A new target for differentiation therapy in AML

Despite major advances in understanding the genetics and epigenetics of acute myelogenous leukemia, there is still a great need to develop more specific and effective therapies. High throughput approaches involving either genetic approaches or small molecule inhibitor screens are beginning to identify promising new therapeutic targets

HoxA9 binds and represses the Cebpa +8 kb enhancer

C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9

Building a Model and Framework for Child Welfare Supervision

This report, Building a Model and Framework for Child Welfare Supervision, presents the findings from an extensive review of the most recent literature combined with interviews of experts in the field of child welfare, currently practicing child welfare administrators, supervisors, frontline practitioners, and trainers. The report is organized into three sections: • Section I introduces seven elements of an emerging model of supervision in child welfare. • Section II presents an integrated organizational framework consisting of four components required to empower child welfare supervisors to effectively carry out their administrative, educational, and supportive functions. • Section III incorporates supports useful to agencies in implementing the recommendations contained in this report. These include our interview protocols, the annotated results of our extensive literature review, a sample job description, and our methodology

Dermanyssus gallinae in layer farms in Kosovo: a high risk for salmonella prevalence

Background The poultry red mite (PRM), Dermanyssus gallinae (D.g.) is a serious ectoparasitic pest of poultry and potential pathogen vector. The prevalence of D. g. and the prevalence of Salmonella spp. within mites on infested laying poultry farms were investigated in Kosovo. Findings In total, 14 populated layer farms located in the Southern Kosovo were assessed for D. g. presence. Another two farms in this region were investigated 6 months after depopulation. Investigated flocks were all maintained in cages, a common housing system in Kosovo. A total of eight farms were found to be infested with D. g. (50%) at varying levels, including the two depopulated farms. The detection of Salmonella spp. from D. g. was carried out using PCR. Out of the eight layer farms infested with D. g., Salmonella spp. was present in mites on three farms (37.5%). Conclusions This study confirms the high prevalence of D. g. in layer flocks in Kosovo and demonstrates the link between this mite and the presence of Salmonella spp. on infested farms

Phase 1 dose escalation study of the allosteric AKT inhibitor BAY 1125976 in advanced solid cancer-Lack of association between activating AKT mutation and AKT inhibition-derived efficacy

This open-label, phase I first-in-human study (NCT01915576) of BAY 1125976, a highly specific and potent allosteric inhibitor of AKT1/2, aimed to evaluate the safety, pharmacokinetics, and maximum tolerated dose of BAY 1125976 in patients with advanced solid tumors. Oral dose escalation was investigated with a continuous once daily (QD) treatment (21 days/cycle) and a twice daily (BID) schedule. A dose expansion in 28 patients with hormone receptor-positive metastatic breast cancer, including nine patients harboring th

Iron Deprivation in Synechocystis : Inference of Pathways, Non-coding RNAs, and Regulatory Elements from Comprehensive Expression Profiling

Iron is an essential cofactor in many metabolic reactions. Mechanisms controlling iron homeostasis need to respond rapidly to changes in extracellular conditions, but they must also keep the concentration of intracellular iron under strict control to avoid the generation of damaging reactive oxygen species. Due to its role as a redox carrier in photosynthesis, the iron quota in cyanobacteria is about 10 times higher than in model enterobacteria. The molecular details of how such a high quota is regulated are obscure. Here we present experiments that shed light on the iron regulatory system in cyanobacteria. We measured time-resolved changes in gene expression after iron depletion in the cyanobacterium Synechocystis sp. PCC 6803 using a comprehensive microarray platform, monitoring both protein-coding and non-coding transcripts. In total, less than a fifth of all protein-coding genes were differentially expressed during the first 72 hr. Many of these proteins are associated with iron transport, photosynthesis, or ATP synthesis. Comparing our data with three previous studies, we identified a core set of 28 genes involved in iron stress response. Among them were genes important for assimilation of inorganic carbon, suggesting a link between the carbon and iron regulatory networks. Nine of the 28 genes have unknown functions and constitute key targets for further functional analysis. Statistical and clustering analyses identified 10 small RNAs, 62 antisense RNAs, four 59UTRs, and seven intragenic elements as potential novel components of the iron regulatory network in Synechocystis. Hence, our genome-wide expression profiling indicates an unprecedented complexity in the iron regulatory network of cyanobacteria.Portuguese Fundacao para a Ciencia e a Tecnologia (FCT) [PTDC/BIA-MIC/101036/2008]; Deutsche Forschungsgemeinschaft (DFG) Focus program "Sensory and regulatory RNAs in Prokaryotes [SPP1258]; FCT [PEst-OE/EQB/LA0023/2011]info:eu-repo/semantics/publishedVersio

Atomic Bose Gas with Negative Scattering Length

We derive the equation of state of a dilute atomic Bose gas with an interatomic interaction that has a negative scattering length and argue that two continuous phase transitions, occuring in the gas due to quantum degeneracy effects, are preempted by a first-order gas-liquid or gas-solid transition depending on the details of the interaction potential. We also discuss the consequences of this result for future experiments with magnetically trapped spin-polarized atomic gasses such as lithium and cesium.Comment: 16 PAGES, REVTEX 3.0, ACCEPTED FOR PUBLICATION IN PHYS. REV.

Long range molecular dynamics study of regulation of eukaryotic glucosamine-6-phosphate synthase activity by UDP-GlcNAc

Glucosamine-6-phosphate (GlcN-6-P) synthase catalyses the first and practically irreversible step in hexosamine metabolism. The final product of this pathway, uridine 5’ diphospho N-acetyl-D-glucosamine (UDP-GlcNAc), is an essential substrate for assembly of bacterial and fungal cell walls. Moreover, the enzyme is involved in phenomenon of hexosamine induced insulin resistance in type II diabetes, which makes it a potential target for antifungal, antibacterial and antidiabetic therapy. The crystal structure of the isomerase domain of GlcN-6-P synthase from human pathogenic fungus Candida albicans, in complex with UDP-GlcNAc has been solved recently but it has not revealed the molecular mechanism of inhibition taking place under UDP-GlcNAc influence, the unique feature of the eukaryotic enzyme. UDP-GlcNAc is a physiological inhibitor of GlcN-6-P synthase, binding about 1 nm away from the active site of the enzyme. In the present work, comparative molecular dynamics simulations of the free and UDP-GlcNAc-bounded structures of GlcN-6-P synthase have been performed. The aim was to complete static X-ray structural data and detect possible changes in the dynamics of the two structures. Results of the simulation studies demonstrated higher mobility of the free structure when compared to the liganded one. Several amino acid residues were identified, flexibility of which is strongly affected upon UDP-GlcNAc binding. Importantly, the most fixed residues are those related to the inhibitor binding process and to the catalytic reaction. The obtained results constitute an important step toward understanding of mechanism of GlcN-6-P synthase inhibition by UDP-GlcNAc molecule

An Investigation of the Role of Macular Pigment in Attenuating Photostress through Comparison between Blue and Green Photostress Recovery Times

Purpose: Photostress recovery time (PSRT) is the time required for the macula to return to its normal functioning after the bleaching of cone photopigments due to light exposure, usually white. This work investigates the role of macular pigment (MP) as an optical filter that attenuates photostress by analyses of PSRT at different wavelengths. Methods: Thirty-nine subjects (19–28 years) were exposed to blue/green photostress varying in irradiance. During photostress, pupil constriction (Cp) was measured. Twenty-seven subjects (20–27 years) were exposed to white photostress. After 25 s of photostress, the time (PSRT) required to read correctly a 0.2 logMAR letter was measured. Correlation was studied between PSRT, CP, and irradiance. Statistical significance of differences between PSRTs was evaluated at Log(irradiance(quanta s−1 cm−2)) = 14 by Student’s t statistics. Results: Cp and PSRT were found linearly correlated to Log(irradiance) for blue, green, and white. At Log(irradiance(quanta s−1 cm−2)) = 14, blue and green mean PSRTs resulted different (p 0.05). Conclusions: MP plays the role of an optical filter attenuating photostress. PSRT was substantially proportional to the number of incident photons corrected for the MP optical absorption, regardless of their wavelength