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Abstract: We explore the potential of Time-Of-Flight Medium Energy Ion Scattering (TOF-MEIS) for thin film analysis and analyze possible difficulties in evaluation of experimental spectra. As a model system high-k material stacks made from ultra-thin films of HfO2 grown on a p-type Si (100) substrate with a 0.5nm SiO2 interface layer have been investigated. By comparison of experimental spectra and computer simulations TOF-MEIS was employed to establish a depth profile of the films and thus obtaining information on stoichiometry and film quality. Nominal film thicknesses were in the range from 1.8 to 12.2nm. A comparison of the results with those from other MEIS approaches is made. Issues regarding different combinations of composition and stopping power as well as the influence of channeling are discussed. As a supporting method Rutherford-Backscattering spectrometry (RBS) was employed to obtain the areal density of Hf atoms in the films. [Copyright &y& Elsevier]

Abstract: Electronic stopping in thin, amorphous, SiC films has been studied by time-of-flight medium energy ion scattering and conventional Rutherford backscattering spectrometry. Amorphous SiC films (8, 21 and 36nm) were prepared by laser ablation using a single crystalline silicon carbide target. Two kinds of substrate films, one with a lower atomic mass (carbon) and one with higher atomic mass (iridium) compared to silicon has been used. Monte Carlo simulations have been used to evaluate electronic stopping from the shift in energy for the signal scattered from Ir with and without SiC. The two kinds of samples are used to illustrate the strength and challenges for ToF-MEIS compared to conventional RBS. [Copyright &y& Elsevier]

Developing vertebrate limbs initiate proximo-distal patterning by interpreting opposing gradients of diffusible signaling molecules. We report two thresholds of proximo-distal signals in the limb bud: a higher threshold that establishes the upper-arm to forearm transition; and a lower one that positions a later transition from forearm to hand. For this last transition to happen, however, the signal environment seems to be insufficient, and we show that a timing mechanism dependent on histone acetylation status is also necessary. Therefore, as a consequence of the time dependence, the lower signaling threshold remains cryptic until the timing mechanism reveals it. We propose that this timing mechanism prevents the distal transition from happening too early, so that the prospective forearm has enough time to expand and form a properly sized segment. Importantly, the gene expression changes provoked by the first transition further regulate proximo-distal signal distribution, thereby coordinating the positioning of the two thresholds, which ensures robustness. This model is compatible with the most recent genetic analyses and underscores the importance of growth during the time-dependent patterning phase, providing a new mechanistic framework for understanding congenital limb defects. [ABSTRACT FROM AUTHOR]

Abstract: Electronic energy loss of hydrogen ions in HfO2 was investigated in a wide energy range in the medium and low energy ion scattering regime. Experiments by Time-Of-Flight Medium-Energy Ion Scattering (TOF-MEIS) with proton and deuteron projectiles were performed in backscattering geometry for nm-films of HfO2 on Si with an ultrathin SiO2 interface layer prepared by ALD. At energies around the stopping maximum excellent agreement is found with earlier results from Behar et al. (2009) [45] and theoretical predictions. Towards lower energies discrepancies between experiment and calculations increase slightly. The low energy data exhibits excellent velocity proportionality and indicates the absence of clear effects due to distinct electronic states. Thus, no apparent velocity threshold can be extrapolated from the experiments within the uncertainty of present data. The magnitude of the energy loss is discussed in terms of a free-electron model and compared with the expected electron densities from plasmon frequencies. [Copyright &y& Elsevier]

Abstract: This paper reports a medium energy ion scattering study of the room temperature deposition of Fe on the five-fold surface of i-Al70Pd21Mn9. At low coverage (~1 ML) growth results in a disordered alloy film with significant Al content. At higher coverage (~11 ML) again an alloy film is formed, but this time with an average composition that slowly varies through the film but is close to stoichiometric Fe3Al. This composition is consistent with magnetic ordering which has been observed in previous experiments on this system. Structural analysis indicates five domains of bcc-like structure in the film, which is oriented with (110) type planes parallel to the five-fold quasicrystal surface. There is a distinct structural transition within the film between a compressed layer near the surface and a slightly expanded layer directly above the quasicrystalline substrate. The sub-surface layer has considerable disorder and the change in layer spacing is attributed to this order/disorder transition within the film. Annealing to 300°C for 10min induces a small amount of further up-diffusion of Al into the film and also some segregation of Al to the surface, although structurally the film remains essentially unchanged, with the order/disorder transition occurring at a similar depth. [Copyright &y& Elsevier]

