Dopamine asymmetry interacts with medication to affect cognition in Parkinson's disease

Contradictory evidence exists regarding the nature and degree of impaired cognitive flexibility in PD. Dopaminergic medication may be expected to ameliorate such cognitive deficits, yet both medicated and unmedicated patients have been reported to perform more poorly than control subjects on tasks of cognitive flexibility, suggesting that such deficits may also be affected by other disease-related variables. The present study examined whether asymmetric dopamine deficiency (revealed by unilateral symptom onset) is related to the performance of spontaneous and reactive flexibility in PD, and the possible interaction of dopaminergic medication with such asymmetry. Thirty-five PD patients with mild motor symptoms and unilateral onset of PD (left-onset=14; right-onset=21) performed the Alternate Uses (AU) and intradimensional/extradimensional shift (IED) tasks. Interaction between side of onset and medication was observed for the number of errors in the AU task and number of reversal errors in the IED task. Significantly more AU errors were made by medicated patients with left-onset, as compared to all other participants. Conversely, medicated patients with right-onset made the most reversal errors. These results suggest that relatively early in the disease process when dopamine deficit in the less-affected hemisphere is mild, optimal dopaminergic medication (with respect to motor function) may involve over-medication of the less-affected hemisphere. Thus, AU errors may be the consequence of hyperdopaminergic state leading to impaired functioning of the left hemisphere, whereas increased reversal errors in right-onset PD patients receiving dopaminergic medication is related to impaired dopamine function in the right hemisphere.     

Lesions of rat infralimbic cortex enhance renewal of extinguished appetitive Pavlovian responding

It is well established that extinction is highly context dependent, and several behavioural phenomena associated with the expression of extinction (spontaneous recovery, reinstatement and renewal) have been described as resulting from this context dependency. It has previously been shown that lesions of the infralimbic (IL) region of the medial prefrontal cortex result in increased levels of spontaneous recovery and reinstatement of an extinguished appetitive Pavlovian conditioned response. The current study shows that lesions of the IL cortex also result in increased renewal of a conditioned response when tested in the acquisition context. Thirteen IL-lesioned and 14 sham-lesioned rats were trained on an appetitive Pavlovian task in one context (Context A) followed by extinction in a different context (Context B); animals were then tested for renewal of responding in both Context A and B. Both groups demonstrated similarly low levels of responding when tested in the extinction context (B), and greater responding (i.e. renewal) when tested in the acquisition context (A). Further, the level of response renewal was greater in IL-lesioned animals. The results are discussed in relation to the possible role of the IL cortex in contextual control of extinction.     

受体蛋白与药物分子对接的研究进展

计算机技术的发展极大地促进了生命科学研究进程。利用分子对接技术研究受体蛋白和药物相互作用是当前的热点课题。通过分别建立蛋白质和药物分子模型,并对它们的相互作用进行研究,进而为发现并设计出更加理想、安全、有效的药物打下深厚的基础。分子模型建立的问题已经得到很好的解决,但是分子与分子间以什么方式对接、怎样对接等问题尚待深入研究。本文就当前分子对接的研究进展作一综述,着重介绍了分子对接的方法和常用工具的研究情况。     

Resistance to high-fat-diet-induced obesity and sexual dimorphism in the metabolic responses of transgenic mice with moderate uncoupling protein 3 overexpression in glycolytic skeletal muscles

Aims/hypothesis Uncoupling protein (UCP) 3 is a mitochondrial inner membrane protein expressed predominantly in glycolytic skeletal muscles. Its role in vivo remains poorly understood. The aim of the present work was to produce a mouse model with moderate overproduction and proper fibre-type distribution of UCP3. Methods Transgenic mice were created with a 16 kb region encompassing the human UCP3 gene. Mitochondrial uncoupling was investigated on permeabilised muscle fibres. Changes in body weight, adiposity and glucose or insulin tolerance were assessed in mice fed chow and high-fat diets. Indirect calorimetry was used to determine whole-body energy expenditure and substrate utilisation. Results Transgenic mice showed a twofold increase in UCP3 protein levels specifically in glycolytic muscles. Mitochondrial respiration revealed an increase of uncoupling in glycolytic but not in oxidative muscles. Transgenic mice gained less weight than wild-type littermates due to lower adipose tissue accretion when fed a high-fat diet. Animals showed a sexual dimorphism in metabolic responses. Female transgenic mice were more glucose-sensitive than wild-type animals, while male transgenic mice with high body weights had impaired glucose and insulin tolerance. Measurements of RQs in mice fed chow and high-fat diets suggested an impairment of metabolic flexibility in transgenic male mice. Conclusions/interpretation Our data show that physiological overproduction of UCP3 in glycolytic muscles results in mitochondrial uncoupling, resistance to high-fat diet-induced obesity and sex specificity regarding insulin sensitivity and whole-body substrate utilisation. C. Tiraby and G. Tavernier contributed equally to this study.     

