NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells

Activating PIK3CA mutations are known “drivers” of human cancer and developmental overgrowth syndromes. We recently demonstrated that the "hotspot" PIK3CAH1047R variant exerts unexpected allele dose-dependent effects on stemness in human pluripotent stem cells (hPSCs). In the present study, we combine high-depth transcriptomics, total proteomics and reverse-phase protein arrays to reveal potentially disease-related alterations in heterozygous cells, and to assess the contribution of activated TGFβ signalling to the stemness phenotype of homozygous PIK3CAH1047R cells. We demonstrate signalling rewiring as a function of oncogenic PI3K signalling strength, and provide experimental evidence that self-sustained stemness is causally related to enhanced autocrine NODAL/TGFβ signalling. A significant transcriptomic signature of TGFβ pathway activation in heterozygous PIK3CAH1047R was observed but was modest and was not associated with the stemness phenotype seen in homozygous mutants. Notably, the stemness gene expression in homozygous PIK3CAH1047R iPSCs was reversed by pharmacological inhibition of NODAL/TGFβ signalling, but not by pharmacological PI3Kα pathway inhibition. Altogether, this provides the first in-depth analysis of PI3K signalling in human pluripotent stem cells and directly links strong PI3K activation to developmental NODAL/TGFβ signalling. This work illustrates the importance of allele dosage and expression when artificial systems are used to model human genetic disease caused by activating PIK3CA mutations

Illness Schema Activation and the Effects of Illness Seasonality on Accessibility of Implicit Illness-Related Information

The Common-Sense Model (CSM) of illness self-regulation is a leading theoretical framework describing the process by which an individual recognizes that he or she is physically ill and subsequently attempts to manage that illness state. The CSM proposes that people possess schematically organized implicit cognitive representations of health threats comprising information about illness such as symptoms, causes, label, duration, consequences, and procedures for managing threat [1, 2, 3, 4]. The proposed function of these stored knowledge structures is to activate a self-regulation process that might protect or restore a state of well-being [5]. The CSM proposes that the schematic representation is centrally activated by detection of deviations from the normal functioning self (i.e., experienced symptoms). The identification of illness and the initiation of self-management attempts follow from the search for illness-relevant cognitive structures and the matching of the content of illness schema to the symptomatic experience. For example, a headache (a symptomatic deviation from normal somatic experience) might activate illness schemata containing the cognitive representation of “headache” such as “hangover,” “dehydration,” or “flu.” The matching of the symptom to a particular illness schema will follow from the search and match to other aspects of plausible illness representations, such as its probable cause or duration (timeline).Full Tex

Temporal changes in frequency of severe hypoglycemia treated by emergency medical services in types 1 and 2 diabetes:a population-based data-linkage cohort study

Background  Almost 20 years ago, the frequencies of severe hypoglycemia requiring emergency medical treatment were reported in people with types 1 and 2 diabetes in the Tayside region of Scotland. With subsequent improvements in the treatment of diabetes, concurrent with changes in the provision of emergency medical care, a decline in the frequency of severe hypoglycemia could be anticipated. The present population-based data-linkage cohort study aimed to ascertain whether a temporal change has occurred in the incidence rates of hypoglycemia requiring emergency medical services in people with types 1 and 2 diabetes.  Methods  The study population comprised all people with diabetes in Tayside, Scotland over the period 1 January 2011 to 31 December 2012. Patients’ data from different healthcare sources were linked anonymously to measure the incidence rates of hypoglycemia requiring emergency medical services that include treatment by ambulance staff and in hospital emergency departments, and necessitated hospital admission. These were compared with data recorded in 1997–1998 in the same region.  Results  In January 2011 to December 2012, 2029 people in Tayside had type 1 diabetes and 21,734 had type 2 diabetes, compared to 977 and 7678, respectively, in June 1997 to May 1998. In people with type 2 diabetes, the proportion treated with sulfonylureas had declined from 36.8 to 22.4% (p<0.001), while insulin-treatment had increased from 11.7 to 18.7% (p<0.001). The incidence rate of hypoglycemia requiring emergency medical treatment had significantly fallen from 0.115 (95% CI: 0.094–0.136) to 0.082 (0.073–0.092) events per person per year in type 1 diabetes (p<0.001), and from 0.118 (0.095–0.141) to 0.037 (0.003–0.041) in insulin-treated type 2 diabetes (p=0.008). However, the absolute annual number of hypoglycemia events requiring emergency treatment was 1.4-fold higher.  Conclusions  Although from 1998 to 2012 the incidences of hypoglycemia requiring emergency medical services appeared to have declined by a third in type 1 diabetes and by two thirds in insulin-treated type 2 diabetes, because the prevalence of diabetes was higher (2.7 fold), the number of severe hypoglycemia events requiring emergency medical treatment was greater

