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losmapimod，一种p38小分子抑制剂，有选择地抑制dux4程序，而没有负面影响FSHD
•FSHD是由D4Z4基因座失去抑制作用引起的，导致骨骼肌中异常DUX4表达，基因表达编程改变和肌肉纤维死亡。•使用优化的MyoTube培养条件，我们将p38 MAPK确定为DUX4表达的关键调节剂。•我们观察到，用p38α/β抑制剂losmapimod治疗导致FSHD患者衍生的肌管中DUX4表达，活性和细胞死亡的降低，对肌发生的影响很小。•RNA-seq研究表明，用Losmapimod处理后，只有少数基因被差异表达，其中约有90％是DUX4的靶标，对肌原编程的主要驱动因素没有负面影响。•体外发现突出了洛斯马皮莫德对FSHD治疗的潜力，这种疾病今天没有批准的疗法。
敏感性，特异性和诊断精度2013
通过表面钙化的paTern识别受体对病原体相关的分子模式（PAMP）的感知激活呼吸道爆发氧化酶同源性D（RBOHD），通过氯曲霉诱导的激酶1（BIK1）直接磷酸化激活呼吸爆发氧化酶同源性D（RBOHD），并诱导反应氧氧的产生（ROS）。rboHD活性必须严格控制以避免ROS的有害影响，但对RBOHD倾斜鲜明的效果知之甚少。要了解RBOHD的调节，我们使用了RBOHD的共免疫沉淀，并通过质谱分析和鉴定的吞噬氧化氧化酶/BEM1P（PB1）结构域的蛋白质（PB1CP）。pb1cp负调节RBOHD和对真菌病原体Colle-totrichum higginsianum的抵抗力。PB1CP与Bik1竞争，在体外与RBOHD结合。更重要的是，PAMP处理增强了PB1CP-RBOHD相互作用，从而导致磷酸化的Bik1与体内RBOHD的解离。pb1CP位于细胞外周的细胞和PAMP治疗中，诱导PB1CP和RBOHD重新定位到相同的小内膜室。此外，PB1CP在拟南芥中的过表达导致RBOHD蛋白的丰度降低，这表明PB1CP可能参与RBOHD内吞作用。我们发现了PB1CP是RBOHD的新型负调节剂，并揭示了其可能的调节机制，涉及从RBOHD中去除磷酸化的Bik1和RBOHD内吞作用的促进。
草甘膦
+ + disrupts the gut microbiome and makes the bees disrupts the gut microbiome and makes the bees more susceptible to disease more susceptible to disease + + disturbs development of bee brood (the eggs, larvae disturbs development of bee brood (the eggs, larvae and pupae of the bees) and pupae of the bees) + + can negatively affect thermoregulation of the bumblebee can对大黄蜂菌落菌落 + +的负面影响对野生蜜蜂的复制产生负面影响，对野生蜜蜂，蜜蜂和蜜蜂的复制 + + + + + + + + +导航的锻造能力和导航 +对蜜蜂的学习能力和记忆的影响 bee
Robust and Durable RNA Editing with Axiomer ...
NTCP Q68R is a variant located inside of a Na + binding pocket and can indirectly affect NTCP function by altering the precise geometry required for BAs binding. 6 One hypothesis is that by potentially increasing affinity for negatively charged substrates, Q68R variant affects protein transport dynamics. ( Fig. 4 and 5 ) Further assessment of Q68R variant in a BAs uptake assay showed a near complete inhibition of BAs (specifically Taurocholic Acid or TCA) uptake in transiently transfected U2OS cells, confirming findings in 3D model and corresponding to the mechanism of interest for AX-0810 program ( Fig. 6 ).
