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通过抑制 P 糖蛋白介导的药物耐受持久细胞中有毒脂质过氧化副产物的清除，有效靶向治疗乳腺癌
Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by chemotherapy, epithelial breast cancer cells adopt a transient drug tolerant phenotype characterized by cell cycle arrest, epithelial-to-mesenchymal transition (EMT) and the reversible upregulation of the multidrug resistance (MDR) efflux transporter P-glycoprotein (P-gp). The drug tolerant persister (DTP) state is reversible, as cells eventually resume proliferation, giving rise to a cell population resembling the initial, drug-naïve cell lines. However, recovery after doxorubicin treatment is almost completely eliminated when DTP cells are cultured in the presence of the P-gp inhibitor Tariquidar. Mechanistically, P-gp contributes to the survival of DTP cells by removing reactive oxygen species-induced lipid peroxidation products resulting from doxorubicin exposure. In vivo, prolonged administration of Tariquidar during doxorubicin treatment holidays resulted in a significant increase of the overall survival of Brca1 − / − ;p53 − / − mammary tumor bearing mice. These results indicate that prolonged administration of a P-gp inhibitor during drug holidays would likely benefit patients without the risk of aggravated side effects related to the concomitantly adminis tered toxic chemotherapy. Effective targeting of DTPs through the inhibition of P-glycoprotein may result in a paradigm shift, changing the focus from countering drug resistance mechanisms to preventing or delaying therapy resistance.
在单原子催化的芬顿样反应中将活性位点和氧化物种相关联
类似芬顿的反应中使用的化学氧化剂涉及过氧化氧化物（H 2 O 2）和硫酸盐（例如过氧硫酸盐（PDS，S 2 O 8 2 - ）和过氧甲硫酸盐（PMS，HSO 5-−S）），可以激活使用同型和Hetogenos of catlyos和Hetogenos Catlyss，它们可以激活其。尽管金属离子（例如，Co 2+，Fe 2+，Cu 2+）及其可溶性复合物在同质系统中有效地应用，16-18这种可溶性催化剂的双方恢复会导致继发性污染，限制其应用（图。1）。相反，异质的芬顿样催化剂通过提高稳定性和易于分离来解决这些问题。19 - 21尤其是一些金属基杂种催化剂，例如纳米金属氧化物，金属纳米颗粒（NPS）和金属单原子催化剂（SAC），引起了人们越来越多的注意力，这是由于其出色的活性引起的芬顿样反应。22 – 24 However, the con ned surface locations of metal active centers in heterogeneous NP catalysts result in inferior catalytic e ffi ciency compared with their homogeneous counterparts, su ff ering from low metal atom utilization e ffi - ciency because of agglomeration of metal atoms and embed- ding in the bulk of NP catalysts.25,26此外，大多数报道的NP催化剂具有不均匀的粒径分布和多功能表面结构的特性，这给探索固有的催化机制带来了巨大的挑战，并在类似芬顿的反应中建立了结构 - 活性关系。24,27,28
BRCA测试请求和同意表格...
仅用于HRD和/或BRCA肿瘤测试：完整形式并前进到组织病理学实验室进行块选择。病理学家将审查可用材料，并选择最合适的测试块。该块将发送到癌症分子诊断（CMD）实验室和发布的报告。肿瘤报告的副本也将发送给组织病理学实验室以获取记录。用于HRD和/或BRCA肿瘤和种系测试的组合：完整的形式和影印本。与血液样本一起包含一份表格的副本。请参阅上面的种系测试样品要求。将其第二份副本转发给组织病理学实验室进行块选择。Information for Pathologists: Please indicate if it is a pre-chemotherapy or a post-chemotherapy biopsy sample as this may impact testing outcome Please select the block with the largest tumour content (ideally >50% high grade serous carcinoma tumour nuclei content, with minimal necrosis for ovarian samples and block with highest tumour cellularity available for prostate samples), however please note this will be还在参考实验室重新评估。HRD分析需要至少30％的肿瘤细胞含量。请在块中包括代表性的H＆E幻灯片。如果块中存在最小的材料，则在加工过程中可能会用尽组织。发送样本，并附有《信使组织病理学报告》的副本，请访问：癌症分子诊断，圣詹姆斯医院，詹姆斯街，都柏林8号，D08 RX0X。
Fixed Point of Interpolative Contraction on Metric Space Endowed with Graph
