Host genetics and HIV-1: the final phase?

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.

Genome-wide scan of copy number variation in late-onset Alzheimer's disease.

Alzheimer's disease is a complex and progressive neurodegenerative disease leading to loss of memory, cognitive impairment, and ultimately death. To date, six large-scale genome-wide association studies have been conducted to identify SNPs that influence disease predisposition. These studies have confirmed the well-known APOE epsilon4 risk allele, identified a novel variant that influences disease risk within the APOE epsilon4 population, found a SNP that modifies the age of disease onset, as well as reported the first sex-linked susceptibility variant. Here we report a genome-wide scan of Alzheimer's disease in a set of 331 cases and 368 controls, extending analyses for the first time to include assessments of copy number variation. In this analysis, no new SNPs show genome-wide significance. We also screened for effects of copy number variation, and while nothing was significant, a duplication in CHRNA7 appears interesting enough to warrant further investigation.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435-474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome.

Polycyclic aromatic hydrocarbons (PAHS) (I): Toxicity, population exposure and involved foods

Food is one of the main exogenous sources of genotoxic compounds. In heated food products, polycyclic aromatic hydrocarbons (PAHs) represent a priority group of genotoxic, mutagenic and/or carcinogenic chemical pollutants with adverse long-term health effects. People can be exposed to these compounds through different environments and via various routes: inhalation, ingestion of foods and water and even percutaneously. The presence of these compounds in food may be due to environmental contamination, to industrial handling and processing of foods and to oil processing and refining. The highest levels of these compounds are found in smoked foods, in seafood which is found in polluted waters, in grilled meats and, to a lesser extent, in vegetable fats and oils. Lower levels of PAHs are found in vegetables and in cereals and its products.

Art and Social Work: an intervention programme for transforming society’s vision to include people with early-onset dementia and Alzheimer’s

This paper presents a program centred on arts and education as tools in social work for the inclusion of people with earlyonset dementia and Alzheimer’s. The objective of the programme is to eradicate the stigma and myths associated with the disease.The program is part of the Junta de Castilla y León and the European Social Fund’s ARS Project (Arte y Salud Alzheimer; Alzheimer’s Art & Health). The programme presents a series of evaluated artistic and educational activities that can be undertaken by people in the early stages of Alzheimer’s disease and that can also be used by caregivers and family when working with this group of people, with the aim of improving their wellbeing, self-esteem and quality of life.

Large carbon isotope fractionation associated with oxidation of methyl halides by methylotrophic bacteria

The largest biological fractionations of stable carbon isotopes observed in nature occur during production of methane by methanogenic archaea. These fractionations result in substantial (as much as 70) shifts in 13C relative to the initial substrate. We now report that a stable carbon isotopic fractionation of comparable magnitude (up to 70) occurs during oxidation of methyl halides by methylotrophic bacteria. We have demonstrated biological fractionation with whole cells of three methylotrophs (strain IMB-1, strain CC495, and strain MB2) and, to a lesser extent, with the purified cobalamin-dependent methyltransferase enzyme obtained from strain CC495. Thus, the genetic similarities recently reported between methylotrophs, and methanogens with respect to their pathways for C1-unit metabolism are also reflected in the carbon isotopic fractionations achieved by these organisms. We found that only part of the observed fractionation of carbon isotopes could be accounted for by the activity of the corrinoid methyltransferase enzyme, suggesting fractionation by enzymes further along the degradation pathway. These observations are of potential biogeochemical significance in the application of stable carbon isotope ratios to constrain the tropospheric budgets for the ozone-depleting halocarbons, methyl bromide and methyl chloride.

Charge-state distribution and Doppler effect in an expanding photoionized plasma.

The charge state distributions of Fe, Na, and F are determined in a photoionized laboratory plasma using high resolution x-ray spectroscopy. Independent measurements of the density and radiation flux indicate unprecedented values for the ionization parameter ���¾=20 25 erg cm s-1 under near steady-state conditions. Line opacities are well fitted by a curve-of-growth analysis which includes the effects of velocity gradients in a one-dimensional expanding plasma. First comparisons of the measured charge state distributions with x-ray photoionization models show reasonable agreement.

Modeling X-ray photoionized plasmas produced at the Sandia Z-facility

In experiments at the high-power Z-facility at Sandia National Laboratory in Albuquerque, New Mexico, we have been able to produce a low density photoionized laboratory plasma of Fe mixed with NaF. The conditions in the experiment allow a meaningful comparison with X-ray emission from astrophysical sources. The charge state distributions of Fe, Na and F are determined in this plasma using high resolution X-ray spectroscopy. Independent measurements of the density and radiation flux indicate unprecedented values for the ionization parameter xi = 20-25 erg cm s(-1) under nearly steady-state conditions. First comparisons of the measured charge state distributions with X-ray photoionization models show reasonable agreement, although many questions remain.

Enlargement and the European Union’s Absorption Capacity: ‘oft-forgotten’ condition or additional obstacle to membership?

The Austrian government may have failed in its efforts in 2005 to have ‘privileged partnership' inserted into the European Union's framework for accession negotiations with Turkey, but this did not prevent the country's Chancellor, Wolfgang Schussel, from claiming that ‘for the first time ever, we have set an extra condition which will yet be very important in the future for Europe, namely the ability of the Union to take in new members'. Indeed, since its inclusion in the framework for negotiations, the EU's ‘capacity to absorb' new members is referred to as a new criterion for further enlargement of the European Union (EU). When opponents of Turkey 's membership, like Schussel, celebrate the emphasis on the EU's ‘absorption capacity', Turks generally regard it as specially-designed extra obstacle to their membership aspirations even if the EU's ‘absorption capacity' is a permanent agenda item whenever the EU discusses enlargement. This article explores the origins of this – supposedly new – condition and argues that the increased emphasis on the EU's ‘absorption capacity' can be explained by the shifts in the dynamics of EU enlargement.

Devotional Culture in Late Medieval England and Europe: Diverse Imaginations of Christ’s Life

Christ’s life, as related through the Gospel narratives and early Apocrypha, was subject to a riot of literary-devotional adaptation in the medieval period. This collection provides a series of groundbreaking studies centring on the devotional and cultural significance of Christianity’s pivotal story during the Middle Ages.

The collection represents an important milestone in terms of mapping the meditative modes of piety that characterize a number of Christological traditions, including the Meditationes vitae Christi and the numerous versions it spawned in both Latin and the vernacular. A number of chapters in the volume track how and why meditative piety grew in popularity to become a mode of spiritual activity advised not only to recluses and cenobites as in the writings of Aelred of Rievaulx, but also reached out to diverse lay audiences through the pastoral regimens prescribed by devotional authors such as the Carthusian prior Nicholas Love in England and the Parisian theologian and chancellor of the University of Paris, Jean Gerson.

Through exploring these texts from a variety of perspectives — theoretical, codicological, theological — and through tracing their complex lines of dissemination in ideological and material terms, this collection promises to be invaluable to students and scholars of medieval religious and literary culture.