Glial Cell Line-Derived Neurotrophic Factor (GDNF) as a Novel Candidate Gene of Anxiety.

Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and drug abuse have also been published but little is known about any effects of these polymorphisms on mood characteristics such as anxiety and depression. Here we present an association study between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms (SNPs) and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results of the allele-wise single marker association analyses provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p = 0.00070 and p = 0.00138 for rs3812047 and rs3096140, respectively), while no such result was obtained on depression scores. Haplotype analysis confirmed the role of these SNPs; mean anxiety scores raised according to the number of risk alleles present in the haplotypes (p = 0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. In conclusion, this is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample

Pre-α-pro-GDNF and Pre-β-pro-GDNF Isoforms Are Neuroprotective in the 6-hydroxydopamine Rat Model of Parkinson's Disease

Glial cell line-derived neurotrophic factor (GDNF) is one of the most studied neurotrophic factors. GDNF has two splice isoforms, full-length pre-alpha-pro-GDNF (u-GDNF) and pre-beta-pro-GDNF (beta-GDNF), which has a 26 amino acid deletion in the pro-region. Thus far, studies have focused solely on the u-GDNF isoform, and nothing is known about the in vivo effects of the shorter beta-GDNF variant. Here we compare for the first time the effects of overexpressed cx-GDNF and beta-GDNF in non-lesioned rat striatum and the partial 6-hydroxydopamine lesion model of Parkinson's disease. GDNF isoforms were overexpressed with their native pre-pro-sequences in the striatum using an adeno-associated virus (AAV) vector, and the effects on motor performance and dopaminergic phenotype of the nigrostriatal pathway were assessed. In the non-lesioned striatum, both isoforms increased the density of dopamine transporter-positive fibers at 3 weeks after viral vector delivery. Although both isoforms increased the activity of the animals in cylinder assay, only u-GDNF enhanced the use of contralateral paw. Four weeks later, the striatal tyrosine hydroxylase (TH)-immunoreactivity was decreased in both u-GDNF and 1-GDNF treated animals. In the neuroprotection assay, both GDNF splice isoforms increased the number of TH-immunoreactive cells in the substantia nigra but did not promote behavioral recovery based on amphetamine-induced rotation or cylinder assays. Thus, the shorter GDNF isoform, beta-GDNF, and the full-length alpha-isoform have comparable neuroprotective efficacy on dopamine neurons of the nigrostriatal circuitry.Peer reviewe

Gene therapy with AAV2-CDNF provides functional benefits in a rat model of Parkinson's disease

Cerebral dopamine neurotrophic factor (CDNF) protein has been shown to protect the nigrostriatal dopaminergic pathway when given as intrastriatal infusions in rat and mouse models of Parkinson's disease (PD). In this study, we assessed the neuroprotective effect of CDNF delivered with a recombinant adeno-associated viral (AAV) serotype 2 vector in a rat 6-hydroxydopamine (6-OHDA) model of PD. AAV2 vectors encoding CDNF, glial cell line-derived neurotrophic factor (GDNF), or green fluorescent protein were injected into the rat striatum. Protein expression analysis showed that our AAV2 vector efficiently delivered the neurotrophic factor genes into the brain and gave rise to a long-lasting expression of the proteins. Two weeks after AAV2 vector injection, 6-OHDA was injected into the rat striatum, creating a progressive degeneration of the nigrostriatal dopaminergic system. Treatment with AAV2-CDNF resulted in a marked decrease in amphetamine-induced ipsilateral rotations while it provided only partial protection of tyrosine hydroxylase (TH)-immunoreactive cells in the rat substantia nigra pars compacta and TH-reactive fibers in the striatum. Results from this study provide additional evidence that CDNF can be considered a potential treatment of Parkinson's disease.Peer reviewe

Compressive stress-mediated p38 activation required for ER alpha plus phenotype in breast cancer

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ER alpha + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ER alpha-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ER alpha + breast cancer models. The ER alpha + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ER alpha is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ER alpha signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ER alpha phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK. Reliable luminal estrogen receptor (ER alpha+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ER alpha expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.Peer reviewe

Compressive stress-mediated p38 activation required for ERα + phenotype in breast cancer

Breast cancer is now globally the most frequent cancer and leading cause of women's death. Two thirds of breast cancers express the luminal estrogen receptor-positive (ER alpha + ) phenotype that is initially responsive to antihormonal therapies, but drug resistance emerges. A major barrier to the understanding of the ER alpha-pathway biology and therapeutic discoveries is the restricted repertoire of luminal ER alpha + breast cancer models. The ER alpha + phenotype is not stable in cultured cells for reasons not fully understood. We examine 400 patient-derived breast epithelial and breast cancer explant cultures (PDECs) grown in various three-dimensional matrix scaffolds, finding that ER alpha is primarily regulated by the matrix stiffness. Matrix stiffness upregulates the ER alpha signaling via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation. The finding that the matrix stiffness is a central cue to the ER alpha phenotype reveals a mechanobiological component in breast tissue hormonal signaling and enables the development of novel therapeutic interventions. Subject terms: ER-positive (ER + ), breast cancer, ex vivo model, preclinical model, PDEC, stiffness, p38 SAPK.Reliable luminal estrogen receptor (ER alpha+) breast cancer models are limited. Here, the authors use patient derived breast epithelial and breast cancer explant cultures grown in several extracellular matrix scaffolds and show that ER alpha expression is regulated by matrix stiffness via stress-mediated p38 activation and H3K27me3-mediated epigenetic regulation.</p

Computational studies of gold-absorbate complexes on modified oxides

While bulk gold is known for its chemical inertness, nanosized gold clusters are active catalysts for a variety of important reactions. For some practical applications gold clusters are supported and the cluster-support interaction can modify the cluster's properties. The knowledge of this interaction can be vital for obtaining desired cluster properties. In this thesis, the adsorption of Au atoms and clusters on modified oxide surfaces is studied using density functional theory (DFT) calculations. The support effects are considered by direct analysis of the adsorbed Au and using other coadsorbates as reactivity probes. Doping the CaO(001) surface by replacing a cation with a high valence dopant such as Mo makes adsorption of electronegative species such as Au, O and O2 more exothermic. The stronger binding is accompanied with a charge transfer from the dopant to the adsorbate. An Au adatom is anionic on a doped oxide as seen from its Bader charge and zero magnetic moment. The charging of the dopant is seen from a PDOS analysis where some of the d-electrons of the dopant are transferred to the Au s-states. Further, the change of the dopant's charge can also be seen by the contraction of the nearest neighbour distances between the dopant and surrounding O anions shows the change in the dopant charge. The superoxo state of O2 on Mo doped CaO(001) is illustrated by its elongated bond length in addition to the Bader charge and magnetic moment of the molecule. A modified Born-Haber (BH) cycle was devised to estimate the effect of different physical processes on the adsorption energy on the doped oxide. The adsorption energy was split into three parts with an iono-covalent energy describing the local interactions, a redox energy accounting for the charge transfer, and a Coulomb energy for the electrostatics between a charged adsorbate and dopant. While the Coulomb energy decays with increasing adsorbate-dopant distance, the redox energy remains more exothermic due to a much shorter distance between the negative anions and the positive dopant. A similar BH cycle for Ag(001) supported MgO thin films showed that while the electrostatic stabilization from the adsorbate-support interaction decays quickly with increasing lm thickness, a compensation occurs in the redox energy becoming more exothermic, leading to more exothermic adsorption also for thicker films. Water is stabilized by electrostatic interaction with anionic Au on MgO/Ag(001); however, no stabilization occurs on bulk MgO when the Au adatom is neutral. The adsorption of water dissociation products H and OH on top of an Au adatom is more exothermic with increasing lm thickness. Isophorone physisorbs on the MgO/Ag(001) surface with energetic preference towards the MgO steps, which is due to stabilizing electrostatic interaction between the step cations and a polar O=C bond in the molecule. The enol tautomers can bind to anionic Au atoms on the surface via a similar interaction with the polar H-O bond. The keto form is not stabilized by Au due to a steric hindrance caused by C atoms near the positive end of the polar O=C bond

Water dissociation and water-gas shift energetics on MgO, MgO/Ag and Au/MgO/Ag surfaces

Water dissociation and the energetics of the WGS reaction on a bulk MgO, an Ag supported MgO thin film and Au/MgO/Ag surfaces is studied based on the density functional theory. The literature results for water splitting on MgO and MgO/Ag surfaces with a step type defect are repeated and further analysis on the origin of the energetically favored dissociative water adsorption are made. The reactivity towards water dissociation on the stepped MgO and MgO/Ag surfaces is attributed to four contributing factors: 1. The change in the interlayer distance of the surface in dissociative adsorption is diminished on the stepped surfaces compared to the flat surfaces. On the flat surfaces the dissociative adsorption of water leads to an increased interlayer distance between the first and second MgO layer while the molecular adsorption does not change the distance. 2. A surface OH group is formed in the H adsorption. On the stepped surface the adsorbed OH and surface OH form aligned dipoles. On the flat surface the adsorbed OH and the surface OH group do not align. 3. The density difference analysis shows that the charge transfer in the co-adsorption of H and OH on the stepped MgO/Ag surface is mainly between the adsorbed H and OH. This leads to an at- tractive Coulomb interaction between the adsorbed species. 4. The p-band center of the edge O atoms show a strong shift towards the Fermi energy compared to the average surface O atoms. On the bulk MgO surfaces the p-band center of the O atom at the H adsorption site is shown to correlate with the H adsorption energy. Similar trend is seen in the MgO/Ag surfaces. The energetics of a WGS reaction on a surface with large Au clusters deposited on an Ag supported MgO thin film is studied. The large Au cluster is modeled with an Au stripe set with the periodic boundary conditions to produce similar distances between the Au atoms as for a large Au cluster. The Bader charges of the edge atoms of the Au stripe are similar to the charges for the edge atoms of a large Au cluster. Water dissociation at the edge of the Au stripe is not deemed probable due to the weak binding of OH to the Au/MgO/Ag surface

Stability limits of elemental 2D metals in graphene pores

Two-dimensional (2D) materials can be used as stabilizing templates for exotic nanostructures, including pore-stabilized, free-standing patches of elemental metal monolayers. Although these patches represent metal clusters under extreme conditions and are thus bound for investigations, they are poorly understood as their energetic stability trends and the most promising elements remain unknown. Here, using density-functional theory simulations and the liquid drop model to explore the properties of 45 elemental metal candidates, we identify metals that enable the largest and most stable patches. Simulations show that pores can stabilize patches up to ∼8 nm2 areas and that the most prominent candidate in a graphene template is Cu. The results, which are generalizable to templates also beyond graphene, provide encouragement for further, even more resolute experimental pursuit of 2D metals.peerReviewe

Free-standing 2D metals from binary metal alloys

Recent experiments have demonstrated the formation of free-standing Au monolayers by exposing the Au–Ag alloy to electron beam irradiation. Inspired by this discovery, we used semi-empirical effective medium theory simulations to investigate monolayer formation in 30 different binary metal alloys composed of late d-series metals such as Ni, Cu, Pd, Ag, Pt, and Au. In qualitative agreement with the experiment, we find that the beam energy required to dealloy Ag atoms from the Au–Ag alloy is smaller than the energy required to break the dealloyed Au monolayer. Our simulations suggest that a similar method could also be used to form Au monolayers from the Au–Cu alloy and Pt monolayers from Pt–Cu, Pt–Ni, and Pt–Pd alloys.peerReviewe