During embryonic development, cells become gradually restricted in their developmental potential and start elaborating lineage-specific transcriptional networks to ultimately acquire a unique differentiated state. Hox genes play a central role in specifying regional identities, thereby providing the cell with critical information on positional value along its differentiation path. The exquisite DNA-binding specificity of the Hox proteins is frequently dependent upon their interaction with members of the TALE family of homeodomain proteins. In addition to their function as Hox-cofactors, TALE homeoproteins control multiple crucial developmental processes through Hox-independent mechanisms. Here, we will review recent findings on the function of both Hox and TALE proteins in cell differentiation, referring mostly to vertebrate species. In addition, we will discuss the direct implications of this knowledge on cell plasticity and cell reprogramming. Developmental Dynamics 243:76-87, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Hox genes encode transcription factors with important roles during embryogenesis and tissue differentiation. Genetic analyses initially demonstrated that interfering with Hox genes has profound effects on the specification of cell identity, suggesting that Hox proteins regulate very specific sets of target genes. However, subsequent biochemical analyses revealed that Hox proteins bind DNA with relatively low affinity and specificity. Furthermore, it became clear that a given Hox protein could activate or repress transcription, depending on the context. A resolution to these paradoxes presented itself with the discovery that Hox proteins do not function in isolation, but interact with other factors in complexes. The first such 'cofactors' were members of the Extradenticle/Pbx and Homothorax/Meis/Prep families. However, the list of Hox-interacting proteins has continued to grow, suggesting that Hox complexes contain many more components than initially thought. Additionally, the activities of the various components and the exact mechanisms whereby they modulate the activity of the complex remain puzzling. Here, we review the various proteins known to participate in Hox complexes and discuss their likely functions. We also consider that Hox complexes of different compositions may have different activities and discuss mechanisms whereby Hox complexes may be switched between active and inactive states. Developmental Dynamics 243:4-15, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Our brain's cognitive performance arises from the coordinated activities of billions of nerve cells. Despite a high degree of morphological and functional differences, all neurons of the vertebrate central nervous system (CNS) arise from a common field of multipotent progenitors. Cell fate specification and differentiation are directed by multistep processes that include inductive/external cues, such as the extracellular matrix or growth factors, and cell-intrinsic determinants, such as transcription factors and epigenetic modulators of proteins and DNA. Here we review recent findings implicating TALE-homeodomain proteins in these processes. Although originally identified as HOX-cofactors, TALE proteins also contribute to many physiological processes that do not require HOX-activity. Particular focus is, therefore, given to HOX-dependent and -independent functions of TALE proteins during early vertebrate brain development. Additionally, we provide an overview about known upstream and downstream factors of TALE proteins in the developing vertebrate brain and discuss general concepts of how TALE proteins function to modulate neuronal cell fate specification. Developmental Dynamics 243:99-116, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

TALE (three amino acids loop extension) homeodomain transcription factors are required in various steps of embryo development, in many adult physiological functions, and are involved in important pathologies. This review focuses on the PREP, MEIS, and PBX sub-families of TALE factors and aims at giving information on their biochemical properties, i.e., structure, interactors, and interaction surfaces. Members of the three sets of protein form dimers in which the common partner is PBX but they can also directly interact with other proteins forming higher-order complexes, in particular HOX. Finally, recent advances in determining the genome-wide DNA-binding sites of PREP1, MEIS1, and PBX1, and their partial correspondence with the binding sites of some HOX proteins, are reviewed. These studies have generated a few general rules that can be applied to all members of the three gene families. PREP and MEIS recognize slightly different consensus sequences: PREP prefers to bind to promoters and to have PBX as a DNA-binding partner; MEIS prefers HOX as partner, and both PREP and MEIS drive PBX to their own binding sites. This outlines the clear individuality of the PREP and MEIS proteins, the former mostly devoted to basic cellular functions, the latter more to developmental functions. Developmental Dynamics 243:59-75, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most diagnosed cancer in males. Understanding the molecular mechanism and investigation of novel ways to block PCa growth or metastasis are vital and a medical necessity. In this study, we examined differential expression of MEIS1/2/3 and its associated factors in PCa cell lines. MEIS1/2/3 content, reactive oxygen species, cell cycle status, metastatic activities were analyzed in PCa cells pre and post MEIS inhibitor (MEISi) treatments, which is developed in our laboratory as a first-in-class small molecule inhibitor. A correlation was detected between MEIS content and MEISi IC50 values of PCa cells. MEISi decreased the viability of PC-3, DU145, 22Rv-1 and LNCaP cells, and significantly increased apoptosis in parallel with the increased cellular ROS content. The efficacy of MEISi was shown to positively correlate with the levels of MEIS1/2/3 proteins and the long-term exposure to MEISi elevated MEIS1/2/3 protein content in PCa cells. Administration of MEISi was also tested in PC-3 and 22Rv1 xenograft models of SCID mice to block in vivo tumor growth and metastasis. Our findings suggest that MEISi could be used to target PCa with high MEIS expression to lower PCa viability and growth, however, further studies are needed to achieve in vivo efficacy. [ABSTRACT FROM AUTHOR]

Abstract: The electronic stopping power of slow Ne ions (v >0.6a.u. per nucleon, i.e. 180keV) in polycrystalline Au was investigated in a backscattering approach. Spectra were recorded in a Time-Of-Flight Medium-Energy Ion Scattering (TOF-MEIS) experiment using a gold thin film of several nm thickness deposited on Si. The stopping power was extracted from fitting energy converted TOF-spectra by Monte-Carlo simulations for the ion trajectories. This permits an accurate disentanglement of elastic losses and inelastic losses which are due to nuclear collisions and interactions of the ion with the electronic system of the solid, respectively. The resulting electronic stopping cross section is found to exhibit excellent velocity proportionality in the whole investigated energy range. Data is compared to other experimental datasets for similar ion energies. [Copyright &y& Elsevier]

