Olfactory Dysfunction and Neurotransmitter Disturbance in Olfactory Bulb of Transgenic Mice Expressing Human A53T Mutant α-Synuclein

Parkinson disease is a multi-system neurodegenerative disease characterized by both motor and non-motor symptoms. Hyposmia is one of the early non-motor symptoms occurring in more than 90% of Parkinson disease cases, which can precede motor symptoms even several years. Up to now, the relationship between hyposmia and Parkinson disease remains elusive. Lack of proper animal models of hyposmia restricts the investigation. In this study we assessed olfactory function in Prp-A53T-α-synuclein transgenic (αSyn^A53T) mice which had been reported to show age-dependent motor impairments and intracytoplasmic inclusions. We also examined cholinergic and dopaminergic systems in olfactory bulb of αSyn^A53T mice by immunofluorescent staining, enzyme linked immunosorbent assay and western blot. We found that compared to wild type littermates, αSyn^A53T mice at 6 months or older displayed a deficit of odor discrimination and odor detection. No significant changes were found in olfactory memory and odor habituation. Furthermore compared to wildtype littermates, in olfactory bulb of αSyn^A53T mice at 10 months old we detected a marked decrease of cholinergic neurons in mitral cell layer and a decrease of acetylcholinesterase activity, while dopaminergic neurons were found increased in glomerular layer, accompanied with an increase of tyrosine hydroxylase protein. Our studies indicate that αSyn^A53T mice have olfactory dysfunction before motor deficits occur, and the cholinergic and dopaminergic disturbance might be responsible for the Parkinson disease-related olfactory dysfunction.     

Cerebral Hemodynamic Changes of Mild Traumatic Brain Injury at the Acute Stage

Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation.     

High-Density Genetic Linkage Map Construction and QTL Mapping of Grain Shape and Size in the Wheat Population Yanda1817 × Beinong6

High-density genetic linkage maps are necessary for precisely mapping quantitative trait loci (QTLs) controlling grain shape and size in wheat. By applying the Infinium iSelect 9K SNP assay, we have constructed a high-density genetic linkage map with 269 F ₈ recombinant inbred lines (RILs) developed between a Chinese cornerstone wheat breeding parental line Yanda1817 and a high-yielding line Beinong6. The map contains 2431 SNPs and 128 SSR & EST-SSR markers in a total coverage of 3213.2 cM with an average interval of 1.26 cM per marker. Eighty-eight QTLs for thousand-grain weight (TGW), grain length (GL), grain width (GW) and grain thickness (GT) were detected in nine ecological environments (Beijing, Shijiazhuang and Kaifeng) during five years between 2010–2014 by inclusive composite interval mapping (ICIM) (LOD≥2.5). Among which, 17 QTLs for TGW were mapped on chromosomes 1A, 1B, 2A, 2B, 3A, 3B, 3D, 4A, 4D, 5A, 5B and 6B with phenotypic variations ranging from 2.62% to 12.08%. Four stable QTLs for TGW could be detected in five and seven environments, respectively. Thirty-two QTLs for GL were mapped on chromosomes 1B, 1D, 2A, 2B, 2D, 3B, 3D, 4A, 4B, 4D, 5A, 5B, 6B, 7A and 7B, with phenotypic variations ranging from 2.62% to 44.39%. QGl.cau-2A.2 can be detected in all the environments with the largest phenotypic variations, indicating that it is a major and stable QTL. For GW, 12 QTLs were identified with phenotypic variations range from 3.69% to 12.30%. We found 27 QTLs for GT with phenotypic variations ranged from 2.55% to 36.42%. In particular, QTL QGt.cau-5A.1 with phenotypic variations of 6.82–23.59% was detected in all the nine environments. Moreover, pleiotropic effects were detected for several QTL loci responsible for grain shape and size that could serve as target regions for fine mapping and marker assisted selection in wheat breeding programs.     

Is Yield Increase Sufficient to Achieve Food Security in China?

Increasing demand for food, driven by unprecedented population growth and increasing consumption, will keep challenging food security in China. Although cereal yields have substantially improved during the last three decades, whether it will keep thriving to meet the increasing demand is not known yet. Thus, an integrated analysis on the trends of crop yield and cultivated area is essential to better understand current state of food security in China, especially on county scale. So far, yield stagnation has extensively dominated the main cereal-growing areas across China. Rice yield is facing the most severe stagnation that 53.9% counties tracked in the study have stagnated significantly, followed by maize (42.4%) and wheat (41.9%). As another important element for production sustainability, but often neglected is the planted area patterns. It has been further demonstrated that the loss in productive arable land for rice and wheat have dramatically increased the pressure on achieving food security. Not only a great deal of the planted areas have stagnated since 1980, but also collapsed. 48.4% and 54.4% of rice- and wheat-growing counties have lost their cropland areas to varying degrees. Besides, 27.6% and 35.8% of them have retrograded below the level of the 1980s. The combined influence (both loss in yield and area) has determined the crop sustainable production in China to be pessimistic for rice and wheat, and consequently no surprise to find that more than half of counties rank a lower level of production sustainability. Therefore, given the potential yield increase in wheat and maize, as well as substantial area loss of rice and wheat, the possible targeted adaptation measures for both yield and cropping area is required at county scale. Moreover, policies on food trade, alongside advocation of low calorie diets, reducing food loss and waste can help to enhance food security.     

