EGFR is required for Wnt9a-Fzd9b signalling specificity in haematopoietic stem cells.

Wnt signalling drives many processes in development, homeostasis and disease; however, the role and mechanism of individual ligand-receptor (Wnt-Frizzled (Fzd)) interactions in specific biological processes remain poorly understood. Wnt9a is specifically required for the amplification of blood progenitor cells during development. Using genetic studies in zebrafish and human embryonic stem cells, paired with in vitro cell biology and biochemistry, we determined that Wnt9a signals specifically through Fzd9b to elicit β-catenin-dependent Wnt signalling that regulates haematopoietic stem and progenitor cell emergence. We demonstrate that the epidermal growth factor receptor (EGFR) is required as a cofactor for Wnt9a-Fzd9b signalling. EGFR-mediated phosphorylation of one tyrosine residue on the Fzd9b intracellular tail in response to Wnt9a promotes internalization of the Wnt9a-Fzd9b-LRP signalosome and subsequent signal transduction. These findings provide mechanistic insights for specific Wnt-Fzd signals, which will be crucial for specific therapeutic targeting and regenerative medicine

Stress factors and stress management interventions: the heuristic of “bottom up” an update from a systematic review

Organizations have increasingly sought to adopt innovative interventions to prevent stress-related issues. In the field of manufacturing, however, the effectiveness of these interventions remains unclear because a systematic and specific review of existing primary evidence has not been undertaken. The present systematic literature review sought to address the foregoing limitation in the literature by summarizing the main source of stress and effectiveness of stress management interventions as grounded in the context of manufacturing. Our review was limited to only randomized clinical trials (RCTs) and quasi-experimental studies and concerned employees from the manufacturing sector. Twenty-two studies on primary, secondary and tertiary interventions across four continents (Asia, Europe, USA and South America) were selected and analyzed in terms of stress factors, methodological properties and outcomes. Most of these were RCT studies (68% Vs 32%) with a majority of secondary interventions (N = 11, 50%), followed by primary (N = 5, 22%), tertiary (N = 3, 13%), and two (9%) mixed interventions. The main outcomes included an improvement of psychological wellbeing, decreased stress reactivity and an increment of general health. There was a predominance of interventions utilizing skills programs and/or cognitive-behavioral techniques. The main source of stress reported related to professional identity, organizational deficiencies, interpersonal conflicts, physical complaints and poor work environment. Taken together, the findings provide important theoretical and practical implications for advancing the study of stress factors and the use of stress management interventions in the workplace. The prerequisite for a successful intervention is to address the real problems experienced by professionals and help them to cope with their difficult situations. The strategy of “bottom-up” offers a potential means of enhancing employees’ health and well-being; however, the most effective means of implementing these interventions needs to be understood better

PORCN moonlights in a wnt-independent pathway that regulates cancer cell proliferation

10.1371/journal.pone.0034532PLoS ONE74

Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Wnt3a deficiency irreversibly impairs hematopoietic stem cell self-renewal and leads to defects in progenitor cell differentiation

Canonical Wnt signaling has been implicated in various aspects of hematopoiesis. Its role is controversial due to different outcomes between various inducible Wnt-signaling loss-of-function models and also compared with gain-of-function systems. We therefore studied a mouse deficient for a Wnt gene that seemed to play a nonredundant role in hematopoiesis. Mice lacking Wnt3a die prenatally around embryonic day (E) 12.5, allowing fetal hematopoiesis to be studied using in vitro assays and transplantation into irradiated recipient mice. Here we show that Wnt3a deficiency leads to a reduction in the numbers of hematopoietic stem cells (HSCs) and progenitor cells in the fetal liver (FL) and to severely reduced reconstitution capacity as measured in secondary transplantation assays. This deficiency is irreversible and cannot be restored by transplantation into Wnt3a competent mice. The impaired long-term repopulation capacity of Wnt3a-/- HSCs could not be explained by altered cell cycle or survival of primitive progenitors. Moreover, Wnt3a deficiency affected myeloid but not B-lymphoid development at the progenitor level, and affected immature thymocyte differentiation. Our results show that Wnt3a signaling not only provides proliferative stimuli, such as for immature thymocytes, but also regulates cell fate decisions of HSC during hematopoiesis

