Transient receptor potential melastatin 2 governs stress-induced depressive-like behaviors.

Major depressive disorder (MDD) is a devastating disease that arises in a background of environmental risk factors, such as chronic stress, that produce reactive oxygen species (ROS) in the brain. The chronic stress-induced ROS production involves Ca2+ signals; however, the mechanism is poorly understood. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+-permeable cation channel that is highly expressed in the brain. Here we show that in animal models of chronic unpredictable stress (CUS), deletion of TRPM2 (Trpm2-/- ) produces antidepressant-like behaviors in mice. This phenotype correlates with reduced ROS, ROS-induced calpain activation, and enhanced phosphorylation of two Cdk5 targets including synapsin 1 and histone deacetylase 5 that are linked to synaptic function and gene expression, respectively. Moreover, TRPM2 mRNA expression is increased in hippocampal tissue samples from patients with MDD. Our findings suggest that TRPM2 is a key agent in stress-induced depression and a possible target for treating depression.

Comparative analysis of codon usage patterns in Rift Valley fever virus.

Rift Valley fever virus (RVFV) is a vector-borne pathogen and is the most widely known virus in the genus Phlebovirus. Since it was first reported, RVFV has spread to western Africa, Egypt and Madagascar from its traditional endemic region, and infections continue to occur in new areas. In this study, we analyzed genomic patterns according to the infection properties of RVFV. Among the four segments of RVFV, the nucleotide composition, overall GC content and the difference of GC composition in the third position of the codons (%GC3) between groups were the largest in the S (NP) segment, showing that more diverse codons were used than in other segments. Furthermore, the results of CAI analysis of the S (NP) segment showed that viruses isolated from regions where no previous infections had been reported had the highest values, indicating greater adaptability to human hosts compared with other viruses. This result suggests that mutations in the S (NP) segment co-evolve with the infected hosts and may lead to expansion of the geographic range. The distinctive codon usage patterns observed in specific genomic regions of a group with similar infection properties may be related to the increasing likelihood of RVFV infections in new areas.

Codon usage patterns of LT-Ag genes in polyomaviruses from different host species.

BACKGROUND: Polyomaviruses (PyVs) have a wide range of hosts, from humans to fish, and their effects on hosts vary. The differences in the infection characteristics of PyV with respect to the host are assumed to be influenced by the biochemical function of the LT-Ag protein, which is related to the cytopathic effect and tumorigenesis mechanism via interaction with the host protein. METHODS: We carried out a comparative analysis of codon usage patterns of large T-antigens (LT-Ags) of PyVs isolated from various host species and their functional domains and sequence motifs. Parity rule 2 (PR2) and neutrality analysis were applied to evaluate the effects of mutation and selection pressure on codon usage bias. To investigate evolutionary relationships among PyVs, we carried out a phylogenetic analysis, and a correspondence analysis of relative synonymous codon usage (RSCU) values was performed. RESULTS: Nucleotide composition analysis using LT-Ag gene sequences showed that the GC and GC3 values of avian PyVs were higher than those of mammalian PyVs. The effective number of codon (ENC) analysis showed host-specific ENC distribution characteristics in both the LT-Ag gene and the coding sequences of its domain regions. In the avian and fish PyVs, the codon diversity was significant, whereas the mammalian PyVs tended to exhibit conservative and host-specific evolution of codon usage bias. The results of our PR2 and neutrality analysis revealed mutation bias or highly variable GC contents by showing a narrow GC12 distribution and wide GC3 distribution in all sequences. Furthermore, the calculated RSCU values revealed differences in the codon usage preference of the LT-AG gene according to the host group. A similar tendency was observed in the two functional domains used in the analysis. CONCLUSIONS: Our study showed that specific domains or sequence motifs of various PyV LT-Ags have evolved so that each virus protein interacts with host cell targets. They have also adapted to thrive in specific host species and cell types. Functional domains of LT-Ag, which are known to interact with host proteins involved in cell proliferation and gene expression regulation, may provide important information, as they are significantly related to the host specificity of PyVs.

