Described is an efficient heterologous expression system for Sulfolobus solfataricus ADH-10 (Alcohol Dehydrogenase isozyme 10) and its use in the dynamic reductive kinetic resolution (DYRKR) of 2-arylpropanal (Profen-type) substrates. Importantly, among the 12 aldehydes tested, a general preference for the (S)-antipode was observed, with high ee’s for substrates corresponding to the NSAIDs (nonsteroidal anti-inflammatory drugs) naproxen, ibuprofen, flurbiprofen, ketoprofen, and fenoprofen. To our knowledge, this is the first application of a dehydrogenase from this Sulfolobus hyperthermophile to asymmetric synthesis and the first example of a DYRKR with such an enzyme. The requisite aldehydes are generated by Buchwald−Hartwig-type Pd(0)-mediated α-arylation of tert-butyl propionate. This is followed by reduction to the aldehyde in one [lithium diisobutyl tert-butoxyaluminum hydride (LDBBA)] or two steps [LAH/Dess−Martin periodinane]. Treatment of the profenal substrates with SsADH in 5% EtOH/phosphate buffer, pH 9, with catalytic NADH at 80 °C leads to efficient DYRKR, with ee’s exceeding 90% for 9 aryl side chains, including those of the aforementioned NSAIDs. An in silico model, consistent with the observed broad side chain tolerance, is presented. Importantly, the SsADH-10 enzyme could be conveniently recycled by exploiting the differential solubility of the organic substrate/product at 80 °C and at rt. Pleasingly, SsADH-10 could be taken through several “thermal cycles,” without erosion of ee, suggesting this as a generalizable approach to enzyme recycling for hyperthermophilic enzymes. Moreover, the robustness of this hyperthermophilic DH, in terms of both catalytic activity and stereochemical fidelity, speaks for greater examination of such archaeal enzymes in asymmetric synthesis.
The degeneracy of the guanine radical cation, which is formed in DNA by oxidation of guanine by electron transfer, was studied by a detailed analysis of the oxidation products of guanine on oligonucleotide duplexes and by labeling experiments. It was shown that imidazolone, the major product of guanine oxidation, is formed through a one-electron oxidation process and incorporates one oxygen atom from O2. The formation of 8-oxo-7,8-dihydroguanine by a two-electron oxidation process was a minor pathway. The two-electron oxidation mechanism was also evidenced by the formation of a tris(hydroxymethyl)aminomethane adduct.
Introduction:
Knowledge about residual deficiencies and their consequences on daily life activities among stroke patients living at home 1-year after the initial event managed in stroke units is poor. This multi-dimensional study assessed the types of deficiencies, their frequency and the consequences that the specific stroke had upon the daily life of patients.
Methods:
A cross-sectional survey, assessing, using standardized scales, 1 year post-stroke disabilities, limitations of activities, participation and quality of life, was carried out by telephone interview and by mail in a sample of stroke patients who returned home after having been initially managed in a stroke unit.
Results:
A total of 161 patients were included (142 able to answer the interview on their own; 19 needing a care-giver). Amongst a sub-group of the patients interviewed, 55.4% (95% Confidence Interval [47.1–63.7]) complained about pain and 60.0% (95% CI [51.4–68.6]) complained of fatigue; about 25% presented neuropsychological or neuropsychiatric disability. Whilst 87.3% (95% CI [81.7–92.9]) were independent for daily life activities, participation in every domains and quality of life scores, mainly in daily activity, pain, and anxiety subscales, were low.
Conclusion:
Despite a good 1-year post-stroke functional outcome, non-motor disabling symptoms are frequent amongst patients returned home and able to be interviewed, contributing to a low level of participation and a poor quality of life. Rehabilitation strategies focused on participation should be developed to break the vicious circle of social isolation and improve quality of life.
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