• 【第二个心脏区域的后部不对称的命运导致对心脏的两个极点的出乎意料的左/右贡献。】 复制标题 收藏 收藏
    DOI:10.1161/CIRCRESAHA.112.271247 复制DOI
    作者列表:Domínguez JN,Meilhac SM,Bland YS,Buckingham ME,Brown NA
    BACKGROUND & AIMS: RATIONALE:The second heart field (SHF) contains progenitors of all heart chambers, excluding the left ventricle. The SHF is patterned, and the anterior region is known to be destined to form the outflow tract and right ventricle. OBJECTIVE:The aim of this study was to map the fate of the posterior SHF (pSHF). METHODS AND RESULTS:We examined the contribution of pSHF cells, labeled by lipophilic dye at the 4- to 6-somite stage, to regions of the heart at 20 to 25 somites, using mouse embryo culture. Cells more cranial in the pSHF contribute to the atrioventricular canal (AVC) and atria, whereas those more caudal generate the sinus venosus, but there is intermixing of fate throughout the pSHF. Caudal pSHF contributes symmetrically to the sinus venosus, but the fate of cranial pSHF is left/right asymmetrical. Left pSHF moves to dorsal left atrium and superior AVC, whereas right pSHF contributes to right atrium, ventral left atrium, and inferior AVC. Retrospective clonal analysis shows the relationships between AVC and atria to be clonal and that right and left progenitors diverge before first and second heart lineage separation. Cranial pSHF cells also contribute to the outflow tract: proximal and distal at 4 somites, and distal only at 6 somites. All outflow tract-destined cells are intermingled with those that will contribute to inflow and AVC. CONCLUSIONS:These observations show asymmetric fate of the pSHF, resulting in unexpected left/right contributions to both poles of the heart and can be integrated into a model of the morphogenetic movement of cells during cardiac looping.
    背景与目标: 理由:第二心脏区域(SHF)包含所有心腔的祖细胞,左心室除外。 SHF被图案化,并且已知前部区域注定会形成流出道和右心室。
    目的:本研究的目的是绘制后SH​​F(pSHF)的命运图。
    方法和结果:我们使用小鼠胚胎培养检查了pSHF细胞在4至6次方酸阶段的亲脂性染料标记对20至25个节段的心脏区域的贡献。 pSHF中颅骨更多的细胞参与了房室管(AVC)和心房,而尾部较多的细胞产生了窦静脉,但整个pSHF中的命运相互混合。尾部pSHF与静脉窦对称地起作用,但颅部pSHF的命运是左右不对称的。左pSHF移至左左心房和上AVC,而右pSHF有助于右心房,腹侧左心房和下AVC。回顾性克隆分析表明,AVC和心房之间的关系是克隆性的,并且在第一个和第二个心脏谱系分离之前,左右祖细胞会发散。颅内pSHF细胞也对流出道有贡献:近端和远端为4个节,远端为6个节。所有以流出道为目的地的细胞都与将有助于流入和AVC的细胞混合在一起。
    结论:这些观察结果显示pSHF的命运不对称,导致心脏的两个极点出现意想不到的左/右贡献,并且可以整合到心脏循环中细胞形态发生运动的模型中。
  • 【固态发酵过程中of去津和毒死rif的命运-过程检查。】 复制标题 收藏 收藏
    DOI:10.1080/03601230009373300 复制DOI
    作者列表:Judge DN,Mullins DE,Berry DF,Walker HL
    BACKGROUND & AIMS: :Solid state fermentation (SSF) was investigated as a means to dispose of two commonly used pesticides, chlorpyrifos (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphorothioate) and atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine). SSF experiments were carried out in bench-scale bioreactors (equipped with CO2 and volatile organic traps) containing a mixture of lignocellulosic materials and a radiolabeled pesticide. Ethyl acetate-extractable, alkali soluble, and alkali insoluble fractions were evaluated for radioactivity following a 60-d incubation period at 40 degrees C. The majority of the [2,6-pyridyl-14C]chlorpyrifos was associated with the ethyl acetate extract (about 74%), 17% was trapped as organic volatiles by polyurethane foam traps and < 0.5% of the chlorpyrifos was mineralized to CO2. Only small amounts of the radioactivity were associated with alkali soluble (0.0003%) and alkali insoluble (0.3%) fractions. In the [14C-U-ring]atrazine bioreactors, very little of the radioactivity volatilized (<0.5%) and less than 0.5% was mineralized to CO2. Approximately 57% of the applied radioactivity was associated with the ethyl acetate extract while 9% and 24% of the radioactivity was associated with the alkali soluble (humic and fulvic acids) and alkali insoluble fractions, respectively. Possible reaction mechanisms by which covalent bonds could be formed between atrazine (or metabolites) and humic substances were investigated. The issue of bound atrazine residue (alkali soluble fraction) was at least partially resolved. Oxidative coupling experiments revealed that formation of covalent bond linkages between amino substituent groups of atrazine residue and humic substances is highly unlikely.