优化基因治疗的可扩展RAAV生产
• Data from a perfusion benchtop bioreactor scale show that Ala, Asn, His, Tyr, and Trp positively correlate with capsid production, while Gln correlates negatively • Analysis of cell culture media from shake flask experiments shows that Asn and other amino acids, including several essential amino acids, deplete during AAV production • Capsid titer per cell increases when Gln is absent from media • The REBEL device enabled通过准确，精确地定量氨基酸的数据驱动的RAAV生产的生物过程开发，用于HEK293细胞中的RAAV生产，从而进一步了解过程•正在进行更多的实验，以优化灌注过程，以获得全面的Capsids
SA车辆市场更新
▪ Vehicle industry is closely correlated to GDP ▪ Industry negatively impacted by geopolitical events, oil prices, volatile Rand, import costs, infrastructure & energy capacity, inflation & high cost of living ▪ Interest rate increase of 475bps post-pandemic has put consumer spending & access to credit under severe strain ▪ Average bureau score of consumers continue to deteriorate ▪ All of the above has led to a contraction of the VAF market ▪ There does however seem to be a shift towards positive sentiment with the appointment of the GNU ▪ Inflation of 4.6% at end July is lowest in 3 years, nearly on the midpoint of the SARB 3%-6% targeted range ▪ Only once the rate cutting cycle commences, will the industry start improving ▪ Currently, consumers are showing preference for cheaper vehicles with the lowest possible instalment payable
ik-930，一种旁系同源物tead抑制剂有效地减弱了耐药的持久性细胞增殖
• The Hippo pathway kinase cascade negatively regulates the activity of transcription cofactor YAP/TAZ in a complex with DNA-bound transcription factor TEAD1-4 • Mutations in the Hippo pathway that result in activation of YAP/TAZ/TEADs are prevalent in multiple cancers ( Lin et al., Nature Genetics 2015; McGowan et al., Genes Cancer 2017 ) • YAP/TAZ/TEADs transcriptional activity can also be induced upon inhibition of oncogenic drivers, leading to the emergence of drug tolerant "persister" cells and disease relapse ( Kurppa et al., Cancer Cell 2020) • IK-930 is a TEAD1 selective palmitoylation inhibitor (see poster #1646) that effectively inhibits the transcriptional activity of YAP • IK-930 combined with EGFRI或MEKI可以防止持久细胞的出现并减轻对这些靶向疗法的抵抗力•IK-930目前处于第一阶段临床发展（NCT05228015）
COVID-19 疫苗接种与互联网信息搜索行为之间的关联：全国横断面研究
Background: The COVID-19 pandemic, declared in March 2020, profoundly affected global health, societal, and economic frameworks. Vaccination became a crucial tactic in combating the virus. Simultaneously, the pandemic likely underscored the internet's role as a vital resource for seeking health information. The proliferation of misinformation on social media was observed, potentially influencing vaccination decisions and timing. Objective: This study aimed to explore the relationship between COVID-19 vaccination rates, including the timing of vaccination, and reliance on internet-based information sources in Japan. Methods: Using a cross-sectional study design using a subset of panel data, this nationwide survey was conducted in 7 waves. A total of 10,000 participants were randomly selected through an internet survey firm, narrowing down to 8724 after applying inclusion and exclusion criteria. The primary outcome was the COVID-19 vaccination date, divided into vaccinated versus unvaccinated and early versus late vaccination groups. The main exposure variable was the use of internet-based information sources. Control variables included gender, family structure, education level, employment status, household income, eligibility for priority COVID-19 vaccination due to pre-existing medical conditions, and a health literacy scale score. Two regression analyses using generalized estimating equations accounted for prefecture-specific correlations, focusing on vaccination status and timing. In addition, chi-square tests assessed the relationship between each information source and vaccination rates. Results: Representing a cross-section of the Japanese population, the regression analysis found a significant association between internet information seeking and higher vaccination rates (adjusted odds ratio [aOR] 1.42 for those younger than 65 years; aOR 1.66 for those aged 65 years and older). However, no significant link was found regarding vaccination timing. Chi-square tests showed positive associations with vaccination for television, government web pages, and web news, whereas blogs and some social networking sites were negatively correlated. Conclusions: Internet-based information seeking is positively linked to COVID-19 vaccination rates in Japan, underscoring the significant influence of online information on public health decisions. Nonetheless, certain online information sources, including blogs and some social networks, negatively affected vaccination rates, warranting caution in their use and recognition. The study highlights the critical role of credible online sources in public health communication and the challenge of combating
20-F - Endava plc (DAVA)
全球范围。尽管全球疫苗接种工作正在进行中，包括我们总部所在的英国在内的某些司法管辖区已重新开放企业和政府机构，但企业的实体运营仍然存在限制，全球金融市场也存在不确定性。COVID-19 疫情对全球宏观经济的这种影响可能会降低我们获取资本的能力，因此可能对我们未来的流动性产生负面影响。此外，COVID-19 疫情蔓延导致的持续全球经济不确定性可能会对我们的业务产生重大影响，包括对我们服务的需求以及我们的 ADS 价值。这种财务不确定性还可能对我们服务的定价产生负面影响，或导致我们的客户大幅减少或推迟其技术支出，这反过来可能会降低对我们服务的需求，并对我们的收入、盈利能力和现金流产生负面影响。全球市场的不确定性增加和混乱也可能对我们的增长机会产生负面影响，无论是有机增长还是通过收购实现的增长。
系统烟雾探测器应用指南
一个典型的电离室由两个电荷板和一个放射源（通常为Americium 241）组成，用于电离板之间的空气。（见图1）放射性源散发出与空气分子一起散发并移出电子的颗粒。由于分子损失电子，它们会变成正带的离子。随着其他分子获得电子的产生，它们变成负电荷的离子。创建了相等数量的正离子和负离子。带正电的离子被带负电荷的电板吸引，而带负电荷的离子被带带正电荷的板吸引。（见图2.）这会产生一个小电离电流，可以通过连接到板的电路（检测器中的“正常”条件）来测量。