Analysis of the codon usage pattern of the RdRP gene of mycovirus infecting Aspergillus spp.

BACKGROUND: Mycoviruses that infect fungi generally do not have a significant effect on the host and, instead, reduce the toxicity of the fungi. However, recent studies have shown that polymycovirus-1, a mycovirus that infects Aspergillus species known to cause disease in humans, is related to increased virulence of the fungus. METHODS: Comparative analysis was performed of RdRP gene codon usage patterns of Aspergillus fumigatus polymycovirus-1 (AfuPmV-1) and other mycoviruses known to infect Aspergillus spp. to examine the genetic characteristics of AfuPmV-1. In addition, codon usage analysis was performed to determine whether the nucleotide composition and codon usage characteristics of AfuPmV-1 were also present in other polymycoviruses and hypervirulence-related mycoviruses. Phylogenetic analysis was also performed to investigate their evolutionary relationship. RESULTS: Analysis of nucleotide composition indicated that AfuPmV-1 had the highest GC content among analyzed mycoviruses and relative synonymous codon usage analysis indicated that all of the codons preferred by AfuPmV-1 ended with C or G, while codons ending with A or U were not observed. Moreover, the effective number of codons, the codon adaptation index, and correspondence analysis showed that AfuPmV-1 had greater codon preference compared with other mycoviruses and that AfuPmV-1 had relatively high adaptability to humans and fungi. These results were generally similar among polymycoviruses. CONCLUSIONS: The codon usage pattern of AfuPmV-1 differs from other mycoviruses that infect Aspergillus spp. This difference may be related to the hypervirulence effect of AfuPmV-1. Analysis of AfuPmV-1 codon usage patterns could contribute to the identification and prediction of virulence effects of mycoviruses with similar genetic characteristics.

Microstructure and Texture of P-Type Bi-Sb-Te Alloy by Using Gas-Atomization and Extrusion Processes.

Microstructure and texture of P-type 75%Sb2Te3-25%Bi2Te3 alloy fabricated by using gas-atomization and extrusion processes was investigated. The microstructure of the gas-atomized powders exhibited fine grains with needle shape. After hot extrusion, grain size was characterized by fine and equiaxed grains due to dynamic recrystallization by severe deformation. (0001) basal planes of the extruded specimens were preferentially orientated parallel to extrusion direction. As extrusion temperature, fraction of the basal planes was increased.

Microstructure and Mechanical Properties of Al-Si-Fe-Cu-Mn-x Zn Alloys Processed by Extrusion.

In this work, Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys with different Zn addition (0, 0.15 and 0.3 wt%) were melted and extruded at 200 °C. The effect of Zn on the microstructure, texture evolution and mechanical properties of Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys was investigated using scanning electron microscope (SEM), equipped with energy-dispersive X-ray spectrometry (EDS) and electron backscatter diffraction (EBSD) and in the present study. In order to evaluate the mechanical properties, we implemented the tensile tests by a universal material test machine. Al-0.15Si-0.2Fe- 0.3Cu-0.9Mn-xZ resulted in the formation of Al-(Fe, Mn)-Si and Al-(Fe, Mn) intermetallic compounds. The formation of the intermetallic compound and this phase was broken in to small particles during extrusion. The ultimate strength and elongation of the as-extruded Al-0.15Si-0.2Fe-0.3Cu- 0.9Mn alloy were 96.51 MPa and 34.01%, while those of the Al-0.15Si-0.2Fe-0.3Cu-0.9Mn-0.3Zn alloy were 99.08 MPa and 36.21%, respectively. Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys with Zn addition resulted in improving the strength with no reduction in elongation.

Study on Microstructure of Nb-Ti Based Alloy by Groove Rolling Process.

