B cell-specific conditional expression of Myd88(p.L252P) leads to the development of diffuse large B cell lymphoma in mice

The adaptor protein MYD88 is critical to relay activation of Toll-like receptor signaling to NF-{kappa}B activation.MYD88 mutations, particularly the p.L265P mutation, have been described in numerous distinct B cell malignancies, including diffuse large B cell lymphoma (DLBCL). 29% of activated B cell (ABC)-type DLBCL, which is characterized by constitutive activation of the NF-{kappa}B pathway, carry the p.L265P mutation. In addition, ABC-DLBCL frequently displays focal copy number gains affecting BCL2. Here, we generated a novel mouse model, in which Cre-mediated recombination, specifically in B cells, leads to the conditional expression of Myd88(p.L252P)(the orthologous position of the human MYD88(p.L265P) mutation) from the endogenous locus. These animals develop a lympho-proliferative disease, and occasional transformation into clonal lymphomas. The clonal disease displays morphological and immunophenotypical characteristics of ABC-DLBCL. Lymphomagenesis can be accelerated by crossing in a further novel allele, which mediates conditional overexpression ofBCL2 Cross-validation experiments in human DLBCL samples revealed that bothMYD88andCD79Bmutations are substantially enriched in ABC-DLBCL, compared to germinal center B cell DLBCL. Furthermore, analyses of human DLBCL genome sequencing data confirmed that BCL2 amplifications frequently co-occur with MYD88 mutations, further validating our approach. Lastly,in silicoexperiments revealed that particularly MYD88-mutant ABC-DLBCL cells display an actionable addiction to BCL2. Altogether, we generated a novel autochthonous mouse model of ABC-DLBCL, which could be used as a preclinical platform for the development and validation of novel therapeutic approaches for the treatment of ABC-DLBCL

Families\u27 healthcare experiences for children with inherited metabolic diseases: Protocol for a mixed methods cohort study

Introduction Children with inherited metabolic diseases (IMDs) often have complex and intensive healthcare needs and their families face challenges in receiving high-quality, family centred health services. Improvement in care requires complex interventions involving multiple components and stakeholders, customised to specific care contexts. This study aims to comprehensively understand the healthcare experiences of children with IMDs and their families across Canada. Methods and analysis A two-stage explanatory sequential mixed methods design will be used. Stage 1: quantitative data on healthcare networks and encounter experiences will be collected from 100 parent/guardians through a care map, 2 baseline questionnaires and 17 weekly diaries over 5-7 months. Care networks will be analysed using social network analysis. Relationships between demographic or clinical variables and ratings of healthcare experiences across a range of family centred care dimensions will be analysed using generalised linear regression. Other quantitative data related to family experiences and healthcare experiences will be summarised descriptively. Ongoing analysis of quantitative data and purposive, maximum variation sampling will inform sample selection for stage 2: a subset of stage 1 participants will participate in one-on-one videoconference interviews to elaborate on the quantitative data regarding care networks and healthcare experiences. Interview data will be analysed thematically. Qualitative and quantitative data will be merged during analysis to arrive at an enhanced understanding of care experiences. Quantitative and qualitative data will be combined and presented narratively using a weaving approach (jointly on a theme-by-theme basis) and visually in a side-by-side joint display. Ethics and dissemination The study protocol and procedures were approved by the Children\u27s Hospital of Eastern Ontario\u27s Research Ethics Board, the University of Ottawa Research Ethics Board and the research ethics boards of each participating study centre. Findings will be published in peer-reviewed journals and presented at scientific conferences

Wetlands for wastewater treatment and subsequent recycling of treated effluent : a review

Due to water scarcity challenges around the world, it is essential to think about non-conventional water resources to address the increased demand in clean freshwater. Environmental and public health problems may result from insufficient provision of sanitation and wastewater disposal facilities. Because of this, wastewater treatment and recycling methods will be vital to provide sufficient freshwater in the coming decades, since water resources are limited and more than 70% of water are consumed for irrigation purposes. Therefore, the application of treated wastewater for agricultural irrigation has much potential, especially when incorporating the reuse of nutrients like nitrogen and phosphorous, which are essential for plant production. Among the current treatment technologies applied in urban wastewater reuse for irrigation, wetlands were concluded to be the one of the most suitable ones in terms of pollutant removal and have advantages due to both low maintenance costs and required energy. Wetland behavior and efficiency concerning wastewater treatment is mainly linked to macrophyte composition, substrate, hydrology, surface loading rate, influent feeding mode, microorganism availability, and temperature. Constructed wetlands are very effective in removing organics and suspended solids, whereas the removal of nitrogen is relatively low, but could be improved by using a combination of various types of constructed wetlands meeting the irrigation reuse standards. The removal of phosphorus is usually low, unless special media with high sorption capacity are used. Pathogen removal from wetland effluent to meet irrigation reuse standards is a challenge unless supplementary lagoons or hybrid wetland systems are used

Cytoplasmic hydrogen ion diffusion coefficient.

