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Previous research has shown that cue sensitivity and stress affect the risk for relapse in alcohol-dependent patients. Theoretically, a link between the two can be expected. However, a clear overview of the interplay of these factors is not yet available. The purpose of this review was to examine the empirical evidence for the influence of stress on sensitivity for alcohol-related cues. 相似文献
104.
Ruan B Palioura S Sabina J Marvin-Guy L Kochhar S Larossa RA Söll D 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(43):16502-16507
A high level of accuracy during protein synthesis is considered essential for life. Aminoacyl-tRNA synthetases (aaRSs) translate the genetic code by ensuring the correct pairing of amino acids with their cognate tRNAs. Because some aaRSs also produce misacylated aminoacyl-tRNA (aa-tRNA) in vivo, we addressed the question of protein quality within the context of missense suppression by Cys-tRNA(Pro), Ser-tRNA(Thr), Glu-tRNA(Gln), and Asp-tRNA(Asn). Suppression of an active-site missense mutation leads to a mixture of inactive mutant protein (from translation with correctly acylated aa-tRNA) and active enzyme indistinguishable from the wild-type protein (from translation with misacylated aa-tRNA). Here, we provide genetic and biochemical evidence that under selective pressure, Escherichia coli not only tolerates the presence of misacylated aa-tRNA, but can even require it for growth. Furthermore, by using mass spectrometry of a reporter protein not subject to selection, we show that E. coli can survive the ambiguous genetic code imposed by misacylated aa-tRNA tolerating up to 10% of mismade protein. The editing function of aaRSs to hydrolyze misacylated aa-tRNA is not essential for survival, and the EF-Tu barrier against misacylated aa-tRNA is not absolute. Rather, E. coli copes with mistranslation by triggering the heat shock response that stimulates nonoptimized polypeptides to achieve a native conformation or to be degraded. In this way, E. coli ensures the presence of sufficient functional protein albeit at a considerable energetic cost. 相似文献
105.
Glycoprotein Ib and glycoprotein IX are fully complexed in the intact platelet membrane 总被引:3,自引:6,他引:3
Two new murine monoclonal antibodies, AK 1 and SZ 1, reactive with the human platelet glycoprotein (GP) Ib-IX complex have been produced by the hybridoma technique. Both AK 1 and SZ 1 immunoprecipitated the GP Ib-IX complex from Triton X-100-solubilized, periodate-labeled platelets. With trypsinized, labeled platelets, AK 1, SZ 1, and FMC 25 (epitope on GP IX) immunoprecipitated a membrane-bound proteolytic fragment of the GP Ib-IX complex consisting of GP IX and an congruent to 25,000 mol wt remnant of the alpha-chain of GP lb disulfide-linked to the beta-subunit. Unexpectedly, although AK 1 and SZ 1 immunoprecipitated purified GP Ib-IX complex, neither antibody immunoprecipitated the individual components of this complex, GP Ib or GP IX. When GP Ib and GP IX were recombined, however, AK 1 and SZ 1 again immunoprecipitated the reformed complex, strongly suggesting that both antibodies were recognizing an epitope present only on the intact complex. Cross-blocking studies indicated that AK 1 and SZ 1 recognized a very similar or identical epitope that was proximal to the epitope for FMC 25. Both AK 1 and SZ 1 bound to a similar number of binding sites (congruent to 25,000) on intact platelets as monoclonal antibodies directed against either GP lb or GP IX. The combined data suggests that GP lb and GP IX are fully complexed in the intact platelet membrane. 相似文献
106.
Wenbin Zhong Zhenyu Shi Surendra H. Mahadevegowda Bo Liu Kaixi Zhang Chong Hui Koh Lin Ruan Yahua Chen Merve S. Zeden Carmen J. E. Pee Kalisvar Marimuthu Partha Pratim De Oon Tek Ng Yabin Zhu Yonggui Robin Chi Paula T. Hammond Liang Yang Yunn-Hwen Gan Kevin Pethe E. Peter Greenberg Angelika Gründling Mary B. Chan-Park 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(49):31376
For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.AMPs and AMP mimics have attracted considerable attention as candidates for therapeutic development (1). The basic design elements include a region of charged residues, generally cationic residues, enabling interaction with bacterial cell surfaces, combined with a hydrophobic nature in AMPs (2). Unfortunately, AMPs and related polymers, in general, have one or more issues that limit their use as broad-spectrum antibiotics. Some are quite toxic to human cells, the potency of some is not adequate for human administration, others are sensitive to salt at levels present in human fluids, and some are too difficult and expensive to synthesize (3, 4). One broad-spectrum antimicrobial peptide, CST has seen increased recent use as a last resort antibiotic. CST is believed to kill bacteria by virtue of its ability to disrupt membrane integrity (5). This antibiotic requires intravenous administration and is nephrotoxic (6). The emergence of CST-resistant pathogens has also become a significant problem (7). We are unaware of any new broad-spectrum AMPs that have advanced to clinical trials.Imidazolium (IM) salts are antimicrobials (8), and there is an emerging literature on antimicrobial activity of side-chain and main-chain polyimidazolium (PIM) salts with chemical structures that are in some ways similar to those we describe. Although PIMs are potent antimicrobials, there are biocompatibility problems hindering their development, and some have somewhat limited activity spectra. As with other AMPs, there have been toxicity issues, potency issues, and delivery issues as many have large molecular masses, and there is little known about mammalian cell toxicity or mechanism of action (9–12).Here we show that members of a series of PIMs we designed and synthesized are potent broad-spectrum antibacterial compounds. We selected two for further analysis and showed they retain activity even against pan-antibiotic-resistant bacteria. Unlike CST and many other AMPs, which disrupt bacterial membranes, our model PIM is bactericidal without disrupting bacterial membranes. Our experiments provide insights about mechanism of action, the potential for the emergence of PIM resistance, and indicate PIMs are effective against a model gram-negative and a model gram-positive pathogen in murine infection models. 相似文献
107.
