Bayesian modelling of an absolute chronology for Egypt's 18th Dynasty by astrophysical and radiocarbon methods

Only a few astrophysical points and synchronisms listed in texts provide anchor points for the absolute chronology of Ancient Egypt. At first we will show how we can re-calculate some of these anchor points by using Sothic dating based on the arcus visionis method, and modelling lunar dates using a Bayesian approach. Then, we will discuss two radiocarbon studies carried out on short-lived Egyptian materials held at the Louvre Museum that could be attributed to particular reigns or other precise periods. Using a Bayesian approach, these dates were combined with the known order of succession and the lengths of reigns. Sothic and lunar dates were integrated as priors in the model. This approach has led to a new proposal for the absolute chronology of Egypt's 18th Dynasty

Variations in patterns of care across neonatal units and their associations with outcomes in very preterm infants: the French EPIPAGE-2 cohort study

OBJECTIVES: To describe patterns of care for very preterm (VP) babies across neonatal intensive care units (NICUs) and associations with outcomes. DESIGN: Prospective cohort study, EPIPAGE-2. SETTING: France, 2011. PARTICIPANTS: 53 (NICUs); 2135 VP neonates born at 27 to 31 weeks. OUTCOME MEASURES: Clusters of units, defined by the association of practices in five neonatal care domains - respiratory, cardiovascular, nutrition, pain management and neurodevelopmental care. Mortality at 2 years corrected age (CA) or severe/moderate neuro-motor or sensory disabilities and proportion of children with scores below threshold on the neurodevelopmental Ages and Stages Questionnaire (ASQ). METHODS: Hierarchical cluster analysis to identify clusters of units. Comparison of outcomes between clusters, after adjustment for potential cofounders. RESULTS: Three clusters were identified: Cluster 1 with higher proportions of neonates free of mechanical ventilation at 24 hours of life, receiving early enteral feeding, and neurodevelopmental care practices (26 units; n=1118 babies); Cluster 2 with higher levels of patent ductus arteriosus and pain screening (11 units; n=398 babies); Cluster 3 with higher use of respiratory, cardiovascular and pain treatments (16 units; n=619 babies). No difference was observed between clusters for the baseline maternal and babies' characteristics. No differences in outcomes were observed between Clusters 1 and 3. Compared with Cluster 1, mortality at 2 years CA or severe/moderate neuro-motor or sensory disabilities was lower in Cluster 2 (adjusted OR 0.46, 95% CI 0.25 to 0.84) but with higher proportion of children with an ASQ below threshold (adjusted OR 1.49, 95% CI 1.07 to 2.08). CONCLUSION: In French NICUs, care practices for VP babies were non-randomly associated. Differences between clusters were poorly explained by unit or population differences, but were associated with mortality and development at 2 years. Better understanding these variations may help to improve outcomes for VPT babies, as it is likely that some of these discrepancies are unwarranted

A strand-passage conformation of DNA gyrase is required to allow the bacterial toxin, CcdB, to access its binding site

DNA gyrase is the only topoisomerase able to introduce negative supercoils into DNA. Absent in humans, gyrase is a successful target for antibacterial drugs. However, increasing drug resistance is a serious problem and new agents are urgently needed. The naturally-produced Escherichia coli toxin CcdB has been shown to target gyrase by what is predicted to be a novel mechanism. CcdB has been previously shown to stabilize the gyrase ‘cleavage complex’, but it has not been shown to inhibit the catalytic reactions of gyrase. We present data showing that CcdB does indeed inhibit the catalytic reactions of gyrase by stabilization of the cleavage complex and that the GyrA C-terminal DNA-wrapping domain and the GyrB N-terminal ATPase domain are dispensable for CcdB's action. We further investigate the role of specific GyrA residues in the action of CcdB by site-directed mutagenesis; these data corroborate a model for CcdB action based on a recent crystal structure of a CcdB–GyrA fragment complex. From this work, we are now able to present a model for CcdB action that explains all previous observations relating to CcdB–gyrase interaction. CcdB action requires a conformation of gyrase that is only revealed when DNA strand passage is taking place