However, [ 8 ] observed that the fixed point obtained in the above Theorem 1.2 is not necessarily unique. Hence, a robust version of the results in [ 7 ] is provided therein. For some extensions of the idea of interpolative contractions in fixed point theory, we refer to [ 9 , 10 ] and the references therein. Following Petruşel and Rus [ 11 ], a self-mapping T of a metric space ( X, d ) is said to be a Picard operator (abbr., PO ) if T has a unique fixed point x ∗ and lim n →∞ T n x = x ∗ for all x ∈ X and T is said to be a weakly Picard operator (abbr. WPO ) if the sequence { T n x } n ∈ N converges, for all x ∈ X and the limit (which may depend on x ) is a fixed point of T . Jachymski [ 12 ] introduced the notion of contraction in metric space endowed with a graph G . Accordingly, let ( X, d ) be a metric space and let ∆ denote the diagonal of the Cartesian product X × X . Consider a directed graph G such that the set V ( G ) of its vertices coincides with X , and the set E ( G ) of its edges contains all loops, i.e., E ( G ) ⊇ ∆ . It is assumed that G has no parallel edges, so G can be identified with the pair ( V ( G ) , E ( G )) . Moreover, G may be treated as a weighted graph (see [ [ 13 ], p. 376]) by assigning to each edge the distance between its vertices. Denote by G − 1 , the conversion of a graph G , i.e., the graph obtained from G by reversing the direction of edges. Therefore,
对腹股沟疝与腹腔镜的机器人方法的经济分析：医疗保健系统可持续吗？
摘要引入的机器人方法对腹股沟疝的快速扩散，主要是在美国，因为它显示出与腹腔镜方法相似的结果，但相关成本的大幅度增加。我们的目标是在我们的环境（西班牙国家卫生系统）中进行成本分析。材料和方法使用机器人方法与腹腔镜方法进行回顾性单中心对腹股沟疝修复的比较研究。结果分析了2021年10月至2023年7月之间的98例接受机器人或腹腔镜的Tapp腹腔镜修复的患者。在这98名患者中，有20名（20.4％）接受了机器人方法治疗，而78例（79.6％）接受了腹腔镜方法。在比较两种方法时，就并发症，复发或再选中没有发现显着差异。However, the robotic group exhibited a longer surgical time (86 ± 33.07 min vs. 40 ± 14.46 min, p < 0.001), an extended hospital stays (1.6 ± 0.503 days vs. 1.13 ± 0.727 days, p < 0.007), as well as higher procedural costs (2318.63 ± 205.15 € vs. 356.81 ± 110.14 €，p <0.001）和总住院费用（3272.48±408.49€vs. 1048.61±460.06€，p <0.001）。在进行单侧和双侧疝的亚组分析时，这些结果是一致的。结论是根据复发率和手术后并发症所观察到的好处，这不能证明国家公共医疗体系内的机器人方法对腹股沟疝的额外费用是合理的。尽管如此，它代表了一种更简单的方法来启动机器人学习曲线，证明其在培训环境中的使用是合理的。
合成生物学的正交遗传系统
genetic systems. The components of a host-orthogonal genetic system include but are not limited to orthogonal DNA polymerase, orthogonal RNA polymerase, orthogonal aminoacyl tRNA synthetases, orthogonal transcription factors, and unnatural amino acids. Constructing a host-orthogonal genetic system is of great significance to the devel- opment of synthetic biology. Similar to a computer program, the genetic system needs to be modified and rewritten to meet different needs in synthetic biology. [2] However, the native genetic system is rigid and complex, [1] which brings challenges to genetic engineering for a fine-tuned con- trol of the genetic system. First, the heterogeneous elements and devices are often incompatible with or interfere with native biological systems. This is like a computer program that is suit- able for one operating system cannot be read in another oper- ating system. It is common for a genetic element which func- tions well in its host organism fails to work in another organism that is more suitable for large-scale industrial applications. [3–4] Second, massive modifications of the native genetic system may lead to the death of the host organism. For example, large phenotypic changes are often inaccessible in the host organism because the substantial genetic changes could harm the expres- sion of host genes. [4–5] To address these limitations, researchers set out to construct host-orthogonal genetic systems. Just like a virtual machine, the orthogonal genetic system separates from the large and unwieldy host operating systems, and shows operational flexibility and minimal impact on the host biolog- ical system. In this review, we will describe the design and con- struction of host-orthogonal genetic systems, highlight some of their applications in the synthetic biology field, and discuss the associated challenges and opportunities.