Highlights: [•] An advanced high-k/metal gate stack is examined by medium energy ion scattering. [•] The effect of the dopant activation anneal on the La2O3 capping layer is studied. [•] Substrate thinning is carried out to enable the backside in-depth investigation. [•] Diffusion of La up to the bottom SiON layer is observed after spike anneal at 1065°C. [Copyright &y& Elsevier]

Editor's suggested further reading in BioEssays ftz Evolution: Findings, hypotheses and speculations (response to DOI ) Abstract On the border of the homeotic function: Re-evaluating the controversial role of cofactor-recruiting motifs Abstract Control of DNA replication: A new facet of Hox proteins? Abstract Classification of sequence signatures: a guide to Hox protein function Abstract [ABSTRACT FROM AUTHOR]

During salamander limb regeneration, only the structures distal to the amputation plane are regenerated, a property known as the rule of distal transformation. Multiple cell types are involved in limb regeneration; therefore, determining which cell types participate in distal transformation is important for understanding how the proximo-distal outcome of regeneration is achieved. We show that connective tissue-derived blastema cells obey the rule of distal transformation. They also have nuclear MEIS, which can act as an upper arm identity regulator, only upon upper arm amputation. By contrast, myogenic cells do not obey the rule of distal transformation and display nuclear MEIS upon amputation at any proximo-distal level. These results indicate that connective tissue cells, but not myogenic cells, are involved in establishing the proximo-distal outcome of regeneration and are likely to guide muscle patterning. Moreover, we show that, similarly to limb development, muscle patterning in regeneration is influenced by β-catenin signalling. [ABSTRACT FROM AUTHOR]

Secondary ion mass spectrometry (SIMS) and medium energy ion scattering (MEIS) have been applied to the characterization of ultra-shallow distributions of arsenic in silicon obtained by ion implantation. A previously developed quantitative model for the correction of results obtained by ultra low energy SIMS was tested on different types of samples. The model deals with the different sputtering regimes in SiO2 and Si and corrects the analysis behaviour at the SiO2/Si interface. Model results were compared with MEIS which yields depth profiles that are more accurate and can be quantified from first principles. The obtained model was tested on samples with or without a pre-amorphization implant step prior to As implantation and subsequently annealed at 550 °C in a partially oxidizing atmosphere. Results show excellent agreement on As peak position and shape; however, MEIS detects differences between profiles of preamorphised and non-preamorphised samples whereas SIMS profiles of these samples are almost identical. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Damage profiles on Si (001) surface via argon gas cluster ion beam sputtering and mono-atomic argon ion beam sputtering were investigated using medium energy ion scattering. The surface thickness damaged by Ar cluster ion beam sputtering was approximately 10 nm for 20 keV, 6.4 nm for 10 keV, and 4.2 nm for 5 keV and the composition of the implanted Ar atoms was 0.2 at% for 20 keV and 0.1 at% for both 10 and 5 keV. The surface thickness damaged by Ar ion beam sputtering was approximately 5.3 nm for 1 keV, 8.5 nm for 2 keV, and 12 nm for 3 keV and the maximum Ar concentration of the implanted Ar atoms in the Si substrate was 5.5 at% for 1 keV, 5.8 at% for 2 keV, and 7.8 at% for 3 keV. The depth of the damaged layers after Ar ion sputtering on Si (001) is proportional to the in-depth distribution of the implanted primary Ar ions. The depth of the damaged layer after the Ar cluster ion beam sputtering did not depend on the implanted Ar atoms because the implanted Ar atoms are negligible. Understanding the details about the damage process via Ar cluster ion beam sputtering can be useful for the practical surface analysis. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Three amino acid loop extension (TALE) homeodomain-containing transcription factors are generally recognized for their role in organogenesis and differentiation during embryogenesis. However, very little is known about the expression and function of Meis, Pbx, and Prep genes during early development. Results: In order to determine whether TALE proteins could contribute to the early cell fate decisions in mammalian development, this study aimed to characterize in a systematic manner the pattern of expression of all Meis, Pbx, and Prep genes from the precompaction to blastocyst stage corresponding to the first step of cell differentiation in mammals. To reveal to what extent TALE genes expression at these early stages is a conserved feature among mammals, this study was performed in parallel in the bovine and mouse models. We demonstrated the transcription and translation of TALE genes, before gastrulation in the two species. At least one member of Meis, Pbx, and Prep subfamilies was found expressed at the RNA and protein levels but different patterns of expression were observed between genes and between species, suggesting specific gene regulations. Conclusions: Taken together, these results suggest a previously unexpected involvement of these factors during the early development in mammals. Developmental Dynamics 241:1827-1835, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

During development, early inducing programs must later be counterbalanced for coordinated tissue maturation. In Xenopus laevis embryos, activation of the Meis3 transcription factor by a mesodermal Wnt3a signal lies at the core of the hindbrain developmental program. We now identify a hindbrain restricting circuit, surprisingly comprising the hindbrain inducers Wnt3a and Meis3, and Tsh1 protein. Functional and biochemical analyses show that upon Tsh1 induction by strong Wnt3a/Meis3 feedback loop activity, the Meis3-Tsh1 transcription complex represses the Meis3 promoter, allowing cell cycle exit and neuron differentiation. Meis3 protein exhibits a conserved dual-role in hindbrain development, both inducing neural progenitors and maintaining their proliferative state. In this regulatory circuit, the Tsh1 co-repressor controls transcription factor gene expression that modulates cell cycle exit, morphogenesis and differentiation, thus coordinating neural tissue maturation. This newly identified Wnt/Meis/Tsh circuit could play an important role in diverse developmental and disease processes. [ABSTRACT FROM AUTHOR]

