Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans

Iminosugar-Based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease

The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects

Pairing of Homologous Regions in the Mouse Genome Is Associated with Transcription but Not Imprinting Status

This work was funded by the BBSRC, grant BB/H088071/1 (www.bbsrc.ac.uk), MRC, grant G0700760 (www.mrc.ac.uk), Wellcome Trust, grant 095645/Z/11/Z (www.wellcome.ac.uk) and the EU through EpiGeneSys (www.epigenesys.eu) and Blueprint (www.blueprint-epigenome.eu). C.K. was funded by the DFG, personal fellowship KR 3317/2-1 (www.dfg.de) and CTR, personal short term fellowship (www.trophoblast.cam.ac.uk). M.J.H. received funding through grant NCI/NIH 2RO1 CA089426 (www.nih.gov)

RhoH Regulates Subcellular Localization of ZAP-70 and Lck in T Cell Receptor Signaling

RhoH is an hematopoietic-specific, GTPase-deficient Rho GTPase that plays a role in T development. We investigated the mechanisms of RhoH function in TCR signaling. We found that the association between Lck and CD3ζ was impaired in RhoH-deficient T cells, due to defective translocation of both Lck and ZAP-70 to the immunological synapse. RhoH with Lck and ZAP-70 localizes in the detergent-soluble membrane fraction where the complex is associated with CD3ζ phosphorylation. To determine if impaired translocation of ZAP-70 was a major determinant of defective T cell development, Rhoh-/- bone marrow cells were transduced with a chimeric myristoylation-tagged ZAP-70. Myr-ZAP-70 transduced cells partially reversed the in vivo defects of RhoH-associated thymic development and TCR signaling. Together, our results suggest that RhoH regulates TCR signaling via recruitment of ZAP-70 and Lck to CD3ζ in the immunological synapse. Thus, we define a new function for a RhoH GTPase as an adaptor molecule in TCR signaling pathway

Changes in Striatal Dopamine Release Associated with Human Motor-Skill Acquisition

The acquisition of new motor skills is essential throughout daily life and involves the processes of learning new motor sequence and encoding elementary aspects of new movement. Although previous animal studies have suggested a functional importance for striatal dopamine release in the learning of new motor sequence, its role in encoding elementary aspects of new movement has not yet been investigated. To elucidate this, we investigated changes in striatal dopamine levels during initial skill-training (Day 1) compared with acquired conditions (Day 2) using 11C-raclopride positron-emission tomography. Ten volunteers learned to perform brisk contractions using their non-dominant left thumbs with the aid of visual feedback. On Day 1, the mean acceleration of each session was improved through repeated training sessions until performance neared asymptotic levels, while improved motor performance was retained from the beginning on Day 2. The 11C-raclopride binding potential (BP) in the right putamen was reduced during initial skill-training compared with under acquired conditions. Moreover, voxel-wise analysis revealed that 11C-raclopride BP was particularly reduced in the right antero-dorsal to the lateral part of the putamen. Based on findings from previous fMRI studies that show a gradual shift of activation within the striatum during the initial processing of motor learning, striatal dopamine may play a role in the dynamic cortico-striatal activation during encoding of new motor memory in skill acquisition

CRIM1 Complexes with ß-catenin and Cadherins, Stabilizes Cell-Cell Junctions and Is Critical for Neural Morphogenesis

In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with ß-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and ß-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions

A critical review of smaller state diplomacy

In The Peloponnesian War, Thucydides (1972: 402) highlights the effects of the general, overall weakness of smaller states vis-à-vis larger, more powerful ones in a key passage, where the Athenians remind the Melians that: “… since you know as well as we do that, as the world goes, right is only in question between equals in power. Meanwhile, the strong do what they can and the weak suffer what they must.” Concerns about the vulnerability of small, weak, isolated states have echoed throughout history: from Thucydides, through the review by Machiavelli (1985) of the risks of inviting great powers to intervene in domestic affairs, through 20th century US-led contemporary political science (Vital, 1971; Handel, 1990) and Commonwealth led scholarship (Commonwealth Secretariat, 1985). In the context of 20th century ‘Balkanization’, the small state could also prove unstable, even hostile and uncooperative, a situation tempting enough to invite the intrusion of more powerful neighbours: a combination, according to Brzezinski (1997: 123-124) of a power vacuum and a corollary power suction2: in the outcome, if the small state is ‘absorbed’, it would be its fault, and its destiny, in the grand scheme of things. In an excellent review of small states in the context of the global politics of development, Payne (2004: 623, 634) concludes that “vulnerabilities rather than opportunities are the most striking consequence of smallness”. It has been recently claimed that, since they cannot defend or represent themselves adequately, small states “lack real independence, which makes them suboptimal participants in the international system” (Hagalin, 2005: 1). There is however, a less notable and acknowledged but more extraordinary strand of argumentation that considers ‘the power of powerlessness’, and the ability of small states to exploit their smaller size in a variety of ways in order to achieve their intended, even if unlikely, policy outcomes. The pursuance of smaller state goals becomes paradoxically acceptable and achievable precisely because such smaller states do not have the power to leverage disputants or pursue their own agenda. A case in point concerns the smallest state of all, the Vatican, whose powers are both unique and ambiguous, but certainly not insignificant (The Economist, 2007). Smaller states have “punched above their weight” (e.g. Edis, 1991); and, intermittently, political scientists confront their “amazing intractability” (e.g. Suhrke, 1973: 508). Henry Kissinger (1982: 172) referred to this stance, with obvious contempt, as “the tyranny of the weak”3. This paper seeks a safe passage through these two, equally reductionist, propositions. It deliberately focuses first on a comparative case analysis of two, distinct ‘small state-big state’ contests drawn from the 1970s, seeking to infer and tease out the conditions that enable smaller ‘Lilliputian’ states (whether often or rarely) to beat their respective Goliaths. The discussion is then taken forward to examine whether similar tactics can work in relation to contemporary concerns with environmental vulnerability, with a focus on two other, small island states. Before that, the semiotics of ‘the small state’ need to be explored, since they are suggestive of the perceptions and expectations that are harboured by decision makers at home and abroad and which tend towards the self-fulfilling prophecy.peer-reviewe

Time trends in leisure time physical activity and physical fitness in elderly people: 20 year follow-up of the Spanish population national health survey (1987-2006)

<p>Abstract</p> <p>Background</p> <p>To estimate trends in leisure time physical activity and physical fitness between 1987-2006 in older Spanish people.</p> <p>Methods</p> <p>We analyzed data collected from the Spanish National Health Surveys conducted in 1987 (n = 29,647), 1993 (n = 20,707), 1995-1997 (n = 12,800), 2001 (n = 21,058), 2003 (n = 21,650), and 2006 (n = 29,478). The number of subjects aged ≥ 65 years included in the current study was 29,263 (1987: n = 4,958-16.7%; 1993: n = 3,751-17.8%; 1995-97: n = 2,229-17.4%; 2001: n = 4,356-20.7%; 2003: 6,134-28.3%; 2006: 7,835-26.5%). Main variables included leisure-time physical activity and physical fitness. We analyzed socio-demographic characteristics, self-rated health status, lifestyle habit and co-morbid conditions using multivariate logistic regression models.</p> <p>Results</p> <p>Women exhibited lower prevalence of leisure time physical activity and physical fitness compared to men (P < 0.05). The multivariate analysis for time trends found that practising leisure time physical activity increased from 1987 to 2006 (P < 0.001). Variables associated with a lower likelihood of practicing leisure time physical activity were: age ≥ 80 years old, ≥ 2 co-morbid chronic conditions, and obesity. Variables associated with lower physical fitness included: age ≥ 80 years, worse self rated health; ≥ 2 medications (only for walking), and obesity.</p> <p>Conclusions</p> <p>We found an increase in leisure time physical activity in the older Spanish population. Older age, married status, co-morbid conditions, obesity, and worse self-perceived health status were associated with lower activity. Identification of these factors can help to identify individuals at risk for physical inactivity.</p