Unraveling the Origin of the Regioselectivity of a Supramolecular Hydroformylation Catalyst

Supramolecular substrate preorganization using DIMPHos ligands, which are bisphosphine ligands equipped with a carboxylate binding site, allows for control over the regioselectivity in the hydroformylation reaction. In all reported examples, the aldehyde product in which the CO was inserted farthest from the directing group, was formed in excess (for terminal alkenes the linear aldehyde). We report here an in-depth DFT study to provide mechanistic insight into this selective transformation. These calculations show large energy differences between the different hydride migration steps of competing pathways that lead to either the linear or branched aldehyde product, in line with the experimentally found selectivity. Through the use of calculated model systems of the catalyst, it is shown that the substrate binding event itself plays an important role in determining these large energy differences. Following ditopic substrate binding, the product forming pathways that lead to the minor isomeric product is particularly disfavored by the steric repulsion between the ditopically bound substrate and the apical coordinated CO ligand

Chronic homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons

Homocystinuria is an inborn error of metabolism characterized by plasma homocysteine levels up to 500μM, premature vascular events and mental retardation. Mild elevations of homocysteine plasma levels up to 25μM, which are common in the general population, are associated with vascular disease, cognitive impairment and neurodegeneration. Several mechanisms of homocysteine neurotoxicity have been investigated. However, information on putative effects of hyperhomocysteinemia on the electrophysiology of neurons is limited. To screen for such effects, we examined primary cultures of mouse hippocampal neurons with the whole-cell patch-clamp technique. Homocysteine was applied intracellularly (100μM), or cell cultures were incubated with 100μM homocysteine for 24h. Membrane voltage was measured in current-clamp mode, and action potential firing was induced with short and prolonged current injections. Single action potentials induced by short current injections (5ms) were not altered by acute application or incubation of homocysteine. When we elicited trains of action potentials with prolonged current injections (200ms), a broadening of action potentials during repetitive firing was observed in control neurons. This spike broadening was unaltered by acute application of homocysteine. However, it was significantly diminished when incubation with homocysteine was extended to 24h prior to recording. Furthermore, the number of action potentials elicited by low current injections was reduced after long-term incubation with homocysteine, but not by the acute application. After 24h of homocysteine incubation, the input resistance was reduced which might have contributed to the observed alterations in membrane excitability. We conclude that homocysteine exposure causes changes in the intrinsic electrophysiological properties of cultured hippocampal neurons as a mechanism of neurological symptoms of hyperhomocysteinemi

Investigating the balance between goal-directed and habitual control in experimental and real-life settings

Do people differ in their propensity to form habits? The current study related individual differences in habitual performance on the slips-of-action task to habit formation in real life. To this end, we developed a novel key-cover procedure that controls for the amount of repetition and motivation within a naturalistic setting. Participants received a key cover for the key to their home, which after several weeks was switched with a key cover that was previously attached to a dummy key. Participants recorded effort, time, attention, and mistakes in the key-selection process. Results were in line with established properties of habits, as attention decreased in the learning phase, yet effort, time, and mistakes increased after the key-cover switch. Performance on the slips-of-action task correlated negatively with changes in attention in the real-life key-cover task. This negative correlation may reflect that flexible behavioral adjustment requires more attention in people with a relatively weak goal-directed system

Pitfalls in the diagnostic evaluation of subacute combined degeneration

We report a case of a 43-year-old man presenting with a 2-week history of painless ascending sensory disturbances, suspected to be suffering from acute inflammatory polyneuropathy. On clinical examination, deep tendon reflexes were preserved and muscle strength was 5/5 everywhere. Gait was ataxic with positive Romberg test. Lumbar puncture was normal and electroneurography demonstrated demyelination. With spinal cord involvement centred on the posterior tracts on MRI, differential diagnosis focused on cobalamin deficiency. Initial laboratory work up showed nearly normal holotranscobalamin (43 pmol/L, normal>50) suggesting no vitamin B12 deficiency. Surprisingly, further testing including methylmalonic acid (3732 nmol/L, normal<271) and homocysteine (48.5 µmol/L, normal<10) showed an impairment of vitamin B12-dependent metabolism leading to the diagnosis of subacute combined degeneration. Only after repeated history taking did the patient remember having taken tablets containing cobalamin for 3 days before hospitalisation. In case of B12 deficiency, holotranscobalamin can rapidly normalise during supplementation, whereas methylmalonic acid and homocysteine might help to detect B12 deficiency in patients who recently started supplementation

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

BACKGROUND: The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA samples homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533G>A, c.1068C>T and IVS10 262C>G. FINDINGS: Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262G than expected from a normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele. CONCLUSION: Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage