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1.

Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

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开发了一套原料处理量为25 kg/h的两步进气下吸式固定床气化系统,并对两步进气直筒形(Stratified)下吸式固定床气化炉的炉型、结构和主体尺寸以及焦油检测系统进行了设计,对鼓风机、引风机、出炭螺旋等关键部件的参数进行了计算。气化炉整体高度为2683 mm,气化炉有效内径为350 mm,所需引风量和鼓风量都是60 m3/h。采用木片为原料,通过冷态实验和热态实验对气化系统进行验证,验证了该气化系统完全满足设计和实验需要。通过对比两步进气和一步进气实验结果,发现两步进气法可有效提升炉体温度,显著提高可燃气中可燃气体组分含量和热值,并有效降低可燃气中焦油含量。  相似文献   
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Weldments were produced using gas tungsten arc welding(GTAW) and pulsed current gas tungsten arc welding(PCGTAW) techniques with ERNiCr-3 filler wire. Macro examination revealed that the resultant weldments were free from defects. A refined microstructure was observed in the weldment fabricated through PCGTAW. Scanning electron microscopy(SEM) analysis revealed secondary phases in the grain boundaries. Energy-dispersive X-ray spectroscopy(EDS) analysis revealed that microsegregation of Cr carbide precipitates was completely eradicated through PCGTAW. The microsegregation of Nb precipitates was observed in the GTA and PCGTA weldments. X-ray diffraction(XRD) analysis revealed the existence of M_(23)C?_6 Cr-rich carbide and Ni_8Nb phases in the GTA weldments. By contrast, in the PCGTA weldments, the Ni_8Nb phase was observed. The Cr_2Ti phase was observed in both the GTA and the PCGTA weldments. Tensile tests showed that the strength and ductility of the PCGTA weldments were slightly higher than those of the GTA weldments.  相似文献   
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Dendritic silver and copper crystals were produced via Galvanic replacement reactions on zinc and aluminum plates, respectively. The growth orientations of these metals were determined using electron microscopy. The results showed that a fast crystal growth associated with a high concentration of metal cations led to kinetically controlled growth along the <112> axes of the cubic close-packed structures. However, a slow growth rate resulted in thermodynamically controlled growth along the [111] axis. The crystal growth was not found to rely upon the direct deposition of metal cations at crystallographic sites on crystal facets, but instead, hydrated metal cations deposited on the crystal surface to form an amorphous coating layer, followed by the reduction of metal cations and crystallization at the crystal/coating interface. Twin defects and stacking faults were often observed across the whole particle and commonly observed ?{422} diffraction spots were explained by stacking faults rather than by the possible presence of any superstructures. The present work offers evidences to claim that both the crystal growth rate and Coulomb interaction between negatively charged crystal surface and metal cations play an important role in the formation of metal dendrites in replacement reactions.  相似文献   
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Effects of macromolecular crowding on structural and functional properties of ordered proteins, their folding, interactability, and aggregation are well documented. Much less is known about how macromolecular crowding might affect structural and functional behaviour of intrinsically disordered proteins (IDPs) or intrinsically disordered protein regions (IDPRs). To fill this gap, this review represents a systematic analysis of the available literature data on the behaviour of IDPs/IDPRs in crowded environment. Although it was hypothesized that, due to the excluded-volume effects present in crowded environments, IDPs/IDPRs would invariantly fold in the presence of high concentrations of crowding agents or in the crowded cellular environment, accumulated data indicate that, based on their response to the presence of crowders, IDPs/IDPRs can be grouped into three major categories, foldable, non-foldable, and unfoldable. This is because natural cellular environment is not simply characterized by the presence of high concentration of “inert” macromolecules, but represents an active milieu, components of which are engaged in direct physical interactions and soft interactions with target proteins. Some of these interactions with cellular components can cause (local) unfolding of query proteins. In other words, since crowding can cause both folding