Abstract: Pax6 is an essential transcription factor for lens, lacrimal gland and pancreas development. Previous transgenic analyses have identified several Pax6 regulatory elements, but their functional significance and binding factors remain largely unknown. In this study, we generated two genomic truncations to delete three elements that were previously shown to bind to the Meis/Prep family homeoproteins. One 3.1kb deletion (Pax6 ∆DP/∆DP ) removed two putative pancreatic enhancers and a previously identified ectodermal enhancer, while a 450bp sub-deletion (Pax6 ∆PE/∆PE ) eliminated only the promoter-proximal pancreatic enhancer. Immunohistochemistry and quantitative RT-PCR showed that the Pax6 ∆PE/∆PE pancreata had a significant decrease in Pax6, glucagon, and insulin expression, while no further reductions were observed in the Pax6 ∆DP/∆DP mice, indicating that only the 450bp region is required for pancreatic development. In contrast, Pax6 ∆DP/∆DP , but not Pax6 ∆PE/∆PE mice, developed stunted lacrimal gland and lens hypoplasia which was significantly more severe than that reported when only the ectodermal enhancer was deleted. This result suggested that the ectodermal enhancer must cooperate with its neighboring sequences to regulate the Pax6 ectodermal expression. Finally, we generated conditional knockouts of Prep1 in the lens and pancreas, but surprisingly, did not observe any developmental defects. Together, these results provide functional evidence for the independent and synergistic roles of the Pax6 upstream enhancers, and they suggest the potential redundancy of Meis/Prep protein in Pax6 regulation. [Copyright &y& Elsevier]

Abstract: A three-dimensional medium energy ion scattering (3D-MEIS) method has been developed using a commercial MEIS apparatus. This method consists of filtering the energy of the ions scattered by the sample and measuring their two-dimensional angular distribution over a large region. These cartographies of the scattered particles reveal the angular positions of the crystallographic directions and atomic planes. The method is also element sensitive and allows depth profiling by selecting the energy of the scattered particles. As an example, the MEIS cartography technique is applied on a 49nm thick compressively strained Si0.7Ge0.3 layer deposited on a Si (100) wafer. [Copyright &y& Elsevier]

Abstract: Scattering cross sections for He+ ions in the energy range of 100eV to 100keV and for Al, Cu and Au target atoms were calculated. Employing the Thomas–Fermi–Molière model the potential strength was tuned by variation of the screening length. The resulting change in scattering cross section was analyzed and the absolute value is compared to cross sections obtained from potentials commonly employed in the medium-energy ion scattering (MEIS) regime. A large influence on the scattering cross section is observed for targets with large atomic number in the very low energy range. For instance, the scattering cross section for 100eV He+-ions scattered from Au by 129° changes by a factor of 2.5 between different potential strengths claimed in the literature to be suitable for low-energy ion scattering (LEIS) energies. An experiment to determine electronic energy loss of very slow ions in metals is presented. It shows how uncertainties in the scattering potential strength can lead to systematically wrong results, although perfect agreement between experimental data and simulations is found. The impact of these results on quantitative surface structure and composition analysis is discussed. [Copyright &y& Elsevier]

Abstract: A series of studies over the past decade has examined empirical evidence of the validity of the Multifactor Emotional Intelligence Test (MEIS) and the Mayer–Salovey–Caruso Emotional Intelligence Scale (MSCEIT), concentrating in particular on whether these tests’ internal structures are consistent with the theory on which they are built. Such evidence has been equivocal, and previous studies have noted the number of indicators per factor as an analytic limitation. The lack of evidence establishing convergence between the two tests has also been noted. This study seeks to (a) examine the convergence between these two tests of emotional intelligence (EI), and (b) reexamine the factor structure of EI using an appropriate number of indicators per factor. A high degree of convergence between the two tests was found, but, consistent with some previous studies, only partial support was found for the proposed factor structure of both tests. These findings are discussed in the context of the larger validity argument surrounding these tests and the emotional intelligence construct. [ABSTRACT FROM AUTHOR]