[目的]评价双胎输血综合征(TTTS)经不同治疗方式,包括羊水减量术(SA)、双极脐带电凝减胎术(BCC)和胎盘吻合血管激光凝固术(LCPV)后,供血胎和受血胎的临床结局.[方法]回顾性分析2008年1月至2013年12月在我院诊断治疗的双胎输血综合征93例,追踪妊娠结局和新生儿情况,分析比较供血胎和受血胎的临床结局.[结果]不同治疗方式组中严重的TTTS(TTTSⅢ期及以上)所占比例分别是:羊水减量术组50.0%(27/54),脐带电凝减胎术组93.9%(31/33),胎盘吻合血管激光凝固术组83.3%(5/6),P<0.001,因此,3种治疗方式妊娠结局比较时仅纳入TTTSⅢ期及以上病例.SA组、BCC组和LCPV组双胎总体存活率分别是53.7%、24.2%和60.0%,P=0.002.SA组、BCC组和LCPV组分娩孕周中位数分别是31e(20+3~38+2)、28+5(20+2~38+6)和27+6((23+3~37+4)周,其差异无统计学意义(P=0.204).SA组胎膜早破的发生率是29.6%而BCC组和LCPV组胎膜早破的发生率分别是32.3%和60.0%,P=0.410.LCPV组28周前分娩的比例较SA组和BCC组高(分别是60.0%、18.5%和48.4%;P=0.033).TTTS双胎中受血胎存活率是44.1%(41/93)而供血胎存活率是46.2%(43/93),P=0.768;受血胎神经系统发育迟缓发生率是2.4%(1/41)而供血胎神经系统发育迟缓发生率是11.6%(5/43),其差异无统计学意义(P=0.202).[结论]胎盘吻合血管激光凝固术可提高TTTS的总体存活率;TTTS受血胎和供血胎的预后无明显差异. 相似文献
108.
摘 要 目的: 建立顶空进样气相色谱法检测比卡鲁胺原料药中7种有机残留溶剂二氯甲烷、正己烷、四氢呋喃、乙醇、乙醚、丙酮和乙酸乙酯的方法。方法: 色谱柱为Agilent DB 624弹性石英毛细管柱(30.0 m×0.25 mm×1.4 μm);进样口温度:200℃;氢火焰离子化检测器(FID)温度:250℃;柱温:程序升温,初始温度35℃,保持13 min,再以100℃/min的速率升至180℃,维持5 min;载气:氮气;流速:1.2 ml·min-1。顶空进样,顶空平衡温度:90℃,顶空平衡时间:30 min;进样体积:1.0 ml;以二甲基亚砜为溶解介质,测定比卡鲁胺中7种溶剂的残留量。结果: 各被测溶剂均能良好分离,各溶剂峰面积与浓度均呈良好的线性关系,回收率均较为理想。 结论:该法适用于比卡鲁胺原料药中残留溶剂的测定。 相似文献
109.
110.
Yucheng Wang Shihong Ren Xiaokang Gong Jiacheng Wang Ning Zhu Danyang Cai Jianwei Ruan 《Medicine》2021,100(4)
Melanoma can spread to the bone by metastasis and is relevant to a poor outcome. However, because of the rarity of melanoma patients with bone metastasis, the prognostic postoperative survival factors of them have not been elucidated. The aim of this special population-based cohort was to elucidate the prognostic factors associated with postoperative survival. The Surveillance, Epidemiology, and End Results database was used to extract postoperative survival data relating to patients with melanoma and bone metastasis at diagnosis between 2010 and 2016, along with data on a range of potential postoperative prognostic factors. We then investigated the potential postoperative prognostic roles of these factors using a Cox regression model and the Kaplan-Meier analysis. In all, the Surveillance, Epidemiology, and End Results database included 186 cases. Regarding overall survival, the 1-, 3-, and 5-year overall survival rates for the entire cohort were 36.2%, 15.4%, and 9.5%, respectively. Regarding cancer-specific survival, the 1-, 3-, and 5-year cancer-specific survival rates were 42.0%, 23.2%, and 16.6%, respectively. Within a cohort of melanoma patients with bone metastasis after surgery, our analysis showed that a smaller tumor size and the lack of metastases at other sites were predictors of survival. 相似文献