Ultrafast solvation dynamics at binding and active sites of photolyases

Dynamic solvation at binding and active sites is critical to protein recognition and enzyme catalysis. We report here the complete characterization of ultrafast solvation dynamics at the recognition site of photoantenna molecule and at the active site of cofactor/substrate in enzyme photolyase by examining femtosecond-resolved fluorescence dynamics and the entire emission spectra. With direct use of intrinsic antenna and cofactor chromophores, we observed the local environment relaxation on the time scales from a few picoseconds to nearly a nanosecond. Unlike conventional solvation where the Stokes shift is apparent, we observed obvious spectral shape changes with the minor, small, and large spectral shifts in three function sites. These emission profile changes directly reflect the modulation of chromophore’s excited states by locally constrained protein and trapped-water collective motions. Such heterogeneous dynamics continuously tune local configurations to optimize photolyase’s function through resonance energy transfer from the antenna to the cofactor for energy efficiency and then electron transfer between the cofactor and the substrate for repair of damaged DNA. Such unusual solvation and synergetic dynamics should be general in function sites of proteins.     

The culture of ‘culture’ in National Health Service policy implementation

The widespread reference to ‘culture’ in UK NHS policy and organisational literature suggests that culture has, in itself, become a cultural phenomenon. This article draws on anthropological thought to explore this trend, and finds it stems from the way that the term ‘culture’ has become analytically empty. Lack of rigour in the way that culture is conceptualised allows it to be used both to suggest an evolved consensus among the workforce, and to validate the imposition of values and beliefs by management. Such manipulation of ‘culture’ is evident in recent NHS policy demanding cultural change to ensure a flexible, empowered and self‐regulating workforce — the type of workforce not only valued by health services, but pivotal to a post‐Fordist economy. The findings from an ethnographic study are drawn upon to consider the relationship between nurses’ cultural practices, corporate culture shaped by NHS policy, and the requirements of the economic domain. It is suggested that a commitment to post‐Fordist priorities of flexibility, empowerment and self‐regulation is not necessarily matched by any shift in the traditional location of power. The article concludes that greater analytical rigour is necessary to challenge the way in which ‘culture’ is manipulated by policy makers.     

Solution conformational analysis of sodium complexed [Gly6]. - and [Gly9]. -antamanide analogs

To investigate the conformational flexibility of metal-complexed cyclodecapeptides, we synthesized and studied two antamanide analogs, in which the phenylalanine residue in position 6 or 9 of the sequence was substituted by Gly. Previous conformational studies on antamanide suggested that these backbone regions are affected by conformational variation. The NMR conformational study showed a high degree of flexibility for the two analogs. With sodium ions, on the other hand, [Gly⁹]. -antamanide was able to form a fairly stable equimolar complex, whereas [Gly⁶]. -antamanide showed a conformational heterogeneity, with one prevailing conformer. For the [Gly⁹]. -antamanide analog, the whole NMR data, combined with extensive theoretical calculations, were consistent with the presence of 1) two (β-turns of type I, centered on Gly⁹-Phe¹⁰ and Ala⁴-Phe⁵, respectively; 2) a central cavity with a six-carbonyl oxygen cage, optimal for a Na⁺ hexacoordination; 3) strongly H-bonded amide protons for residues 1 and 6, both involved in the formation of the two type I β-turns, which, however, exhibited some fluctuations during the molecular dynamics simulations. For the [Gly⁶]. -antamanide-Na⁺ complex the prevailing conformer was consistent with a more open structure, with the partial solvent exposure of all the amide protons; that is, the Gly residue in position 6 increases the flexibility of this critical site more than does the Gly in position 9. These data in some way parallel the results of the cytotoxicity tests on B16-F10 transformed cells for the two analogs: [Gly⁹]. -antamanide is cytotoxic after 48 h exposure, whereas [Gly⁶]. -antamanide is almost inactive. On the contrary, both analogs are practically inactive in vivo against phalloidin.     

Motor flexibility problems as a marker for genetic susceptibility to attention-deficit/hyperactivity disorder.

BACKGROUND: Since many children with attention-deficit/hyperactivity disorder (ADHD) have fine visuomotor problems that are already evident at a young age, motor dysfunctioning is investigated in family-genetic perspective. We hypothesized that if fine motor problems may be a marker for genetic susceptibility to ADHD, nonaffected siblings of ADHD probands would experience motor problems similar to those of their ADHD siblings. METHODS: Twenty-five carefully phenotyped ADHD probands with a family history of ADHD, their nonaffected siblings (n = 25), and 48 normal control subjects (aged 6 to 17) completed a motor fluency task and a motor flexibility task. The motor fluency task involved completion of a familiar, automatized trajectory, whereas the motor flexibility task required continuous adjustment of movement to complete an unpredictable random trajectory. RESULTS: On the motor fluency task, the performance of the nonaffected children was significantly better than that of the ADHD probands; strikingly, on the motor flexibility task, they performed as well as their ADHD siblings. CONCLUSIONS: Nonaffected siblings experience complex motor problems similar to their ADHD siblings but only in nonautomatized movements that require controlled processing. The results suggest that higher-order controlled motor deficits in ADHD may be associated with genetic susceptibility for ADHD.