Myeloid ecotropic insertion site (Meis)2 is a homeodomain protein containing a conserved homothorax (Hth) domain that is present in all Meis and Prep family proteins and in the Drosophila Hth protein. The Hth domain mediates interaction with Pbx homeodomain proteins, allowing for efficient DNA binding. Here we show that, like Meis1, Meis2 has a strong C-terminal transcriptional activation domain, which is required for full activation of transcription by homeodomain protein complexes composed of Meis2 and Pbx1. We also show that the activity of the activation domain is inhibited by the Hth domain, and that this autoinhibition can be partially relieved by the interaction of Pbx1 with the Hth domain of Meis2. Targeting of the Hth domain to DNA suggests that it is not a portable trans-acting repression domain. However, the Hth domain can inhibit a linked activation domain, and this inhibition is not limited to the Meis2 activation domain. Database searching reveals that the Meis3.2 splice variant, which is found in several vertebrate species, disrupts the Hth domain by removing 17 codons from the 5′-end of exon 6. We show that the equivalent deletion in Meis2 derepresses the C-terminal activation domain and weakens interaction with Pbx1. This work suggests that the transcriptional activity of all members of the Meis/Prep Hth protein family is subject to autoinhibition by their Hth domains, and that the Meis3.2 splice variant encodes a protein that bypasses this autoinhibitory effect. Structured digital abstract • , , , , , : Meis2d (uniprotkb: ) physically interacts ( ) with PBX1 (uniprotkb: ) by anti tag coimmunoprecipitation ( ) • : Meis2e (uniprotkb: ) physically interacts ( ) with PBX1 (uniprotkb: ) by anti tag coimmunoprecipitation ( ) [ABSTRACT FROM AUTHOR]

Abstract: During vertebrate development, the initial wave of hematopoiesis produces cells that help to shape the developing circulatory system and oxygenate the early embryo. The differentiation of primitive erythroid and myeloid cells occurs within a short transitory period, and is subject to precise molecular regulation by a hierarchical cascade of transcription factors. The TALE-class homeodomain transcription factors Meis and Pbx function to regulate embryonic hematopoiesis, but it is not known where Meis and Pbx proteins participate in the hematopoietic transcription factor cascade. To address these questions, we have ablated Meis1 and Pbx proteins in zebrafish, and characterized their molecular effects on known markers of primitive hematopoiesis. Embryos lacking Meis1 and Pbx exhibit a severe reduction in the expression of gata1, the earliest marker of erythroid cell fate, and fail to produce visible circulating blood cells. Concomitant with a loss of gata1, Meis1- and Pbx-depleted embryos exhibit downregulated embryonic hemoglobin (hbae3) expression, and possess increased numbers of pu.1-positive myeloid cells. gata1-overexpression rescues hbae3 expression in Pbx-depleted; meis1-morphant embryos, placing Pbx and Meis1 upstream of gata1 in the erythropoietic transcription factor hierarchy. Our study conclusively demonstrates that Meis1 and Pbx act to specify the erythropoietic cell lineage and inhibit myelopoiesis. [Copyright &y& Elsevier]

Abstract: Aberrant expression of the TLX1/HOX11 proto-oncogene is associated with a significant subset of T-cell acute lymphoblastic leukemias (T-ALL). Yet the manner in which TLX1 contributes to oncogenesis is not fully understood. Since, typically, interactions of HOX and TALE homeodomain proteins are determinant of HOX function, and HOX/MEIS co-expression has been shown to accelerate some leukemias, we systematically examined whether TLX1 interacts with MEIS and PBX proteins. Here, we report that TLX1 and MEIS proteins both interact and are co-expressed in T-ALL, and suggest that co-operation between TLX1 and MEIS proteins may have a significant role in T-cell leukemogenesis. [Copyright &y& Elsevier]

Abstract: The interface between Al and tris-(8-hydroquinoline) aluminum (Alq3) was studied using in situ medium energy ion scattering spectroscopy. We compared two interfaces of Al/LiF/Alq3 and Al/Alq3 with the elemental depth profile of each interface. The thin LiF changes the interfacial structures significantly; the excess Li in the LiF layer diffuses into Alq3 while F does not. In addition, the Al diffusion into the Alq3 layer during the initial stages of Al deposition is reduced significantly compared to the interface without the LiF interlayer. The LiF interlayer makes a more abrupt metal–organic interface, which would contribute to the efficiency and stability of the organic light-emitting device. [Copyright &y& Elsevier]

HOXA4 gene expression is a predictor for outcome in normal karyotypic acute myeloid leukaemia (AML) patients. Given that Meis1 is a co-factor for Hox genes, we hypothesized that the combined expression of HOXA4 and MEIS1 might add prognostic information in these patients. When diagnostic samples from 246 AML patients were divided into three main groups based on gene expression levels of HOXA4 combined with MEIS1 we found that within the group of patients exhibiting low levels of HOXA4, those with a high expression of MEIS1 had a significantly worse outcome than those exhibiting low MEIS1 expression ( P = 0.025). Moreover, this prediction was independent of cytogenetics, mutational status of the NPM1 and FLT3 genes as well as upon WBC and age. To evaluate the possible contribution of regulatory events underlying these observations, 157 patient samples were subjected to promoter hypermethylation analysis. We observed that 77% were HOXA4- and 15% MEIS1 hypermethylated and that this epigenetic alteration was highly correlated to the gene expression level ( MEIS1: P = 0.001; HOXA4: P = 0.007). Finally, we found a higher expression level and a higher frequency of hypermethylation of HOXA4 among patients with NPM1 mutations. In conclusion, our data show that the combination of low HOXA4 and low MEIS1 gene expression is a favourable predictor for outcome in all AML patients and that the expression levels are governed by the methylation state of these genes. [ABSTRACT FROM AUTHOR]

