Molecular Genetics of T Cell Development

T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment

Shape-selected bimetallic nanoparticle electrocatalysts: evolution of their atomic-scale structure, chemical composition, and electrochemical reactivity under various chemical environments

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Solid surfaces generally respond sensitively to their environment. Gas phase or liquid phase species may adsorb and react with individual surface atoms altering the solid-gas and solid-liquid electronic and chemical properties of the interface. A comprehensive understanding of chemical and electrochemical interfaces with respect to their responses to external stimuli is still missing. The evolution of the structure and composition of shape-selected octahedral PtNi nanoparticles (NPs) in response to chemical (gas-phase) and electrochemical (liquid-phase) environments was studied, and contrasted to that of pure Pt and spherical PtNi NPs. The NPs were exposed to thermal annealing in hydrogen, oxygen, and vacuum, and the resulting NP surface composition was analyzed using X-ray photoelectron spectroscopy (XPS). In gaseous environments, the presence of O2 during annealing (300 °C) lead to a strong segregation of Ni species to the NP surface, the formation of NiO, and a Pt-rich NP core, while a similar treatment in H2 lead to a more homogenous Pt-Ni alloy core, and a thinner NiO shell. Further, the initial presence of NiO species on the as-prepared samples was found to influence the atomic segregation trends upon low temperature annealing (300 °C). This is due to the fact that at this temperature nickel is only partially reduced, and NiO favors surface segregation. The effect of electrochemical cycling in acid and alkaline electrolytes on the structure and composition of the octahedral PtNi NPs was monitored using image-corrected high resolution transmission electron microscopy (TEM) and high-angle annular dark field scanning TEM (HAADF-STEM). Sample pretreatments in surface active oxygenates, such as oxygen and hydroxide anions, resulted in oxygen-enriched Ni surfaces (Ni oxides and/or hydroxides). Acid treatments were found to strongly reduce the content of Ni species on the NP surface, via its dissolution in the electrolyte, leading to a Pt-skeleton structure, with a thick Pt shell and a Pt-Ni core. The presence of Ni hydroxides on the NP surface was shown to improve the kinetics of the electrooxidation of CO and the electrocatalytic hydrogen evolution reactions. The affinity to water and the oxophilicity of Ni hydroxides are proposed as likely origin of the observed effects.DFG, EXC 314, Unifying Concepts in Catalysi

Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome

Mutations in CCAAT/enhancer binding protein α (CEBPA) are seen in 5% to 14% of acute myeloid leukemia (AML) and have been associated with a favorable clinical outcome. Most AMLs with CEBPA mutations simultaneously carry 2 mutations (CEBPAdouble-mut), usually biallelic, whereas single heterozygous mutations (CEBPAsingle-mut) are less frequently seen. Using denaturing high-performance liquid chromatography and nucleotide sequencing, we identified among a cohort of 598 newly diagnosed AMLs a subset of 41 CEBPA mutant cases (28 CEBPAdouble-mut and 13 CEBPA single-mut cases) CEBPAdouble-mut associated with a unique gene expression profile as well as favorable overall and event-free survival, retained in multi-variable analysis that included cytoge-netic risk, FZT3-ITD and NPM1 mutation, white blood cell count, and age. In contrast, CEBPA single-mut AMLs did not express a discriminating signature and could not be distinguished from wild-type cases as regards clinical outcome. These results demonstrate significant underlying heterogeneity within CEBPA mutation-positive AML with prognostic relevance

Identification of two distinct pathways of human myelopoiesis

Human myelopoiesis has been proposed to occur through oligopotent common myeloid progenitor (CMP) and lymphoid-primed multipotent progenitor (LMPP) populations. However, other studies have proposed direct commitment of multipotent cells to unilineage fates, without specific intermediary lineage cosegregation patterns. We here show that distinct human myeloid progenitor populations generate the neutrophil/monocyte and mast cell/basophil/eosinophil lineages as previously shown in mouse. Moreover, we find that neutrophil/monocyte potential selectively cosegregates with lymphoid lineage and mast cell/basophil/eosinophil potentials with megakaryocyte/erythroid potential early during lineage commitment. Furthermore, after this initial commitment step, mast cell/basophil/eosinophil and megakaryocyte/erythroid potentials colocalize at the single-cell level in restricted oligopotent progenitors. These results show that human myeloid lineages are generated through two distinct cellular pathways defined by complementary oligopotent cell populations

