Alternative Complement Pathway Deficiency Ameliorates Chronic Smoke-Induced Functional and Morphological Ocular Injury

Background

Age-related macular degeneration (AMD), a complex disease involving genetic variants and environmental insults, is among the leading causes of blindness in Western populations. Genetic and histologic evidence implicate the complement system in AMD pathogenesis; and smoking is the major environmental risk factor associated with increased disease risk. Although previous studies have demonstrated that cigarette smoke exposure (CE) causes retinal pigment epithelium (RPE) defects in mice, and smoking leads to complement activation in patients, it is unknown whether complement activation is causative in the development of CE pathology; and if so, which complement pathway is required.

Methods

Mice were exposed to cigarette smoke or clean, filtered air for 6 months. The effects of CE were analyzed in wildtype (WT) mice or mice without a functional complement alternative pathway (AP; CFB^−/−) using molecular, histological, electrophysiological, and behavioral outcomes.

Results

CE in WT mice exhibited a significant reduction in function of both rods and cones as determined by electroretinography and contrast sensitivity measurements, concomitant with a thinning of the nuclear layers as measured by SD-OCT imaging and histology. Gene expression analyses suggested that alterations in both photoreceptors and RPE/choroid might contribute to the observed loss of function, and visualization of complement C3d deposition implies the RPE/Bruch''s membrane (BrM) complex as the target of AP activity. RPE/BrM alterations include an increase in mitochondrial size concomitant with an apical shift in mitochondrial distribution within the RPE and a thickening of BrM. CFB^−/− mice were protected from developing these CE-mediated alterations.

Conclusions

Taken together, these findings provide clear evidence that ocular pathology generated in CE mice is dependent on complement activation and requires the AP. Identifying animal models with RPE/BrM damage and verifying which aspects of pathology are dependent upon complement activation is essential for developing novel complement-based treatment approaches for the treatment of AMD.     

Verapamil Sensitive Ventricular Tachycardia Associated With A Cardiac Hemangioma In The Right Ventricular Outflow Tract

Primary tumors of the heart are rare, but they are often associated with refractory arrhythmias. Vascular tumors of the heart comprise a small minority of primary cardiac tumors. In patients with structurally normal hearts, ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT) can be sensitive to adenosine, vagal maneuvers, and calcium channel blockers. In this report, we describe a case of ventricular tachycardia originating from within a hemangioma in the RVOT that was ultimately controlled with verapamil.     

Cholinomimetics Increase Glutamate Outflow via an Action on the Corticostriatal Pathway: Implications for Alzheimer's Disease

Abstract: Physostigmine, the acetylcholinesterase inhibitor (0.3 mg/kg, i.m.), increased extracellular glutamate but not aspartate concentrations in the striatum of anaesthetised rats, determined using microdialysis and HPLC. The rise was both tetrodotoxin and calcium dependent. In contrast, neither physostigmine (10 µ M ) added to the perfusion fluid nor vehicle (injected intramuscularly) affected amino acid concentrations. To obtain evidence that the action of acetylcholine was to modulate positively cortical pyramidal neurone activity via the M₁ receptor, the selective M₁ agonist PD 142505-0028 (10 µ M ) was topically applied to the frontal cortex. Like physostigmine, PD 142505-0028 rapidly increased glutamate but not aspartate concentrations in the striatum. Moreover, the effect of intramuscular physostigmine was blocked by a topically applied M₁ antagonist. These new data add to our hypothesis that cholinomimetics increase pyramidal neurone function.     

Respiratory Gas Bladders in Teleosts: Functional Conservatism and Morphological Diversity

SYNOPSIS. Respiratory gas bladders are found in the Osteoglossomorpha,Elopomorpha and Euteleostei and are absent in the Clupeomorpha.All teleosts with respiratory gas bladders share a common patternof air ventilation: during the transfer phase gas is transferredpassively from the gas bladder to the buccal cavity. Subsequently,gas is expelled during the active expulsion phase mediated byaction of the geniohyoideus muscle causing a positive pressurepulse in the buccal cavity. This is followed by an active intakephase by action of the sternohyoideus muscle creating a negativepressure pulse, which is succeeded by an extensive compressivephase by action of the geniohyoideus muscle forcing fresh airinto the gas bladder. Saltatory evolution of gas bladders andtheir buccal pumps seems to have proceeded by major transformationsin structural design without appreciable changes in the patternof neural control. The hypothesis of symmorphosis in gas bladderdesign is well corroborated by the independent evolution ofaccessory esophageal pumps in three unrelated lineages. Evolutionaryreversals (Primitive lung evolving into nonrespiratory hydrostaticswim bladder which subsequently reverts back to become a respiratorygas bladder) have occurred repeatedly. Such reversed shiftsare facilitated by the conserved neuromuscular pattern duringfunctional transformations. Experimental comparative evidenceis offered for the notion that evolutionary innovations mayinvolve the addition of entirely new functions (respiratory)of a structural complex (gas bladder) while the original functions(hydrostatic, hearing and sound production) are rigidly retained.The paucity in Elopomorpha and absence in Clupeomorpha of respiratorygas bladders reflect the lack of functional demands for newhabits in the environment rather than the absence of essentialpreexisting building blocks.     

