Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically

Work-related psychological health among clergywomen in Australia

Drawing on the classic model of balanced affect, the Francis Burnout Inventory conceptualises good work-related psychological health among clergy in terms of negative affect being balanced by positive affect. This paper sets out to explore the relationship between work-related psychological health and psychological type (as assessed by the Francis Psychological-Type Scales) among a sample of 212 Australian clergywomen who completed the National Church Life Survey Form L in 2006. The data supported the internal consistency reliability of the Francis Burnout Inventory and Francis Psychological-Type Scales and found that work-related psychological health was positively related to extraversion and sensing

Neonatal-onset multisystem inflammatory disease responsive to interleukin-1 beta inhibition

BACKGROUND:Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation.METHODS:We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare.RESULTS:All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events.CONCLUSIONS:Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations

Diagnosing Dementia in the Clinical Setting: Can Amyloid PET Provide Additional Value Over Cerebrospinal Fluid?

Cerebrospinal fluid (CSF) measures of amyloid and tau are the first-line Alzheimer's disease biomarkers in many clinical centers. We assessed if and when the addition of amyloid PET following CSF measurements provides added diagnostic value. Twenty patients from a cognitive clinic, who had undergone detailed assessment including CSF measures, went on to have amyloid PET. The treating neurologist's working diagnosis, and degree of diagnostic certainty, was assessed both before and after the PET. Amyloid PET changed the diagnosis in 7/20 cases. Amyloid PET can provide added diagnostic value, particularly in young-onset, atypical dementias, where CSF results are borderline and diagnostic uncertainty remains

Nitrogen and phosphorus availability interact to modulate leaf trait scaling relationships across six plant functional types in a controlled-environment study

Nitrogen (N) and phosphorus (P) have key roles in leaf metabolism, resulting in a strong coupling of chemical composition traits to metabolic rates in field-based studies. However, in such studies, it is difficult to disentangle the effects of nutrient supply per se on trait-trait relationships. Our study assessed how high and low N (5 mM and 0.4 mM, respectively) and P (1 mM and 2 μM, respectively) supply in 37 species from six plant functional types (PTFs) affected photosynthesis (A) and respiration (R) (in darkness and light) in a controlled environment. Low P supply increased scaling exponents (slopes) of area-based log-log A-N or R-N relationships when N supply was not limiting, whereas there was no P effect under low N supply. By contrast, scaling exponents of A-P and R-P relationships were altered by P and N supply. Neither R : A nor light inhibition of leaf R was affected by nutrient supply. Light inhibition was 26% across nutrient treatments; herbaceous species exhibited a lower degree of light inhibition than woody species. Because N and P supply modulates leaf trait-trait relationships, the next generation of terrestrial biosphere models may need to consider how limitations in N and P availability affect trait-trait relationships when predicting carbon exchange

The Red Sea, Coastal Landscapes, and Hominin Dispersals

This chapter provides a critical assessment of environment, landscape and resources in the Red Sea region over the past five million years in relation to archaeological evidence of hominin settlement, and of current hypotheses about the role of the region as a pathway or obstacle to population dispersals between Africa and Asia and the possible significance of coastal colonization. The discussion assesses the impact of factors such as topography and the distribution of resources on land and on the seacoast, taking account of geographical variation and changes in geology, sea levels and palaeoclimate. The merits of northern and southern routes of movement at either end of the Red Sea are compared. All the evidence indicates that there has been no land connection at the southern end since the beginning of the Pliocene period, but that short sea crossings would have been possible at lowest sea-level stands with little or no technical aids. More important than the possibilities of crossing the southern channel is the nature of the resources available in the adjacent coastal zones. There were many climatic episodes wetter than today, and during these periods water draining from the Arabian escarpment provided productive conditions for large mammals and human populations in coastal regions and eastwards into the desert. During drier episodes the coastal region would have provided important refugia both in upland areas and on the emerged shelves exposed by lowered sea level, especially in the southern sector and on both sides of the Red Sea. Marine resources may have offered an added advantage in coastal areas, but evidence for their exploitation is very limited, and their role has been over-exaggerated in hypotheses of coastal colonization

Pointing errors in non-metric virtual environments

There have been suggestions that human navigation may depend on representations that have no metric, Euclidean interpretation but that hypothesis remains contentious. An alternative is that observers build a consistent 3D representation of space. Using immersive virtual reality, we measured the ability of observers to point to targets in mazes that had zero, one or three ‘wormholes’ – regions where the maze changed in configuration (invisibly). In one model, we allowed the configuration of the maze to vary to best explain the pointing data; in a second model we also allowed the local reference frame to be rotated through 90, 180 or 270 degrees. The latter model outperformed the former in the wormhole conditions, inconsistent with a Euclidean cognitive map

Varieties of living things: Life at the intersection of lineage and metabolism

publication-status: Publishedtypes: Articl

Enabling large-scale design, synthesis and validation of small molecule protein-protein antagonists

Although there is no shortage of potential drug targets, there are only a handful known low-molecular-weight inhibitors of protein-protein interactions (PPIs). One problem is that current efforts are dominated by low-yield high-throughput screening, whose rigid framework is not suitable for the diverse chemotypes present in PPIs. Here, we developed a novel pharmacophore-based interactive screening technology that builds on the role anchor residues, or deeply buried hot spots, have in PPIs, and redesigns these entry points with anchor-biased virtual multicomponent reactions, delivering tens of millions of readily synthesizable novel compounds. Application of this approach to the MDM2/p53 cancer target led to high hit rates, resulting in a large and diverse set of confirmed inhibitors, and co-crystal structures validate the designed compounds. Our unique open-access technology promises to expand chemical space and the exploration of the human interactome by leveraging in-house small-scale assays and user-friendly chemistry to rationally design ligands for PPIs with known structure. © 2012 Koes et al