five patients with recent-onset type 1 diabetes and five control subjects without diabetes. Islet cell antibodies or GAD antibodies or both were detected in all five patients. We used double-immunofluorescence to detect the expression of CXCL10 and CXCR3 (the receptor of CXCL10). CXCL10 was detected in the islets of all five patients. Almost all (84.2 ± 10.3 %, mean ± SD) CXCL10-positive cells were insulin-positive in the islet area. CXCL10-positive cells with glucagons, somatostatins or pancreatic polypeptides were not detected at all. CXCL10 expression was not seen in any islet without beta cells. CXCR3 was detected in the islet areas of all five patients. Almost all (80.3 ± 13.4 %, mean ± SD) CXCR3-positive cells were CD3-positive T cells. Our study showed that CXCL10 was expressed in the remaining beta cells, and the infiltrating T cells expressed CXCR3, in pancreatic islets of patients with recent-onset type 1 diabetes. The interaction of CXCL10 and CXCR3 would contribute to the selective destruction of beta cells in the development of type 1 diabetes.
Infusion-related hypersensitivity reactions during natalizumab treatment (2006)

As with many biologic therapeutics, hypersensitivity reactions occurred during natalizumab treatment in the AFFIRM study.1 These hypersensitivity reactions included all events reported as hypersensitivity, allergic reaction, or anaphylactic/anaphylactoid by the investigator as well as any report of urticaria, allergic dermatitis, or hives. If a hypersensitivity reaction was observed, natalizumab was immediately discontinued and the patient was not retreated (per protocol). Twenty-five (4%) patients in the natalizumab-treated group experienced 27 hypersensitivity reactions (table); two patients were redosed after experiencing a hypersensitivity reaction; therefore, there were two protocol violations. Fifteen of these 27 hypersensitivity reactions occurred by the second infusion and an additional eight occurred between the third and seventh infusions. Eight hypersensitivity reactions were reported as serious adverse events (seven in the natalizumab group and one in the placebo group). The incidence of serious systemic hypersensitivity reactions, classified as anaphylactoid or anaphylactic reactions, was <1%. Seventeen of the 25 (68%) natalizumab patients with hypersensitivity reactions, which included all the patients with serious systemic reactions, were persistently positive for antibodies to natalizumab. In the SENTINEL study, 11 (1.9%) natalizumab-treated patients experienced hypersensitivity reactions; however, no anaphylactic or anaphylactoid reactions were observed.2



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Table Hypersensitivity reactions in the AFFIRM study 



Treatment of hypersensitivity reactions was at the discretion of …
VALUATION LINKS: FORMALLY EXTENDING THE COMPUTATIONAL POWER OF HYPERTEXT (1991)

We view hypertext as an inherently dynamic concept to incorporate in the interface of dynamic information systems. What challenges does hypertext face in a constantly changing environment? In this paper, we discuss the benefits and the problems we face in our research into hypertext-oriented decision support systems. Then we focus on a new hypertext construct beneficial to this domain: valuation links. Valuation links support the dynamic spreading of computation via a well defined link traversal operation. We present two classes of such links: static and dynamic, and specify an algorithm for their traversal. We also show how these constructs can be used in sophisticated DSS environments.
IL-6-inducing Whole Yeast-based Immunotherapy Directly Controls IL-12-dependent CD8 T-cell Responses (2011)

In current clinical trails, whole yeast-based immunotherapy expressing hepatitis C viral antigens demonstrated statistically significant improvement in end of treatment responses when combined with type I interferon based standard of care, even in standard of care resistant patients. Although preclinical data suggest yeast vaccination, such as type I interferon, facilitates CD8 T-cell immunity, the capacity of yeast to generate immunity in patients resistant to type I interferon calls into question the mechanism(s) underpinning the efficacy of this approach. We show yeast and a Toll-like receptor exclusive agonist, Pam3Cys, differ in CD8 T-cell generation when combined with an agonistic CD40 antibody. Although both yeast and PamCys were largely Toll-like receptor dependent, the primary CD8 response generated by yeast was significantly less than Pam3Cys in wild-type hosts even in a CD4 T-cell-deficient setting. In addition, immunization of IL6 mice with yeast produced a 3-fold to 6-fold increased CD8 response while the Pam3Cys response was unaffected. The yeast but not Pam3Cys-driven CD8 response was inhibited in both wild-type and IL-6 hosts by blocking interleukin (IL)-12. In addition, IL6 mice had increased CD86 expression on their dendritic cells after yeast immunization also inhibited by IL-12 blockade. Collectively, our results indicate the CD8 T-cell response to yeast but not Pam3Cys is influenced by IL-6-mediated control of IL-12 critical for dendritic cell activation. To our knowledge this is the first demonstration that yeast directly influence IL-12-associated CD8 T-cell immunity providing an additional route whereby recombinant yeast may provide efficacy independent of type I interferon.
Preparation and Optical Absorption Spectra of Dye-Coated Au, Ag, and Au/Ag Colloidal Nanoparticles in Aqueous Solutions and in Alternate Assemblies (2001)