Sevoflurane Inhibits Nuclear Factor-κB Activation in Lipopolysaccharide-Induced Acute Inflammatory Lung Injury via Toll-Like Receptor 4 Signaling

Background

Infection is a common cause of acute lung injury (ALI). This study was aimed to explore whether Toll-like receptors 4 (TLR₄) of airway smooth muscle cells (ASMCs) play a role in lipopolysaccharide (LPS)-induced airway hyperresponsiveness and potential mechanisms.

Methods

In vivo: A sensitizing dose of LPS (50 µg) was administered i.p. to female mice before anesthesia with either 3% sevoflurane or phenobarbital i.p. After stabilization, the mice were challenged with 5 µg of intratracheal LPS to mimic inflammatory attack. The effects of sevoflurane were assessed by measurement of airway responsiveness to methacholine, histological examination, and IL-1, IL-6, TNF-α levels in bronchoalveolar lavage fluid (BALF). Protein and gene expression of TLR₄ and NF-κB were also assessed. In vitro: After pre-sensitization of ASMCs and ASM segments for 24h, levels of TLR₄ and NF-κB proteins in cultured ASMCs were measured after continuous LPS exposure for 1, 3, 5, 12 and 24h in presence or absence of sevoflurane. Constrictor and relaxant responsiveness of ASM was measured 24 h afterwards.

Results

The mRNA and protein levels of NF-κB and TLR₄ in ASM were increased and maintained at high level after LPS challenge throughout 24h observation period, both in vivo and in vitro. Sevoflurane reduced LPS-induced airway hyperresponsiveness, lung inflammatory cell infiltration and proinflammatory cytokines release in BALF as well as maximal isometric contractile force of ASM segments to acetylcholine, but it increased maximal relaxation response to isoproterenol. Treatment with specific NF-κB inhibitor produced similar protections as sevoflurane, including decreased expressions of TLR₄ and NF-κB in cultured ASMCs and improved pharmacodynamic responsiveness of ASM to ACh and isoproterenol.

Conclusions

This study demonstrates the crucial role of TLR₄ activation in ASMCs during ALI in response to LPS. Sevoflurane exerts direct relaxant and anti-inflammatory effects in vivo and in vitro via inhibition of TLR₄/NF-κB pathway.     

Decreased Expression of DREAM Promotes the Degeneration of Retinal Neurons

The intrinsic mechanisms that promote the degeneration of retinal ganglion cells (RGCs) following the activation of N-Methyl-D-aspartic acid-type glutamate receptors (NMDARs) are unclear. In this study, we have investigated the role of downstream regulatory element antagonist modulator (DREAM) in NMDA-mediated degeneration of the retina. NMDA, phosphate-buffered saline (PBS), and MK801 were injected into the vitreous humor of C57BL/6 mice. At 12, 24, and 48 hours after injection, expression of DREAM in the retina was determined by immunohistochemistry, western blot analysis, and electrophoretic mobility-shift assay (EMSA). Apoptotic death of cells in the retina was determined by terminal deoxynucleotidyl transferace dUTP nick end labeling (TUNEL) assays. Degeneration of RGCs in cross sections and in whole mount retinas was determined by using antibodies against Tuj1 and Brn3a respectively. Degeneration of amacrine cells and bipolar cells was determined by using antibodies against calretinin and protein kinase C (PKC)-alpha respectively. DREAM was expressed constitutively in RGCs, amacrine cells, bipolar cells, as well as in the inner plexiform layer (IPL). NMDA promoted a progressive decrease in DREAM levels in all three cell types over time, and at 48 h after NMDA-treatment very low DREAM levels were evident in the IPL only. DREAM expression in retinal nuclear proteins was decreased progressively after NMDA-treatment, and correlated with its decreased binding to the c-fos-DRE oligonucleotides. A decrease in DREAM expression correlated significantly with apoptotic death of RGCs, amacrine cells and bipolar cells. Treatment of eyes with NMDA antagonist MK801, restored DREAM expression to almost normal levels in the retina, and significantly decreased NMDA-mediated apoptotic death of RGCs, amacrine cells, and bipolar cells. Results presented in this study show for the first time that down-regulation of DREAM promotes the degeneration of RGCs, amacrine cells, and bipolar cells.     

Comparison of Short- and Medium-Term Clinical Outcomes between Transradial Approach and Transfemoral Approach in a High-Volume PCI Heart Center in China

Background

Transradial approach (TRA) outweighed transfemoral approach (TFA) in acute coronary syndrome patients because the former has better short-term outcomes in high-volume percutaneous coronary intervention (PCI) centers. Our study was one of the limited studies specifically in comparing the short- and medium-term effects of TRA and those of TFA in patients undergoing elective PCIs.

Methods

A total of 21,242 patients who underwent elective PCI with stent implantation were included. Using propensity score methodology, 1,634 patient pairs were matched. Major clinical outcomes and PCI-related complications between TRA and TFA were compared.

Results

In the propensity score-matched patients, the rates of in-hospital net adverse clinical events, which included death, myocardial infarction (MI), target vessel revascularization (TVR), stroke, and major bleeding, were much lower with TRA than with TFA (1.8% vs. 3.9%, P < 0.001). This difference was mainly due to the lower rate of major bleeding (0.6% vs. 1.8%, P < 0.001) and the decreased rate of MI (1.1% vs. 1.9%, P = 0.060). PCI-related dissection and thrombosis were similar between the TRA and TFA groups (both P > 0.05). Meanwhile, one-year incidence rates of major adverse cardiovascular events, which included death, MI, and TVR, were also similar (4.1% vs. 4.9%, P = 0.272) in TRA and TFA. Multivariable regression analyses showed that TRA was an independent predictor of the low rate of in-hospital net adverse clinical events (odds ratio, 0.53; 95% confidence interval, 0.40 to 0.71), but not of major adverse cardiovascular events at one-year follow-up (hazard ratio, 1.01; 95% confidence interval, 0.96 to 1.06).

Conclusions

In patients undergoing elective PCI, TRA patients had lower rates of in-hospital net adverse clinical outcomes compared with TFA patients. TRA might be recommended as a routine approach in high-volume PCI hospitals for elective PCIs.     

The Effects of Extraversion,Social Support on the Posttraumatic Stress Disorder and Posttraumatic Growth of Adolescent Survivors of the Wenchuan Earthquake

Objective

The aim of this study was to examine the relationships among extraversion, social support, posttraumatic stress disorder and posttraumatic growth among adolescent survivors of the Wenchuan earthquake.

Methods

Six hundred thirty-eight participants were selected from the survivors of the 2008 Wenchuan earthquake. Participants completed four main questionnaires, including the Extraversion Subscale, the Social Support Scale, the Child PTSD Symptom Scale, and the Posttraumatic Growth Inventory.

Results

A bivariate correlation analysis revealed significant correlations among extraversion, social support, posttraumatic stress disorder and posttraumatic growth. Extraversion had significant indirect effects on posttraumatic stress disorder (β = −.037, p < .01) and posttraumatic growth (β = .077, p < .001) through social support. The results also indicated that extraversion had a significant direct effect on posttraumatic growth and a nonsignificant direct effect on posttraumatic stress disorder.

Conclusions

Social support fully mediates the relationship between extraversion and posttraumatic stress disorder and partially mediates the relationship between extraversion and posttraumatic growth. Psychological interventions and care for survivors of the earthquake should include the various functions and sources of social support and how they serve to benefit individuals.     

Circulating Mitochondrial DAMPs Are Not Effective Inducers of Proteinuria and Kidney Injury in Rodents

Mitochondria in eukaryotic cells are derived from bacteria in evolution. Like bacteria, mitochondria contain DNA with unmethylated CpG motifs and formyl peptides, both of which have recently been shown to be damage associated molecular patterns (DAMPs) and induce immune response and cell injury. Based on the facts that circulating mitochondrial DAMPs (mtDAMPs) are increased in the patients of trauma or burn injury who also have proteinuria, that mtDAMPs can activate immune cells which in turn secrete glomerular permeability factors, that renal intrinsic cells express a variety of DAMP receptors, and that mtDAMPs can directly increase endothelial cell permeability in vitro, we hypothesized that mtDAMPs may be novel circulating factors inducing proteinuria and kidney injury. We tested this hypothesis by directly injecting mtDAMPs into rodents and examining urinary protein and kidney histology. We prepared mtDAMP samples, including mitochondrial DNA (mtDNA) and mitochondrial debris (MTD), from rodent liver. In mice, injection of mtDNA for 20 μg/ml initial concentration in circulation (much higher than the clinical range), did not cause any renal manifestations. However, an increased dose leading to 45 μg/ml initial concentration in circulation resulted in a transient, slight increase in urinary albumin. In rats, MTD injection resulting in 450 μg/ml initial concentration of MTD protein in circulation, which was much higher than the clinical range, caused mild, transient proteinuria and lung lesions. Multiple injections of such large amount of either mtDNA or MTD into rodents on 3 consecutive days also failed in inducing proteinuria and kidney injury. In summary, clinical levels of circulating mtDAMPs do not induce proteinuria and clinically irrelevant high levels of mtDAMPs cause only a transient and slight increase in urinary protein in rodents, suggesting that circulating mtDAMPs may not be responsible for the proteinuria and kidney injury in patients with trauma, burn injury, and other diseases.