and unfolding of an IDP or its regions, the outputs of the placing of a query protein to the crowded environment would depend on the balance between these two processes. As a result, and because of the spatio-temporal heterogeneity in structural organization of IDPs, macromolecular crowding can differently affect structures of different IDPs. Recent studies indicate that some IDPs are able to undergo liquid–liquid-phase transitions leading to the formation of various proteinaceous membrane-less organelles (PMLOs). Although interiors of such PMLOs are self-crowded, being characterized by locally increased concentrations of phase-separating IDPs, these IDPs are minimally foldable or even non-foldable at all (at least within the physiologically safe time-frame of normal PMLO existence).  相似文献   
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The protein kinase D (PKD) family of proteins are important regulators of tumor growth, development, and progression. CRT0066101, an inhibitor of PKD, has antitumor activity in multiple types of carcinomas. However, the effect and mechanism of CRT0066101 in bladder cancer are not understood. In the present study, we show that CRT0066101 suppressed the proliferation and migration of four bladder cancer cell lines in vitro. We also demonstrate that CRT0066101 blocked tumor growth in a mouse flank xenograft model of bladder cancer. To further assess the role of PKD in bladder carcinoma, we examined the three PKD isoforms and found that PKD2 was highly expressed in eight bladder cancer cell lines and in urothelial carcinoma tissues from the TCGA database, and that short hairpin RNA (shRNA)-mediated knockdown of PKD2 dramatically reduced bladder cancer growth and invasion in vitro and in vivo, suggesting that the effect of the compound in bladder cancer is mediated through inhibition of PKD2. This notion was corroborated by demonstrating that the levels of phospho-PKD2 were markedly decreased in CRT0066101-treated bladder tumor explants. Furthermore, our cell cycle analysis by flow cytometry revealed that CRT0066101 treatment or PKD2 silencing arrested bladder cancer cells at the G2/M phase, the arrest being accompanied by decreases in the levels of cyclin B1, CDK1 and phospho-CDK1 (Thr161) and increases in the levels of p27Kip1 and phospho-CDK1 (Thr14/Tyr15). Moreover, CRT0066101 downregulated the expression of Cdc25C, which dephosphorylates/activates CDK1, but enhanced the activity of the checkpoint kinase Chk1, which inhibits CDK1 by phosphorylating/inactivating Cdc25C. Finally, CRT0066101 was found to elevate the levels of Myt1, Wee1, phospho-Cdc25C (Ser216), Gadd45α, and 14-3-3 proteins, all of which reduce the CDK1-cyclin B1 complex activity. These novel findings suggest that CRT0066101 suppresses bladder cancer growth by inhibiting PKD2 through induction of G2/M cell cycle arrest, leading to the blockade of cell cycle progression.  相似文献   
10.
Cell stress such as hypoxia elicits adaptive responses, also on the level of mitochondria, and in part is mediated by the hypoxia-inducible factor (HIF) 1α. Adaptation of mitochondria towards acute hypoxic conditions is reasonably well understood, while regulatory mechanisms, especially of respiratory chain assembly factors, under chronic hypoxia remains elusive. One of these assembly factors is transmembrane protein 126B (TMEM126B). This protein is part of the mitochondrial complex I assembly machinery. We identified changes in complex I abundance under chronic hypoxia, in association with impaired substrate-specific mitochondrial respiration. Complexome profiling of isolated mitochondria of the human leukemia monocytic cell line THP-1 revealed HIF-1α-dependent deficits in complex I assembly and mitochondrial complex I assembly complex (MCIA) abundance. Of all mitochondrial MCIA members, we proved a selective HIF-1-dependent decrease of TMEM126B under chronic hypoxia. Mechanistically, HIF-1α induces the E3-ubiquitin ligase F-box/WD repeat-containing protein 1A (β-TrCP1), which in turn facilitates the proteolytic degradation of TMEM126B. Attenuating a functional complex I assembly appears critical for cellular adaptation towards chronic hypoxia and is linked to destruction of the mitochondrial assembly factor TMEM126B.  相似文献   
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