    背景与目标: :固态发酵(SSF)作为处理两种常用农药的方法进行了研究,毒死((O,O-二乙基O-(3,5,6-三氯-2-吡啶基)硫代磷酸酯)和azine去津(2-氯-4-乙基氨基-6-异丙基氨基-1,3,5-三嗪)。 SSF实验是在台式规模的生物反应器(配有CO2和挥发性有机捕集器)中进行的,该反应器包含木质纤维素材料和放射性标记的农药的混合物。在40℃下孵育60天后,评估了可萃取乙酸乙酯,碱溶性和碱不溶性馏分的放射性。大多数[2,6-吡啶基-14C]毒死rif均与乙酸乙酯提取物相关联(约74%),17%被聚氨酯泡沫捕集阱捕集为有机挥发物,而少于0.5%的毒死rif被矿化为CO2。只有少量的放射性与碱溶性(0.0003%)和碱不溶性(0.3%)馏分相关。在[14C-U-环] r去津生物反应器中,极少有挥发的放射性(<0.5%)和不到0.5%的矿化成CO2。施加的放射性的约57%与乙酸乙酯提取物有关,而放射性的9%和24%分别与碱溶性(腐殖酸和黄腐酸)和碱不溶性部分有关。研究了at去津(或代谢产物)与腐殖质之间可能形成共价键的可能的反应机理。结合的r去津残基(碱溶部分)的问题至少得到部分解决。氧化偶联实验表明,在r去津残基的氨基取代基与腐殖质之间形成共价键的可能性极小。
  • 【肝移植前后溃疡性结肠炎和原发性硬化性胆管炎结肠炎的不定性和低度异型增生的命运。】 复制标题 收藏 收藏
    DOI:10.1111/apt.12469 复制DOI
    作者列表:Eaton JE,Smyrk TC,Imam M,Pardi DS,Loftus EV Jr,Owens VL,Talwalkar JA
    BACKGROUND & AIMS: BACKGROUND:Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) are at an increased risk of colorectal neoplasia, but it is unknown if liver transplantation (LT) alters neoplasia progression. AIM:To examine the natural history of indefinite dysplasia (IND) and low-grade dysplasia (LGD) that develop in patients with PSC-UC with and without LT. METHODS:We performed a retrospective review of patients with PSC and UC evaluated at our institution between 1993 and 2011 who were diagnosed with IND or LGD before or after LT for PSC. The primary end point was neoplasia progression or persistent LGD. RESULTS:Ninety-six patients (non-LT n = 63, LT n = 33) were examined. For the IND group, multifocal lesions were significantly associated with time to neoplasia progression [hazard ratio (HR), 3.5; 95% confidence interval (CI), 1.3-9.7], while 5-aminosalicylate (5-ASA) use was protective (HR, 0.2; 95% CI, 0.1-0.6). For patients with LGD, multifocal lesions were significantly associated with the primary end point (HR, 7.1; 95% CI, 1.7-28.3), while LT was protective (HR, 0.3; 95% CI, 0.1-0.9). CONCLUSIONS:In PSC-UC patients with IND, 5-ASA use was associated with a decreased the risk of neoplasia progression, regardless of transplant status. In contrast, multifocal IND and LGD were associated with neoplasia progression or persistent LGD. Patients who developed LGD following LT for PSC were less likely to have progressive neoplasia or persistent LGD, compared with those who had not been transplanted.
    背景与目标: 背景:原发性硬化性胆管炎(PSC)和溃疡性结肠炎(UC)的患结直肠癌的风险增加,但尚不知道肝移植(LT)是否会改变肿瘤的发展。
    目的:研究患有或不伴有LT的PSC-UC患者发展为不定型发育异常(IND)和低度不典型增生(LGD)的自然史。
    方法:我们对1993至2011年间在我们机构评估的PSC和UC患者进行了回顾性评估,这些患者在LT进行PSC之前或之后被诊断为IND或LGD。主要终点是肿瘤发展或持续性LGD。
    结果:检查了96例患者(非LT n = 63,LT n = 33)。对于IND组,多灶性病变与肿瘤形成的时间显着相关[危险比(HR)为3.5; 95%置信区间(CI)为1.3-9.7],而5-氨基水杨酸酯(5-ASA)的使用具有保护性(HR,0.2; 95%CI,0.1-0.6)。对于LGD患者,多灶性病变与主要终点显着相关(HR,7.1; 95%CI,1.7-28.3),而LT具有保护性(HR,0.3; 95%CI,0.1-0.9)。
    结论:在患有IND的PSC-UC患者中,无论移植状态如何,使用5-ASA可降低肿瘤发展的风险。相反,多灶性IND和LGD与瘤形成进展或持续性LGD相关。与未移植的患者相比,LT进行PSC后发生LGD的患者发生进行性瘤形成或持续LGD的可能性较小。
  • 【Trk受体信号转导和感觉神经元命运受到Gars突变引起的人类神经病变的干扰。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.1614557114 复制DOI
    作者列表:Sleigh JN,Dawes JM,West SJ,Wei N,Spaulding EL,Gómez-Martín A,Zhang Q,Burgess RW,Cader MZ,Talbot K,Yang XL,Bennett DL,Schiavo G
    BACKGROUND & AIMS: :Charcot-Marie-Tooth disease type 2D (CMT2D) is a peripheral nerve disorder caused by dominant, toxic, gain-of-function mutations in the widely expressed, housekeeping gene, GARS The mechanisms underlying selective nerve pathology in CMT2D remain unresolved, as does the cause of the mild-to-moderate sensory involvement that distinguishes CMT2D from the allelic disorder distal spinal muscular atrophy type V. To elucidate the mechanism responsible for the underlying afferent nerve pathology, we examined the sensory nervous system of CMT2D mice. We show that the equilibrium between functional subtypes of sensory neuron in dorsal root ganglia is distorted by Gars mutations, leading to sensory defects in peripheral tissues and correlating with overall disease severity. CMT2D mice display changes in sensory behavior concordant with the afferent imbalance, which is present at birth and nonprogressive, indicating that sensory neuron identity is prenatally perturbed and that a critical developmental insult is key to the afferent pathology. Through in vitro experiments, mutant, but not wild-type, GlyRS was shown to aberrantly interact with the Trk receptors and cause misactivation of Trk signaling, which is essential for sensory neuron differentiation and development. Together, this work suggests that both neurodevelopmental and neurodegenerative mechanisms contribute to CMT2D pathogenesis, and thus has profound implications for the timing of future therapeutic treatments.