Cyclic AMP Responsive Element Binding Proteins Are Involved in ‘Emergency’ Granulopoiesis through the Upregulation of CCAAT/Enhancer Binding Protein β

In contrast to the definitive role of the transcription factor, CCAAT/Enhancer binding protein α (C/EBPα), in steady-state granulopoiesis, previous findings have suggested that granulopoiesis during emergency situations, such as infection, is dependent on C/EBPβ. In this study, a novel lentivirus-based reporter system was developed to elucidate the molecular switch required for C/EBPβ-dependency. The results demonstrated that two cyclic AMP responsive elements (CREs) in the proximal promoter region of C/EBPβ were involved in the positive regulation of C/EBPβ transcription during granulocyte-macrophage colony-stimulating factor (GM-CSF)–induced differentiation of bone marrow cells. In addition, the transcripts of CRE binding (CREB) family proteins were readily detected in hematopoietic stem/progenitor cells. CREB was upregulated, phosphorylated and bound to the CREs in response to GM-CSF stimulation. Retroviral transduction of a dominant negative CREB mutant reduced C/EBPβ mRNA levels and significantly impaired the proliferation/differentiation of granulocyte precursors, while a constitutively active form of CREB facilitated C/EBPβ transcription. These data suggest that CREB proteins are involved in the regulation of granulopoiesis via C/EBPβ upregulation

Upstream open reading frames: Molecular switches in (patho)physiology

Conserved upstream open reading frames (uORFs) are found within many eukaryotic transcripts and are known to regulate protein translation. Evidence from genetic and bioinformatic studies implicates disturbed uORF-mediated translational control in the etiology of human diseases. A genetic mouse model has recently provided proof-of-principle support for the physiological relevance of uORF-mediated translational control in mammals. The targeted disruption of the uORF initiation codon within the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) gene resulted in deregulated C/EBPβ protein isoform expression, associated with defective liver regeneration and impaired osteoclast differentiation. The high prevalence of uORFs in the human transcriptome suggests that intensified search for mutations within 5′ RNA leader regions may reveal a multitude of alterations affecting uORFs, causing pathogenic deregulation of protein expression

Ni-based bimetallic heterogeneous catalysts for energy and environmental applications

Bimetallic catalysts have attracted extensive attention for a wide range of applications in energy production and environmental remediation due to their tunable chemical/physical properties. These properties are mainly governed by a number of parameters such as compositions of the bimetallic systems, their preparation method, and their morphostructure. In this regard, numerous efforts have been made to develop “designer” bimetallic catalysts with specific nanostructures and surface properties as a result of recent advances in the area of materials chemistry. The present review highlights a detailed overview of the development of nickel-based bimetallic catalysts for energy and environmental applications. Starting from a materials science perspective in order to obtain controlled morphologies and surface properties, with a focus on the fundamental understanding of these bimetallic systems to make a correlation with their catalytic behaviors, a detailed account is provided on the utilization of these systems in the catalytic reactions related to energy production and environmental remediation. We include the entire library of nickel-based bimetallic catalysts for both chemical and electrochemical processes such as catalytic reforming, dehydrogenation, hydrogenation, electrocatalysis and many other reactions

Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis

CCAAT/enhancer binding protein alpha (CEBPA) mutations in AML are associated with favourable prognosis and are divided into N- and C-terminal mutations. The majority of AML patients have both types of mutations. We assessed the prognostic significance of single (n=7) and double (n=12) CEBPA mutations among 224 AML patients. Double CEBPA mutations conferred a decisively favourable overall (P=0.006) and disease-free survival (P=0.013). However, clinical outcome of patients with single CEBPA mutations was not different from CEBPA wild-type patients. In a multivariable analysis, only double – but not single – CEBPA mutations were identified as independent prognostic factors. These findings indicate heterogeneity within AML patients with CEBPA mutations