Abstract: The TALE homeodomain-containing PBC and MEIS proteins play multiple roles during metazoan development. Mutations in these proteins can cause various disorders, including cancer. In this study, we examined the roles of MEIS proteins in mesoderm development in C. elegans using the postembryonic mesodermal M lineage as a model system. We found that the MEIS protein UNC-62 plays essential roles in regulating cell fate specification and differentiation in the M lineage. Furthermore, UNC-62 appears to function together with the PBC protein CEH-20 in regulating these processes. Both unc-62 and ceh-20 have overlapping expression patterns within and outside of the M lineage, and they share physical and regulatory interactions. In particular, we found that ceh-20 is genetically required for the promoter activity of unc-62, providing evidence for another layer of regulatory interactions between MEIS and PBC proteins. [Copyright &y& Elsevier]

Abstract: Trilayers of Al/Fe/Al and Al/Fe multilayers produced by magnetron sputtering both with and without ion assistance have been depth profiled using Auger electron spectroscopy and medium energy ion scattering. Important differences are observed in the layer structure, with ion assisted deposition giving the narrowest Al/Fe interfaces and so maintaining the most clearly defined layer structure. Both types of sputtering result in some oxygen contamination, particularly at the surface that modeling shows to be associated with the Al layers. [Copyright &y& Elsevier]

As junction depths in advanced semiconductor devices move to below 20 nm, the process of disorder evolution during ion implantation at ultra low energies becomes increasingly influenced by the surface. This may also hold for shallow regrowth and dopant redistribution processes during subsequent thermal annealing of the substrate. The investigation of these near-surface processes requires analytical techniques with a depth resolution of≤1 nm. Medium energy ion scattering (MEIS) has the unique capability of simultaneously providing quantitative, high-resolution depth distributions of implant disorder (displaced Si lattice atoms) and of implanted atoms, albeit not of light species. We report here a comparative MEIS investigation into the growth mode of shallow disordered/amorphised layers during≤1 keV B+ and 2.5 keV As+ ion implantation into Si. In both cases the growth of the damage depth profiles differs significantly from the energy deposition function, as it is strongly determined on the one hand by the proximity of the surface acting as a nucleation site for migrating point defects formed during implantation, which results in planar growth of the amorphous layer, and on the other by the dynamic annealing processes operating at room temperature. When such defect recombination processes are inhibited, e.g. for low dose, ultra shallow 200 eV B+ implants, MEIS shows that defect production yields exceeding the Kinchin-Pease model predictions are achieved. For As implants, a correlation is observed between the movement of the As and the depth of the growing, planar amorphous layer. Thermal annealing of As implanted samples at different temperatures and durations leads to solid phase epitaxial regrowth. During regrowth, MEIS shows that there is a close correlation between damage dissolution, the movement of nearly half of the As dopant into substitutional sites and the snowploughing of a fraction of the As in front of the advancing amorphous/crystalline interface leading to the formation of a less than 1 nm wide As pile-up layer trapped under the oxide. [ABSTRACT FROM AUTHOR]

Abstract: Mutations that aberrantly activate trithorax-group proteins, Hox transcription factors and TALE-class Hox cofactors promote leukemogenesis, but their target genes critical for leukemogenesis remain largely unknown. Through genetic analyses in C. elegans, we find that the trithorax-group gene lin-59 and the TALE-class Hox cofactor unc-62 are required for survival of the VC motor neurons. With the goal of providing a model for how aberrantly active Hox complexes might promote leukemia, we elucidate the mechanism through which these new inhibitors of programmed cell death act: lin-59 maintains transcription of the Hox gene lin-39, while unc-62 promotes nuclear localization of the TALE-class Hox cofactor ceh-20. A LIN-39/CEH-20 complex binds the promoter of the pro-apoptotic BH3-only gene egl-1, repressing its transcription and ensuring survival of the VC neurons. In the absence of this regulatory mechanism, egl-1 is transcribed and the VC neurons die. Furthermore, ectopic expression of the Hox gene lin-39, as occurs for human Hox genes in leukemia, is sufficient to block death of some cells. This work identifies BH3-only pro-apoptotic genes as targets of Hox-mediated repression and suggests that aberrant activation of Hox networks may promote leukemia in part by inhibiting apoptosis. [Copyright &y& Elsevier]

Abstract: Patterning of the vertebrate hindbrain involves a segmentation process leading to the formation of seven rhombomeres along the antero-posterior axis. While recent studies have shed light on the mechanisms underlying progressive subdivision of the posterior hindbrain into individual rhombomeres, the early events involved in anterior hindbrain patterning are still largely unknown. In this paper we demonstrate that two zebrafish Iroquois transcription factors, Irx7 and Irx1b, are required for the proper formation and specification of rhombomeres 1 to 4 and, in particular, for krox20 activation in r3. We also show that Irx7 functionally interacts with Meis factors to activate the expression of anterior hindbrain markers, such as hoxb1a, hoxa2 and krox20, ectopically in the anterior neural plate. Then, focusing on krox20 expression, we show that the effect of Irx7 and Meis1.1 is mediated by element C, a conserved cis-regulatory element involved in krox20 activation in the hindbrain. Together, our data point to an essential function of Iroquois transcription factors in krox20 activation and, more generally, in anterior hindbrain specification. [Copyright &y& Elsevier]

The article discusses a study on the relation of deficiencies in Pbx and Meis with congenital heart disease. It was found that the reduction or absence of Pbx2 and Pbx3 result to the haploinsufficiency of Pbx1, which can lead to truncus arteriosus. Also, the disruption of Meis1, an encoder of a Pbx DNA-binding partner, is seen to be a cause of cardiac anomalies that are similar to those of Pbx mutations.