    背景与目标: :2D型夏洛特-玛丽牙齿疾病(CMT2D)是一种外周神经疾病,由广泛表达的管家基因GARS中的显性,有毒,功能获得性突变引起。造成了CMT2D与V型等位基因紊乱的远端脊髓性肌萎缩症区别开来的轻度至中度感觉障碍的原因。为了阐明造成潜在传入神经病理的机制,我们检查了CMT2D小鼠的感觉神经系统。我们表明,背根神经节的感觉神经元功能亚型之间的平衡被Gars突变扭曲,导致周围组织的感觉缺陷,并与总体疾病严重程度相关。 CMT2D小鼠的感觉行为发生变化,与传入失衡相伴,后者在出生时和非渐进时均存在,表明感觉神经元身份在出生前受到干扰,关键的发育损伤是传入病理的关键。通过体外实验,GlyRS突变型而非野生型GlyRS被证明与Trk受体异常相互作用并引起Trk信号转导失活,这对于感觉神经元的分化和发育至关重要。总之,这项工作表明神经发育和神经退行性机制都有助于CMT2D发病机理,因此对未来治疗的时机具有深远的影响。
  • 【移植到左前降支的乳内动脉的命运受天然血管狭窄和存活心肌的影响。】 复制标题 收藏 收藏
    DOI:10.1177/0003319708316010 复制DOI
    作者列表:Yilmaz MB,Guray Y,Altay H,Demirkan B,Caldir V,Guray U,Biyikoglu SF,Sasmaz H,Kisacik HL,Korkmaz S
    BACKGROUND & AIMS: :In this study, factors leading to the failure of internal mammary artery grafting was investigated among patients with coronary bypass. In all, 1323 patients were evaluated. It was found that lower grade diameter stenosis in the native vessel during postoperative angiogram and wall motion score index independently affected the fate of internal mammary artery as a graft. Grafting with internal mammary artery to native vessels with lower grade stenosis and to myocardium with poor wall score might not be a rational approach.
    背景与目标: :在这项研究中,对导致冠状动脉搭桥术的患者进行了导致乳内动脉移植失败的因素进行了研究。总共评估了1323例患者。发现在术后血管造影和壁运动评分指数期间,天然血管中较低等级的直径狭窄独立地影响了作为植入物的乳内动脉的命运。用乳腺内动脉移植到狭窄程度较低的天然血管和壁评分较差的心肌可能不是一种合理的方法。
  • 【Notch信号调节斑马鱼中神经前体的分配和二进制神经元命运的决定。】 复制标题 收藏 收藏
    DOI:10.1242/dev.001602 复制DOI
    作者列表:Shin J,Poling J,Park HC,Appel B
    BACKGROUND & AIMS: :Notch signaling plays a well-described role in regulating the formation of neurons from proliferative neural precursors in vertebrates but whether, as in flies, it also specifies sibling cells for different neuronal fates is not known. Ventral spinal cord precursors called pMN cells produce mostly motoneurons and oligodendrocytes, but recent lineage-marking experiments reveal that they also make astrocytes, ependymal cells and interneurons. Our own clonal analysis of pMN cells in zebrafish showed that some produce a primary motoneuron and KA' interneuron at their final division. We investigated the possibility that Notch signaling regulates a motoneuron-interneuron fate decision using a combination of mutant, transgenic and pharmacological manipulations of Notch activity. We show that continuous absence of Notch activity produces excess primary motoneurons and a deficit of KA' interneurons, whereas transient inactivation preceding neurogenesis results in an excess of both cell types. By contrast, activation of Notch signaling at the neural plate stage produces excess KA' interneurons and a deficit of primary motoneurons. Furthermore, individual pMN cells produce similar kinds of neurons at their final division in mib mutant embryos, which lack Notch signaling. These data provide evidence that, among some postmitotic daughters of pMN cells, Notch promotes KA' interneuron identity and inhibits primary motoneuron fate, raising the possibility that Notch signaling diversifies vertebrate neuron type by mediating similar binary fate decisions.
