The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates

Degeneration of nigrostriatal dopaminergic neurons is the primary histopathological feature of Parkinson's disease. The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces a neurological syndrome in man and non-human primates very similar to idiopathic Parkinson's disease by selectively destroying dopaminergic nigrostriatal neurons. This gives rise to the hypothesis that Parkinson's disease may be caused by endogenous or environmental toxins. Endogenous excitatory amino acids (EAAs) such as L-glutamate could be involved in neurodegenerative disorders including Parkinson's disease. We report in this study that the competitive NMDA antagonist CPP (3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid) protects nigral tyrosine hydroxylase (TH) positive neurons from degeneration induced by systemic treatment with MPTP in common marmosets. This indicates that EAAs are involved in the pathophysiological cascade of MPTP-induced neuronal cell death and that EAA antagonists may offer a neuroprotective therapy for Parkinson's disease

The inherited blindness protein AIPL1 regulates the ubiquitin-like FAT10 pathway

Mutations in AIPL1 cause the inherited blindness Leber congenital amaurosis (LCA). AIPL1 has previously been shown to interact with NUB1, which facilitates the proteasomal degradation of proteins modified with the ubiquitin-like protein FAT10. Here we report that AIPL1 binds non-covalently to free FAT10 and FAT10ylated proteins and can form a ternary complex with FAT10 and NUB1. In addition, AIPL1 antagonised the NUB1-mediated degradation of the model FAT10 conjugate, FAT10-DHFR, and pathogenic mutations of AIPL1 were defective in inhibiting this degradation. While all AIPL1 mutants tested still bound FAT10-DHFR, there was a close correlation between the ability of the mutants to interact with NUB1 and their ability to prevent NUB1-mediated degradation. Interestingly, AIPL1 also co-immunoprecipitated the E1 activating enzyme for FAT10, UBA6, suggesting AIPL1 may have a role in directly regulating the FAT10 conjugation machinery. These studies are the first to implicate FAT10 in retinal cell biology and LCA pathogenesis, and reveal a new role of AIPL1 in regulating the FAT10 pathway

p53 Activation following Rift Valley Fever Virus Infection Contributes to Cell Death and Viral Production

Rift Valley fever virus (RVFV) is an emerging viral zoonosis that is responsible for devastating outbreaks among livestock and is capable of causing potentially fatal disease in humans. Studies have shown that upon infection, certain viruses have the capability of utilizing particular cellular signaling pathways to propagate viral infection. Activation of p53 is important for the DNA damage signaling cascade, initiation of apoptosis, cell cycle arrest and transcriptional regulation of multiple genes. The current study focuses on the role of p53 signaling in RVFV infection and viral replication. These results show an up-regulation of p53 phosphorylation at several serine sites after RVFV MP-12 infection that is highly dependent on the viral protein NSs. qRT-PCR data showed a transcriptional up-regulation of several p53 targeted genes involved in cell cycle and apoptosis regulation following RVFV infection. Cell viability assays demonstrate that loss of p53 results in less RVFV induced cell death. Furthermore, decreased viral titers in p53 null cells indicate that RVFV utilizes p53 to enhance viral production. Collectively, these experiments indicate that the p53 signaling pathway is utilized during RVFV infection to induce cell death and increase viral production

Weak Responses to Auditory Feedback Perturbation during Articulation in Persons Who Stutter: Evidence for Abnormal Auditory-Motor Transformation