Niobium-titanium alloy is attractive materials for industrials as a superconducting magnets to high critical magnetic field and supercurrent density at -283 °C. The Nb-Ti alloy has been shown in earlier work to exhibit Van Gosh Sky microstructures. They may also be accentuated by plastic deformation due to work and temperature exposure during deformation. In order to miniaturize the magnet generating the same magnetic field, it is necessary to increase the critical current density of the superconducting wire. When fabricating superconducting wires, it is important to increase critical current density by optimizing processing and annealing conditions. When the α-phase of the Ti rich phase is uniformly precipitated by the heat treatment, the non-superconducting α-phase is dispersed in the superconducting Nb-Ti matrix. It becomes a pinning point that serves to fix the magnetic flux, which improves the critical current density. Also, if the shape of the precipitate is changed by machining, the superconducting and non-superconducting characteristics are further improved. In the present study, we studied the fraction of α-Ti phase of strain amount through groove rolling and heat treatment. The specimens were processed by groove rolling at room temperature and strain of 2.0, 3.16, 4.28 and 5.57. A microstructural analysis of the Nb-Ti alloys was performed by field emission scanning electron microscopy (FESEM).

High Temperature Deformation Characteristics of Al-Zn-Mg Alloy Modified with CaO-Added Mg.

Hot torsion tests were performed on an Al-Zn-Mg alloy modified with CaO-added Mg to investigate the effects of the Mg additive on the high temperature deformation characteristics. Effective stress- strain curves and processing maps were established from the experimental results under a range of deformation conditions. The fracture strain of the CaO-added Al-Zn-Mg alloy was higher than that of the Al-Zn-Mg alloy. The CaO-added Al-Zn-Mg alloy did not show an instability region in the processing map but the commercial Al-Zn-Mg alloy exhibited adiabatic shear bands at low temperatures and at a high strain rate. The results shown in this study were attributed to the reduction of the second phase by the addition of CaO-added Mg.

Evaluation of the Hot Workability of Commercially Pure Ti Using Hot Torsion Tests.

Optimum processing conditions were obtained by evaluating the hot working behavior of commercially pure Ti using hot torsion tests. Hot torsion tests were conducted at temperatures ranging from 800 °C-1000 °C and strain rates ranging from 0.1-10 s-1. The flow curves show that the peak stress increases as the temperature decreases and the strain rate increases. The optimum processing conditions were derived by comparing the processing and activation energy maps. The microstructure was characterized based on various regions of the processing map. The activation energy for plastic deformation was obtained using the constitutive equation. The activation energy differs depending on the constituent phases.

Effects of Heat-Treatment Conditions on Densification, Microstructure, and Magnetic Properties of Fe Powder.

In this study, the effects of heat-treatment conditions on the densification, microstructure, and magnetic properties of Fe powder were investigated. The oxygen content of the Fe powders heat-treated in Ar and Ar-H2 atmosphere was much lower than that of the Fe powder heat-treated in air atmosphere. The density of the compacts of the Fe powder heat-treated in Ar and Ar + H2 atmosphere was higher than that of the compacts of Fe powders heat-treated in air. Oxygen content in the heat-treatment conditions played a significant role in the improvement of the densification and magnetic properties.

The Effects of Dy Addition on Microstructure and Mechanical Properties of the As-Cast Mg-5Al-3Ca-2Nd Alloys.

The microstructure of the as-cast Mg-5Al-3Ca-2Nd-xDy alloys consists of α-Mg matrix, (Mg, Al)2Ca eutectic phase, Al-Nd and Al-Dy intermetallic compounds. α-Mg matrix morphology was changed from dendritic to equiaxed with the increase Dy addition. And grain size was remarkably refined. As Dy content was increased, yield strength was improved due to the refined grains and the homogeneous distribution of Al-Dy phase.

Microstructure and Mechanical Properties of Mg-11Li-6Zn-0.6Zr-0.4Ag-0.2Ca-x Y Alloys.

Magnesium and its alloys are potential candidates for many automotive and aerospace applications due to their low density and high specific strength. However, the use of magnesium as wrought products is limited because of its poor workability at ambient temperatures. Mg-Li alloys containing 5-11 wt.% Li exhibit a two-phase structure consisting of a α (hcp) Mg-rich phase and a ß (bcc) Li-rich phase. Mg-Li alloys with Li content greater than 11 wt.% exhibit a single-phase structure consisting of only the ß phase. In the present study, we studied the effects of Y addition on the microstructure and mechanical properties of Mg-11Li-6Zn-0.6Zr-0.4Ag-0.2Ca based alloys. The melt was maintained at 720 °C for 20 min and poured into a mold. Then, the as-cast Mg alloys were homogenized at 350 °C for 4 h and were hot-extruded onto a 4-mm-thick plate with a reduction ratio of 14:1. The as-cast Mg-11Li-6Zn-0.6Zr-0.4Ag-0.2Ca-xY (x 0, 1, 3, and 5 wt.%) alloys were composed of α-Mg, ß-Li, γ-Mg2Zn3Li, I-Mg3YZn6, W-Mg3Y2Zn3, and X-Mg12YZn phases. By increasing the Y content from 0 to 5 wt.%, the composition of the W-Mg3Y2Zn3 phase increased. With increasing Y content, from 0 to 1, 3, and 5 wt.%, the average grain size and ultimate tensile of the as-extruded Mg alloys decreased slightly, from 8.4, to 3.62, 3.56, and 3.44 µm and from 228.92 to 215.57, 187.47, and 161.04 MPa, respectively, at room temperature.

Characteristics of Nano Grained AA1050/AA5052 Al Sheets Fabricated by Accumulative Roll-Bonding.

Accumulative roll-bonding (ARB) is the most appropriate process for sheet-shaped materials because it can be carried out readily by utilizing the conventional rolling apparatus. In this study, a nanostructured AA1050/AA5052 Al alloy sheet was successfully fabricated by four-layer stack ARB process. The ARB of AA1050 and AA5052 alloy sheets was performed up to 6 cycles without a lubricant at ambient temperature. The sample fabricated by the ARB was a multi-layer aluminum alloy sheet in which AA1050 and AA5052 layers are alternately stacked. The layer thickness of the each alloy became thinner and elongated to the rolling direction with the number of ARB cycles. The grain size decreased with increasing of the number of ARB cycles, after 6 cycles it became about 180 nm in thickness. The fraction of high angle grain boundaries increased with the number of ARB cycles. The tensile strength also increased with the ARB, it reached 305 MPa which is about 2.1 times that of the as-received AA1050. The mechanical properties of a multi-layer AA1050/AA5052 alloy fabricated by the ARB were compared to those of the other materials.

Study on Microstructure and Mechanical Properties of Al-Li Based Alloys Processed by Extrusion.

Aluminum and its alloys, due to their low density, high specific strength and high corrosion resistance amongst various structural materials, are used in a wide range of industrial applications for different aqueous solutions. In the present study, we studied effects of Ce addition on microstructure and mechanical properties of Al-2Li-1Cu-0.8Mg-0.1Zr alloys. The melt was held at 780 °C for 20 min and poured into a mold. And as-cast Al alloys were hot-extruded into a plate that was 4 mm in thickness with a reduction ratio of 14:1. The extruded plates were held at 540 °C for 4 hr in water quenching to solution treatment them. As-extruded Al-2Li-1Cu-0.8Mg-0.1Zr-xCe (x = 0.3, 0.6, 0.9 and 1.2 wt.%) alloys are composed of Al, AlLi, AlCuLi and Al11Ce3 phases. By increasing the Ce content from 0 to 1.2 wt.%, the Al11Ce3 phase is increased, after solution treatment the AlLi and AlCuLi phases are decreased. With increasing Ce addition from 0 to 1.2 wt.%, the average grain size of the as-extruded Al alloys were decreased slightly from 100.7, 113.74, 84.3, 74.7 and 61.7 µm and ultimate tensile strength was decreased slightly from 267.59, 264.92, 237.40, 220.93 and 207.83 MPa at room temperature. After solution treatment, ultimate tensile strength was measured with 205.13, 198.12, 195.50, 198.27 and 208.01 MPa at room temperature.

Effect of Mn and AlTiB Addition and Heattreatment on the Microstructures and Mechanical Properties of Al-Si-Fe-Cu-Zr Alloy.

