A novel lysophosphatidic acid acyltransferase enzyme (LPAAT4) with a possible role for incorporating docosahexaenoic acid into brain glycerophospholipids

AbstractGlycerophospholipids are important components of cellular membranes, required for constructing structural barriers, and for providing precursors of bioactive lipid mediators. Lysophosphatidic acid acyltransferases (LPAATs) are enzymes known to function in the de novo glycerophospholipid biosynthetic pathway (Kennedy pathway), using lysophosphatidic acid (LPA) and acyl-CoA to form phosphatidic acid (PA). Until now, three LPAATs (LPAAT1, 2, and 3) have been reported from the 1-acyl-glycerol-3-phosphate O-acyltransferase (AGPAT) family. In this study, we identified a fourth LPAAT enzyme, LPAAT4, previously known as an uncharacterized enzyme AGPAT4 (LPAATδ), from the AGPAT family. Although LPAAT4 was known to contain AGPAT motifs essential for acyltransferase activities, detailed biochemical properties were unknown. Here, we found that mouse LPAAT4 (mLPAAT4) possesses LPAAT activity with high acyl-CoA specificity for polyunsaturated fatty acyl-CoA, especially docosahexaenoyl-CoA (22:6-CoA, DHA-CoA). mLPAAT4 was distributed in many tissues, with relatively high expression in the brain, rich in docosahexaenoic acid (DHA, 22:6). mLPAAT4 siRNA in a neuronal cell line, Neuro 2A, caused a decrease in LPAAT activity with 22:6-CoA, suggesting that mLPAAT4 functions endogenously. siRNA in Neuro 2A cells caused a decrease in 18:0–22:6 PC, whereas mLPAAT4 overexpression in Chinese hamster ovary (CHO)-K1 cells caused an increase in this species. Although DHA is considered to have many important functions for the brain, the mechanism of its incorporation into glycerophospholipids is unknown. LPAAT4 might have a significant role for maintaining DHA in neural membranes. Identification of LPAAT4 will possibly contribute to understanding the regulation and the biological roles of DHA-containing glycerophospholipids in the brain

Fluoxetine-induced dematuration of hippocampal neurons and adult cortical neurogenesis in the common marmoset

The selective serotonin reuptake inhibitor fluoxetine (FLX) is widely used to treat depression and anxiety disorders. Chronic FLX treatment reportedly induces cellular responses in the brain, including increased adult hippocampal and cortical neurogenesis and reversal of neuron maturation in the hippocampus, amygdala, and cortex. However, because most previous studies have used rodent models, it remains unclear whether these FLX-induced changes occur in the primate brain. To evaluate the effects of FLX in the primate brain, we used immunohistological methods to assess neurogenesis and the expression of neuronal maturity markers following chronic FLX treatment (3 mg/kg/day for 4 weeks) in adult marmosets (n = 3 per group). We found increased expression of doublecortin and calretinin, markers of immature neurons, in the hippocampal dentate gyrus of FLX-treated marmosets. Further, FLX treatment reduced parvalbumin expression and the number of neurons with perineuronal nets, which indicate mature fast-spiking interneurons, in the hippocampus, but not in the amygdala or cerebral cortex. We also found that FLX treatment increased the generation of cortical interneurons; however, significant up-regulation of adult hippocampal neurogenesis was not observed in FLX-treated marmosets. These results suggest that dematuration of hippocampal neurons and increased cortical neurogenesis may play roles in FLX-induced effects and/or side effects. Our results are consistent with those of previous studies showing hippocampal dematuration and increased cortical neurogenesis in FLX-treated rodents. In contrast, FLX did not affect hippocampal neurogenesis or dematuration of interneurons in the amygdala and cerebral cortex

Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis

It is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call “dematuration, ” in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer’s disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases

Light-Induced Degradation Mechanism in Poly(3-hexylthiophene)/Fullerene Blend Solar Cells

The mechanism of light-induced degradation in organic solar cells based on regioregular poly(3-hexylthiophene) and indene-C60 bisadduct is studied by transient absorption (TA) and electron spin resonance (ESR) measurements. After 45 h light exposure under simulated solar illumination at 100 mW cm-2, the short-circuit current density, open-circuit voltage, and fill factor are all degraded by about 20%-30% relative to the initial photovoltaic parameters. For the assignment of limiting conversion processes in the degraded solar cells, exciton diffusion into a donor/acceptor interface, charge transfer at the interface, charge dissociation into free charge carriers, and charge collection to each electrode are observed before and after the light exposure by the TA measurement. As a result, it is found that the charge collection deteriorates after the light exposure because of light-induced charge trap formation in the bulk of the active layer. The origin of charge traps is further discussed on the basis of ESR measurements and density functional theory calculation

Does municipal mergers internalize spatial spillover effects? Empirical evidence from Japanese municipalities