Previous empirical observations have led researchers to propose that auditory feedback (the auditory perception of self-produced sounds when speaking) functions abnormally in the speech motor systems of persons who stutter (PWS). Researchers have theorized that an important neural basis of stuttering is the aberrant integration of auditory information into incipient speech motor commands. Because of the circumstantial support for these hypotheses and the differences and contradictions between them, there is a need for carefully designed experiments that directly examine auditory-motor integration during speech production in PWS. In the current study, we used real-time manipulation of auditory feedback to directly investigate whether the speech motor system of PWS utilizes auditory feedback abnormally during articulation and to characterize potential deficits of this auditory-motor integration. Twenty-one PWS and 18 fluent control participants were recruited. Using a short-latency formant-perturbation system, we examined participants’ compensatory responses to unanticipated perturbation of auditory feedback of the first formant frequency during the production of the monophthong [ε]. The PWS showed compensatory responses that were qualitatively similar to the controls’ and had close-to-normal latencies (~150 ms), but the magnitudes of their responses were substantially and significantly smaller than those of the control participants (by 47% on average, p<0.05). Measurements of auditory acuity indicate that the weaker-than-normal compensatory responses in PWS were not attributable to a deficit in low-level auditory processing. These findings are consistent with the hypothesis that stuttering is associated with functional defects in the inverse models responsible for the transformation from the domain of auditory targets and auditory error information into the domain of speech motor commands

Working conditions and Work-Family Conflict in German hospital physicians: psychosocial and organisational predictors and consequences

<p>Abstract</p> <p>Background</p> <p>Germany currently experiences a situation of major physician attrition. The incompatibility between work and family has been discussed as one of the major reasons for the increasing departure of German physicians for non-clinical occupations or abroad. This study investigates predictors for one particular direction of Work-Family Conflict – namely work interfering with family conflict (WIF) – which are located within the psychosocial work environment or work organisation of hospital physicians. Furthermore, effects of WIF on the individual physicians' physical and mental health were examined. Analyses were performed with an emphasis on gender differences. Comparisons with the general German population were made.</p> <p>Methods</p> <p>Data were collected by questionnaires as part of a study on <it>Psychosocial work hazards and strains of German hospital physicians </it>during April–July 2005. Two hundred and ninety-six hospital physicians (response rate 38.9%) participated in the survey. The Copenhagen Psychosocial Questionnaire (COPSOQ), work interfering with family conflict scale (WIF), and hospital-specific single items on work organisation were used to assess WIF, its predictors, and consequences.</p> <p>Results</p> <p>German hospital physicians reported elevated levels of WIF (mean = 74) compared to the general German population (mean = 45, <it>p </it>< .01). No significant gender difference was found. Predictors for the WIF were lower age, high quantitative demands at work, elevated number of days at work despite own illness, and consequences of short-notice changes in the duty roster. Good sense of community at work was a protective factor. Compared to the general German population, we observed a significant higher level of quantitative work demands among hospital physicians (mean = 73 vs. mean = 57, <it>p </it>< .01). High values of WIF were significantly correlated to higher rates of personal burnout, behavioural and cognitive stress symptoms, and the intention to leave the job. In contrast, low levels of WIF predicted higher job satisfaction, better self-judged general health status, better work ability, and higher satisfaction with life in general. Compared to the German general population, physicians showed significantly higher levels of individual stress and quality of life as well as lower levels for well-being. This has to be judged as an alerting finding regarding the state of physicians' health.</p> <p>Conclusion</p> <p>In our study, work interfering with family conflict (WIF) as part of Work-Family Conflict (WFC) was highly prevalent among German hospital physicians. Factors of work organisation as well as factors of interpersonal relations at work were identified as significant predictors for WIF. Some of these predictors are accessible to alteration by improving work organisation in hospitals.</p

Influence of bleeding order on plasma corticosterone concentration in the mouse

The influence of the order of bleeding on corticosterone release in the mouse was examined. Female C57/BL6 mice were housed in groups of five animals in a low noise environment. After 10 days, they were successively captured and sacrificed every 2 minutes. The corticosterone levels increased in the fourth and fifth mice in a cage, i.e. within the time intervals from 4 to 6 minutes and from 6 to 8 minutes after the capture of the first animal. These results suggest that quiescent corticosterone levels can be measured only when the blood samples are obtained within 4 minutes following the capture of the first mouse