Influence of interaction force levels on degree of motor adaptation in a stable dynamic force field

Studies have shown that the point-to-point reaching movements of subjects seated in a dark, rotating room demonstrate errors in movement trajectories and endpoints, consistent with the direction of the Coriolis force perturbations created by room rotation. Adaptation of successive reaches and the presence of postrotation aftereffects have indicated that subjects form internal models of the Coriolis field dynamics in order to make appropriate movement corrections. It has been argued that these findings are inconsistent with predictions of peripheral stabilization assumed in equilibrium-point models of motor control. A possibility that has been raised, however, is that the Coriolis field findings may in fact stem from changes in control commands elicited due to the magnitude and destabilizing nature of the Coriolis perturbations. That is, it has been suggested that a perturbation threshold exists, below which central reactions are not necessary in order to maintain movement stability. We tested the existence of a perturbation threshold in normal-speed reaching movements. Twelve normal human subjects performed non-visually guided reaching movements while grasping a robotic manipulandum. The endpoints and trajectory deviations of their movements were measured before, during, and after a position-dependent force field (similar to a Coriolis field in terms of the time history of applied forces) was applied to their movements. We examined the responses to a range of perturbation field strengths from small to considerable. Our experimental results demonstrated a substantial adaptation response over the entire range of perturbation field magnitudes examined. Neither the amount of adaptation after 5 trials nor after 25 trials was found to change as disturbance magnitudes decreased. These findings indicate that there is an adaptive response even for small perturbations; i.e., threshold behavior was not found. This result contradicts the assertion that peripheral stabilization mechanisms enable the central controller to ignore small details of peripheral or environmental dynamics. Our findings instead point to a central dynamic modeler that is both highly sensitive and continually active. The results of our study also showed that subjects were able to maintain baseline pointing accuracies despite exposure to perturbation forces of sizeable magnitude (more than 7 N).     

Patient mutations alter ATRX targeting to PML nuclear bodies

ATRX is a SWI/SNF-like chromatin remodeling protein mutated in several X-linked mental retardation syndromes. Gene inactivation studies in mice demonstrate that ATRX is an essential protein and suggest that patient mutations likely retain partial activity. ATRX associates with the nuclear matrix, pericentromeric heterochromatin, and promyelocytic leukemia nuclear bodies (PML-NBs) in a speckled nuclear staining pattern. Here, we used GFP-ATRX fusion proteins to identify the specific domains of ATRX necessary for subnuclear targeting and the effect of patient mutations on this localization. We identified two functional nuclear localization signals (NLSs) and two domains that target ATRX to nuclear speckles. One of the latter domains is responsible for targeting ATRX to PML-NBs. Surprisingly, this domain encompassed motifs IV-VI of the SNF2 domain suggesting that in addition to chromatin remodeling, it may also have a role in subnuclear targeting. More importantly, four different patient mutations within this domain resulted in an approximately 80% reduction in the number of transfected cells with ATRX nuclear speckles and PML colocalization. These results demonstrate that patient mutations have a dramatic effect on subnuclear targeting to PML-NBs. Moreover, these findings support the hypothesis that ATRX patient mutations represent functional hypomorphs and suggest that loss of proper targeting to PML-NBs is an important contributor to the pathogenesis of the ATR-X syndrome.     

Neonatal endotoxin exposure modifies the acoustic startle response and circulating levels of corticosterone in the adult rat but only following acute stress

A variety of early life stressors have consistently been implicated in the development of psychopathology in adulthood. The current study investigates a rarely considered form of early life stress, bacterial infection, for its ability to induce psychopathology-like symptoms in adult rat. Specifically, neonatal rats were exposed to a simulated bacterial infection. In adulthood the acoustic startle response of these animals was evaluated both prior to and following exposure to restraint stress. Our results indicate that animals neonatally exposed to infection exhibit a significantly exaggerated acoustic startle response but only following exposure to stress. Additionally, we observed that adult animals neonatally exposed to infection, exhibited increased production of circulating corticosterone following stress, indicating potentiated hypothalamic pituitary adrenal axis activity as well as altered novelty seeking behaviour and locomotor activity. These results extend upon existing pre-clinical findings that indicate certain stressful early life events can predispose the adult animal to exhibit abnormal behaviour in adulthood.     

Chronic mucocutaneous candidiasis due to gain‐of‐function mutation in STAT1

Chronic mucocutaneous candidiasis (CMC) is a heterogenous group of primary immunodeficiency diseases characterised by susceptibility to chronic or recurrent superficial Candida infection of skin, nails and mucous membranes. Gain‐of‐function mutations in the STAT1 gene (STAT1‐GOF) are the most common genetic aetiology for CMC, and mutation analysis should be considered. These mutations lead to defective responses in Type 1 and Type 17 helper T cells (Th1 and Th17), which, depending on the mutation, also predispose to infection with Staphylococci, Mycobacteria and Herpesviridae. We describe the clinical and genetic findings for three patients with CMC due to gain‐of‐function mutations in the STAT1 gene.     