This paper investigates whether municipal mergers could internalize spatial spillover effects by comparing mergers before and after they occur, especially focusing on local public library services in Japan. A spatial spillover effect occurs when the benefit of a local public service spreads across not only its own administrative district but also into neighboring ones. A free rider problem among municipalities might be caused when a municipality makes a policy decision regarding how much it supplies to its own local public service under a decentralization system, recognizing the existence of a spatial spillover effect. Under such circumstances, spatial spillover effects might be internalized through municipal mergers. In Japan, the boundaries of administrative districts—including those of municipalities—have been determined based on traditional or historical reasons. However, large-scale municipal mergers took place in FY2004 and FY2005 due to serious fiscal deficits and a rapidly aging population. Consequently, the number of municipalities in Japan has decreased from 3,232 to 1,820. In light of these facts, we examine whether municipal mergers internalize spatial spillover effects, focusing on Japanese local public library services, by applying cross-sectional spatial autoregressive models. As a result, we found that there are spatial spillover effects in public library services both in FY2001 (before) and in FY2008 (after). We also found that the impact of such spillovers in FY2008 is smaller than that in FY2001. The results imply that municipal mergers could at least partially internalize spatial spillover effects among municipalities

Does municipal mergers internalize spatial spillover effects? Empirical evidence from Japanese municipalities

This paper investigates whether municipal mergers could internalize spatial spillover effects by comparing mergers before and after they occur, especially focusing on local public library services in Japan. A spatial spillover effect occurs when the benefit of a local public service spreads across not only its own administrative district but also into neighboring ones. A free rider problem among municipalities might be caused when a municipality makes a policy decision regarding how much it supplies to its own local public service under a decentralization system, recognizing the existence of a spatial spillover effect. Under such circumstances, spatial spillover effects might be internalized through municipal mergers. In Japan, the boundaries of administrative districts—including those of municipalities—have been determined based on traditional or historical reasons. However, large-scale municipal mergers took place in FY2004 and FY2005 due to serious fiscal deficits and a rapidly aging population. Consequently, the number of municipalities in Japan has decreased from 3,232 to 1,820. In light of these facts, we examine whether municipal mergers internalize spatial spillover effects, focusing on Japanese local public library services, by applying cross-sectional spatial autoregressive models. As a result, we found that there are spatial spillover effects in public library services both in FY2001 (before) and in FY2008 (after). We also found that the impact of such spillovers in FY2008 is smaller than that in FY2001. The results imply that municipal mergers could at least partially internalize spatial spillover effects among municipalities

Tracheal intubation by paramedics under limited indication criteria may improve the short-term outcome of out-of-hospital cardiac arrests with noncardiac origin.

PURPOSE: It is not clear whether advanced airway management (AAM) with an endotracheal tube (ET) by paramedics may improve the outcome of out-of-hospital cardiac arrest (OHCA) compared with the use of a bag-valve-mask device (BVMD) and other AAM devices. METHODS: We analyzed 2,586 adult cases of OHCA without administration of adrenaline, witnessed or recognized by citizens in subjects transported to hospital by paramedics between 1 July 2004 and 31 March 2008 in Ishikawa, Japan, to determine whether AAM with an ET used under limited indication criteria may improve the outcome of OHCA. RESULTS: The airway was managed with an ET in 263 cases, other AAM devices in 660 cases, and a BVMD in 1,539 cases. The AAM failed or was discontinued in 124 cases, which were excluded from the analysis. The incidence of sustained return of spontaneous circulation (ROSC) was significantly higher in cases of AAM with an ET (30%) than in AAM with other devices (20.2%) and in the standard procedure with a BVMD (21.3%). The AAM with an ET did not significantly affect 1-year survival. Multiple regression analysis indicated that tracheal intubation (odds ratio = 1.503, 95% confidence interval 1.081-2078), but not patient management by paramedics qualified for ET use, was an independent factor associated with sustained ROSC. CONCLUSION: When subjects with difficult airway are excluded, tracheal intubation according to the limited indication criteria and well-organized protocol in Japan may improve the short-term outcome of OHCA of noncardiac origin. A large prospective study is needed to determine the general effects of tracheal intubation on the long-term outcome of OHCA with disturbed ventilation

TRH RELEASE MEASURED BY MICRODIALYSIS

To measure the thyrotropin-releasing hormone (TRH) release from the hypothalamus in euthyroid and hyperthyroid states, we investigated the changes in TRH levels in the anterior pituitary of conscious male rats using an in vivo microdialysis technique. In the euthyroid rats (n = 18), TRH levels in the extracellular dialysates of the anterior pituitary varied from 1.0 to 101.0 pg/ml in a pulsatile fashion: 15.9 +/- 13.9 (mean +/- SD) pg/ml with 5.8 +/- 1.5 pulses/24 h. In the hyperthyroid rats (n = 5) who received L-thyroxine at 10 micrograms/100 g body weight for 7 days, TRH levels in the dialysates during 6 h was 3.6 +/- 1.7 pg/ml, and significantly lower (P < 0.05) than those of the control rats (15.5 +/- 14.1 pg/ml); the pulse frequency was unchanged. These findings demonstrated for the first time the existence of pulsatile TRH release from the hypothalamus, and showed that thyroid hormone inhibits TRH release by the reduction of pulse amplitude, but not of pulse frequency