A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

釉面分相对无铅CuO-MnO2系金属光泽釉的影响

以钙系生料釉为基础,引入结晶剂CuO、MnO₂制备无铅CuO-MnO₂系金属光泽釉;结合XRD、SEM-EDS进行物相组成定性分析和显微结构表征,系统探究外加TiO₂、V₂O₅以及玻璃粉对金属光泽釉釉面分相的影响。研究表明:一定量的TiO₂、V₂O₅引入能有效促进釉面的分相,将玻璃粉部分替换基础釉中的钾长石能使得釉熔体的高温粘度降低,并进一步加剧釉面分相,促进CuMn₂O₄铜锰尖晶石在釉层表面的析出和富集;当TiO₂引入量为2%,V₂O₅引入量为1%,玻璃粉引入量为25%(同为质量分数)时,金属光泽釉釉面效果最佳。     

上水口环形吹氩对中间包内渣眼形成的影响

 中间包上水口环形吹氩可以在塞棒周围形成清洗钢液的环形气幕，同时部分氩气泡随钢液进入上水口内，可以减少非金属夹杂物在水口内壁的黏附，起到防止水口堵塞的作用。然而，不合理的吹氩量会导致中间包内液面渣层受过强的气液羽流冲击而形成渣眼，使得钢液裸露并发生二次氧化，严重影响铸坯质量。采用标准 k ε 湍流模型研究中间包内流体流动，采用DPM模型和VOF模型耦合方法，研究上水口环形吹氩条件下渣眼的形成及演化规律。结果表明，上水口环形吹氩在塞棒周围形成较强的上升流，塞棒上部邻近区域存在多个涡流区；在钢液涡流的影响下，中间包液渣下层远离塞棒区域，上层向塞棒区域迁移；随着吹氩量的增大，平均湍动能增大，塞棒附近钢液速度逐渐增大，钢渣界面钢液速度先增大后减小，渣眼边缘钢液速度先增大后减小然后再增大，速度与垂直方向夹角逐渐减小；增大吹氩量，中间包熔池液面形成以塞棒为中心的渣眼，渣眼面积逐渐增大。试验条件下不产生渣眼的临界吹氩量为4.2 L/min，对应的钢渣界面最大速度为0.247 m/s，与垂直方向夹角为70°。     

基于低碳排放的城市空间规划策略研究

面对现代城市污染加剧的问题,做好城市规划对减少城市的碳排放具有决定性的作用。本文以低碳排放作为城市规划的出发点,从现代节能减排技术入手,构建城市空间规划立体网络,为低碳城市建设提供参考。     

锦纶长丝染色均匀度判色新方法

锦纶长丝的染色均匀度测试方法一直是采用人工判色方法,其判色结果会因人眼目光的不同导致经常会存在一定的误差,对企业节约成本和实际生产应用相当不利。本文提出了一种利用测试锦纶DTY长丝热收缩应力的方法,用热应力测试结果对锦纶染色性能进行预判,不需要进行织袜染色,为企业节约大量的人工成本。     

Effect of an abrupt change in pulling rate on microstructures of directionally solidified Al2O3-Er3Al5O12 eutectic and off-eutectic composite ceramics

Directionally solidified microstructures of Al₂O₃-Er₃Al₅O₁₂ eutectic and off-eutectic in situ composite ceramics were explored under abrupt-change pulling rate conditions. Corresponding temperature distributions and interface locations were studied. In eutectic composition, fluctuation of eutectic spacing occurred when the pulling rate increased abruptly. A gradually increase or abrupt increase in eutectic spacing was observed when the pulling rate decreased abruptly. In hypoeutectic and hypereutectic compositions, formation of the primary phases were suppressed when the pulling rate increased abruptly from 10?µm/s to 100?µm/s, while primary phases precipitated when the pulling rate decreased abruptly from 100?µm/s to 10?µm/s. The interface altitude decreased after the pulling rate increased abruptly, but increased after the pulling rate decreased abruptly. The liquid composition restriction (around the eutectic composition) at the eutectic interface plays an important role in the suppression of the primary dendrite and coupled eutectic oxides can be obtained in off-eutectic compositions even under higher solidification rate conditions.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

基于门控联合池化自编码器的通用性文本表征

为了学习文本的语义表征,以往的研究者主要依赖于复杂的循环神经网络(recurrent neural networks, RNNs)和监督式学习方法。该文提出了一种门控联合池化自编码器(gated mean-max AAE)用于学习中英文的文本语义表征。该文的自编码器完全通过多头自注意力机制(multi-head self-attention mechanism)来构建编码器和解码器网络。在编码阶段,提出了均值—最大化(mean-max)联合表征策略,即同时运用平均池化(mean pooling)和最大池化(max pooling)操作来捕获输入文本中多样性的语义信息。为促使联合池化表征可以全面地指导重构过程,解码器采用门控操作进行动态关注。通过在大规模中英文未标注语料上训练模型,获得了高质量的句子编码器。在重构文本段落的实验中,该文模型在实验效果和计算效率上均超越了传统的RNNs模型。将公开训练好的文本编码器,使其可以方便地运用于后续的研究。