Transcriptomic analysis of probable asymptomatic and symptomatic alzheimer brains

Individuals with intact cognition and neuropathology consistent with Alzheimer's disease (AD) are referred to as asymptomatic AD (AsymAD). These individuals are highly likely to develop AD, yet transcriptomic changes in the brain which might reveal mechanisms for their AD vulnerability are currently unknown. Entorhinal cortex, frontal cortex, temporal cortex and cerebellum tissue from 27 control, 33 AsymAD and 52 AD human brains were microarray expression profiled. Differential expression analysis identified a significant increase of transcriptomic activity in the frontal cortex of AsymAD subjects, suggesting fundamental changes in AD may initially begin within the frontal cortex region prior to AD diagnosis. Co-expression analysis identified an overactivation of the brain "glutamate-glutamine cycle", and disturbances in the brain energy pathways in both AsymAD and AD subjects, while the connectivity of key hub genes in this network indicates a shift from an already increased cell proliferation in AsymAD subjects to stress response and removal of amyloidogenic proteins in AD subjects. This study provides new insight into the earliest biological changes occurring in the brain prior to the manifestation of clinical AD symptoms and provides new potential therapeutic targets for early disease intervention

Thoracic load carriage-induced respiratory muscle fatigue.

We investigated the effect of carrying a 25 kg backpack upon exercise-induced respiratory muscle fatigue, pulmonary function and physiological and perceptual responses to exercise.N/

Disability quotas: past or future policy?

This article considers the issues associated with the use of quota systems for the employment of workers with a disability. It examines the use and experiences of such quotas in Italy, Russia and the United Kingdom. Italy has a long established quota for the employment of such workers, whilst the modern Russian system it is a more recent innovation. In contrast the UK abandoned its quotas in the 1990s. We draw on the experiences of the three countries to consider generally whether the use of quotas is either an acceptable means of encouraging employers to take on disabled workers, or is necessary to achieve this objective

Determinants of quality of life in children with psychiatric disorders

Objective: To assess factors that, in addition to childhood psychopathology, are associated with Quality of Life (QoL) in children with psychiatric problems. Methods: In a referred sample of 252 8 to 18-year-olds, information concerning QoL, psychopathology and a broad range of child, parent, and family/ social network factors was obtained from children, parents, teachers and clinicians. Results: Poor child, parent, and clinician reported QoL was associated with child psychopathology, but given the presence of psychopathology, also with child factors, such as low self-esteem, and poor social skills, and family/social network factors, such as poor family functioning, and poor social support. In multiple linear regression analyses the importance of parent factors, such as parenting stress, was almost negligible. Conclusion: To increase QoL of children with psychiatric problems, treatment of symptoms is important, but outcome might improve if treatment is also focussed on other factors that may affect QoL. Results are discussed in relation to current treatment programs. © Springer 2005

SLC5A3-dependent myo-inositol auxotrophy in acute myeloid leukemia.

An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1, which encodes the rate limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1. We use gain- and loss-of-function experiments to reveal a synthetic lethal genetic interaction between ISYNA1 and SLC5A3 in AML, which function redundantly to sustain intracellular myo-inositol. Transcriptional silencing and DNA hyper-methylation of ISYNA1 occur in a recurrent manner in human AML patient samples, in association with IDH1/IDH2 and CEBPA mutations. Our findings reveal myo-inositol as a nutrient dependency in AML caused by the aberrant silencing of a biosynthetic enzyme

Active Zone Protein Bassoon Co-Localizes with Presynaptic Calcium Channel, Modifies Channel Function, and Recovers from Aging Related Loss by Exercise