The apparent cytoplasmic proton diffusion coefficient was measured using pH electrodes and samples of cytoplasm extracted from the giant neuron of a marine invertebrate. By suddenly changing the pH at one surface of the sample and recording the relaxation of pH within the sample, an apparent diffusion coefficient of 1.4 +/- 0.5 x 10(-6) cm2/s (N = 7) was measured in the acidic or neutral range of pH (6.0-7.2). This value is approximately 5x lower than the diffusion coefficient of the mobile pH buffers (approximately 8 x 10(-6) cm2/s) and approximately 68x lower than the diffusion coefficient of the hydronium ion (93 x 10(-6) cm2/s). A mobile pH buffer (approximately 15% of the buffering power) and an immobile buffer (approximately 85% of the buffering power) could quantitatively account for the results at acidic or neutral pH. At alkaline pH (8.2-8.6), the apparent proton diffusion coefficient increased to 4.1 +/- 0.8 x 10(-6) cm2/s (N = 7). This larger diffusion coefficient at alkaline pH could be explained quantitatively by the enhanced buffering power of the mobile amino acids. Under the conditions of these experiments, it is unlikely that hydroxide movement influences the apparent hydrogen ion diffusion coefficient

Isolation of a chromium hydride single-component ethylene polymerization catalyst

Reaction of the divalent complex [(t-Bu)NPN(t-Bu)]2Cr (1) with different stoichiometric ratios of Al(i-Bu)3 afforded {µ-[(t-Bu)NP(i-Bu)N(t-Bu)]Al(i-Bu)2}2Cr (2) and [{(i-Bu)P{µ-N(t-Bu)}2Al(i-Bu)2}Cr(µ-H)]2 (3) as part of the same reaction sequence. Complex 2 arises from association of alane and the two ligands via alkylation of the P atom and retention of the AlR2 unit. Complex 3 appears to be generated from subsequent dissociation of one alkylated ligand and possible transfer of an i-Bu group to Cr followed by ß-H elimination or transfer of a hydride originating from isobutyl elimination of the aluminum-containing residue. Both species are potent ethylene polymerization catalysts with no need for further activation. It is assumed that 2 is transformed in situ into 3 under the influence of ethylene. Reactions with ethylene carried out in the presence of excess of Al(i-Bu)3 switch the selectivity completely toward selective trimerization

Preparation and characterization of a switchable single-component chromium trimerization catalyst

Reaction of [(Ar)NPN(t-Bu)]2Cr (2) with Me3Al afforded {[(Ar)NP(Me)N(t-Bu)]AlMe2}Cr{[(Ar)NP(Me)(AlMe3)N(t-Bu)]AlMe(µ-Me)} (3), in which the ligands P atom has been alkylated and one AlR2 residue retained by the chelating framework. One of the two ligands also retained an additional Me3Al unit via coordination to the alkylated P atom. Complex 3 provides the first case of a selective ethylene trimerization catalyst with high activity and excellent selectivity, producing 1-hexene upon exposure to ethylene at 80 °C. Furthermore, upon treatment with MAO, complex 3 acts as a nonselective catalyst, producing a statistical mixture of oligomers with the highest ever observed activity. In addition, upon treatment with [(i-Bu)2Al]2O, the complex acts as a highly active polymerization catalyst

Isolation of a chromium hydride single-component ethylene polymerization catalyst

Reaction of the divalent complex [(t-Bu)NPN(t-Bu)]2Cr (1) with different stoichiometric ratios of Al(i-Bu)3 afforded {µ-[(t-Bu)NP(i-Bu)N(t-Bu)]Al(i-Bu)2}2Cr (2) and [{(i-Bu)P{µ-N(t-Bu)}2Al(i-Bu)2}Cr(µ-H)]2 (3) as part of the same reaction sequence. Complex 2 arises from association of alane and the two ligands via alkylation of the P atom and retention of the AlR2 unit. Complex 3 appears to be generated from subsequent dissociation of one alkylated ligand and possible transfer of an i-Bu group to Cr followed by ß-H elimination or transfer of a hydride originating from isobutyl elimination of the aluminum-containing residue. Both species are potent ethylene polymerization catalysts with no need for further activation. It is assumed that 2 is transformed in situ into 3 under the influence of ethylene. Reactions with ethylene carried out in the presence of excess of Al(i-Bu)3 switch the selectivity completely toward selective trimerization

Chromium catalysts supported by a nonspectator NPN ligand: Isolation of single-component chromium polymerization catalysts

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