Gap width modification on fully screen-printed coplanar Zn|MnO2 batteries

Fully printed primary zinc-manganese dioxide (Zn|MnO2) batteries in coplanar configuration were fabricated by sequential screen printing. While electrode dimensions and transferred active masses were kept at constant levels, electrode separating gaps were incrementally enlarged from 1 mm to 5 mm. Calendering of solely zinc anodes increased interparticle contact of active material within the electrodes while the porosity of manganese dioxide based electrodes was maintained by non-calendering. Chronopotentiometry revealed areal capacities for coplanar batteries up to 2.8 mAh cm−2. Galvanostatic electrochemical impedance spectroscopy measurements and short circuit measurements were used to comprehensively characterise the effect of gap width extension on bulk electrolyte resistance and charge transfer resistance values. Linear relationships between nominal gap widths, short circuit currents and internal resistances were evidenced, but showed only minor impact on actual discharge capacities. The findings contradict previous assumptions to minimise gap widths of printed coplanar batteries to a sub-millimetre range in order to retain useful discharge capacities. The results presented in this study may facilitate process transfer of printed batteries to an industrial environment

Multifaceted roles of GSK-3 and Wnt/β-catenin in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention

Glycogen synthase kinase-3 (GSK-3) is well documented to participate in a complex array of critical cellular processes. It was initially identified in rat skeletal muscle as a serine/threonine kinase that phosphorylated and inactivated glycogen synthase. This versatile protein is involved in numerous signaling pathways that influence metabolism, embryogenesis, differentiation, migration, cell cycle progression and survival. Recently, GSK-3 has been implicated in leukemia stem cell pathophysiology and may be an appropriate target for its eradication. In this review, we will discuss the roles that GSK-3 plays in hematopoiesis and leukemogenesis as how this pivotal kinase can interact with multiple signaling pathways such as: Wnt/β-catenin, phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/extracellular signal-regulated kinase (ERK), Notch and others. Moreover, we will discuss how targeting GSK-3 and these other pathways can improve leukemia therapy and may overcome therapeutic resistance. In summary, GSK-3 is a crucial regulatory kinase interacting with multiple pathways to control various physiological processes, as well as leukemia stem cells, leukemia progression and therapeutic resistance. GSK-3 and Wnt are clearly intriguing therapeutic targets

Völkisch und sozial? : Neonazistische Agitation gegen die neue EU-Freizügigkeit für Arbeitnehmerinnen

Wnt/β-catenin signalling pathway is crucial for the formation of many tissues and organs during development. In recent years, this pathway has also been found to regulate the biology of stem cells in the intestine and probably in other organs in adult life. Abnormal activation of Wnt/β-catenin signalling, which controls the expression of a high number of genes, is critical for the initiation and progression of most colorectal cancers. In line with this, the gene expression signature induced by activation of the Wnt/β-catenin pathway defines the intestinal stem cells present at the bottom of the crypts and also colon cancer stem cells. This supports the importance of inhibitors of the Wnt/β-catenin pathway as potential agents in colorectal cancer therapy. However, the complexity, wide activity in the organism modulating the biology of several cell types, and characteristics of this pathway have delayed the identification of suitable targets and so, the development of such inhibitors that are only now reaching the clinic.Peer reviewe

Addressing Barriers to Resident & Faculty

Incident reporting has been recognized as a critical strategy for improving patient safety (PS) as is the focus area/pathway ACGME’s Clinical Learning Environment Review (CLER). Yet despite its importance, physician incident reporting remains limited hindering efforts to learn and develop processes to prevent future occurrences. An often cited barrier to physician reporting is that submissions go into a “black hole” with no process for learning. Through collaboration with incident reporting leaders, we developed an approach whereby residency program directors review incidents related to their program from an educational perspective