Non-steroidal anti-inflammatory drugs and gastric DNA synthesis

In vitro incubation of endoscopic gastric antral biopsy specimens with tritiated thymidine, with confirmatory autoradiography, was used to assess gastric epithelial cell turnover in man and to investigate the effects of chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs). In the absence of NSAID administration, macroscopic erosions and ulceration in the antrum were associated with enhanced gastric epithelial cell proliferation. In patients taking NSAIDs erosions occurred without a compensatory increase in epithelial cell DNA synthesis. The failure to respond to injury by enhancing epithelial cell proliferation is likely to be an important factor in NSAID-induced gastric damage and supports a role for prostaglandins in enhancing mucosal repair by increasing epithelial cell generation.     

Chromosome aberrations determined by sFISH and G-banding in lymphocytes from workers with internal deposits of plutonium

Purpose: To examine the influence of α-particle radiation exposure from internally deposited plutonium on chromosome aberration frequencies in peripheral blood lymphocytes of workers from the Sellafield nuclear facility, UK. Materials and methods: Chromosome aberration data from historical single colour fluorescence in situ hybridization (sFISH) and Giemsa banding (G-banding) analyses, together with more recent sFISH results, were assessed using common aberration analysis criteria and revised radiation dosimetry. The combined sFISH group comprised 29 men with a mean internal red bone marrow dose of 21.0 mGy and a mean external γ-ray dose of 541 mGy. The G-banding group comprised 23 men with a mean internal red bone marrow dose of 23.0 mGy and a mean external γ-ray dose of 315 mGy. Results: Observed translocation frequencies corresponded to expectations based on age and external γ-ray dose with no need to postulate a contribution from α-particle irradiation of the red bone marrow by internally deposited plutonium. Frequencies of stable cells with complex aberrations, including insertions, were similar to those in a group of controls and a group of workers with external radiation exposure only, who were studied concurrently. In a similar comparison there is some suggestion of an increase in cells with unstable complex aberrations and this may reflect recent direct exposure to circulating lymphocytes. Conclusions: Reference to in vitro dose response data for the induction of stable aberrant cells by α-particle irradiation indicates that the low red bone marrow α-particle radiation doses received by the Sellafield workers would not result in a discernible increase in translocations, thus supporting the in vivo findings. Therefore, the greater risk from occupational radiation exposure of the bone marrow resulting in viable chromosomally aberrant cells comes from, in general, much larger γ-ray exposure in comparison to α-particle exposure from plutonium.     

Applications of synchrotron radiation to protein crystallography: preliminary results.

X-ray diffraction photographs of protein single crystals have been obtained using synchrotron radiation produced by an electron-positron storage ring. The diffracted intensities observed with this unconventional source are a factor of at least 60 greater than those obtained with a sealed x-ray tube using the same crystal and instrumental parameters. Diffraction data have been collected by the precession method to higher resolution and using smaller protein crystals than would have been possible with a conventional source. The crystal decay rate in the synchrotron beam for several proteins appears to be substantially less than that observed with Ni-filtered Cu radiation. The tunable nature of the source (which allows selective optimization of anomalous contributions to the scattering factors) and the low angular divergence of the beam make the source very useful for single crystal protein diffraction studies.     

Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D₂ receptors by antipsychotics, respectively. Adenosine A_2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal (“indirect”) pathway, where they appear to operate in concert with D₂ receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A_2A receptor activation contributes to the overdrive of the indirect pathway. A_2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A_2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A_2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A_2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3–3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.     

Rights-based services for adolescents living with HIV: adolescent self-efficacy and implications for health systems in Zambia

A rights-based approach in HIV service delivery for adults is increasingly taking root in sub-Saharan Africa in the context of greater availability of antiretroviral therapy. Yet there has been comparatively little progress in strengthening a rights-based approach to adolescent HIV services, which we learned during a qualitative study in 2010 among 111 adolescents living with HIV, 21 parents and 38 health providers in three districts in Zambia. Adolescents in the study expressed a range of information and support needs and wanted locally relevant interventions to meet those needs. They wanted greater access to HIV, sexual and reproductive health information, information on how to protect themselves, privacy and confidentiality in service sites, skills training so as to be able to earn money, and better control over disclosure of their HIV status to others. Both health workers and parents acknowledged that information and services needed to be improved to meet those needs far better. This paper provides examples of successful programmes in Zimbabwe, Uganda, Tanzania, Botswana and South Africa and calls for adolescent services to be linked to both paediatric and adult services, peer networks to be established to increase adolescents' ability to collectively voice their concerns and support each other, interventions supporting adolescents' control over self-disclosure, and lastly that adolescent health should become a training specialty in sub-Saharan Africa.     

Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5‐associated malformations include bottom‐of‐the‐sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway. Ann Neurol 2014;75:782–787