    背景与目标: Notch信号在调节脊椎动物增殖性神经前体神经元的形成中起着众所周知的作用,但与蝇类一样,它是否也为不同神经元命运指定同胞是未知的。腹侧脊髓前体称为pMN细胞,主要产生运动神经元和少突胶质细胞,但最近的谱系标记实验表明,它们还制造星形胶质细胞,室间隔膜细胞和中间神经元。我们对斑马鱼中pMN细胞的克隆分析表明,有些在最终分裂时会产生原代运动神经元和KA'中间神经元。我们调查了Notch信号调节Notch活性的突变,转基因和药理操作相结合的可能性,调节运动神经元-interneuronron命运的决定。我们显示持续缺刻活动的缺席产生多余的原运动神经元和KA'interneurons的不足,而神经发生之前的瞬时失活导致两种细胞类型的过量。相比之下,在神经板期激活Notch信号会产生过量的KA'中间神经元和初级运动神经元缺陷。此外,单个pMN细胞在mib突变体胚胎的最终分裂中会产生类似种类的神经元,而这些神经元缺少Notch信号传导。这些数据提供了证据,在pMN细胞的某些有丝分裂后代的女儿中,Notch促进KA'中间神经元身份并抑制原运动神经元命运,从而提高了Notch信号通过介导相似的二元命运决定而使脊椎动物神经元类型多样化的可能性。
  • 【抗原遭遇和其他早期B细胞信号的亲和力决定了B细胞的命运。】 复制标题 收藏 收藏
    DOI:10.1016/j.coi.2007.04.009 复制DOI
    作者列表:Benson MJ,Erickson LD,Gleeson MW,Noelle RJ
    BACKGROUND & AIMS: :Three possible effector fates await the naïve follicular B cell following antigen stimulation in thymus-dependent reactions. Short-lived plasma cells produce an initial burst of germline-encoded protective antibodies, and long-lived plasma cells and memory B cells arise from the germinal center and function to enhance and sustain the humoral immune response. The inherent B-cell receptor affinity of naïve follicular B cells and the contribution of other early B-cell signals pre-determines the pattern of transcription factor expression and the differentiation path taken by these cells. High initial B-cell receptor affinity shunts naïve follicular B-cell clones towards the short-lived plasma cell fate, whereas modest-affinity clones are skewed towards a plasma cell fate and low-affinity clones are recruited into the germinal center and are selected for both long-lived plasma cells and memory B cell pathways. In the germinal center reaction, increased levels of the transcription factor interferon regulatory factor-4 drive the molecular program that dictates differentiation into the long-lived plasma cell phenotype but has no impact on the memory B cell compartment. We hypothesize that graded interferon regulatory factor-4 levels driven by signals to B cells, including B-cell receptor signal strength, are responsible for this branch point in the B-cell terminal differentiation pathway.
    背景与目标: :在胸腺依赖性反应中,在抗原刺激后,幼稚的滤泡性B细胞正在等待三种可能的效应子命运。短暂的浆细胞会产生初始的种系编码保护性抗体爆发,而长寿的浆细胞和记忆B细胞则从生发中心产生,并具有增强和维持体液免疫反应的功能。幼稚卵泡B细胞固有的B细胞受体亲和力和其他早期B细胞信号的贡献预先确定了转录因子表达的模式和这些细胞采取的分化途径。高的初始B细胞受体亲和力使幼稚的滤泡性B细胞克隆流向了短暂的浆细胞命运,而适度的亲和克隆则偏向浆细胞命运,而低亲和力的克隆被募集到生发中心,并被选择用于长寿浆细胞和记忆B细胞通路。在生发中心反应中,转录因子干扰素调节因子4水平的提高驱动了分子程序,该程序指示分化为长寿浆细胞表型,但对记忆B细胞区室没有影响。我们假设由B细胞信号驱动的分级干扰素调节因子4水平(包括B细胞受体信号强度)是B细胞末端分化途径中的这个分支点。
  • 【实验室规模后处理阶段内分泌干扰物化学物质的去除和去向。使用光,氧气和微藻类进行去除评估。】 复制标题 收藏 收藏
    DOI:10.1016/j.biortech.2013.09.051 复制DOI
    作者列表:Abargues MR,Ferrer J,Bouzas A,Seco A
    BACKGROUND & AIMS: :The aim of this study was to assess the effect of light, oxygen and microalgae on micropollutants removal. The studied micropollutants were 4-(1,1,3,3-tetramethylbutyl)phenol (OP), technical-nonylphenol (t-NP), 4-n-nonylphenol (4-NP), Bisphenol-A (BPA). In order to study the effect of the three variables on the micropollutants removal, a factorial design was developed. The experiments were carried out in four batch reactors which treated the effluent of an anaerobic membrane bioreactor. The gas chromatography mass spectrometry was used for the measurement of the micropollutants. The results showed that light, oxygen and microalgae affected differently to the degradation ratios of each micropollutant. The results showed that under aerated conditions removal ratios higher than 91% were achieved, whereas for non-aerated conditions the removal ratios were between 50% and 80%, except for 4-NP which achieved removal ratios close to 100%. Besides, mass balance showed that the degradation processes were more important than the sorption processes.
