Cdkn1c (p57Kip2) is the major regulator of embryonic growth within its imprinted domain on mouse distal chromosome 7

Background: Cdkn1c encodes an embryonic cyclin-dependant kinase inhibitor that acts to negatively regulate cell proliferation and, in some tissues, to actively direct differentiation. This gene, which is an imprinted gene expressed only from the maternal allele, lies within a complex region on mouse distal chromosome 7, called the IC2 domain, which contains several other imprinted genes. Studies on mouse embryos suggest a key role for genomic imprinting in regulating embryonic growth and this has led to the proposal that imprinting evolved as a consequence of the mismatched contribution of parental resources in mammals. Results: In this study, we characterised the phenotype of mice carrying different copy number integrations of a bacterial artificial chromosome spanning Cdkn1c. Excess Cdkn1c resulted in embryonic growth retardation that was dosage-dependent and also responsive to the genetic background. Two-fold expression of Cdkn1c in a subset of tissues caused a 10–30% reduction in embryonic weight, embryonic lethality and was associated with a reduction in the expression of the potent, non-imprinted embryonic growth factor, Igf1. Conversely, loss of expression of Cdkn1c resulted in embryos that were 11% heavier with a two-fold increase in Igf1. Conclusion: We have shown that embryonic growth in mice is exquisitely sensitive to the precise dosage of Cdkn1c. Cdkn1c is a maternally expressed gene and our findings support the prediction of the parental conflict hypothesis that that the paternal genome silences genes that have an inhibitory role in embryonic growth. Within the IC2 imprinted domain, Cdkn1c encodes the major regulator of embryonic growth and we propose that Cdkn1c was the focal point of the selective pressure for imprinting of this domain

The Proper Splicing of RNAi Factors Is Critical for Pericentric Heterochromatin Assembly in Fission Yeast

Heterochromatin preferentially assembles at repetitive DNA elements, playing roles in transcriptional silencing, recombination suppression, and chromosome segregation. The RNAi machinery is required for heterochromatin assembly in a diverse range of organisms. In fission yeast, RNA splicing factors are also required for pericentric heterochromatin assembly, and a prevailing model is that splicing factors provide a platform for siRNA generation independently of their splicing activity. Here, by screening the fission yeast deletion library, we discovered four novel splicing factors that are required for pericentric heterochromatin assembly. Sequencing total cellular RNAs from the strongest of these mutants, cwf14Δ, showed intron retention in mRNAs of several RNAi factors. Moreover, introducing cDNA versions of RNAi factors significantly restored pericentric heterochromatin in splicing mutants. We also found that mutations of splicing factors resulted in defective telomeric heterochromatin assembly and mis-splicing the mRNA of shelterin component Tpz1, and that replacement of tpz1+ with its cDNA partially rescued heterochromatin defects at telomeres in splicing mutants. Thus, proper splicing of RNAi and shelterin factors contributes to heterochromatin assembly at pericentric regions and telomeres

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

Correlates of Snake Entanglement in Erosion Control Blankets

In road construction projects across the United States, erosion control methods (e.g., erosion control blankets [ECBs]), are mandated to stimulate seedbed regeneration and prevent soil loss. Previous reports have suggested that snakes are vulnerable to entanglement in ECBs. We conducted a literature review, field surveys, and an entanglement experiment to examine what factors increase a snake’s risk of ECB entanglement. Our literature review produced reports of 175 reptiles entangled in mesh products, 89.1% of which were snakes, with 43.6% of snake entanglements occurring in erosion control products. During our field surveys, we found 10 entangled snakes (n = 2 alive; n = 8 dead). From our experiment, we found that ECBs that contain fixed‐intersection, small‐diameter mesh consisting of polypropylene were significantly more likely to entangle snakes compared with ECBs with larger diameter polypropylene mesh or ECBs that have woven mesh made of natural fibers. Snake body size was also associated with entanglement; for every 1‐mm increase in body circumference, the probability of entanglement increased 4%. These results can help construct a predictive framework to determine those species and individuals that are most vulnerable to entanglement

On the observability of individual Population III stars and their stellar-mass black hole accretion disks through cluster caustic transits

We summarize panchromatic Extragalactic Background Light data to place upper limits on the integrated near-infrared surface brightness (SB) that may come from Population III stars and possible accretion disks around their stellar-mass black holes (BHs) in the epoch of First Light, broadly taken from z$\simeq$7-17. Theoretical predictions and recent near-infrared power-spectra provide tighter constraints on their sky-signal. We outline the physical properties of zero metallicity Population III stars from MESA stellar evolution models through helium-depletion and of BH accretion disks at z$\gtrsim$7. We assume that second-generation non-zero metallicity stars can form at higher multiplicity, so that BH accretion disks may be fed by Roche-lobe overflow from lower-mass companions. We use these near-infrared SB constraints to calculate the number of caustic transits behind lensing clusters that the James Webb Space Telescope and the next generation ground-based telescopes may observe for both Population III stars and their BH accretion disks. Typical caustic magnifications can be $\mu$$\simeq$10$^4$-10$^5$, with rise times of hours and decline times of $\lesssim$1 year for cluster transverse velocities of $v_{T}$$\lesssim$1000 km s$^{-1}$. Microlensing by intracluster medium objects can modify transit magnifications, but lengthen visibility times. Depending on BH masses, accretion-disk radii and feeding efficiencies, stellar-mass BH accretion-disk caustic transits could outnumber those from Population III stars. To observe Population III caustic transits directly may require to monitor 3-30 lensing clusters to AB$\lesssim$29 mag over a decade.Comment: 53 pages, 5 figures, Accepted for publication in ApJ