Developmental cascades of social inhibition and friendships in preterm and full‐term children

Friendships are crucial to children's socioemotional development and quality of life. Children born preterm (<37 weeks gestation) have an increased risk for social relationship difficulties, including fewer friends, but the mechanisms underlying the link between lower gestational age and fewer friendships are not clear. The prospective Bavarian Longitudinal Study investigated potential cascading effects on N = 1,181 children's friendships at 8 years. Path modelling indicated that higher gestational age predicted good early parent–infant relationship quality, good inhibitory control, and higher friendship scores. Good parent–infant relationship quality predicted good inhibitory control, which subsequently predicted low social inhibition at 6 years and higher friendship scores at 8 years. There is evidence of cascading effects from gestational age to early parent–infant relationships, to toddlers' inhibitory control, and to social inhibition, which partially explain differences in children's friendships at 8 years of age

Impairment of Adolescent Hippocampal Plasticity in a Mouse Model for Alzheimer's Disease Precedes Disease Phenotype

The amyloid precursor protein (APP) was assumed to be an important neuron-morphoregulatory protein and plays a central role in Alzheimer's disease (AD) pathology. In the study presented here, we analyzed the APP-transgenic mouse model APP23 using 2-dimensional gel electrophoresis technology in combination with DIGE and mass spectrometry. We investigated cortex and hippocampus of transgenic and wildtype mice at 1, 2, 7 and 15 months of age. Furthermore, cortices of 16 days old embryos were analyzed. When comparing the protein patterns of APP23 with wildtype mice, we detected a relatively large number of altered protein spots at all age stages and brain regions examined which largely preceded the occurrence of amyloid plaques. Interestingly, in hippocampus of adolescent, two-month old mice, a considerable peak in the number of protein changes was observed. Moreover, when protein patterns were compared longitudinally between age stages, we found that a large number of proteins were altered in wildtype mice. Those alterations were largely absent in hippocampus of APP23 mice at two months of age although not in other stages compared. Apparently, the large difference in the hippocampal protein patterns between two-month old APP23 and wildtype mice was caused by the absence of distinct developmental changes in the hippocampal proteome of APP23 mice. In summary, the absence of developmental proteome alterations as well as a down-regulation of proteins related to plasticity suggest the disturption of a normally occurring peak of hippocampal plasticity during adolescence in APP23 mice. Our findings are in line with the observation that AD is preceded by a clinically silent period of several years to decades. We also demonstrate that it is of utmost importance to analyze different brain regions and different age stages to obtain information about disease-causing mechanisms

Modeling the Influence of Local Environmental Factors on Malaria Transmission in Benin and Its Implications for Cohort Study

Malaria remains endemic in tropical areas, especially in Africa. For the evaluation of new tools and to further our understanding of host-parasite interactions, knowing the environmental risk of transmission—even at a very local scale—is essential. The aim of this study was to assess how malaria transmission is influenced and can be predicted by local climatic and environmental factors

Special Care and School Difficulties in 8-Year-Old Very Preterm Children: The Epipage Cohort Study