Mortality after discharge from long-term psychiatric care in Scotland, 1977 – 94: a retrospective cohort study

BACKGROUND: Recent United Kingdom strategies focus on preventable suicide deaths in former psychiatric in-patients, but natural causes of death, accidents and homicide may also be important. This study was intended to find the relative importance of natural and unnatural causes of death in people discharged from long-term psychiatric care in Scotland in 1977 –1994. METHODS: People discharged alive from psychiatric hospitals in Scotland in 1977 – 94 after a stay of one year or longer were identified using routine hospital records. Computer record linkage was used to link hospital discharges to subsequent death records. Mortality was described using a person-years analysis, and compared to the general population rates. RESULTS: 6,776 people were discharged in the time period. 1,994 people (29%) died by the end of follow-up, 732 more deaths than expected. Deaths from suicide, homicide, accident and undetermined cause were increased, but accounted for only 197 of the excess deaths. Deaths from respiratory disease were four times higher than expected, and deaths from other causes, including cardiovascular disease, were also elevated. CONCLUSION: Suicide is an important cause of preventable mortality, but natural causes account for more excess deaths. Prevention activities should not focus only on unnatural causes of death

Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous Δ11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

Cord blood calcium, phosphate, magnesium, and alkaline phosphatase gestational age-specific reference intervals for preterm infants

<p>Abstract</p> <p>Background</p> <p>The objective was to determine the influence of gestational age, maternal, and neonatal variables on reference intervals for cord blood bone minerals (calcium, phosphate, magnesium) and related laboratory tests (alkaline phosphatase, and albumin-adjusted calcium), and to develop gestational age specific reference intervals based on infants without influential pathological conditions.</p> <p>Methods</p> <p>Cross-sectional study. 702 babies were identified as candidates for this study in a regional referral neonatal unit. After exclusions (for anomalies, asphyxia, maternal magnesium sulfate administration, and death), relationships were examined between cord blood serum laboratory analytes (calcium, phosphate, magnesium, alkaline phosphatase, and albumin-adjusted calcium) with gestation age and also with maternal and neonatal variables using multiple linear regression. Infants with influential pathological conditions were omitted from the development of gestational age specific reference intervals for the following categories: 23-27, 28-31, 32-34, 35-36 and > 36 weeks.</p> <p>Results</p> <p>Among the 506 preterm and 54 terms infants included in the sample. Phosphate, magnesium, and alkaline phosphatase in cord blood serum decreased with gestational age, calcium increased with gestational age. Those who were triplets, small for gestational age, and those whose mother had pregnancy-induced hypertension were influential for most of the analytes. The reference ranges for the preterm infants ≥ 36 weeks were: phosphate 1.5 to 2.6 mmol/L (4.5 to 8.0 mg/dL), calcium: 2.1 to 3.1 mmol/L (8.3 to 12.4 mg/dL); albumin-adjusted calcium: 2.3 to 3.2 mmol/L (9.1 to 12.9 mg/dL); magnesium 0.6 to 1.0 mmol/L (1.4 to 2.3 mg/dL), and alkaline phosphatase 60 to 301 units/L.</p> <p>Conclusions</p> <p>These data suggest that gestational age, as well as potentially pathogenic maternal and neonatal variables should be considered in the development of reference intervals for preterm infants.</p

Rapid Reactivation of Extralymphoid CD4 T Cells during Secondary Infection

After infection, extralymphoid tissues are enriched with effector and memory T cells of a highly activated phenotype. The capacity for rapid effector cytokine response from extralymphoid tissue-memory T cells suggests these cells may perform a ‘sentinel’ function in the tissue. While it has been demonstrated that extralymphoid CD4+ T cells can directly respond to secondary infection, little is known about how rapidly this response is initiated, and how early activation of T cells in the tissue may affect the innate response to infection. Here we use a mouse model of secondary heterosubtypic influenza infection to show that CD4+ T cells in the lung airways are reactivated within 24 hours of secondary challenge. Airway CD4+ T cells initiate an inflammatory cytokine and chemokine program that both alters the composition of the early innate response and contributes to the reduction of viral titers in the lung. These results show that, unlike a primary infection, extralymphoid tissue-memory CD4+ T cells respond alongside the innate response during secondary infection, thereby shaping the overall immune profile in the airways. These data provide new insights into the role of extralymphoid CD4+ T cells during secondary immune responses