    背景与目标: :这项研究的目的是评估光,氧气和微藻类对微污染物去除的影响。研究的微量污染物为4-(1,1,3,3-四甲基丁基)苯酚(OP),工业壬基苯酚(t-NP),4-正壬基苯酚(4-NP),双酚A(BPA)。为了研究这三个变量对微污染物去除的影响,开发了析因设计。实验在四个分批反应器中进行,该反应器处理厌氧膜生物反应器的流出物。气相色谱质谱法用于微量污染物的测量。结果表明,光,氧和微藻对每种微污染物的降解率的影响不同。结果表明,在充气条件下,去除率高于91%,而在非充气条件下,去除率在50%至80%之间,除了4-NP去除率接近100%。此外,质量平衡表明降解过程比吸附过程更为重要。
  • 【德里(印度)的污水处理厂和接收废水的亚穆纳河的入水和出水中所选人类抗生素的发生和归宿。】 复制标题 收藏 收藏
    DOI:10.1007/s10661-013-3398-6 复制DOI
    作者列表:Mutiyar PK,Mittal AK
    BACKGROUND & AIMS: :Antibiotics consumption has increased worldwide, and their residues are frequently reported in aquatic environments. It is believed that antibiotics reach aquatic water bodies through sewage. Medicine consumed for healthcare practices are often released into sewage, and after sewage treatment plant, it reaches the receiving water bodies of lakes or rivers. In the present study, we determined the fate of some commonly used antibiotics in a sewage treatment plant (STP) located in Delhi and the environmental concentration of these antibiotics in the Yamuna River, which receives the sewage and industrial effluent of Delhi. There are many reports on antibiotics occurrences in STP and river water worldwide, but monitoring data from the Indian subcontinent is sparse. Samples were taken from a STP and from six sampling sites on the Yamuna River. Several antibiotics were tested for using offline solid-phase extraction followed by high-performance liquid chromatography equipped with photodiode array analysis. Recoveries varied from 25.5-108.8 %. Ampicillin had the maximum concentration in wastewater influents (104.2 ± 98.11 μg l(-1)) and effluents (12.68 ± 8.38 μg l(-1)). The fluoroquinolones and cephalosporins had the lower concentrations. Treatment efficiencies varied between 55 and 99 %. Significant amounts of antibiotics were discharged in effluents and were detected in the receiving water body. The concentration of antibiotics in the Yamuna River varied from not detected to 13.75 μg l(-1) (ampicillin) for the compounds investigated.
    背景与目标: 全球范围内,抗生素的消费量增加了,其残留物经常在水生环境中被报道。据信,抗生素通过污水到达水生水体。用于医疗保健实践的药物通常会释放到污水中,经过污水处理厂后,它会到达湖泊或河流的接收水体。在本研究中,我们确定了位于德里的污水处理厂(STP)中一些常用抗生素的命运,以及接受德里的污水和工业废水的Yamuna河中这些抗生素的环境浓度。关于全球范围内的污水处理厂和河水中存在抗生素的报道很多,但是来自印度次大陆的监测数据很少。从STP和Yamuna河上的六个采样点采样。测试了几种抗生素的脱机固相萃取,然后进行了配备光电二极管阵列分析的高效液相色谱法。回收率从25.5-108.8%不等。氨苄西林在废水进水中(104.2±98.11μgl(-1))和废水中的最高浓度(12.68±8.38μgl(-1))。氟喹诺酮类和头孢菌素类的浓度较低。治疗效率在55%至99%之间。大量的抗生素被排放到废水中,并在接收水体中被检测到。 Yamuna河中抗生素的浓度从未检出到所研究化合物的13.75μgl(-1)(氨苄西林)不等。
  • 【关联有害突变在谱系污染下有益突变的动力学和命运。】 复制标题 收藏 收藏
    DOI:10.1534/genetics.116.194597 复制DOI
    作者列表:Pénisson S,Singh T,Sniegowski P,Gerrish P
    BACKGROUND & AIMS: :Beneficial mutations drive adaptive evolution, yet their selective advantage does not ensure their fixation. Haldane's application of single-type branching process theory showed that genetic drift alone could cause the extinction of newly arising beneficial mutations with high probability. With linkage, deleterious mutations will affect the dynamics of beneficial mutations and might further increase their extinction probability. Here, we model the lineage dynamics of a newly arising beneficial mutation as a multitype branching process. Our approach accounts for the combined effects of drift and the stochastic accumulation of linked deleterious mutations, which we call lineage contamination We first study the lineage-contamination phenomenon in isolation, deriving dynamics and survival probabilities (the complement of extinction probabilities) of beneficial lineages. We find that survival probability is zero when [Formula: see text] where U is deleterious mutation rate and [Formula: see text] is the selective advantage of the beneficial mutation in question, and is otherwise depressed below classical predictions by a factor bounded from below by [Formula: see text] We then put the lineage contamination phenomenon into the context of an evolving population by incorporating the effects of background selection. We find that, under the combined effects of lineage contamination and background selection, ensemble survival probability is never zero but is depressed below classical predictions by a factor bounded from below by [Formula: see text] where [Formula: see text] is mean selective advantage of beneficial mutations, and [Formula: see text] This factor, and other bounds derived from it, are independent of the fitness effects of deleterious mutations. At high enough mutation rates, lineage contamination can depress fixation probabilities to values that approach zero. This fact suggests that high mutation rates can, perhaps paradoxically, (1) alleviate competition among beneficial mutations, or (2) potentially even shut down the adaptive process. We derive critical mutation rates above which these two events become likely.