The P/Q-type voltage-dependent calcium channels (VDCCs) are essential for synaptic transmission at adult mammalian neuromuscular junctions (NMJs); however, the subsynaptic location of VDCCs relative to active zones in rodent NMJs, and the functional modification of VDCCs by the interaction with active zone protein Bassoon remain unknown. Here, we show that P/Q-type VDCCs distribute in a punctate pattern within the NMJ presynaptic terminals and align in three dimensions with Bassoon. This distribution pattern of P/Q-type VDCCs and Bassoon in NMJs is consistent with our previous study demonstrating the binding of VDCCs and Bassoon. In addition, we now show that the interaction between P/Q-type VDCCs and Bassoon significantly suppressed the inactivation property of P/Q-type VDCCs, suggesting that the Ca2+ influx may be augmented by Bassoon for efficient synaptic transmission at NMJs. However, presynaptic Bassoon level was significantly attenuated in aged rat NMJs, which suggests an attenuation of VDCC function due to a lack of this interaction between VDCC and Bassoon. Importantly, the decreased Bassoon level in aged NMJs was ameliorated by isometric strength training of muscles for two months. The training increased Bassoon immunoreactivity in NMJs without affecting synapse size. These results demonstrated that the P/Q-type VDCCs preferentially accumulate at NMJ active zones and play essential role in synaptic transmission in conjunction with the active zone protein Bassoon. This molecular mechanism becomes impaired by aging, which suggests altered synaptic function in aged NMJs. However, Bassoon level in aged NMJs can be improved by muscle exercise

The Cerebral Microvasculature in Schizophrenia: A Laser Capture Microdissection Study

BACKGROUND: Previous studies of brain and peripheral tissues in schizophrenia patients have indicated impaired energy supply to the brain. A number of studies have also demonstrated dysfunction of the microvasculature in schizophrenia patients. Together these findings are consistent with a hypothesis of blood-brain barrier dysfunction in schizophrenia. In this study, we have investigated the cerebral vascular endothelium of schizophrenia patients at the level of transcriptomics. METHODOLOGY/PRINCIPAL FINDINGS: We used laser capture microdissection to isolate both microvascular endothelial cells and neurons from post mortem brain tissue from schizophrenia patients and healthy controls. RNA was isolated from these cell populations, amplified, and analysed using two independent microarray platforms, Affymetrix HG133plus2.0 GeneChips and CodeLink Whole Human Genome arrays. In the first instance, we used the dataset to compare the neuronal and endothelial data, in order to demonstrate that the predicted differences between cell types could be detected using this methodology. We then compared neuronal and endothelial data separately between schizophrenic subjects and controls. Analysis of the endothelial samples showed differences in gene expression between schizophrenics and controls which were reproducible in a second microarray platform. Functional profiling revealed that these changes were primarily found in genes relating to inflammatory processes. CONCLUSIONS/SIGNIFICANCE: This study provides preliminary evidence of molecular alterations of the cerebral microvasculature in schizophrenia patients, suggestive of a hypo-inflammatory state in this tissue type. Further investigation of the blood-brain barrier in schizophrenia is warranted

Transcriptional Activation of REST by Sp1 in Huntington's Disease Models

In Huntington's disease (HD), mutant huntingtin (mHtt) disrupts the normal transcriptional program of disease neurons by altering the function of several gene expression regulators such as Sp1. REST (Repressor Element-1 Silencing Transcription Factor), a key regulator of neuronal differentiation, is also aberrantly activated in HD by a mechanism that remains unclear. Here, we show that the level of REST mRNA is increased in HD mice and in NG108 cells differentiated into neuronal-like cells and expressing a toxic mHtt fragment. Using luciferase reporter gene assay, we delimited the REST promoter regions essential for mHtt-mediated REST upregulation and found that they contain Sp factor binding sites. We provide evidence that Sp1 and Sp3 bind REST promoter and interplay to fine-tune REST transcription. In undifferentiated NG108 cells, Sp1 and Sp3 have antagonistic effect, Sp1 acting as an activator and Sp3 as a repressor. Upon neuronal differentiation, we show that the amount and ratio of Sp1/Sp3 proteins decline, as does REST expression, and that the transcriptional role of Sp3 shifts toward a weak activator. Therefore, our results provide new molecular information to the transcriptional regulation of REST during neuronal differentiation. Importantly, specific knockdown of Sp1 abolishes REST upregulation in NG108 neuronal-like cells expressing mHtt. Our data together with earlier reports suggest that mHtt triggers a pathogenic cascade involving Sp1 activation, which leads to REST upregulation and repression of neuronal genes