Surface-initiated growth of copper using isonicotinic acid-functionalized aluminum oxide surfaces

Isonicotinate self-assembled monolayers (SAM) were prepared on alumina surfaces (A) using isonicotinic acid (iNA). These functionalized layers (iNA-A) were used for the seeded growth of copper films (Cu-iNA-A) by hydrazine hydrate-initiated electroless deposition. The films were characterized by scanning electron microscopy (SEM), electron-dispersive X-ray spectroscopy, atomic force microscopy, X-ray photoelectron spectroscopy, X-ray diffraction, and advancing contact angle measurements. The films are Cu0 but with surface oxidation, and show a faceted morphology, which is more textured (Rq = 460 ± 90 nm) compared to the SAM (Rq = 2.8 ± 0.5 nm). In contrast, growth of copper films by SnCl2/PdCl2 catalyzed electroless deposition, using formaldehyde (CH2O) as the reducing agent, shows a nodular morphology on top of a relatively smooth surface. No copper films are observed in the absence of the isonicotinate SAM. The binding of Cu2+ to the iNA is proposed to facilitate reduction to Cu0 and create the seed for subsequent growth. The films show good adhesion to the functionalized surface

Mechanism of endothelial progenitor cell recruitment into neo-vessels in adjacent non-tumor tissues in hepatocellular carcinoma

Abstract Background We investigated the distribution and clinical significance of mobilized endothelial progenitor cells (EPCs) in hepatocellular carcinoma (HCC). We found that many more EPCs were recruited to nonmalignant liver tissue (especially into adjacent non-tumor tissues (AT)) than to tumor vessels. These results suggest that the mechanism underlying the recruitment of EPCs into microvessels in AT merits further investigation Methods Angiogenic factors were detected in three tissue microarrays comprising normal liver, paired tumor tissue (TT) and AT from 105 patients (who had undergone hepatectomy for HCC) using immunohistochemistry. Also, the number of EPCs (positive for Sca-1, Flk-1 and c-Kit) in the blood and liver of cirrhotic mice were determined by flow cytometry and immunohistochemistry. The distribution of these labeled EPCs in tumor and non-tumor tissues was then studied. Results The results from the tissue microarrays showed that the expression levels of VEGF-A, bFGF, TGF-β, MCP-1, TSP-1, MMP-9, TIMP-2, and endostatin were significantly higher in AT than in either normal liver or TT (p Conclusions Both liver cirrhosis and HCC led to increased expression of pro-angiogenic factors, which resulted in the recruitment of EPCs into AT. Also, EPCs were mobilized, recruited and homed to cirrhotic liver. The unique pathology of HCC coupled with liver cirrhosis may, therefore, be associated with the distribution and function of EPCs.</p

Network-Based Elucidation of Human Disease Similarities Reveals Common Functional Modules Enriched for Pluripotent Drug Targets

Current work in elucidating relationships between diseases has largely been based on pre-existing knowledge of disease genes. Consequently, these studies are limited in their discovery of new and unknown disease relationships. We present the first quantitative framework to compare and contrast diseases by an integrated analysis of disease-related mRNA expression data and the human protein interaction network. We identified 4,620 functional modules in the human protein network and provided a quantitative metric to record their responses in 54 diseases leading to 138 significant similarities between diseases. Fourteen of the significant disease correlations also shared common drugs, supporting the hypothesis that similar diseases can be treated by the same drugs, allowing us to make predictions for new uses of existing drugs. Finally, we also identified 59 modules that were dysregulated in at least half of the diseases, representing a common disease-state “signature”. These modules were significantly enriched for genes that are known to be drug targets. Interestingly, drugs known to target these genes/proteins are already known to treat significantly more diseases than drugs targeting other genes/proteins, highlighting the importance of these core modules as prime therapeutic opportunities

A trehalose biosynthetic enzyme doubles as an osmotic stress sensor to regulate bacterial morphogenesis