    背景与目标: :有益突变驱动适应性进化,但其选择性优势并不能确保其固定性。 Haldane在单一类型分支过程理论中的应用表明,仅遗传漂移就很有可能导致新出现的有益突变的灭绝。通过连锁,有害突变将影响有益突变的动力学,并可能进一步增加其灭绝的可能性。在这里,我们将新出现的有益突变的谱系动力学建模为多类型分支过程。我们的方法考虑了漂移和链接的有害突变的随机积累的综合影响,我们称其为谱系污染。我们首先单独研究谱系污染现象,得出有益谱系的动力学和生存概率(灭绝概率的补充)。我们发现,当[公式:参见文本]时,生存概率为零,其中U是有害突变率,而[公式:参见文本]是所讨论的有益突变的选择优势,而在经典预测之下,则受以下因素的限制:然后,通过结合背景选择的影响,将血统污染现象纳入不断发展的种群的背景中。我们发现,在谱系污染和背景选择的共同作用下,整体生存概率永远不会为零,但在经典预测之下却受到以下因素的压制:[公式:参见文本]其中[公式:参见文本]是平均选择性的有益突变的优势,以及[公式:参见文本]此因子以及由此衍生的其他范围与有害突变的适应性效果无关。在足够高的突变率下,谱系污染会使固定概率降低到接近零的值。这一事实表明,高突变率可能(可能反常的是)(1)减轻了有益突变之间的竞争,或者(2)甚至可能关闭适应性过程。我们得出临界突变率,高于这两个事件就有可能发生。
  • 【胞吞作用,细胞内运输和基于细胞穿透肽的结合物和纳米颗粒的命运。】 复制标题 收藏 收藏
    DOI:10.2174/13816128113199990297 复制DOI
    作者列表:Cleal K,He L,Watson PD,Jones AT
    BACKGROUND & AIMS: :The insides of cells can be viewed as a treasure trove of targets for therapeutic intervention of diseases or as deposits for contrasting agents. Increasingly the molecules that need to be delivered to the inside of cells for these purposes are macromolecular and membrane impermeable. Cell penetrating peptides (CPPs) have proven abilities to deliver a range of macromolecular cargo into cells thus raising their profile as potential delivery vectors for wide-ranging applications. There is evidence to suggest that CPPs first enter cells through endocytosis and that cytosolic delivery is mediated across endolysosomal membranes. Their capacity to do this, over direct plasma membrane translocation, is likely to depend on the nature and size of the cargo. Cells use a range of endocytic routes to facilitate entry from well characterised pathways regulated by clathrin to more recently discovered and less characterised pathways regulated by clathrin independent mechanisms. These are likely to determine the intracellular fate of cell delivery vectors including those based on cell penetrating peptides. Thus gaining accurate knowledge of their endocytic uptake and traffic is an important characterisation criteria for progress in this field. This review describes the different endocytic pathways that have been identified in mammalian cells and specific reports that have studied the uptake mechanisms and endocytic traffic of cell penetrating peptides and their associated cargo. These cargoes range from short peptides to an increasing library of nanoparticles such as quantum dots, liposomes and polymeric dendrimers. The studies highlight the effectiveness of cell penetrating peptides for delivering these entities into a diverse array of cell types using different endocytic pathways. This is shown using microscopy based colocalisation analysis with the few specific endocytic probes available, and chemical inhibitors of endocytosis that suffer from lack of specificity. Overall, more specific probes, inhibitors and novel technologies are required for accurate characterisation of cellular dynamics of cell penetrating peptide conjugates thus allowing them to reach their full potential as vectors for therapeutics and other payloads.