The Polycomb group (PcG) of genes is important for differentiation and cell-cycle regulation and is aberrantly expressed in several cancers. To analyse the role of deregulated PcG genes in acute myeloid leukaemia (AML), we determined by RQ-PCR the expression of the PcG genes BMI-1, MEL18, SCML2, YY1 and EZH2, and the downstream PcG targets HOXA4, HOXA9 and MEIS1 in diagnostic bone marrow samples from 126 AML patients. There was a general overexpression of the genes in AML patients compared to 20 healthy donors, except of HOXA4 and MEL18, which both displayed a wide range of expression levels within the AML subgroups. Among the AML patients with normal karyotype, a low HOXA4 level was associated with a shorter overall survival ( P = 0.005). In addition, expression levels of MEL18 and EZH2 were significantly ( P < 0.025) higher in patients with complex karyotype and lower in CBF-mutated patients. The t(8;21) vs. inv(16) positive patients showed significantly different expression of SCML2, BMI-1, YY1, HOXA9 and MEIS1 ( P ≤ 0.01). Comparisons between the PcG and PcG-regulated genes and a number of clinical and molecular data revealed correlations to genes involved in DNA methylation ( DNMT1, DNMT3B), apoptosis ( BAX, CASPASE 3) and multidrug-resistance ( MDR1, MRP ) ( P < 0.01). In conclusion, our data suggest that the role of PcG and PcG-regulated genes in leukaemogenesis varies between, as well as within karyotypic subgroups. [ABSTRACT FROM AUTHOR]

Abstract: Neurons of cranial sensory ganglia are derived from the neural crest and ectodermal placodes, but the mechanisms that control the relative contributions of each are not understood. Crest cells of the second branchial arch generate few facial ganglion neurons and no vestibuloacoustic ganglion neurons, but crest cells in other branchial arches generate many sensory neurons. Here we report that the facial ganglia of Hoxa2 mutant mice contain a large population of crest-derived neurons, suggesting that Hoxa2 normally represses the neurogenic potential of second arch crest cells. This may represent an anterior transformation of second arch neural crest cells toward a fate resembling that of first arch neural crest cells, which normally do not express Hoxa2 or any other Hox gene. We additionally found that overexpressing Hoxa2 in cultures of P19 embryonal carcinoma cells reduced the frequency of spontaneous neuronal differentiation, but only in the presence of cotransfected Pbx and Meis Hox cofactors. Finally, expression of Hoxa2 and the cofactors in chick neural crest cells populating the trigeminal ganglion also reduced the frequency of neurogenesis in the intact embryo. These data suggest an unanticipated role for Hox genes in controlling the neurogenic potential of at least some cranial neural crest cells. [Copyright &y& Elsevier]

Abstract: The transcription cofactor Pbx3 is critical for the function of hindbrain circuits controlling respiration in mammals, but the perinatal lethality caused by constitutively null mutations has hampered investigation of other roles it may play in neural development and function. Here we report that the conditional loss of Pbx3 function in most tissues caudal to the hindbrain resulted in progressive deficits of posture, locomotion, and sensation that became apparent during adolescence. In adult mutants, the size of the dorsal horn of the spinal cord and the numbers of calbindin-, PKC-γ, and calretinin-expressing neurons in laminae I–III were markedly reduced, but the ventral cord and peripheral nervous system appeared normal. In the embryonic dorsal horn, Pbx3 expression was restricted to a subset of glutamatergic neurons, but its absence did not affect the initial balance of excitatory and inhibitory interneuron phenotypes. By embryonic day 15 a subset of Meis(+) glutamatergic neurons assumed abnormally superficial positions and the number of calbindin(+) neurons was increased three-fold in the mutants. Loss of Pbx3 function thus leads to the incorrect specification of some glutamatergic neurons in the dorsal horn and alters the integration of peripheral sensation into the spinal circuitry regulating locomotion. [Copyright &y& Elsevier]

The adsorption of atomic hydrogen on Cu(111) has been studied using the techniques of helium atom scattering (HAS) and medium-energy ion scattering (MEIS). Ion scattering investigations of the saturated (3 × 3)-H/Cu(111) system indicate that no reconstruction of the Cu substrate exists along the high symmetry directions of the surface. The HAS hydrogen cross-section for H/Cu(111) has been determined to be (12.5 ± 2.5 Å2). The symmetry of the HAS diffraction pattern shows that the (3 × 3)-H/Cu(111) system is formed of a single domain structure. [ABSTRACT FROM AUTHOR]

