Electron superhalogens as positronium superhalogens.

Positronium (Ps) exhibits the ability to form energetically stable complexes with atoms and molecules before annihilation occurs. In particular, F, a halogen, shows the highest reported positronium binding energy (2.95 eV) in the periodic table. Superhalogens are defined as molecules with electron affinities exceeding that of Cl (3.61 eV), the atom with the highest electron affinity. Building upon the concept of superhalogens, we can define Ps-superhalogens as molecules with Ps binding energies surpassing that of F. This study explores structural and energetic aspects of positronium and positron binding to neutral and anionic superhalogen molecules of the MXk+1 family (M = Li, Na, Be, Mg, B, Al, Si, P; X = F, Cl, Br), respectively and where k represents the highest formal valence of M. We perform multicomponent MP2 calculations for positron systems, which reveal how positron affinities vary with the type and number of halogen atoms present. The analysis of the results emphasizes the predominant role of electrostatic interactions in determining the positron affinity, with negligible effects of electronic and geometric relaxation upon positron attachment. We predict the energetic stability of 22 of the 24 PsMXk+1 complexes with respect to the chemically relevant dissociation channels: e+ emission, Ps emission and M-X bond breaking. Our findings reveal six MFk+1 systems that qualify as Ps-superhalogens, showing a positronium binding energy exceeding 2.95 eV. Of these, AlF4 stands out by setting a new record for the highest positronium binding energy among neutral molecules, reaching 4.36 eV.

Tristetraprolin: A cytosolic regulator of mRNA turnover moonlighting as transcriptional corepressor of gene expression.

Tristetraprolin (TTP) is a nucleocytoplasmic 326 amino acid protein whose sequence is characterized by possessing two CCCH-type zinc finger domains. In the cytoplasm TTP function is to promote the degradation of mRNAs that contain adenylate/uridylate-rich elements (AREs). Mechanistically, TTP promotes the recruitment of poly(A)-specific deadenylases and exoribonucleases. By reducing the half-life of about 10% of all the transcripts in the cell TTP has been shown to participate in multiple cell processes that include regulation of gene expression, cell proliferation, metabolic homeostasis and control of inflammation and immune responses. However, beyond its role in mRNA decay, in the cell nucleus TTP acts as a transcriptional coregulator by interacting with chromatin modifying enzymes. TTP has been shown to repress the transactivation of NF-κB and estrogen receptor suggesting the possibility that it participates in the transcriptional regulation of hundreds of genes in human cells and its possible involvement in breast cancer progression. In this review, we discuss the cytoplasmic and nuclear functions of TTP and the effect of the dysregulation of its protein levels in the development of human diseases. We suggest that TTP be classified as a moonlighting tumor supressor protein that regulates gene expression through two different mechanims; the decay of ARE-mRNAs and a transcriptional coregulatory function.

Theory of 2D crystals: graphene and beyond.

This tutorial review presents an overview of the basic theoretical aspects of two-dimensional (2D) crystals. We revise essential aspects of graphene and the new families of semiconducting 2D materials, like transition metal dichalcogenides or black phosphorus. Minimal theoretical models for various materials are presented. Some of the exciting new possibilities offered by 2D crystals are discussed, such as manipulation and control of quantum degrees of freedom (spin and pseudospin), confinement of excitons, control of the electronic and optical properties with strain engineering, or unconventional superconducting phases.

Strong Modulation of Optical Properties in Black Phosphorus through Strain-Engineered Rippling.

Controlling the bandgap through local-strain engineering is an exciting avenue for tailoring optoelectronic materials. Two-dimensional crystals are particularly suited for this purpose because they can withstand unprecedented nonhomogeneous deformations before rupture; one can literally bend them and fold them up almost like a piece of paper. Here, we study multilayer black phosphorus sheets subjected to periodic stress to modulate their optoelectronic properties. We find a remarkable shift of the optical absorption band-edge of up to ∼0.7 eV between the regions under tensile and compressive stress, greatly exceeding the strain tunability reported for transition metal dichalcogenides. This observation is supported by theoretical models that also predict that this periodic stress modulation can yield to quantum confinement of carriers at low temperatures. The possibility of generating large strain-induced variations in the local density of charge carriers opens the door for a variety of applications including photovoltaics, quantum optics, and two-dimensional optoelectronic devices.

Two translation initiation codons direct the expression of annexin VI 64kDa and 68kDa isoforms.

Annexin A6 is a multicompetent, multifunctional protein involved in several biological processes within and outside of the cell. Whereas HeLa cells express annexin A6 only as a 68/67-kDa doublet, indicating alternative splicing (Smith PD et al. (1994) Proc Natl Acad Sci USA 91, 2713-2717), the GMO2784 human fibroblast cell line expresses two additional isoforms at 64 and 58kDa. In both cell lines, annexin A6 is located intracellularly and on the plasma membrane. In vitro eukaryotic protein synthesis of pIRESneoAnxA6 cDNA and pIRESneoAnxA6/Met1- or Met33- using a reticulocyte lysate coupled transcription/translation system revealed that this gene contains two translation start codons, Met1 and Met33. Immunoprecipitation of the products obtained from the transcription/translation system using various anti-annexin A6 antibodies confirmed the presence of several isoforms and suggested that this protein might be present in different configurations.

SIP1/NHERF2 enhances estrogen receptor alpha transactivation in breast cancer cells.

The estrogen receptor alpha (ERα) is a ligand-activated transcription factor that possesses two activating domains designated AF-1 and AF-2 that mediate its transcriptional activity. The role of AF-2 is to recruit coregulator protein complexes capable of modifying chromatin condensation status. In contrast, the mechanism responsible for the ligand-independent AF-1 activity and for its synergistic functional interaction with AF-2 is unclear. In this study, we have identified the protein Na+/H+ Exchanger RegulatoryFactor 2 (NHERF2) as an ERα-associated coactivator that interacts predominantly with the AF-1 domain of the nuclear receptor. Overexpression of NHERF2 in breast cancer MCF7 cells produced an increase in ERα transactivation. Interestingly, the presence of SRC-1 in NHERF2 stably overexpressing MCF7 cells produced a synergistic increase in ERα activity. We show further that NHERF2 interacts with ERα and SRC-1 in the promoter region of ERα target genes. The binding of NHERF2 to ERα in MCF7 cells increased cell proliferation and the ability of MCF7 cells to form tumors in a mouse model. We analyzed the expression of NHERF2 in breast cancer tumors finding a 2- to 17-fold increase in its mRNA levels in 50% of the tumor samples compared to normal breast tissue. These results indicate that NHERF2 is a coactivator of ERα that may participate in the development of estrogen-dependent breast cancer tumors.

Dielectric screening in atomically thin boron nitride nanosheets.

Two-dimensional (2D) hexagonal boron nitride (BN) nanosheets are excellent dielectric substrate for graphene, molybdenum disulfide, and many other 2D nanomaterial-based electronic and photonic devices. To optimize the performance of these 2D devices, it is essential to understand the dielectric screening properties of BN nanosheets as a function of the thickness. Here, electric force microscopy along with theoretical calculations based on both state-of-the-art first-principles calculations with van der Waals interactions under consideration, and nonlinear Thomas-Fermi theory models are used to investigate the dielectric screening in high-quality BN nanosheets of different thicknesses. It is found that atomically thin BN nanosheets are less effective in electric field screening, but the screening capability of BN shows a relatively weak dependence on the layer thickness.

Holocarboxylase synthetase acts as a biotin-independent transcriptional repressor interacting with HDAC1, HDAC2 and HDAC7.

In human cells, HCS catalyzes the biotinylation of biotin-dependent carboxylases and mediates the transcriptional control of genes involved in biotin metabolism through the activation of a cGMP-dependent signal transduction pathway. HCS also targets to the cell nucleus in association with lamin-B suggesting additional gene regulatory functions. Studies from our laboratory in Drosophila melanogaster showed that nuclear HCS is associated with heterochromatin bands enriched with the transcriptionally repressive mark histone 3 trimethylated at lysine 9. Further, HCS was shown to be recruited to the core promoter of the transcriptionally inactive hsp70 gene suggesting that it may participate in the repression of gene expression, although the mechanism involved remained elusive. In this work, we expressed HCS as a fusion protein with the DNA-binding domain of GAL4 to evaluate its effect on the transcription of a luciferase reporter gene. We show that HCS possesses transcriptional repressor activity in HepG2 cells. The transcriptional function of HCS was shown by in vitro pull down and in vivo co-immunoprecipitation assays to depend on its interaction with the histone deacetylases HDAC1, HDAC2 and HDAC7. We show further that HCS interaction with HDACs and its function in transcriptional repression is not affected by mutations impairing its biotin-ligase activity. We propose that nuclear HCS mediates events of transcriptional repression through a biotin-independent mechanism that involves its interaction with chromatin-modifying protein complexes that include histone deacetylases.

Plasmons and screening in monolayer and multilayer black phosphorus.

Black phosphorus exhibits a high degree of band anisotropy. However, we find that its in-plane static screening remains relatively isotropic for momenta relevant to elastic long-range scattering processes. On the other hand, the collective electronic excitations in the system exhibit a strong anisotropy. Band nonparabolicity, due to interband couplings, leads to a plasmon frequency which scales as nß, where n is the carrier concentration, and ß<1/2. Screening and charge distribution in the out-of-plane direction are also studied using a nonlinear Thomas-Fermi model.

Local strain engineering in atomically thin MoS2.

Controlling the bandstructure through local-strain engineering is an exciting avenue for tailoring optoelectronic properties of materials at the nanoscale. Atomically thin materials are particularly well-suited for this purpose because they can withstand extreme nonhomogeneous deformations before rupture. Here, we study the effect of large localized strain in the electronic bandstructure of atomically thin MoS2. Using photoluminescence imaging, we observe a strain-induced reduction of the direct bandgap and funneling of photogenerated excitons toward regions of higher strain. To understand these results, we develop a nonuniform tight-binding model to calculate the electronic properties of MoS2 nanolayers with complex and realistic local strain geometries, finding good agreement with our experimental results.

Chemical Composition and Nutritive Value of Almond Hulls from Two Almond Varieties and Influence of Including Almond Hulls in the Diet on In Vitro Ruminal Fermentation and Methane Production.

Almond hulls (AH) are frequently used in dairy ruminant feeding, but information on variability of their nutritive value and their potential effects on CH4 production is still scarce. The influence of almond variety (Guara vs. Soleta) on chemical composition and energy value of AH was investigated using 10 samples per variety collected in 2 consecutive years. Guara-AH had greater (p ≤ 0.015) ash, protein, and fat content, but lower (p ≤ 0.001) fiber than Soleta-AH. The metabolizable energy content estimated from chemical composition and in vitro gas production was 8.5% greater for Guara than for Soleta samples. Harvesting year significantly affected most of the chemical fractions. The in vitro ruminal fermentation of diets for dairy ruminants including increasing amounts of dried AH (8, 16 and 24% of the total diet; fresh matter basis) indicated that AH can be included up to 16% of the diet, partially substituting corn, wheat bran and sugar beet pulp without detrimental effects on in vitro volatile fatty acid (VFA) production. In contrast, when AH replaced alfalfa hay and corn, VFA production was reduced at all levels of AH inclusion. No antimethanogenic effects of AH were detected in the in vitro incubations.

Piezoelectricity in Monolayer Hexagonal Boron Nitride.

2D hexagonal boron nitride (hBN) is a wide-bandgap van der Waals crystal with a unique combination of properties, including exceptional strength, large oxidation resistance at high temperatures, and optical functionalities. Furthermore, in recent years hBN crystals have become the material of choice for encapsulating other 2D crystals in a variety of technological applications, from optoelectronic and tunneling devices to composites. Monolayer hBN, which has no center of symmetry, is predicted to exhibit piezoelectric properties, yet experimental evidence is lacking. Here, by using electrostatic force microscopy, this effect is observed as a strain-induced change in the local electric field around bubbles and creases, in agreement with theoretical calculations. No piezoelectricity is found in bilayer and bulk hBN, where the center of symmetry is restored. These results add piezoelectricity to the known properties of monolayer hBN, which makes it a desirable candidate for novel electromechanical and stretchable optoelectronic devices, and pave a way to control the local electric field and carrier concentration in van der Waals heterostructures via strain. The experimental approach used here also shows a way to investigate the piezoelectric properties of other materials on the nanoscale by using electrostatic scanning probe techniques.

IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells.

The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα-positive breast cancer tumors.

How Substitutional Point Defects in Two-Dimensional WS2 Induce Charge Localization, Spin-Orbit Splitting, and Strain.

Control of impurity concentrations in semiconducting materials is essential to device technology. Because of their intrinsic confinement, the properties of two-dimensional semiconductors such as transition metal dichalcogenides (TMDs) are more sensitive to defects than traditional bulk materials. The technological adoption of TMDs is dependent on the mitigation of deleterious defects and guided incorporation of functional foreign atoms. The first step toward impurity control is the identification of defects and assessment of their electronic properties. Here, we present a comprehensive study of point defects in monolayer tungsten disulfide (WS2) grown by chemical vapor deposition using scanning tunneling microscopy/spectroscopy, CO-tip noncontact atomic force microscopy, Kelvin probe force spectroscopy, density functional theory, and tight-binding calculations. We observe four different substitutional defects: chromium (CrW) and molybdenum (MoW) at a tungsten site, oxygen at sulfur sites in both top and bottom layers (OS top/bottom), and two negatively charged defects (CD type I and CD type II). Their electronic fingerprints unambiguously corroborate the defect assignment and reveal the presence or absence of in-gap defect states. CrW forms three deep unoccupied defect states, two of which arise from spin-orbit splitting. The formation of such localized trap states for CrW differs from the MoW case and can be explained by their different d shell energetics and local strain, which we directly measured. Utilizing a tight-binding model the electronic spectra of the isolectronic substitutions OS and CrW are mimicked in the limit of a zero hopping term and infinite on-site energy at a S and W site, respectively. The abundant CDs are negatively charged, which leads to a significant band bending around the defect and a local increase of the contact potential difference. In addition, CD-rich domains larger than 100 nm are observed, causing a work function increase of 1.1 V. While most defects are electronically isolated, we also observed hybrid states formed between CrW dimers. The important role of charge localization, spin-orbit coupling, and strain for the formation of deep defect states observed at substitutional defects in WS2 as reported here will guide future efforts of targeted defect engineering and doping of TMDs.

Management of a patient with holocarboxylase synthetase deficiency.

We investigated in a patient with holocarboxylase synthetase deficiency, the relation between the biochemical and genetic factors of the mutant protein with the pharmacokinetic factors of successful biotin treatment. A girl exhibited abnormal skin at birth, and developed in the first days of life neonatal respiratory distress syndrome and metabolic abnormalities diagnostic of multiple carboxylase deficiency. Enzyme assays showed low carboxylase activities. Fibroblast analysis showed poor incorporation of biotin into the carboxylases, and low transfer of biotin by the holocarboxylase synthetase enzyme. Kinetic studies identified an increased Km but a preserved Vmax. Mutation analysis showed the child to be a compound heterozygote for a new nonsense mutation Q379X and for a novel missense mutation Y663H. This mutation affects a conserved amino acid, which is located the most 3' of all recorded missense mutations thus far described, and extends the region of functional biotin interaction. Treatment with biotin 100mg/day gradually improved the biochemical abnormalities in blood and in cerebrospinal fluid (CSF), corrected the carboxylase enzyme activities, and provided clinical stability and a normal neurodevelopmental outcome. Plasma concentrations of biotin were increased to more than 500 nM, thus exceeding the increased Km of the mutant enzyme. At these pharmacological concentrations, the CSF biotin concentration was half the concentration in blood. Measuring these pharmacokinetic variables can aid in optimizing treatment, as individual tailoring of dosing to the needs of the mutation may be required.

Strain engineering in semiconducting two-dimensional crystals.

One of the fascinating properties of the new families of two-dimensional crystals is their high stretchability and the possibility to use external strain to manipulate, in a controlled manner, their optical and electronic properties. Strain engineering, understood as the field that study how the physical properties of materials can be tuned by controlling the elastic strain fields applied to it, has a perfect platform for its implementation in the atomically thin semiconducting materials. The object of this review is to give an overview of the recent progress to control the optical and electronics properties of 2D crystals, by means of strain engineering. We will concentrate on semiconducting layered materials, with especial emphasis in transition metal dichalcogenides (MoS2, WS2, MoSe2 and WSe2). The effect of strain in other atomically thin materials like black phosphorus, silicene, etc, is also considered. The benefits of strain engineering in 2D crystals for applications in nanoelectronics and optoelectronics will be revised, and the open problems in the field will be discussed.

Progression of chronic hepatitis C to liver fibrosis and cirrhosis in patients coinfected with hepatitis C virus and human immunodeficiency virus.

To evaluate the factors associated with the evolution of chronic hepatitis C in human immunodeficiency virus (HIV)-infected patients, a cross-sectional analysis of 41 HIV-infected patients with chronic hepatitis C (known as "HIV-HCV [hepatitis C virus]-coinfected patients") and a control group of patients with chronic hepatitis C who did not have HIV infection (known as "non-HIV-infected patients") was performed. The association of histological variables with demographic parameters, HCV load and genotype, HIV load, CD4(+) T cell count, and response to highly active antiretroviral therapy (HAART) was evaluated. HIV-HCV-coinfected patients showed a significantly higher HCV load, more-advanced fibrosis, and a higher liver fibrosis progression rate (FPR) than did non-HIV-infected patients. A high HCV load and a low CD4(+) T cell count were associated with a higher FPR. The immune response induced by HAART did not influence this progression. In conclusion, HIV-HCV-infected patients, mainly such patients with a high HCV load and an immunodepressed state, have a higher FPR. An independent effect of the immune response to HAART was not evident.

Impaired biotinidase activity disrupts holocarboxylase synthetase expression in late onset multiple carboxylase deficiency.

Biotinidase catalyzes the hydrolysis of the vitamin biotin from proteolytically degraded biotin-dependent carboxylases. This key reaction makes the biotin available for reutilization in the biotinylation of newly synthesized apocarboxylases. This latter reaction is catalyzed by holocarboxylase synthetase (HCS) via synthesis of 5'-biotinyl-AMP (B-AMP) from biotin and ATP, followed by transfer of the biotin to a specific lysine residue of the apocarboxylase substrate. In addition to carboxylase activation, B-AMP is also a key regulatory molecule in the transcription of genes encoding apocarboxylases and HCS itself. In humans, genetic deficiency of HCS or biotinidase results in the life-threatening disorder biotin-responsive multiple carboxylase deficiency, characterized by a reduction in the activities of all biotin-dependent carboxylases. Although the clinical manifestations of both disorders are similar, they differ in some unique neurological characteristics whose origin is not fully understood. In this study, we show that biotinidase deficiency not only reduces net carboxylase biotinylation, but it also impairs the expression of carboxylases and HCS by interfering with the B-AMP-dependent mechanism of transcription control. We propose that biotinidase-deficient patients may develop a secondary HCS deficiency disrupting the altruistic tissue-specific biotin allocation mechanism that protects brain metabolism during biotin starvation.