    背景与目标: :细胞内部可被视为治疗疾病的靶标宝库或可作为造影剂的沉积物。为了这些目的,越来越需要传递到细胞内部的分子是大分子和膜不可渗透的。细胞穿透肽(CPP)具有将多种大分子货物递送到细胞中的能力,从而提高了其作为广泛应用的潜在递送载体的特性。有证据表明,CPPs首先通过胞吞作用进入细胞,并且胞质传递是通过溶酶体膜介导的。他们在直接质膜移位方面的能力可能取决于货物的性质和大小。细胞使用一系列内吞途径来促进从网格蛋白调节的特征明确的途径进入由网格蛋白独立机制调节的较新发现和特征较少的途径。这些可能确定细胞递送载体的细胞内命运,包括基于细胞穿透肽的载体。因此,获得有关其内吞摄取和运输的准确知识是该领域进展的重要表征标准。这篇综述描述了在哺乳动物细胞中已经鉴定出的不同的内吞途径以及研究了细胞穿透肽及其相关物质的摄取机制和内吞运输的具体报告。这些货物的范围从短肽到不断增加的纳米颗粒库,例如量子点,脂质体和聚合物树状聚合物。这些研究突出了细胞穿透肽通过不同的内吞途径将这些实体传递到多种细胞类型中的有效性。使用基于显微镜的共定位分析和少数可用的特异性内吞探针,以及缺乏特异性的内吞化学抑制剂,可以证明这一点。总体而言,准确表征细胞穿透肽缀合物的细胞动力学需要更特异性的探针,抑制剂和新技术,从而使它们能够充分发挥其作为治疗剂和其他有效载荷载体的潜力。
  • 【BMP4足以诱导源自胚胎干细胞的神经上皮祖细胞的脉络丛上皮命运。】 复制标题 收藏 收藏
    DOI:10.1523/JNEUROSCI.3227-12.2012 复制DOI
    作者列表:Watanabe M,Kang YJ,Davies LM,Meghpara S,Lau K,Chung CY,Kathiriya J,Hadjantonakis AK,Monuki ES
    BACKGROUND & AIMS: :Choroid plexus epithelial cells (CPECs) have essential developmental and homeostatic roles related to the CSF and blood-CSF barrier they produce. Accordingly, CPEC dysfunction has been implicated in many neurological disorders, such as Alzheimer's disease, and transplant studies have provided proof-of-concept for CPEC-based therapies. However, such therapies have been hindered by the inability to expand or generate CPECs in culture. During development, CPECs differentiate from preneurogenic neuroepithelial cells and require bone morphogenetic protein (BMP) signaling, but whether BMPs suffice for CPEC induction is unknown. Here we provide evidence for BMP4 sufficiency to induce CPEC fate from neural progenitors derived from mouse embryonic stem cells (ESCs). CPEC specification by BMP4 was restricted to an early time period after neural induction in culture, with peak CPEC competency correlating to neuroepithelial cells rather than radial glia. In addition to molecular, cellular, and ultrastructural criteria, derived CPECs (dCPECs) had functions that were indistinguishable from primary CPECs, including self-assembly into secretory vesicles and integration into endogenous choroid plexus epithelium following intraventricular injection. We then used BMP4 to generate dCPECs from human ESC-derived neuroepithelial cells. These findings demonstrate BMP4 sufficiency to instruct CPEC fate, expand the repertoire of stem cell-derived neural derivatives in culture, and herald dCPEC-based therapeutic applications aimed at the unique interface between blood, CSF, and brain governed by CPECs.
    背景与目标: :脉络丛上皮细胞(CPEC)与它们产生的CSF和血液CSF屏障有关,具有重要的发育和体内平衡作用。因此,CPEC功能障碍与许多神经系统疾病有关,例如阿尔茨海默氏病,移植研究为基于CPEC的疗法提供了概念验证。但是,这种疗法由于无法在培养物中扩增或产生CPEC而受到阻碍。在发育过程中,CPEC与神经原性神经上皮细胞有所区别,并需要骨形态发生蛋白(BMP)信号传导,但是BMP是否足以满足CPEC的诱导尚不清楚。在这里,我们提供了BMP4足以诱导来自小鼠胚胎干细胞(ESC)的神经祖细胞的CPEC命运的证据。 BMP4的CPEC规范仅限于培养中神经诱导后的早期时段,其峰值CPEC能力与神经上皮细胞而不是radial神经胶质细胞有关。除了分子,细胞和超微结构标准外,衍生的CPEC(dCPEC)具有与主要CPEC不可区分的功能,包括自组装成分泌小泡以及在心室内注射后整合入内源性脉络丛上皮。然后,我们使用BMP4从人ESC衍生的神经上皮细胞生成dCPEC。这些发现表明,BMP4足以指导CPEC的命运,扩大文化中干细胞衍生的神经衍生物的种类,并预示了基于dCPEC的治疗应用,其目标是血液,CSF和受CPEC支配的大脑之间的独特界面。
  • 【Wnt5a / Ror2通路与确定血管钙化中骨髓间充质干细胞的分化命运有关。】 复制标题 收藏 收藏
    DOI:10.3892/ijmm.2013.1242 复制DOI
    作者列表:Xin H,Xin F,Zhou S,Guan S
    BACKGROUND & AIMS: :Accumulating evidence have demonstrated that mesenchymal stem cells (MSCs) are involved in the initiation and progression of various vascular diseases. Canonical Wnt signaling controls the fate of MSCs, and plays an important role in vascular calcification. However, vascular calcification can be inhibited by the non-canonical Wnt signaling pathway Wnt5a/Ror2. This study aimed to investigate whether the Wnt5a/Ror2 pathway is associated with determination of the differentiation fate of MSCs in vascular calcification. Direct co-cultures were established by seeding smooth muscle cells (SMCs) or calcified SMCs and MSCs together at ratios of SMCs or calcified SMCs 15x104; SMCs or calcified SMCs 5x104: MSCs 10x104, SMCs or calcified SMCs 10x104: MSCs 5x104. Osteosynthesis-inducing medium (OS) was added to the culture medium in the groups of MSCs with non-calcified SMCs. Cells were cultured for nine days. Osteoblastic differentiation was evaluated by cell morphology and the activity of alkaline phosphatase (ALP) in cell lysates and ALP staining. Furthermore, we investigated the inhibition of Wnt signaling, and observed that the members of the non-canonical signaling pathway Wnt5a/Ror2 were expressed in each group. Additionally, MSCs cultured in culture media with OS did not differentiate into an osteoblast phenotype when in direct contact with non-calcified SMCs, irrespective of the number of MSCs. However, an osteoblast phenotype was observed when MSCs were cultured in media without OS differentiation towards direct contact with calcified SMCs, and the levels of osteoblastic markers had a direct correlation with the number of MSCs. Of note, the Wnt5a protein was associated with the levels of calcification, thus, although rarely detected in non-calcification, Ror2 mRNA in the non-calcified groups was significantly higher compared to that in the calcified groups. Therefore, the Wnt5a/Ror2 pathway is associated with determination of the differentiation fate of bone marrow mesenchymal stem cells in vascular calcification.