OBJECTIVES: To investigate school difficulties, special care and behavioral problems in 8 year-old very preterm (VPT) children. PATIENT AND METHODS: Longitudinal population-based cohort in nine regions of France of VPT children and a reference group born at 39-40 weeks of gestation (WG). The main outcome measures were information about school, special care and behavioral problems using Strengths and Difficulties Questionnaire from a questionnaire to parents. RESULTS: Among the 1439 VPT children, 5% (75/1439) were in a specialised school or class, 18% (259/1439) had repeated a grade in a mainstream class and 77% (1105/1439) were in the appropriate grade-level in mainstream class; these figures were 1% (3/327) , 5% (16/327) and 94% (308/327) , respectively, for the reference group. Also, 15% (221/1435) of VPT children in a mainstream class received support at school versus 5% (16/326) of reference group. More VPT children between the ages of five and eight years received special care (55% (794/1436)) than children born at term (38% (124/325)); more VPT children (21% (292/1387)) had behavioral difficulties than the reference group (11% (35/319)). School difficulties, support at school, special care and behavioral difficulties in VPT children without neuromotor or sensory deficits varied with gestational age, socioeconomic status, and cognitive score at the age of five. CONCLUSIONS: Most 8-year-old VPT children are in mainstream schools. However, they have a high risk of difficulty in school, with more than half requiring additional support at school and/or special care. Referral to special services has increased between the ages of 5 and 8 years, but remained insufficient for those with borderline cognitive scores

Cell Nucleus-Targeting Zwitterionic Carbon Dots

An innovative nucleus-targeting zwitterionic carbon dot (CD) vehicle has been developed for anticancer drug delivery and optical monitoring. The zwitterionic functional groups of the CDs introduced by a simple one-step synthesis using beta-alanine as a passivating and zwitterionic ligand allow cytoplasmic uptake and subsequent nuclear translocation of the CDs. Moreover, multicolor fluorescence improves the accuracy of the CDs as an optical code. The CD-based drug delivery system constructed by non-covalent grafting of doxorubicin, exhibits superior antitumor efficacy owing to enhanced nuclear delivery in vitro and tumor accumulation in vivo, resulting in highly effective tumor growth inhibition. Since the zwitterionic CDs are highly biocompatible and effectively translocated into the nucleus, it provides a compelling solution to a multifunctional nanoparticle for substantially enhanced nuclear uptake of drugs and optical monitoring of translocation.open

Development of transgenic rats producing human β-amyloid precursor protein as a model for Alzheimer's disease: Transgene and endogenous APP genes are regulated tissue-specifically

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is a devastating neurodegenerative disorder that affects a large and growing number of elderly individuals. In addition to idiopathic disease, AD is also associated with autosomal dominant inheritance, which causes a familial form of AD (FAD). Some instances of FAD have been linked to mutations in the β-amyloid protein precursor (APP). Although there are numerous mouse AD models available, few rat AD models, which have several advantages over mice, have been generated.</p> <p>Results</p> <p>Fischer 344 rats expressing human APP driven by the ubiquitin-C promoter were generated via lentiviral vector infection of Fischer 344 zygotes. We generated two separate APP-transgenic rat lines, APP21 and APP31. Serum levels of human amyloid-beta (Aβ)₄₀were 298 pg/ml for hemizygous and 486 pg/ml for homozygous APP21 animals. Serum Aβ₄₂levels in APP21 homozygous rats were 135 pg/ml. Immunohistochemistry in brain showed that the human APP transgene was expressed in neurons, but not in glial cells. These findings were consistent with independent examination of enhanced green fluorescent protein (eGFP) in the brains of eGFP-transgenic rats. APP21 and APP31 rats expressed 7.5- and 3-times more APP mRNA, respectively, than did wild-type rats. Northern blots showed that the human APP transgene, driven by the ubiquitin-C promoter, is expressed significantly more in brain, kidney and lung compared to heart and liver. A similar expression pattern was also seen for the endogenous rat APP. The unexpected similarity in the tissue-specific expression patterns of endogenous rat APP and transgenic human APP mRNAs suggests regulatory elements within the cDNA sequence of APP.</p> <p>Conclusion</p> <p>This manuscript describes the generation of APP-transgenic inbred Fischer 344 rats. These are the first human AD model rat lines generated by lentiviral infection. The APP21 rat line expresses high levels of human APP and could be a useful model for AD. Tissue-specific expression in the two transgenic rat lines and in wild-type rats contradicts our current understanding of APP gene regulation. Determination of the elements that are responsible for tissue-specific expression of APP may enable new treatment options for AD.</p