The microstructure and mechanical properties of as-extruded Al-0.1 wt%Si-0.2 wt%Fe- 0.4 wt%Cu-0.04 wt%Zr-xMn-xAlTiB (x = 1.0 wt%) alloys under various annealing processes were investigated and compared. After the as-cast billets were kept at 400 °C for 1 hr, hot extrusion was carried out with a reduction ratio of 38:1. In the case of the as-extruded Al-Si-Fe-Cu-Zr alloy at annealed at 620 °C, large equiaxed grain was observed. When the Mn content is 1.0 wt%, the phase exhibits a skeleton morphology, the phase formation in which Mn participated. Also, the volume fraction of the intermetallic compounds increased with Mn and AlTiB addition. For the Al-0.1Si-0.2Fe-0.4Cu-0.04Zr alloy with Mn and AlTiB addition from 1.0 wt%, the ultimate tensile strength increased from 100.47 to 119.41 to 110.49 MPa. The tensile strength of the as-extruded alloys improved with the addition of Mn and AlTiB due to the formation of Mn and AlTiB-containing intermetallic compounds.

Grain Refinement of Al-Si-Fe-Cu-Zn-Mn Based Alloy by Al-Ti-B Alloy and Its Effect on Mechanical Properties.

We investigated the effects of Al-5.0wt%Ti-1.0wt%B addition on the microstructure and mechanical properties of the as-extruded Al-0.15wt%Si-0.2wt%Fe-0.3wt%Cu-0.15wt%Zn-0.9wt%Mn based alloys. The Aluminum alloy melt was held at 800 °C and then poured into a mould at 200 °C. Aluminum alloys were hot-extruded into a rod that was 12 mm in thickness with a reduction ratio of 38:1. AlTiB addition to Al-0.15Si-0.2Fe-0.3Cu-0.15Zn-0.9Mn based alloys resulted in the formation of Al3Ti and TiB2 intermetallic compounds and grain refinement. With increasing of addition AlTiB, ultimate tensile strength increased from 93.38 to 99.02 to 100.01 MPa. The tensile strength of the as-extruded alloys was improved due to the formation of intermetallic compounds and grain refinement.

Hot Deformation Behavior of Hot-Extruded AA7175 Through Hot Torsion Tests.

The hot deformation behavior of hot-extruded AA7175 was investigated with flow curves and processing maps through hot torsion tests. The flow curves and the deformed microstructures revealed that dynamic recrystallization (DRX) occurred in the hot-extruded AA7175 during hot working. The failure strain was highest at medium temperature. This was mainly influenced by the dynamic precipitation of fine rod-shaped MgZn2. The processing map determined the optimal deformation condition for the alloy during hot working.

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats.

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.

The antidepressant action of 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid is mediated by phosphorylation of histone deacetylase 5.

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP.

Hippocampal VEGF is necessary for antidepressant-like behaviors but not sufficient for antidepressant-like effects of ketamine in rats.

We investigated the effects of ketamine on both the temporal and spatial profiles of neural precursor cells located in the hippocampus, and on antidepressant-like behaviors in rats. A single dose of ketamine resulted in a significant increase in the number of 5-bromo-2-deoxyuridine-positive (BrdU(+)) cells in the dentate gyrus (DG) of rats at 24h, but not at 28days, after treatment completion. Ketamine caused antidepressant-like behaviors in the forced swim test (FST) and novelty suppressed feeding test (NSFT). Viral-mediated hippocampal knockdown of vascular endothelial growth factor (VEGF) produced depressive-like behaviors in the FST and NSFT, which were partially recovered by ketamine to the level observed in the control group. The behavioral effects of VEGF knock down were accompanied by a decrease in hippocampal neurogenesis, which was also partially recovered by ketamine. Our results suggest that basal hippocampal VEGF expression is necessary for ketamine-induced antidepressant-like behaviors in rats, but ketamine-induced VEGF expression only partially contributes to hippocampal neurogenesis and the antidepressant-like effects of ketamine.