Do Time Trade-off values fully capture attitudes that are relevant to health related choices?

Previous research has shown that demographics, beliefs and self-reported own health influence TTO values. Our hypothesis is that attitudes towards length and quality of life influence TTO values, but should no longer affect a set of related choices that are based on respondents’ own TTO scores. A representative sample of 1339 respondents was asked their level of agreement to four statements relating to the importance of quality and length of life. Respondents then went on to value 4 EQ-5D 5L states using an online interactive survey and a related set of 6 pairwise health related choice questions, set up so that respondents should be indifferent between choice options. We explored the impact of attitudes using regression analysis for TTO values and a logit model for choices. TTO values were correlated with the attitudes and were found to have a residual impact on the choices. In particular, those respondents who preferred quality of life over length of life gave less weight to the differences in years and more weight to differences in quality of life in these choice. We conclude that although the TTO responses reflect attitudes, these attitudes continue to affect health related choices

V_H replacement in rearranged immunoglobulin genes

Examples suggesting that all or part of the V<sub>H</sub> segment of a rearranged V<sub>H</sub>DJ<sub>H</sub> may be replaced by all or part of another V<sub>H</sub> have been appearing since the 1980s. Evidence has been presented of two rather different types of replacement. One of these has gained acceptance and has now been clearly demonstrated to occur. The other, proposed more recently, has not yet gained general acceptance because the same effect can be produced by polymerase chain reaction artefact. We review both types of replacement including a critical examination of evidence for the latter. The first type involves RAG proteins and recombination signal sequences (RSS) and occurs in immature B cells. The second was also thought to be brought about by RAG proteins and RSS. However, it has been reported in hypermutating cells which are not thought to express RAG proteins but in which activation-induced cytidine deaminase (AID) has recently been shown to initiate homologous recombination. Re-examination of the published sequences reveals AID target sites in V<sub>H</sub>-V<sub>H</sub> junction regions and examples that resemble gene conversion

Abnormal motor activity during anaesthesia in a dog: a case report

Seizures or convulsions that occur during anaesthesia in veterinary patients are infrequently reported in the literature. Consequently, the incidence of such events is unknown. Several drugs commonly used in clinical veterinary anaesthesia have been shown to induce epileptiform activity in both human clinical patients and experimental candidates. The present case report describes convulsions in a four-year old male Bernese mountain dog during maintenance of anaesthesia with isoflurane after premedication with acepromazine and methadone followed by co-induction with propofol and ketamine. The dog had no history of previous convulsions. The use of several sedative and anaesthetic drugs makes it difficult to find one single causative pharmaceutical

When Do Stalled Stars Resume Spinning Down? Advancing Gyrochronology with Ruprecht 147

This is the final version. Available on open access from IOP Publishing via the DOI in this recordRecent measurements of rotation periods () in the benchmark open clusters Praesepe (670 Myr), NGC 6811 (1 Gyr), and NGC 752 (1.4 Gyr) demonstrate that, after converging onto a tight sequence of slowly rotating stars in mass-period space, stars temporarily stop spinning down. These data also show that the duration of this epoch of stalled spin-down increases toward lower masses. To determine when stalled stars resume spinning down, we use data from the K2 mission and the Palomar Transient Factory to measure for 58 dwarf members of the 2.7 Gyr old cluster Ruprecht 147, 39 of which satisfy our criteria designed to remove short-period or near-equal-mass binaries. Combined with the Kepler data for the approximately coeval cluster NGC 6819 (30 stars with M ∗ > 0.85, our new measurements more than double the number of ≈2.5 Gyr benchmark rotators and extend this sample down to ≈0.55. The slowly rotating sequence for this joint sample appears relatively flat (22 ± 2 days) compared to sequences for younger clusters. This sequence also intersects the Kepler intermediate-period gap, demonstrating that this gap was not created by a lull in star formation. We calculate the time at which stars resume spinning down and find that 0.55 stars remain stalled for at least 1.3 Gyr. To accurately age-date low-mass stars in the field, gyrochronology formulae must be modified to account for this stalling timescale. Empirically tuning a core-envelope coupling model with open cluster data can account for most of the apparent stalling effect. However, alternative explanations, e.g., a temporary reduction in the magnetic braking torque, cannot yet be ruled out.National Science Foundation (NSF)European Union Horizon 2020NASADunlap FellowshipDanish National Research FoundationPennsylvania State UniversityEberly College of Scienc

