To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain ...antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-Ag7 and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-Ag7, which activated autoreactive CD4+ T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-Ag7 RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-Ag7 RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries.
An endogenous pentapeptide (Gln-Tyr-Asn-Ala-Asp; QYNAD) that is present at elevated levels in human CSF from patients with demyelinating diseases has been reported to block voltage-gated sodium ...channels at low (10 micro M) concentrations. Objective : Because of the potential importance of sodium channel blocking activity in demyelinating disorders, this study attempted to determine the sensitivity to QYNAD of different sodium channel subtypes, including Na(v)1.6, the major sodium channel at nodes of Ranvier, and Na(v)1.2, which is expressed in axons with abnormal myelin.
Sodium channel function was assayed using patch-clamp recordings, both in heterologous expression systems and in intact neurons.
QYNAD synthesized in 10 different batches by four different facilities failed to block sodium currents, even at concentrations as high as 500 micro M (50-fold higher than the blocking concentration originally reported). QYNAD had no effect on the currents produced by recombinant Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.7 sodium channels or on the sodium currents that are produced by native channels in adult hippocampal or dorsal root ganglion neurons. QYNAD did not interfere with conduction in the optic nerve, a myelinated fiber tract that is often affected in MS.
These experiments do not show any sodium channel blocking effect of QYNAD. The conclusion that QYNAD contributes to the pathophysiology of inflammatory neurologic disorders by blocking voltage-gated sodium channels should therefore be viewed with caution.
It is proved that a finite intersection of special preenveloping ideals in an exact category (A;E) is a special preenveloping ideal. Dually, a finite intersection of special precovering ideals is a ...special precovering ideal. A counterexample of Happel and Unger shows that the analogous statement about special preenveloping subcategories does not hold in classical approximation theory. If the exact category has exact coproducts, resp., exact products, these results extend to intersections of infinite families of special preenveloping, resp., special precovering, ideals. These techniques yield the Bongartz-Eklof-Trlifaj Lemma: if a:A→B is a morphism in A, then the ideal a⊥ is special preenveloping. This is an ideal version of the Eklof-Trlifaj Lemma, but the proof is based on that of Bongartz' Lemma. The main consequence is that the ideal cotorsion pair generated by a small ideal is complete.
Intensive glucose management, if begun early, diminishes the long-term complications of diabetes. Whether the cognitive domain also benefits from such therapy is not clear, and has remained subject ...to investigation. Do the new results from the ACCORD-MIND study settle the issue?
Human plasma is a biofluid that is high in information content, making it an excellent candidate for metabolomic studies.
1
H NMR has been a popular technique to detect several dozen metabolites in ...blood plasma. In order for
1
H NMR to become an automated, high-throughput method, challenges related to (1) the large signal from lipoproteins and (2) spectral overlap between different metabolites have to be addressed. Here diffusion-weighted
1
H NMR is used to separate lipoprotein and metabolite signals based on their large difference in translational diffusion. The metabolite
1
H NMR spectrum is then quantified through spectral fitting utilizing full prior knowledge on the metabolite spectral signatures. Extension of the scan time by 3 min or 15 % per sample allowed the acquisition of a
1
H NMR spectrum with high diffusion weighting. The metabolite
1
H NMR spectra could reliably be modeled with 28 metabolites. Excellent correlation was found between results obtained with diffusion NMR and ultrafiltration. The combination of minimal sample preparation together with minimal user interaction during processing and quantification provides a metabolomics technique for automated, quantitative
1
H NMR of human plasma.
Nanopatterning as a surface area enhancement method has the potential to increase signal and sensitivity of biosensors. Platinum-based bulk metallic glass (Pt-BMG) is a biocompatible material with ...electrical properties conducive for biosensor electrode applications, which can be processed in air at comparably low temperatures to produce nonrandom topography at the nanoscale. Work presented here employs nanopatterned Pt-BMG electrodes functionalized with glucose oxidase enzyme to explore the impact of nonrandom and highly reproducible nanoscale surface area enhancement on glucose biosensor performance. Electrochemical measurements including cyclic voltammetry (CV) and amperometric voltammetry (AV) were completed to compare the performance of 200 nm Pt-BMG electrodes vs Flat Pt-BMG control electrodes. Glucose dosing response was studied in a range of 2 mM to 10 mM. Effective current density dynamic range for the 200 nm Pt-BMG was 10–12 times greater than that of the Flat BMG control. Nanopatterned electrode sensitivity was measured to be 3.28 μA/cm2/mM, which was also an order of magnitude greater than the flat electrode. These results suggest that nonrandom nanotopography is a scalable and customizable engineering tool which can be integrated with Pt-BMGs to produce biocompatible biosensors with enhanced signal and sensitivity.
PDF