Au, Ag, and Au/Ag colloidal nanoparticles coated with the J-aggregate of an anionic cyanine dye, 3,3‘-disulfopropyl-5,5‘-dichlorothiacyanine sodium salt (TC), have been prepared for the first time. The absorption spectrum of TC-coated Au colloidal nanoparticles is not a simple sum of the contributions of colloidal gold and TC but is characterized by an evident absorption dip at the position corresponding to the J-band of TC. These spectral features are reproduced by the simulation based on the Maxwell−Garnett-type treatment of Gao et al. The alternate adsorption technique allowed us to deposit dye-coated Au/Ag composite nanoparticles at the surface of a cationic polymer, poly(diallyldimethylammonium chroride).
Unique cardioprotective potential of angiotensin converting enzyme inhibitors: a hypothesis still to be tested on humans (1991)

'Primary cardioprotection' has, arguably, already been shown with thiazide diuretics and probably with beta-blockers. The proven safety and efficacy of these established drugs override any theoretical or experimental considerations in favour of ACE inhibitors. It is unfortunate that, as yet, the number of hypotheses generated in support of ACE inhibitors has not been matched by large scale clinical trials employing these drugs. The first report of the clinical use of an ACE inhibitor was in 1984; it is high time comparative studies with conventional, and proven, agents were undertaken. With regard to 'secondary cardioprotection', there is overwhelming evidence in favour of the use of beta-blockers in patients with myocardial ischaemia. Indeed, we would argue that ACE inhibitors should be used with caution in such patients to avoid impairment of coronary infusion. In the patient with acute myocardial infarction, intravenous nitrates are cheap, easy to use, safe and seem to be effective (in preventing early remodelling and reducing mortality). In the subacute phase, beta-blockers improve prognosis and, according to the currently available evidence in humans, nitrates are as effective as captopril in altering late remodelling; as in the acute situation, nitrates are cheaper, simpler to use and have a track record of long-term safety. ACE inhibitors improve symptoms, exercise capacity and prognosis in chronic heart failure. In this condition, they have been a major therapeutic advance and, on the available evidence, are to be initially preferred to other vasodilators though they should be given in addition to diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)
Chapter 8. Bending and Compaction of DNA by Proteins (2008)

Essentially all active and passive reactions involving DNA require the duplex to undergo considerable and often dramatic gymnastics. Active processes include transcription, replication and recombination reactions where nucleoprotein complexes that usually require DNA bending both within and between ...
Heme: a determinant of life and death in renal tubular epithelial cells (2004)

Heme oxygenase-1 (HO-1) and p21 influence cell fate, and genetic HO-1 overexpression upregulates p21 and confers resistance to apoptosis. The present study examined the effects of heme, a metabolite incriminated in renal injury, on sensitivity to apoptosis and cell growth in conjunction with cellular expression of HO-1 and p21. Immortalized rat proximal tubular epithelial cells (IRPTCs) were exposed to hemin (10 microM) in serum-deplete media (0.1% FBS) and in standard cell culture media (5.0% FBS). In the presence of 0.1% FBS media, hemin induced p21 through an HO-dependent, p53-independent mechanism; certain products of HO activity (iron and carbon monoxide), but not others (ferritin, apoferritin, bilirubin), recapitulated these inductive effects on p21 expression. Along with this inductive effect on HO-1 and p21, hemin worsened apoptosis, the latter exacerbated by the inhibition of HO activity and loss of p21 expression. In IRPTCs maintained in 5% FBS, hemin induced HO-dependent p21 expression, provoked cell cycle arrest, and inhibited cell growth without inducing apoptosis; this inhibitory effect of hemin on cell growth was blocked by the concomitant inhibition of HO activity and loss of p21 expression. We conclude that hemin is a potent HO-dependent inducer of p21 and that hemin increases the sensitivity to apoptosis in serum-deplete conditions and decreases cell growth in serum-replete conditions; inhibiting HO activity and concomitantly ablating p21 expression exacerbate apoptosis and reverse the growth-inhibitory actions of hemin. We suggest that these effects of heme may influence the nature of, and recovery from, ischemic and nephrotoxic insults to the kidney.