Hepatitis B Virus X Protein Drives Multiple Cross-Talk Cascade Loops Involving NF-κB, 5-LOX, OPN and Capn4 to Promote Cell Migration

Hepatitis B virus X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). However, the mechanism remains unclear. Recently, we have reported that HBx promotes hepatoma cell migration through the upregulation of calpain small subunit 1 (Capn4). In addition, several reports have revealed that osteopontin (OPN) plays important roles in tumor cell migration. In this study, we investigated the signaling pathways involving the promotion of cell migration mediated by HBx. We report that HBx stimulates several factors in a network manner to promote hepatoma cell migration. We showed that HBx was able to upregulate the expression of osteopontin (OPN) through 5-lipoxygenase (5-LOX) in HepG2-X/H7402-X (stable HBx-transfected cells) cells. Furthermore, we identified that HBx could increase the expression of 5-LOX through nuclear factor-κB (NF-κB). We also found that OPN could upregulate Capn4 through NF-κB. Interestingly, we showed that Capn4 was able to upregulate OPN through NF-κB in a positive feedback manner, suggesting that the OPN and Capn4 proteins involving cell migration affect each other in a network through NF-κB. Importantly, NF-κB plays a crucial role in the regulation of 5-LOX, OPN and Capn4. Thus, we conclude that HBx drives multiple cross-talk cascade loops involving NF-κB, 5-LOX, OPN and Capn4 to promote cell migration. This finding provides new insight into the mechanism involving the promotion of cell migration by HBx

Distinct Patterns of DNA Damage Response and Apoptosis Correlate with Jak/Stat and PI3Kinase Response Profiles in Human Acute Myelogenous Leukemia

BACKGROUND:Single cell network profiling (SCNP) utilizing flow cytometry measures alterations in intracellular signaling responses. Here SCNP was used to characterize Acute Myeloid Leukemia (AML) disease subtypes based on survival, DNA damage response and apoptosis pathways. METHODOLOGY AND PRINCIPAL FINDINGS:Thirty four diagnostic non-M3 AML samples from patients with known clinical outcome were treated with a panel of myeloid growth factors and cytokines, as well as with apoptosis-inducing agents. Analysis of induced Jak/Stat and PI3K pathway responses in blasts from individual patient samples identified subgroups with distinct signaling profiles that were not seen in the absence of a modulator. In vitro exposure of patient samples to etoposide, a DNA damaging agent, revealed three distinct "DNA damage response (DDR)/apoptosis" profiles: 1) AML blasts with a defective DDR and failure to undergo apoptosis; 2) AML blasts with proficient DDR and failure to undergo apoptosis; 3) AML blasts with proficiency in both DDR and apoptosis pathways. Notably, AML samples from clinical responders fell within the "DDR/apoptosis" proficient profile and, as well, had low PI3K and Jak/Stat signaling responses. In contrast, samples from clinical non responders had variable signaling profiles often with in vitro apoptotic failure and elevated PI3K pathway activity. Individual patient samples often harbored multiple, distinct, leukemia-associated cell populations identifiable by their surface marker expression, functional performance of signaling pathway in the face of cytokine or growth factor stimulation, as well as their response to apoptosis-inducing agents. CONCLUSIONS AND SIGNIFICANCE:Characterizing and tracking changes in intracellular pathway profiles in cell subpopulations both at baseline and under therapeutic pressure will likely have important clinical applications, potentially informing the selection of beneficial targeted agents, used either alone or in combination with chemotherapy