Sensitivity of a national coronial database for monitoring unnatural deaths among ex-prisoners in Australia

<p>Abstract</p> <p>Background</p> <p>The period immediately after release from custody is a time of marked vulnerability and increased risk of death for ex-prisoners. Despite this, there is currently no routine, national system for monitoring ex-prisoner mortality in Australia. This study subsequently aimed to evaluate the sensitivity of Australia's National Coroners Information System (NCIS) for identifying reportable deaths among prisoners and ex-prisoners.</p> <p>Findings</p> <p>Prisoner and ex-prisoner deaths identified through an independent search of the NCIS were compared with 'gold standard' records of prisoner and ex-prisoner deaths, generated from a national monitoring system and a state-based record linkage study, respectively. Of 294 known deaths in custody from 2001-2007, an independent search of the NCIS identified 229, giving a sensitivity of 77.9% (72.8%-82.3%). Of 677 known deaths among ex-prisoners from 2001-2007, an independent search of the NCIS identified 37, giving a sensitivity of 5.5% (4.0-7.4%). Ex-prisoner deaths that were detected were disproportionately drug-related, occurring within the first four weeks post-release, among younger prisoners and among those with more than two prior prison admissions.</p> <p>Conclusions</p> <p>Although a search of the NCIS detected the majority of reportable deaths among prisoners, it was only able to detect a small minority of reportable deaths among ex-prisoners. This suggests that the NCIS is not effective for monitoring mortality among ex-prisoners in Australia. Given the elevated rates of mortality among ex-prisoners in Australia and elsewhere, there remains an urgent need to establish a process for routine monitoring of ex-prisoner mortality, preferably through record linkage.</p

Potential for ecological nonlinearities and thresholds to inform Pacific salmon management

AbstractEcology is often governed by nonlinear dynamics. Nonlinear ecological relationships can include thresholds—incremental changes in drivers that provoke disproportionately large ecological responses. Among the species that experience nonlinear and threshold dynamics are Pacific salmon (Oncorhynchus spp.). These culturally, ecologically, and economically significant fishes are in many places declining and management focal points. Often, managers can influence or react to ecological conditions that salmon experience, suggesting that nonlinearities, especially thresholds, may provide opportunities to inform decisions. However, nonlinear dynamics are not always invoked in management decisions involving salmon. Here, we review reported nonlinearities and thresholds in salmon ecology, describe potential applications that scientists and managers could develop to leverage nonlinear dynamics, and offer a path toward decisions that account for ecological nonlinearities and thresholds to improve salmon outcomes. It appears that nonlinear dynamics are not uncommon in salmon ecology and that many management arenas may potentially leverage them to enable more effective or efficient decisions. Indeed, decisions guided by nonlinearities and thresholds may be particularly desirable considering salmon management arenas are often characterized by limited resources and mounting ecological stressors, practical constraints, and conservation challenges. More broadly, many salmon systems are data‐rich and there are an extensive range of ecological contexts in which salmon are sensitive to anthropogenic decisions. Approaches developed to leverage nonlinearities in salmon ecology may serve as examples that may inform analogous approaches in other systems and taxa

Influence of family and friend smoking on intentions to smoke and smoking-related attitudes and refusal self-efficacy among 9-10 year old children from deprived neighbourhoods: a cross-sectional study.

BACKGROUND: Smoking often starts in early adolescence and addiction can occur rapidly. For effective smoking prevention there is a need to identify at risk groups of preadolescent children and whether gender-specific intervention components are necessary. This study aimed to examine associations between mother, father, sibling and friend smoking and cognitive vulnerability to smoking among preadolescent children living in deprived neighbourhoods. METHODS: Cross-sectional data was collected from 9-10 year old children (n =1143; 50.7% girls; 85.6% White British) from 43 primary schools in Merseyside, England. Children completed a questionnaire that assessed their smoking-related behaviour, intentions, attitudes, and refusal self-efficacy, as well as parent, sibling and friend smoking. Data for boys and girls were analysed separately using multilevel linear and logistic regression models, adjusting for individual cognitions and school and deprivation level. RESULTS: Compared to girls, boys had lower non-smoking intentions (P = 0.02), refusal self-efficacy (P = 0.04) and were less likely to agree that smoking is 'definitely' bad for health (P < 0.01). Friend smoking was negatively associated with non-smoking intentions in girls (P < 0.01) and boys (P < 0.01), and with refusal self-efficacy in girls (P < 0.01). Sibling smoking was negatively associated with non-smoking intentions in girls (P < 0.01) but a positive association was found in boys (P = 0.02). Boys who had a smoking friend were less likely to 'definitely' believe that the smoke from other people's cigarettes is harmful (OR 0.57, 95% CI: 0.35 to 0.91, P = 0.02). Further, boys with a smoking friend (OR 0.38, 95% CI: 0.21 to 0.69, P < 0.01) or a smoking sibling (OR 0.45, 95% CI: 0.21 to 0.98) were less likely to 'definitely' believe that smoking is bad for health. CONCLUSION: This study indicates that sibling and friend smoking may represent important influences on 9-10 year old children's cognitive vulnerability toward smoking. Whilst some differential findings by gender were observed, these may not be sufficient to warrant separate prevention interventions. However, further research is needed

Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma

We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma