Molecular evolution of the MAGUK family in metazoan genomes

Background  

Development, differentiation and physiology of metazoans all depend on cell to cell communication and subsequent intracellular signal transduction. Often, these processes are orchestrated via sites of specialized cell-cell contact and involve receptors, adhesion molecules and scaffolding proteins. Several of these scaffolding proteins important for synaptic and cellular junctions belong to the large family of membrane-associated guanylate kinases (MAGUK). In order to elucidate the origin and the evolutionary history of the MAGUKs we investigated full-length cDNA, EST and genomic sequences of species in major phyla.     

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis

BackgroundObservational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.ConclusionsThis IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.     

Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90

With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.     

Variation in grain arsenic assessed in a diverse panel of rice (Oryza sativa) grown in multiple sites

? Inorganic arsenic (As(i) ) in rice (Oryza sativa) grains is a possible threat to human health, with risk being strongly linked to total dietary rice consumption and consumed rice As(i) content. This study aimed to identify the range and stability of genetic variation in grain arsenic (As) in rice. ? Six field trials were conducted (one each in Bangladesh and China, two in Arkansas, USA over 2 yr, and two in Texas, USA comparing flooded and nonflood treatments) on a large number of common rice cultivars (c. 300) representing genetic diversity among international rice cultivars. ? Within each field there was a 3-34 fold range in grain As concentration which varied between rice subpopulations. Importantly, As(i) correlated strongly with total As among a subset of 40 cultivars harvested in Bangladesh and China. ? Genetic variation at all field sites was a large determining factor for grain As concentration, indicating that cultivars low in grain As could be developed through breeding. The temperate japonicas exhibited lower grain As compared with other subpopulations. Effects for year, location and flooding management were also statistically significant, suggesting that breeding strategies must take into account environmental factors.     

Emergency health care use and follow-up among sociodemographic groups of children who visit emergency departments for mental health crises

Background:

Previous studies of differences in mental health care associated with children’s sociodemographic status have focused on access to community care. We examined differences associated with visits to the emergency department.

Methods:

We conducted a 6-year population-based cohort analysis using administrative databases of visits (n = 30 656) by children aged less than 18 years (n = 20 956) in Alberta. We measured differences in the number of visits by socioeconomic and First Nations status using directly standardized rates. We examined time to return to the emergency department using a Cox regression model, and we evaluated time to follow-up with a physician by physician type using a competing risks model.

Results:

First Nations children aged 15–17 years had the highest rate of visits for girls (7047 per 100 000 children) and boys (5787 per 100 000 children); children in the same age group from families not receiving government subsidy had the lowest rates (girls: 2155 per 100 000 children; boys: 1323 per 100 000 children). First Nations children (hazard ratio [HR] 1.64; 95% confidence interval [CI] 1.30–2.05), and children from families receiving government subsidies (HR 1.60, 95% CI 1.30–1.98) had a higher risk of return to an emergency department for mental health care than other children. The longest median time to follow-up with a physician was among First Nations children (79 d; 95% CI 60–91 d); this status predicted longer time to a psychiatrist (HR 0.47, 95% CI 0.32–0.70). Age, sex, diagnosis and clinical acuity also explained post-crisis use of health care.

Interpretation:

More visits to the emergency department for mental health crises were made by First Nations children and children from families receiving a subsidy. Sociodemographics predicted risk of return to the emergency department and follow-up care with a physician.Emergency departments are a critical access point for mental health care for children who have been unable to receive care elsewhere or are in crisis.¹ Care provided in an emergency department can stabilize acute problems and facilitate urgent follow-up for symptom management and family support.^1,2Race, ethnic background and socioeconomic status have been linked to a crisis-oriented care patterns among American children.^3,4 Minority children are less likely than white children to have received mental health treatment before an emergency department visit,^3,4 and uninsured children are less likely to receive an urgent mental health evaluation when needed.⁴ Other studies, however, have shown no relation between sociodemographic status and mental health care,^5,6 and it may be that different health system characteristics (e.g., pay-for-service, insurance coverage, publicly funded care) interact with sociodemographic status to influence how mental health resources are used. Canadian studies are largely absent in this discussion, despite a known relation between lower income and poorer mental health status,⁷ nationwide documentation of disparities faced by Aboriginal children,^8–10 and government-commissioned reviews that highlight deficits in universal access to mental health care.¹¹We undertook the current study to examine whether sociodemographic differences exist in the rates of visits to emergency departments for mental health care and in the use of post-crisis health care services for children in Alberta. Knowledge of whether differences exist for children with mental health needs may help identify children who could benefit from earlier intervention to prevent illness destabilization and children who may be disadvantaged in the period after the emergency department visit. We hypothesized that higher rates of emergency department use, lower rates of follow-up physician visits after the initial emergency department visit, and a longer time to physician follow-up would be observed among First Nations children and children from families receiving government social assistance.     