A PHABULOSA-Controlled Genetic Pathway Regulates Ground Tissue Patterning in the Arabidopsis Root

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Nrf2 信号通路及其在肝组织中的作用

肝脏是一个多方面高度调节的防御性器官,能够抵御多种化学/ 氧化应激,而在这个防御系统的最前线是一群被称作转录因子的特殊蛋白,这些蛋白能识别并结合于特异性基因启动子区域中特异的DNA 元件,从而调节多种细胞保护性基因的基础型和诱导型表达,发挥细胞保护作用。而转录因子NF-E2 相关因子2（Nrf2）是细胞防御化学/ 氧化应激的重要调节因子之一。综述Nrf2 信号通路中主要调控因子的相互作用、Nrf2 的激活与失活机制以及Nrf2 信号通路在肝组织中的作用。     

原花青素的生物合成途径、功能基因和代谢工程

原花青素（PA）广泛分布于高等植物中,与农作物的多种品质性状密切相关。虽长期受到关注,但其生物合成途径和主要功能基因的解析则是近年来随着拟南芥等植物突变体研究的深入才取得突破的。PA经公共苯丙烷。核心类黄酮一原花青素复合途径而合成,先后涉及12个关键酶（PAL、C4H、4CL、CHS、CHI、F3H、F3’H、DFR、LDOX／ANS、LAR、ANR、LAC）的催化反应和3种转运蛋白（GST、MATE、ATPase）的胞内转运,并有6种转录因子（WhD-ZF、MYB、bHLH、WD40、WRKY、MADS）参与调控PA的合成与积累。这些基因在拷贝数、表达特征、蛋白亚细胞定位、蛋白互作、突变体表型等方面具有显著特点。PA的代谢工程在牧草品质改良、农产品脱涩、油菜黄籽材料创新、葡萄和葡萄酒品质改良、茶多酚分子育种、作物抗病虫性提高、新型作物拓展等方向具有重要的应用前景,目前仅在少数方向有所启动,更待广泛关注和深入研究。     

三色锦鲤皮肤转录组测序与功能分析

为进一步发掘锦鲤(Cyprinus carpio)皮肤组织功能基因,以三色锦鲤墨色、红色、白色皮肤组织为研究对象,采用Illumina Hiseq 2500技术进行转录组测序和数据分析,共获得425 813 488条原始读序(reads),总碱基数为63.88 Gb.对测序所获得的reads进行组装和拼接,获得56 0...     

Dermatology: Current Concerns With Collagen for Soft Tissue Augmentation

The Scientific Board of the California Medical Association presents the following inventory of items of progress in dermatology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, or scholars to stay abreast of these items of progress in dermatology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another.The items of progress listed below were selected by the Advisory Panel to the Section on Dermatology of the California Medical Association, and the summaries were prepared under its direction.     

The Functional Significance of the Pentose Phosphate Pathway in Synaptosomes: Protection Against Peroxidative Damage by Catecholamines and Oxidants

Abstract: Catecholamines added in vitro in rat brain synaptosomes activate the decarboxylation of glucose radioactively labelled on carbon 1, suggesting an effective activation of the pentose phosphate pathway. Stimulation also occurred with phenazine methosulphate, reduced glutathione and hydrogen peroxide. The activation of the pentose phosphate pathway by 5-hydroxytryptamine, noradrenaline and dopamine is ascribed to the activation of monoamine oxidase, producing both the respective biogenic aldehyde and hydrogen peroxide. Evidence is presented that the further metabolism of the aldehyde by aldehyde reductase and the removal of hydrogen peroxide by glutathione peroxidase both release the limitation of N ADP⁺ availability for the pentose phosphate pathway by leading to the oxidation of NADPH. The relevance of the maintenance of reduced NADP⁺ on brain is discussed in relation to the metabolism of glutathione and to lipid peroxidation.     

Morphological and Metabolic Changes in the Nigro-Striatal Pathway of Synthetic Proteasome Inhibitor (PSI)-Treated Rats: A MRI and MRS Study

Systemic administration of a Synthetic Proteasome Inihibitor (PSI) in rats has been described as able to provide a model of Parkinson’s disease (PD), characterized by behavioral and biochemical modifications, including loss of dopaminergic neurons in the substantia nigra (SN), as assessed by post-mortem studies. With the present study we aimed to assess in-vivo by Magnetic Resonance (MR) possible morphological and metabolic changes in the nigro-striatal pathway of PSI-treated rats. 10 animals were subcutaneously injected with PSI 6.0 mg/kg dissolved in DMSO 100%. Injections were made thrice weekly over the course of two weeks. 5 more animals injected with DMSO 100% with the same protocol served as controls. The animals underwent MR sessions before and at four weeks after the end of treatment with either PSI or vehicle. MR Imaging was performed to measure SN volume and Proton MR Spectroscopy (¹H-MRS) was performed to measure metabolites changes at the striatum. Animals were also assessed for motor function at baseline and at 4 and 6 weeks after treatment. Dopamine and dopamine metabolite levels were measured in the striata at 6 weeks after treatment. PSI-treated animals showed volumetric reduction of the SN (p<0.02) at 4 weeks after treatment as compared to baseline. Immunofluorescence analysis confirmed MRI changes in SN showing a reduction of tyrosine hydroxylase expression as compared to neuron-specific enolase expression. A reduction of N-acetyl-aspartate/total creatine ratio (p = 0.05) and an increase of glutamate-glutamine-γ amminobutirrate/total creatine were found at spectroscopy (p = 0.03). At 6 weeks after treatment, PSI-treated rats also showed motor dysfunction compared to baseline (p = 0.02), accompanied by dopamine level reduction in the striatum (p = 0.02). Treatment with PSI produced morphological and metabolic modifications of the nigro-striatal pathway, accompanied by motor dysfunction. MR demonstrated to be a powerful mean to assess in-vivo the nigro-striatal pathway morphology and metabolism in the PSI-based PD animal model.