    背景与目标: :越来越多的证据表明,间充质干细胞(MSCs)参与各种血管疾病的发生和发展。规范的Wnt信号控制MSC的命运,并在血管钙化中起重要作用。但是,非典型的Wnt信号通路Wnt5a / Ror2可以抑制血管钙化。这项研究旨在调查Wnt5a / Ror2通路是否与确定血管钙化中MSCs的分化命运有关。通过将平滑肌细胞(SMC)或钙化的SMCs和MSCs以SMCs或钙化的SMCs的比例15x104一起接种来建立直接共培养。 SMC或钙化SMC 5x104:MSC 10x104,SMC或钙化SMC 10x104:MSC 5x104。将骨合成诱导培养基(OS)添加到具有非钙化SMC的MSC组的培养基中。将细胞培养9天。通过细胞形态和细胞裂解液中碱性磷酸酶(ALP)的活性以及ALP染色来评估成骨细胞的分化。此外,我们研究了Wnt信号的抑制作用,并观察到非经典信号通路Wnt5a / Ror2的成员在每组中都有表达。另外,与非钙化SMC直接接触时,在具有OS的培养基中培养的MSC不分化为成骨细胞表型,而与MSC的数量无关。然而,当在没有OS分化而直接接触钙化SMC的培养基中培养MSC时,观察到了成骨细胞表型,成骨细胞标志物的水平与MSC的数量直接相关。值得注意的是,Wnt5a蛋白与钙化水平有关,因此,尽管在非钙化中很少检测到,但非钙化组的Ror2 mRNA明显高于钙化组。因此,Wnt5a / Ror2通路与确定血管钙化中骨髓间充质干细胞的分化命运有关。
  • 【创伤后骨关节炎的发病机制:在不稳定环境中的软骨细胞行为和命运。】 复制标题 收藏 收藏
    DOI:10.3390/ijms21051560 复制DOI
    作者列表:Riegger J,Brenner RE
    BACKGROUND & AIMS: :Traumatic injuries of the knee joint result in a wide variety of pathomechanisms, which contribute to the development of so-called posttraumatic osteoarthritis (PTOA). These pathogenetic processes include oxidative stress, excessive expression of catabolic enzymes, release of damage-associated molecular patterns (DAMPs), and synovial inflammation. The present review focuses on the underlying pathomechanisms of PTOA and in particular the behavior and fate of the surviving chondrocytes, comprising chondrocyte metabolism, regulated cell death, and phenotypical changes comprising hypertrophy and senescence. Moreover, possible therapeutic strategies, such as chondroanabolic stimulation, anti-oxidative and anti-inflammatory treatment, as well as novel therapeutic targets are discussed.
    背景与目标: :膝关节的外伤导致多种致病机制,导致所谓的创伤后骨关节炎(PTOA)的发展。这些致病过程包括氧化应激,分解代谢酶的过度表达,损伤相关分子模式(DAMP)的释放以及滑膜炎症。本综述着重于PTOA的潜在发病机制,尤其是存活的软骨细胞的行为和命运,包括软骨细胞的代谢,调节的细胞死亡以及包括肥大和衰老的表型改变。此外,还讨论了可能的治疗策略,例如软骨刺激,抗氧化和抗炎治疗以及新的治疗靶标。
  • 15 The fate of new bacterial genes. 复制标题 收藏 收藏

    【新细菌基因的命运。】 复制标题 收藏 收藏
    DOI:10.1111/j.1574-6976.2008.00140.x 复制DOI
    作者列表:Kuo CH,Ochman H
    BACKGROUND & AIMS: :Bacteria experience a continual influx of novel genetic material from a wide range of sources and yet their genomes remain relatively small. This aspect of bacterial evolution indicates that most newly arriving sequences are rapidly eliminated; however, numerous new genes persist, as evident from the presence of unique genes in almost all bacterial genomes. This review summarizes the methods for identifying new genes in bacterial genomes and examines the features that promote the retention and elimination of these evolutionary novelties.
    背景与目标: :细菌不断从各种来源涌入新的遗传物质,但它们的基因组仍然相对较小。细菌进化的这一方面表明,大多数新到达的序列被迅速消除。然而,从几乎所有细菌基因组中都存在独特基因可以证明,许多新基因持续存在。这篇综述总结了在细菌基因组中鉴定新基因的方法,并研究了促进保留和消除这些进化新奇的特征。

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