The dissacharide trehalose is an important intracellular osmoprotectant and the OtsA/B pathway is the principal pathway for trehalose biosynthesis in a wide range of bacterial species. Scaffolding proteins and other cytoskeletal elements play an essential role in morphogenetic processes in bacteria. Here we describe how OtsA, in addition to its role in trehalose biosynthesis, functions as an osmotic stress sensor to regulate cell morphology in Arthrobacter strain A3. In response to osmotic stress, this and other Arthrobacter species undergo a transition from bacillary to myceloid growth. An otsA null mutant exhibits constitutive myceloid growth. Osmotic stress leads to a depletion of trehalose-6-phosphate, the product of the OtsA enzyme, and experimental depletion of this metabolite also leads to constitutive myceloid growth independent of OtsA function. In vitro analyses indicate that OtsA can self-assemble into protein networks, promoted by trehalose-6-phosphate, a property that is not shared by the equivalent enzyme from E. coli, despite the latter's enzymatic activity when expressed in Arthrobacter. This, and the localization of the protein in non-stressed cells at the mid-cell and poles, indicates that OtsA from Arthrobacter likely functions as a cytoskeletal element regulating cell morphology. Recruiting a biosynthetic enzyme for this morphogenetic function represents an intriguing adaptation in bacteria that can survive in extreme environments

CRIM1 Complexes with ß-catenin and Cadherins, Stabilizes Cell-Cell Junctions and Is Critical for Neural Morphogenesis

In multicellular organisms, morphogenesis is a highly coordinated process that requires dynamically regulated adhesion between cells. An excellent example of cellular morphogenesis is the formation of the neural tube from the flattened epithelium of the neural plate. Cysteine-rich motor neuron protein 1 (CRIM1) is a single-pass (type 1) transmembrane protein that is expressed in neural structures beginning at the neural plate stage. In the frog Xenopus laevis, loss of function studies using CRIM1 antisense morpholino oligonucleotides resulted in a failure of neural development. The CRIM1 knockdown phenotype was, in some cases, mild and resulted in perturbed neural fold morphogenesis. In severely affected embryos there was a dramatic failure of cell adhesion in the neural plate and complete absence of neural structures subsequently. Investigation of the mechanism of CRIM1 function revealed that it can form complexes with ß-catenin and cadherins, albeit indirectly, via the cytosolic domain. Consistent with this, CRIM1 knockdown resulted in diminished levels of cadherins and ß-catenin in junctional complexes in the neural plate. We conclude that CRIM1 is critical for cell-cell adhesion during neural development because it is required for the function of cadherin-dependent junctions

Structure-Function Analysis of Barley NLR Immune Receptor MLA10 Reveals Its Cell Compartment Specific Activity in Cell Death and Disease Resistance

Plant intracellular immune receptors comprise a large number of multi-domain proteins resembling animal NOD-like receptors (NLRs). Plant NLRs typically recognize isolate-specific pathogen-derived effectors, encoded by avirulence (AVR) genes, and trigger defense responses often associated with localized host cell death. The barley MLA gene is polymorphic in nature and encodes NLRs of the coiled-coil (CC)-NB-LRR type that each detects a cognate isolate-specific effector of the barley powdery mildew fungus. We report the systematic analyses of MLA10 activity in disease resistance and cell death signaling in barley and Nicotiana benthamiana. MLA10 CC domain-triggered cell death is regulated by highly conserved motifs in the CC and the NB-ARC domains and by the C-terminal LRR of the receptor. Enforced MLA10 subcellular localization, by tagging with a nuclear localization sequence (NLS) or a nuclear export sequence (NES), shows that MLA10 activity in cell death signaling is suppressed in the nucleus but enhanced in the cytoplasm. By contrast, nuclear localized MLA10 is sufficient to mediate disease resistance against powdery mildew fungus. MLA10 retention in the cytoplasm was achieved through attachment of a glucocorticoid receptor hormone-binding domain (GR), by which we reinforced the role of cytoplasmic MLA10 in cell death signaling. Together with our data showing an essential and sufficient nuclear MLA10 activity in disease resistance, this suggests a bifurcation of MLA10-triggered cell death and disease resistance signaling in a compartment-dependent manner

Preferred response of the East Asian summer monsoon to local and non-local anthropogenic sulphur dioxide emissions

In this study, the atmospheric component of a state-of-the-art climate model (HadGEM2-ES) that includes earth system components such as interactive chemistry and eight species of tropospheric aerosols considering aerosol direct, indirect, and semi-direct effects, has been used to investigate the impacts of local and non-local emissions of anthropogenic sulphur dioxide on the East Asian summer monsoon (EASM). The study focuses on the fast responses (including land surface feedbacks, but without sea surface temperature feedbacks) to sudden changes in emissions from Asia and Europe. The initial responses, over days 1–40, to Asian and European emissions show large differences. The response to Asian emissions involves a direct impact on the sulphate burden over Asia, with immediate consequences for the shortwave energy budget through aerosol–radiation and aerosol–cloud interactions. These changes lead to cooling of East Asia and a weakening of the EASM. In contrast, European emissions have no significant impact on the sulphate burden over Asia, but they induce mid-tropospheric cooling and drying over the European sector. Subsequently, however, this cold and dry anomaly is advected into Asia, where it induces atmospheric and surface feedbacks over Asia and the Western North Pacific (WNP), which also weaken the EASM. In spite of very different perturbations to the local aerosol burden in response to Asian and European sulphur dioxide emissions, the large scale pattern of changes in land–sea thermal contrast, atmospheric circulation and local precipitation over East Asia from days 40 onward exhibits similar structures, indicating a preferred response, and suggesting that emissions from both regions likely contributed to the observed weakening of the EASM. Cooling and drying of the troposphere over Asia, together with warming and moistening over the WNP, reduces the land–sea thermal contrast between the Asian continent and surrounding oceans. This leads to high sea level pressure (SLP) anomalies over Asia and low SLP anomalies over the WNP, associated with a weakened EASM. In response to emissions from both regions warming and moistening over the WNP plays an important role and determines the time scale of the response

Structural Basis for Apoptosis Inhibition by Epstein-Barr Virus BHRF1

Epstein-Barr virus (EBV) is associated with human malignancies, especially those affecting the B cell compartment such as Burkitt lymphoma. The virally encoded homolog of the mammalian pro-survival protein Bcl-2, BHRF1 contributes to viral infectivity and lymphomagenesis. In addition to the pro-apoptotic BH3-only protein Bim, its key target in lymphoid cells, BHRF1 also binds a selective sub-set of pro-apoptotic proteins (Bid, Puma, Bak) expressed by host cells. A consequence of BHRF1 expression is marked resistance to a range of cytotoxic agents and in particular, we show that its expression renders a mouse model of Burkitt lymphoma untreatable. As current small organic antagonists of Bcl-2 do not target BHRF1, the structures of it in complex with Bim or Bak shown here will be useful to guide efforts to target BHRF1 in EBV-associated malignancies, which are usually associated with poor clinical outcomes

Rasl11b Knock Down in Zebrafish Suppresses One-Eyed-Pinhead Mutant Phenotype

The EGF-CFC factor Oep/Cripto1/Frl1 has been implicated in embryogenesis and several human cancers. During vertebrate development, Oep/Cripto1/Frl1 has been shown to act as an essential coreceptor in the TGFβ/Nodal pathway, which is crucial for germ layer formation. Although studies in cell cultures suggest that Oep/Cripto1/Frl1 is also implicated in other pathways, in vivo it is solely regarded as a Nodal coreceptor. We have found that Rasl11b, a small GTPase belonging to a Ras subfamily of putative tumor suppressor genes, modulates Oep function in zebrafish independently of the Nodal pathway. rasl11b down regulation partially rescues endodermal and prechordal plate defects of zygotic oep−/− mutants (Zoep). Rasl11b inhibitory action was only observed in oep-deficient backgrounds, suggesting that normal oep expression prevents Rasl11b function. Surprisingly, rasl11b down regulation does not rescue mesendodermal defects in other Nodal pathway mutants, nor does it influence the phosphorylation state of the downstream effector Smad2. Thus, Rasl11b modifies the effect of Oep on mesendoderm development independently of the main known Oep output: the Nodal signaling pathway. This data suggests a new branch of Oep signaling that has implications for germ layer development, as well as for studies of Oep/Frl1/Cripto1 dysfunction, such as that found in tumors