Abstract: Three amino-acid loop extension (TALE) homeobox proteins MEIS and PBX are cofactors for HOX-class homeobox proteins, which control growth and differentiation during embryogenesis and homeostasis. We showed that MEIS and PBX expression are related to cisplatin resistance in ovarian cancer cell lines. Therefore, MEIS1, MEIS2 and PBX expression were investigated immunohistochemically in a tissue microarray (N =232) of ovarian cancers and ovarian surface epithelium (N =15). Results were related to clinicopathologic characteristics and survival. All cancers expressed MEIS1, MEIS2 and PBX in nucleus and cytoplasm. MEIS1 and 2 only stained nuclear in surface epithelium. Nuclear MEIS2 was negatively related to stage, grade and overall survival in univariate analyses. Additionally, MEIS and PBX RNA expression in ovarian surface epithelium and other normal tissues and ovarian cancer versus other tumour types using public array data sets were studied. In ovarian cancer, MEIS1 is highly expressed compared to other cancer types. In conclusion, MEIS and PBX are extensively expressed in ovarian carcinomas and may play a role in ovarian carcinogenesis. [Copyright &y& Elsevier]

TALE homeodomain proteins are an ancient subgroup within the group of homeodomain transcription factors that play important roles in animal, plant, and fungal development. We have extracted the full complement of TALE superclass homeobox genes from the genome projects of seven protostomes, seven deuterostomes, and Nematostella. This was supplemented with TALE homeobox genes from additional species and phylogenetic analyses were carried out with 276 sequences. We found 20 homeobox genes and 4 pseudogenes in humans, 21 genes in mouse, 8 genes in Drosophila, and 5 genes plus one truncated gene in Caenorhabditis elegans. Apart from the previously identified TALE classes MEIS, PBC, IRO, and TGIF, a novel class is identified, termed MOHAWK (MKX). Further, we show that the MEIS class can be divided into two families, PREP and MEIS. Prep genes have previously only been described in vertebrates but are lacking in Drosophila. Here we identify orthologues in other insect taxa as well as in the cnidarian Nematostella. In C. elegans, a divergent Prep protein has lost the homeodomain. Full-length multiple sequence alignment of the protostome and deuterostome sequences allowed us to identify several novel conserved motifs within the MKX, TGIF, and MEIS classes. Phylogenetic analyses revealed fast-evolving PBC class genes; in particular, some X-linked PBC genes in nematodes are subject to rapid evolution. In addition, several instances of gene loss were identified. In conclusion, our comprehensive analysis provides a defining framework for the classification of animal TALE homeobox genes and the understanding of their evolution. [ABSTRACT FROM AUTHOR]

Abstract: In standard computer codes for the analysis of RBS data, the energy straggling is taken to be a Gaussian function. This leads to unphysical simulations whenever the energy spread is comparable to the average energy loss and to the system resolution, which may happen in the near surface region. We propose to use the gamma distribution for the energy straggling, since it asymptotically approaches the Gaussian distribution for small values of the energy spread relative to average energy loss, while it has no high energy tail above the initial beam energy. This was implemented in the code NDF. We compare the results with calculations made with the stochastic model for 100keV protons in Hf delta layers in Si and show that a major improvement is obtained with regard to the Gaussian distribution. We also show calculations for 1.5MeV 4He+ experiments. [Copyright &y& Elsevier]

Abstract: sonic hedgehog (shh) is expressed in anterior endoderm, where it is required to repress pancreas gene expression and to pattern the endoderm, but the pathway controlling endodermal shh expression is unclear. We find that expression of meis3, a TALE class homeodomain gene, coincides with shh expression in the endoderm of zebrafish embryos. Using a dominant negative construct or anti-sense morpholino oligos (MOs) to disrupt meis3 function, we observe ectopic insulin expression in anterior endoderm. This phenotype is also observed when meis3 MOs are targeted to the endoderm, suggesting that meis3 acts within the endoderm to restrict insulin expression. We also find that meis3 is required for endodermal shh expression, indicating that meis3 acts upstream of shh to restrict insulin expression. Loss of pbx4, a TALE gene encoding a Meis cofactor, produces the same phenotype as loss of meis3, consistent with Meis3 acting in a complex with Pbx4 as reported in other systems. Lastly, we observe a progressive anterior displacement of endoderm-derived organs upon disruption of meis3 or pbx4, apparently as a result of underdevelopment of the pharyngeal region. Our data indicate that meis3 and pbx4 regulate shh expression in anterior endoderm, thereby influencing patterning and growth of the foregut. [Copyright &y& Elsevier]

Abstract: The early work of the FOM-AMOLF group in Amsterdam clearly demonstrated the potential of medium energy ion scattering (MEIS), typically using 100keV H+ incident ions, to investigate the structure of surfaces, but most current applications of the method are focussed on near-surface compositional studies of non-crystalline films. However, the key strengths of the MEIS technique, notably the use of blocking curves in double-alignment experiments and absolute yield measurements, are extremely effective in providing detailed near-surface structural information for a wide range of crystalline materials. This potential and the underlying methodology, is illustrated through examples of applications to the study of layer-dependent composition and structure in alloy surfaces, in studies of the surface crystallography of an oxide surface (rutile TiO2(110)) and in investigations of complex adsorbate-induced reconstruction of metal surfaces, including the pseudo-(100) reconstruction of Cu(111) induced by adsorption of atomic N and molecular methylthiolate (CH3S–). In addition to the use of calibrated blocking curves, the use of the detailed spectral shape of the surface peak in the scattered ion energy spectra, as a means of providing single-atomic layer resolution of the surface structure, is also discussed. [Copyright &y& Elsevier]