A new method of cleaning InP substrates under molecular beam epitaxy conditions involving heating to ⩾500 °C in an As4 flux (JAs4 ≃1015–1016 cm−2 s−1) is described. Evidence of surface cleanliness, good morphology, ordered surface reconstruction, and integrity of chemical composition at the interface is given. Lattice-matched layers of Ga0.47In0.53As grown on InP substrates cleaned in this way showed excellent electrical properties: e.g. a room-temperature mobility μ300=8600 cmPu2 V−1 s−1 at n300 =1016 cm−3.
The end-product of coagulation is a clot with a fibrin meshwork. Fibrin, however, is not a permanent structure, but stimulates a biochemical pathway that leads to its lysis pathway and fragmentation of the clot. Essential components of this, as a consequence, are the plasminogen activators (PAs). PAs convert the zymogen plasminogen to the ultimate fibrinolytic enzyme plasmin (Fig. 1). At least two types of PAs have been identified in plasma: one produced and secreted by endothelial cells (first isolated in urine), called tissue-type PA (t-PA), and another called urinary-type PA or urokinase (UK). UK was later also identified in plasma, mainly as a proenzyme known as pro-urokinase (pro-UK). t-PA and pro-UK both activate plasminogen, preferentially in the presence of fibrin, but by different mechanisms (for review, see [5]).
A novel method of intentionally doping molecular beam epitaxy grown GaAs n- type is described. The donor atoms are sulfur, from a beam of S2, generated in a low temperature (200 °C), electrochemical Knudsen cell. The galvanic cell is Pt/Ag/AgI/Ag2S/Pt, where the flow of current through the cell, with the positive pole at the Ag2S is a measure of the sulfur flux effusing from the cell. Net carrier concentrations n between ∼1015 and ∼1018 cm−3 have been obtained. There is no detectable accumulation of S at the surface for high donor concentrations (∼1018 cm−3) in the bulk. This novel method of sulfur generation has a particularly fast (<1 sec) response time—much faster than the thermal equilibration times of conventional thermal Knudsen sources. Complicated doping profiles are shown to be produced relatively easily with a single doping source using this technique. Free-electron mobilities μ300 K = 6000 cm2/V sec and μ77 K = 17 000 cm2/V sec have been obtained for sulfur doped layers with n = 1.1016 cm−3.
To develop a rational and robust antibody family specific for disease-misfolded TDP-43.
Background:
Misfolded molecular species of TDP-43 have been implicated in the neurotoxicity and prion-like cell-to-cell propagation in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). We have found that a tryptophan (Trp68) in the TDP-43 N-terminal domain (NTD) participates in the cross-seeding of SOD1 misfolding propagation (Pokrishevsky et al, submitted), despite being inaccessible in the natively folded NTD (e.g., Afroz et al, Nature Comm 2017). We hypothesized that NTD Trp68 becomes exposed when TDP-43 is cytosolically mislocalized/aggregated.
Design/Methods:
We immunized rabbits with an unfolded NTD linear peptide epitope including Trp68 to generate polyclonal and monoclonal antibodies (pAb, mAb). mAb antibody affinity to the immunizing peptide was determined by surface plasmon resonance (SPR). NTD was expressed in E. coli, and properly folded monomer status was confirmed by size exclusion chromatography, followed by studies with denaturing and native gel electrophoresis and immunoblotting. Antibody specificity was confirmed by immunohistochemistry (IHC) on patient samples, and immunocytochemistry (ICC) of HEK293 cells transfected with TDP-43 triple-tandem mutation of the nuclear localization sequence (ΔNLS).
Results:
SPR of mAbs revealed picomolar affinity to the epitope. Recombinant NTD displayed pAb immunoreactivity only under denaturing conditions. IHC of ALS/FTLD CNS sections, but not normal CNS, was reactive to antibodies. ICC revealed immunoreactivity for mislocalized/aggregated ΔNLS-TDP-43, but not nuclear wild-type TDP-43. Antibodies also failed to recognize TDP-43 in physiologic stress granules in HEK293 cells. A ΔNLS-TDP-43 construct in which Trp68 was mutated to serine did not display Immunoreactivity in transfected cells, indicating that Trp68 is immunodominant in the immunizing peptide.
Conclusions:
We have developed a family of antibodies sensitive to solvent exposure of NTD Trp68 that are selective for misfolded/aggregated, disease-associated TDP-43 while sparing physiologically important molecular species, which may find utility in biomarker and immunotherapy applications for TDP-43 associated diseases. Disclosure: Dr. Cashman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ProMIS Neurosciences. Dr. Cashman has received compensation for serving on the Board of Directors of ProMIS Neurosciences. Dr. Cashman has received royalty, license fees, or contractual rights payments from ProMIS Neurosciences. Dr. Cashman holds stock and/or stock options in ProMIS Neurosciences which sponsored research in which Dr. Cashman was involved as an investigator. Dr. Cashman holds stock and/or stock options in ProMIS Neurosciences. Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Louadi has nothing to disclose. Dr. Roman has nothing to disclose. Dr. Gibbs has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ProMIS Neurosciences. Dr. Dijkstra has nothing to disclose. Dr. Kaplan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ProMIS Neurosciences. Dr. Kaplan holds stock and/or stock options in ProMIS Neurosciences which sponsored research in which Dr. Kaplan was involved as an investigator. Dr. Kaplan has received research support from ProMIS Neurosciences.
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