Regulation of Erk1/2 activation by osteopontin in PC3 human prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Osteopontin (OPN) has been shown to play many roles in the progression of cancer. We have recently demonstrated the activation of Akt by OPN. Integrin-linked kinase and PI3-kinase are integral proteins in OPN/AKT pathway in PC3 cells. To investigate the role of the extracellular receptors in OPN signaling, we have examined the spatio-temporal regulation of CD44 and integrin αvβ3 receptor in OPN-induced Akt activation in PC3 cells.</p> <p>Results</p> <p>Here, our studies demonstrate that OPN can activate Akt either through the α_Vβ₃integrin or the CD44 cell surface receptor. Members of the Mitogen Activated Protein Kinase (MAPK) family have been shown to be up-regulated in a variety of human cancers and have been implicated in the metastatic behavior. Our studies have demonstrated an increase in the phosphorylation of c-Raf at Ser259 and Ser338 in PC3 cells over-expressing OPN. This increase matches up with the Erk1/2 phosphorylation at Thr202/204 and activation. However, the inhibition of Akt activity augments the phosphorylation state of ERK1/2 to two to three fold with a concomitant reduction in the phosphorylation state of c-Raf at Ser259.</p> <p>Conclusions</p> <p>Regulation c-Raf phosphorylation at Ser259 has a role in the anti-apoptotic pathways mediated by Akt or Raf/MEK/ERK proteins. OPN may have dual effects in the activation of Erk1/2. We propose this based on the observations that while OPN activates c-Raf and Erk1/2; it also acts to inhibit c-Raf and Erk1/2 activation through Akt pathway. Our observations suggest that the activation of c-Raf-ERK cascade may promote cell cycle arrest in prostate cancer cells and OPN signaling has a role in the anti-apoptotic mechanism.</p

Post-traumatic stress disorder in children exposed to violence

Objectives. To investigate to what extent local children exposed to community violence develop post-traumatic stress disorder (PTSD), whether the symptom profile is typical or atypical, and how detection can be improved.Design. A cross-sectional study of two samples of children with a high risk of past exposure to violence.Setting and subjects. Sixty Xhosa-speaking children aged 10 - 16 years; 30 from the Children's Home which serves Khayelitsha, and 30 from a school in a violent area of KhayelitshaOutcome measures. A shortened version of the Survey of Exposure to Community Violence (SECV) was administered to determine exposure to violence. Structured questionnaires and a clinical assessment were used to elicit symptoms and make psychiatric diagnoses.Results. All 60 children reported exposure to indirect violence, 57 (95%) had witnessed violence, and 34 (56%) had experienced violence themselves. Twenty-four (40%) met the criteria for one or more DSM-III-R diagnoses and 13 (21.7%) met the criteria lor PTSD.Conclusions. Community violence places children at a high risk of developing serious psychiatric disorders and many children develop PTSD. None of the children in the school sample had received intervention prior to the study, pointing towards an urgent need for increased community and professional awareness of children at risk

Genome wide analysis of the complete GlnR nitrogen-response regulon in Mycobacterium smegmatis

BACKGROUND: Nitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms. RESULTS: We investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding. CONCLUSIONS: We have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions

A model for estimating mental health service needs in South Africa

Objective. To develop a model for estimating the services and human resources needed. to care for people with severe psychiatric conditions in a hypothetical population of 100 000 people in South Africa.Method. Annual mental health service needs were estimated. in terms of numbers of daily patient visits (DPV) in ambulatory care, the number of beds required, and staffing_ Developed within a spreadsheet format, the model allows for the adjustment of key service variables according.to estimated or existing service data.Results. At 100% coverage, 87 DPV, 28 acute beds, and 10 medium-long stay beds are necessary for a population of 100 000 people. This would require 352 full-time equivalent mental health staff: 21.3 for inpatient care, 12.0 for ambulatory care, and 1.9 for management.Conclusion. Because the model can produce a range of service recommendations, the assumptions that inform it should be clearly stated. and justified.. This method makes the assumptions on which services are planned. explicit and allows for a rational approach to decision making

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Background: Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. Results: We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. Conclusions: This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers

Cognitive rehabilitation for early stage Alzheimer’s disease: a pilot study with an Irish population

Objectives Research shows that cognitive rehabilitation (CR) has the potential to improve goal performance and enhance well-being for people with early stage Alzheimer’s disease (AD). This single subject, multiple baseline design (MBD) research investigated the clinical efficacy of an 8-week individualised CR intervention for individuals with early stage AD. Methods Three participants with early stage AD were recruited to take part in the study. The intervention consisted of eight sessions of 60–90 minutes of CR. Outcomes included goal performance and satisfaction, quality of life, cognitive and everyday functioning, mood, and memory self-efficacy for participants with AD; and carer burden, general mental health, quality of life, and mood of carers. Results Visual analysis of MBD data demonstrated a functional relationship between CR and improvements in participants’ goal performance. Subjective ratings of goal performance and satisfaction increased from baseline to post-test for three participants and were maintained at follow-up for two. Baseline to post-test quality of life scores improved for three participants, whereas cognitive function and memory self-efficacy scores improved for two. Conclusions Our findings demonstrate that CR can improve goal performance, and is a socially acceptable intervention that can be implemented by practitioners with assistance from carers between sessions. This study represents one of the promising first step towards filling a practice gap in this area. Further research and randomised-controlled trials are required

Dorsal striatum mediates cognitive control, not cognitive effort per se, in decision-making: An event-related fMRI study

Objective: Whether the dorsal striatum (DS) mediates cognitive control or cognitive effort per se in decision-making is unclear given that these effects are highly correlated. As the cognitive control requirements of a neuropsychological task intensify, cognitive effort increases proportionately. We implemented a task that disentangled cognitive control and cognitive effort to specify the particular function DS mediates in decision-making. Methods: Sixteen healthy young adults completed a number Stroop task with simultaneous blood-oxygenation-level-dependent response (BOLD) measurement using functional magnetic resonance imaging. Participants selected the physically larger number of a pair of single-digit integers. Discriminating smaller versus larger physical size differences between a number pair requires greater cognitive effort, but does not require greater cognitive control. We also investigated the effect of conflict between the physical and numerical dimensions of targets (e.g., 2 6). Selections in this incongruent case are more cognitively effortful and require greater cognitive control to suppress responding to the irrelevant dimension. Enhancing cognitive effort or cognitive control demands increases errors and response times. Despite similar behavioural profiles, our aim was to determine whether DS mediates cognitive control or simply indexes cognitive effort, using the same data set. Results: As expected, behavioural interference effects occurred for both enhanced cognitive control and/or cognitive effort conditions. Despite similar degrees of behavioural interference, DS BOLD signal only correlated with interference arising due to increased cognitive control demands in the incongruent case. DS was not preferentially activated for discriminations of smaller relative to larger physical size differences between number pairs, even when using liberal statistical criteria. However, our incongruent and physical size effects conjointly activated regions related to effortful processing (e.g., anterior cingulate cortex). Interpretation: We interpret these findings as support for the increasingly accepted notion that DS mediates cognitive control specifically and does not simply index cognitive effort per se

Posterior Interosseous Nerve of the Elbow

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135289/1/jum2010295691.pd