Linkage disequilibrium and heritability of copy-number polymorphisms within duplicated regions of the human genome

Studies of copy-number variation and linkage disequilibrium (LD) have typically excluded complex regions of the genome that are rich in duplications and prone to rearrangement. In an attempt to assess the heritability and LD of copy-number polymorphisms (CNPs) in duplication-rich regions of the genome, we profiled copy-number variation in 130 putative "rearrangement hotspot regions" among 269 individuals of European, Yoruba, Chinese, and Japanese ancestry analyzed by the International HapMap Consortium. Eighty-four hotspot regions, corresponding to 257 bacterial artificial chromosome (BAC) probes, showed evidence of copy-number differences. Despite a predisposing genetic architecture, no polymorphism was ever observed in the remaining 46 "rearrangement hotspots," and we suggest these represent excellent candidate sites for pathogenic rearrangements. We used a combination of BAC-based and high-density customized oligonucleotide arrays to resolve the molecular basis of structural rearrangements. For common variants (frequency >10%), we observed a distinct bias against copy-number losses, suggesting that deletions are subject to purifying selection. Heritability estimates did not differ significantly from 1.0 among the majority (30 of 34) of loci analyzed, consistent with normal Mendelian inheritance. Some of the CNPs in duplication-rich regions showed strong LD with nearby single-nucleotide polymorphisms (SNPs) and were observed to segregate on ancestral SNP haplotypes. However, LD with the best available SNP markers was weaker than has been reported for deletion polymorphisms in less complex regions of the genome. These observations may be accounted for by a low density of SNP data in duplicated regions, challenges in mapping and typing the CNPs, and the possibility that CNPs in these regions have rearranged on multiple haplotype backgrounds. Our results underscore the need for complete maps of genetic variation in duplication-rich regions of the genome.     

Cytoglobin is a stress-responsive hemoprotein expressed in the developing and adult brain.

Cytoglobin (Cygb) is a novel tissue hemoprotein relatively similar to myoglobin (Mb). Because Cygb shares several structural features with Mb, we hypothesized that Cygb functions in the modulation of oxygen and nitric oxide metabolism or in scavenging free radicals within a cell. In the present study we examined the spatial and temporal expression pattern of Cygb during murine embryogenesis. Using in situ hybridization, RT-PCR, and Northern blot analyses, limited Cygb expression was observed during embryogenesis compared with Mb expression. Cygb expression was primarily restricted to the central nervous system and neural crest derivatives during the latter stages of development. In the adult mouse, Cygb is expressed in distinct regions of the brain as compared with neuroglobin (Ngb), another globin protein, and these regions are responsive to oxidative stress (i.e., hippocampus, thalamus, and hypothalamus). In contrast to Ngb, Cygb expression in the brain is induced in response to chronic hypoxia (10% oxygen). These results support the hypothesis that Cygb is an oxygen-responsive tissue hemoglobin expressed in distinct regions of thenormoxic and hypoxic brain and may play a key role in the response of the brain to ahypoxic insult.     

Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats

Cerebral blood flow (CBF) is maintained constant despite changes in systemic blood pressure (BP) through multiple mechanisms of autoregulation such as vascular myogenic reactivity. Our aim was to determine myogenic characteristics of cannulated middle cerebral arteries (MCA) in male and female stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) at 12 wk of age under pressurised no-flow conditions. MCA pressure-diameter relationships (20-200 mmHg) were constructed in active (with calcium) and passive (without calcium) conditions, and myogenic and mechanical properties were determined. Myogenic reactivity in WKY (P < 0.05) and SHRSP (P < 0.05) males was impaired compared with their female counterparts. Comparison of SHRSP with WKY in males revealed similar myogenic reactivity, but in females SHRSP exhibited augmented myogenic reactivity (P < 0.05). In both sexes, myogenic tone yielded at lower pressure in SHRSP compared with WKY vessels (120-140 vs. 140-180 mmHg). Stress-strain relationships and elastic moduli in WKY rats showed that vessels were stiffer in females than in males. Conversely, in SHRSP, male vessels were stiffer than female vessels. Comparison of strains in males indicated that stiffness was increased in SHRSP compared with WKY vessels, whereas the converse was observed in females. These findings demonstrate that MCA myogenic and distensibility characteristics exhibit significant sex- and strain-dependent differences. Inappropriate myogenic adaptation and augmented vascular stiffness, particularly in male SHRSP, are potential limiting factors in blood flow autoregulation and may increase the predisposition for stroke-related cerebrovascular events.