Plexin-A3 and plexin-A4 restrict the migration of sympathetic neurons but not their neural crest precursors

AbstractDuring development, the semaphorin family of guidance molecules is required for proper formation of the sympathetic nervous system. Plexins are receptors that mediate semaphorin signaling, but how plexins function during sympathetic development is not fully understood. Using phenotypic analyses of mutant mice in vivo, expression pattern studies, and in vitro assays, we show that plexin-A3 and plexin-A4 are essential for normal sympathetic development. This study confirms our previous in vitro findings that the two plexins differentially regulate the guidance of sympathetic axons. In addition, we find that semaphorin signaling through plexin-A3 and plexin-A4 restricts the migration of sympathetic neurons, but these two plexins function redundantly since migration defects are only observed in plexin-A3/-A4 double mutants. Surprisingly, our analysis also indicates that plexin-A3 and plexin-A4 are not required for guiding neural crest precursors prior to reaching the sympathetic anlagen. Immunoprecipitation studies suggest that these two plexins independently mediate secreted semaphorin signaling. Thus, plexin-A3 and plexin-A4 are expressed in newly-differentiated sympathetic neurons, but not their neural crest precursors. They function cooperatively to regulate the migration of sympathetic neurons and then differentially to guide the sympathetic axons

Numerical earthquake models of the 2013 Nantou, Taiwan, earthquake series: Characteristics of source rupture processes, strong ground motions and their tectonic implication

On 27 March and 2 June 2013, two large earthquakes with magnitudes of ML 6.2 and ML 6.5, named the Nantou earthquake series, struck central Taiwan. These two events were located at depths of 15–20 km, which implied that the mid-crust of central Taiwan is an active seismogenic area even though the subsurface structures have not been well established. To determine the origins of the Nantou earthquake series, we investigated both the rupture processes and seismic wave propagations by employing inverse and forward numerical simulation techniques. Source inversion results indicated that one event ruptured from middle to shallow crust in the northwest direction, while the other ruptured towards the southwest. Simulations of 3-D wave propagation showed that the rupture characteristics of the two events result in distinct directivity effects with different amplified shaking patterns. From the results of numerical earthquake modeling, we deduced that the occurrence of the Nantou earthquake series may be related to stress release from the easternmost edge of a preexistent strong basement in central Taiwan

Regulation of axon repulsion by MAX-1 SUMOylation and AP-3.

During neural development, growing axons express specific surface receptors in response to various environmental guidance cues. These axon guidance receptors are regulated through intracellular trafficking and degradation to enable navigating axons to reach their targets. In Caenorhabditis elegans, the UNC-5 receptor is necessary for dorsal migration of developing motor axons. We previously found that MAX-1 is required for UNC-5-mediated axon repulsion, but its mechanism of action remained unclear. Here, we demonstrate that UNC-5-mediated axon repulsion in C. elegans motor axons requires both max-1 SUMOylation and the AP-3 complex β subunit gene, apb-3 Genetic interaction studies show that max-1 is SUMOylated by gei-17/PIAS1 and acts upstream of apb-3 Biochemical analysis suggests that constitutive interaction of MAX-1 and UNC-5 receptor is weakened by MAX-1 SUMOylation and by the presence of APB-3, a competitive interactor with UNC-5. Overexpression of APB-3 reroutes the trafficking of UNC-5 receptor into the lysosome for protein degradation. In vivo fluorescence recovery after photobleaching experiments shows that MAX-1 SUMOylation and APB-3 are required for proper trafficking of UNC-5 receptor in the axon. Our results demonstrate that SUMOylation of MAX-1 plays an important role in regulating AP-3-mediated trafficking and degradation of UNC-5 receptors during axon guidance

A strong-motion hot spot of the 2016 Meinong, Taiwan, earthquake (M_w = 6.4)

Despite a moderate magnitude, M_w = 6.4, the 5 February 2016 Meinong, Taiwan, earthquake caused significant damage in Tainan City and the surrounding areas. Several seismograms display an impulsive S-wave velocity pulse with an amplitude of about 1 m s-1, which is similar to large S-wave pulses recorded for the past several larger damaging earthquakes, such as the 1995 Kobe, Japan, earthquake (M_w = 6.9) and the 1994 Northridge, California, earthquake (M_w = 6.7). The observed PGV in the Tainan area is about 10 times larger than the median PGV of M_w = 6.4 crustal earthquakes in Taiwan. We investigate the cause of the localized strong ground motions. The peak-to-peak ground-motion displacement at the basin sites near Tainan is about 35 times larger than that at a mountain site with a similar epicentral distance. At some frequency bands (0.9 - 1.1 Hz), the amplitude ratio is as large as 200. Using the focal mechanism of this earthquake, typical “soft” and “hard” crustal structures, and directivity inferred from the observed waveforms and the slip distribution, we show that the combined effect yields an amplitude ratio of 17 to 34. The larger amplitude ratios at higher frequency bands can be probably due to the effects of complex 3-D basin structures. The result indicates that even from a moderate event, if these effects simultaneously work together toward amplifying ground motions, the extremely large ground motions as observed in Tainan can occur. Such occurrences should be taken into consideration in hazard mitigation measures in the place with frequent moderate earthquakes

A strong-motion hot spot of the 2016 Meinong, Taiwan, earthquake (M_w = 6.4)

Despite a moderate magnitude, M_w = 6.4, the 5 February 2016 Meinong, Taiwan, earthquake caused significant damage in Tainan City and the surrounding areas. Several seismograms display an impulsive S-wave velocity pulse with an amplitude of about 1 m s-1, which is similar to large S-wave pulses recorded for the past several larger damaging earthquakes, such as the 1995 Kobe, Japan, earthquake (M_w = 6.9) and the 1994 Northridge, California, earthquake (M_w = 6.7). The observed PGV in the Tainan area is about 10 times larger than the median PGV of M_w = 6.4 crustal earthquakes in Taiwan. We investigate the cause of the localized strong ground motions. The peak-to-peak ground-motion displacement at the basin sites near Tainan is about 35 times larger than that at a mountain site with a similar epicentral distance. At some frequency bands (0.9 - 1.1 Hz), the amplitude ratio is as large as 200. Using the focal mechanism of this earthquake, typical “soft” and “hard” crustal structures, and directivity inferred from the observed waveforms and the slip distribution, we show that the combined effect yields an amplitude ratio of 17 to 34. The larger amplitude ratios at higher frequency bands can be probably due to the effects of complex 3-D basin structures. The result indicates that even from a moderate event, if these effects simultaneously work together toward amplifying ground motions, the extremely large ground motions as observed in Tainan can occur. Such occurrences should be taken into consideration in hazard mitigation measures in the place with frequent moderate earthquakes

A strong-motion hot spot of the 2016 Meinong, Taiwan, earthquake (Mw = 6.4)

Despite a moderate magnitude, Mw = 6.4, the 5 February 2016 Meinong, Taiwan, earthquake caused significant damage in Tainan City and the surrounding areas. Several seismograms display an impulsive S-wave velocity pulse with an amplitude of about 1 m s-1, which is similar to large S-wave pulses recorded for the past several larger damaging earthquakes, such as the 1995 Kobe, Japan, earthquake (Mw = 6.9) and the 1994 Northridge, California, earthquake (Mw = 6.7). The observed PGV in the Tainan area is about 10 times larger than the median PGV of Mw = 6.4 crustal earthquakes in Taiwan. We investigate the cause of the localized strong ground motions. The peak-to-peak ground-motion displacement at the basin sites near Tainan is about 35 times larger than that at a mountain site with a similar epicentral distance. At some frequency bands (0.9 - 1.1 Hz), the amplitude ratio is as large as 200. Using the focal mechanism of this earthquake, typical “soft” and “hard” crustal structures, and directivity inferred from the observed waveforms and the slip distribution, we show that the combined effect yields an amplitude ratio of 17 to 34. The larger amplitude ratios at higher frequency bands can be probably due to the effects of complex 3-D basin structures. The result indicates that even from a moderate event, if these effects simultaneously work together toward amplifying ground motions, the extremely large ground motions as observed in Tainan can occur. Such occurrences should be taken into consideration in hazard mitigation measures in the place with frequent moderate earthquakes

Second-Hand Smoke–Induced Cardiac Fibrosis Is Related to the Fas Death Receptor Apoptotic Pathway without Mitochondria-Dependent Pathway Involvement in Rats

Exposure to environmental tobacco smoke has been epidemiologically linked to heart disease among nonsmokers. However, the molecular mechanism behind the pathogenesis of cardiac disease is unknown. In this study, we found that Wistar rats, exposed to tobacco cigarette smoke at doses of 5, 10, or 15 cigarettes for 30 min twice a day for 1 month, had a dose-dependently reduced heart weight to body weight ratio and enhanced interstitial fibrosis as identified by histopathologic analysis. The mRNA and activity of matrix metalloprotease-2 (MMP-2), representing the progress of cardiac remodeling, were also elevated in the heart. In addition, we used reverse-transcriptase polymerase chain reaction and Western blotting to demonstrate significantly increased levels of the apoptotic effecter caspase-3 in treated animal hearts. Dose-dependently elevated mRNA and protein levels of Fas, and promoted apoptotic initiator caspase-8 (active form), a molecule of a death-receptor–dependent pathway, coupled with unaltered or decreased levels of cytosolic cytochrome c and the apoptotic initiator caspase-9 (active form), molecules of mitochondria-dependent pathways, may be indicative of cardiac apoptosis, which is Fas death-receptor apoptotic-signaling dependent, but not mitochondria pathway dependent in rats exposed to second-hand smoke (SHS). With regard to the regulation of survival pathway, using dot blotting, we found cardiac insulin-like growth factor-1 (IGF-1) and IGF-1 receptor mRNA levels to be significantly increased, indicating that compensative effects of IGF-1 survival signaling could occur. In conclusion, we found that the effects of SHS on cardiomyocyte are mediated by the Fas death-receptor–dependent apoptotic pathway and might be related to the epidemiologic incidence of cardiac disease of SHS-exposed non-smokers

Decreased Circulating Endothelial Progenitor Cell Levels and Function in Patients with Nonalcoholic Fatty Liver Disease

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is associated with advanced atherosclerosis and a higher risk of cardiovascular disease. Increasing evidence suggests that injured endothelial monolayer is regenerated by circulating bone marrow derived-endothelial progenitor cells (EPCs), and levels of circulating EPCs reflect vascular repair capacity. However, the relation between NAFLD and EPC remains unclear. Here, we tested the hypothesis that patients with nonalcoholic fatty liver disease (NAFLD) might have decreased endothelial progenitor cell (EPC) levels and attenuated EPC function. METHODS AND RESULTS: A total of 312 consecutive patients undergoing elective coronary angiography because of suspected coronary artery disease were screened and received examinations of abdominal ultrasonography between July 2009 and November 2010. Finally, 34 patients with an ultrasonographic diagnosis of NAFLD, and 68 age- and sex-matched controls without NAFLD were enrolled. Flow cytometry with quantification of EPC markers (defined as CD34(+), CD34(+)KDR(+), and CD34(+)KDR(+)CD133(+)) in peripheral blood samples was used to assess circulating EPC numbers. The adhesive function, and migration, and tube formation capacities of EPCs were also determined in NAFLD patients and controls. Patients with NAFLD had a significantly higher incidence of metabolic syndrome, previous myocardial infarction, hyperuricemia, and higher waist circumference, body mass index, fasting glucose and triglyceride levels. In addition, patients with NAFLD had significantly decreased circulating EPC levels (all P<0.05), attenuated EPC functions, and enhanced systemic inflammation compared to controls. Multivariate logistic regression analysis showed that circulating EPC level (CD34(+)KDR(+) [cells/10(5) events]) was an independent reverse predictor of NAFLD (Odds ratio: 0.78; 95% confidence interval: 0.69-0.89, P<0.001). CONCLUSIONS: NAFLD patients have decreased circulating EPC numbers and functions than those without NAFLD, which may be one of the mechanisms to explain atherosclerotic disease progression and enhanced cardiovascular risk in patients with NAFLD