Preliminary evaluation of a school-based resilience-promoting intervention in a high-risk population: Application of an exploratory two-cohort treatment/control design

Applying innovative methodology, we explored the efficacy of SPARK Resilience Programme––a new universal school-based resilience-promoting programme––regarding effects on depression symptoms and resilience in a high risk population in England. Quantitative and qualitative methods were combined in an exploratory two cohort treatment/control design with one cohort serving as the control group (single assessment) and a subsequent cohort as the treatment group (assessed before and immediately after treatment as well as 6 and 12 months after treatment ended), involving a total of 438 11–13 year old girls, According to analyses, depression symptoms were significantly lower directly after treatment and at 6 months but no longer at 12 months. Resilience scores, on the other hand, were significantly higher in the treatment cohort compared to the year-ahead control cohort at post-treatment and both follow-up assessments. Qualitative results demonstrated beneficial teacher experience overall. The current study provides first evidence for the efficacy of SPARK Resilience Programme. Furthermore, the applied two cohort treatment/control mixed methods design proved helpful for the preliminary testing of a school-based universal intervention programme efficacy in an authentic setting

Functional Characterization of FLT3 Receptor Signaling Deregulation in Acute Myeloid Leukemia by Single Cell Network Profiling (SCNP)

Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative.Using single cell network profiling (SCNP), cells were treated with extracellular modulators and their functional responses were quantified by multiparametric flow cytometry. Intracellular signaling responses were compared between healthy bone marrow myeloblasts (BMMb) and AML leukemic blasts characterized as FLT3 wild type (FLT3-WT) or FLT3-ITD. Compared to healthy BMMb, FLT3-WT leukemic blasts demonstrated a wide range of signaling responses to FLT3 ligand (FLT3L), including elevated and sustained PI3K and Ras/Raf/Erk signaling. Distinct signaling and apoptosis profiles were observed in FLT3-WT and FLT3-ITD AML samples, with more uniform signaling observed in FLT3-ITD AML samples. Specifically, increased basal p-Stat5 levels, decreased FLT3L induced activation of the PI3K and Ras/Raf/Erk pathways, decreased IL-27 induced activation of the Jak/Stat pathway, and heightened apoptotic responses to agents inducing DNA damage were observed in FLT3-ITD AML samples. Preliminary analysis correlating these findings with clinical outcomes suggests that classification of patient samples based on signaling profiles may more accurately reflect FLT3 signaling deregulation and provide additional information for disease characterization and management.These studies show the feasibility of SCNP to assess modulated intracellular signaling pathways and characterize the biology of individual AML samples in the context of genetic alterations

Cellular therapies for treating pain associated with spinal cord injury

Spinal cord injury leads to immense disability and loss of quality of life in human with no satisfactory clinical cure. Cell-based or cell-related therapies have emerged as promising therapeutic potentials both in regeneration of spinal cord and mitigation of neuropathic pain due to spinal cord injury. This article reviews the various options and their latest developments with an update on their therapeutic potentials and clinical trialing

LIF-Dependent Signaling: New Pieces in the Lego

LIF, a member of the IL6 family of cytokine, displays pleiotropic effects on various cell types and organs. Its critical role in stem cell models (e.g.: murine ES, human mesenchymal cells) and its essential non redundant function during the implantation process of embryos, in eutherian mammals, put this cytokine at the core of many studies aiming to understand its mechanisms of action, which could benefit to medical applications. In addition, its conservation upon evolution raised the challenging question concerning the function of LIF in species in which there is no implantation. We present the recent knowledge about the established and potential functions of LIF in different stem cell models, (embryonic, hematopoietic, mesenchymal, muscle, neural stem cells and iPSC). We will also discuss EVO-DEVO aspects of this multifaceted cytokine