内容CN-21-9
摘要：精神分裂症是一种慢性且严重的精神障碍，其症状簇中具有高异质性。药物治疗对该疾病的有效性远非令人满意。，如果我们旨在了解其遗传/神经生物学机制并找到更有效的治疗方法，那么使用有效动物模型的研究是必不可少的。The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e ., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket大鼠和罗马高避免（RHA）大鼠。引人注目的是，所有菌株都表现出脉搏预抑制（PPI）的损害，在大多数情况下，这显着与新颖性诱导的超量化，社会行为的缺陷，潜在抑制和COG-nitive抑制和额叶前五额外的五额外抑制作用或额叶前五额外的Cortex Cortex（PFC）功能有关。However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains这可能是与精神分裂症相关的特征和药物添加脆弱性的有效模型（因此是双重诊断）。我们通过在研究领域标准（RDOC）框架的背景下将基于这些基于这些遗传选择的大鼠模型的研究结束，这表明使用有选择的培育菌株以RDOC为导向的研究计划可能有助于与SCHIZOPHRENIA相关研究的各个方面的进展有助于与SCHIZOPHIAS相关研究的各个方面的进步。
国家生物多样性偏移会议3.0
提供特定的地面物种的偏移需要许多要素以增加成功的机会，这符合管理计划的目的和目标。The key elements include o Knowledge of the species being offset o A proponent that is committed to the delivery of the Offset o Management actions that will result in targets being met o Long-term protection of the Offset area o Time o Reporting and compliance against Offset criteria The Goyder South Renewable Energy Project is required to deliver an on-ground offset for the nationally vulnerable Pygmy Blue-tongue Lizard (Tiliqua adelaidensis) （PBTL）。在2022年底建立的偏移区域制定并批准了偏移区域的管理计划。The PBTL Offset is set up for success based on the following: o The species has been researched since the mid 1990's, and we are always learning more, however there is a lot known about the species and its habitat requirements o Neoen Australia (project proponent) has shown a strong commitment to the project and committed extensive funding over the long term o The management plan details the actions required to improve the habitat quality for PBTL with significant actions already undertaken o The offset area, and its surrounds, has recently been declared a National Park offering protection in perpetuity o The offset plan will be implemented over a 40 year timeframe allowing time to meet the Management Plan requirements o Annual reporting will be implemented Whilst not guaranteeing success, the PBTL Offset has all the right ingredients to increase the chances of successfully offsetting the impacts of the Goyder South Renewable Energy project for the species.此偏移的交付将为该地区的类似偏移项目设定基准。
吸入的mRNA疗法用于治疗囊性纤维化
酒精使用障碍（AUD）的特征是强迫性饮酒（clad），尽管后果负面影响可能是主要的临床障碍。几乎没有可用于AUD的治疗选择，因此非常需要新颖的疗法。去甲肾上腺素能系统是调节应力反应和适应不良的酒精驱动器的重要枢纽。研究表明，靶向α1肾上腺素能受体（AR）的药物可能代表病理饮用的药理治疗方法。However, the involvement of β ARs for treating human drinking has received scant investigation, and thus we sought to provide pre- clinical validation for possible AR utility for CLAD by analyzing whether β AR antagonists propranolol ( β 1/2), betaxolol ( β 1), and ICI, 118 551 ( β 2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats.我们发现，最高剂量的普萘洛尔在系统地测试（10mg/kg）可以降低酒精饮用，而5mg/kg普萘洛尔降低了饮酒，其趋势比AOD造成的趋势高，没有2.5mg/kg的影响。betaxolol（2.5mg/kg）也减少了饮酒，而ICI 118.551没有影响。另外，尽管AR化合物可能具有AUD的实用性，但它们也可能导致不良的副作用。在这里，无效剂量的普萘洛尔和prazosin的结合减少了外壳和AOD。最后，我们研究了与病理饮酒，前岛（AINS）和内侧前额叶皮层（MPFC）有关的两个大脑区域中普萘洛尔和Betaxolol的影响。令人惊讶的是，AIN或MPFC中的普萘洛尔（1-10μg）不会影响clad或aod。一起，我们的发现为饮酒的去甲肾上腺素能调节提供了新的药理见解，这可能会为AUD治疗提供信息。
乌干达
乌干达共和国在战略上位于东非，由于其丰富的自然资源，稳定的宏观经济环境以及迅速增长的4550万人口，提供了可赚钱的可再生能源投资机会，大约是北京人口的两倍（218.4万），并且预测指示到59400万，到203030年，> 2030年。123然而，北京的可再生能力为2181兆瓦，超过了乌干达的1222兆瓦。这意味着需要提出乌干达的可再生能源努力，以满足人口不断增长的电力需求。乌干达在非洲的第十三大经济中有一个强大的区域综合经济排名，而东非第三大，GDP为523.9亿美元。4农业在该国经济中起着很大的作用，因为它拥有约68％的人口，对其GDP贡献了25％，占出口收益的90％。However, its susceptibility to climate change and weather-related shocks has led the government to place great focus on other sectors such as the energy sector which is seen as a catalyst for achieving economic diversification and socio-economic goals which among others include achieving middle- income status and climate resilience by 2030.5在其发展计划中也证明了这一承诺，例如国家发展计划（NDP），以及乌干达的愿景2040，以及能源和矿产开发部门发展计划，这些计划涉及清晰的路线图，以将可持续的清洁电网访问增加80％和90％的可再生能源混合。6此外，乌干达的全国确定的贡献（NDC）还包括无条件的承诺，即通过成本效益，可再生能源促进和提高能源效率，到2030年降低了5.9％的排放量。7上述因素清楚地表明了乌干达对推进和投资其可再生能源部门的坚定承诺，这强调了中国投资者抓住的重要机会。