A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here we show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which we call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.
Mannose impairs tumour growth and enhances chemotherapy
甘露糖能损害肿瘤生长增强化疗效果
▲ 作者：Pablo Sierra Gonzalez、James O’Prey、Simone Cardaci、Valentin J. A. Barthet、Kevin M. Ryan，et al
▲ 链接：
https://www.nature.com/articles/s41586-018-0729-3
▲ 摘要：
许多肿瘤会经历代谢变化，表现出葡萄糖摄取增加，由此引出了一个问题：服用不同类型的糖能否影响肿瘤生长。
研究人员通过饲管（一周三次）和饮水（持续性地）让肿瘤小鼠服用甘露糖。结果显示这种疗法耐受良好，而且无论单独施用还是结合阿霉素施用，似乎都减缓了肿瘤生长。
细胞对甘露糖的敏感性与较低水平的磷酸甘露糖异构酶（PMI）相关。研究人员测试了不同人类肿瘤细胞（卵巢癌、肾癌、乳腺癌、前列腺癌和结直肠癌）中的PMI水平，结果参差不齐。
其中，结直肠肿瘤的PMI水平较低，这意味着它们可能对甘露糖更敏感。这项研究前景可观，但是仍需要进一步的研究加以验证。
▲ Abstract
It is now well established that tumours undergo changes in cellular metabolism. As this can reveal tumour cell vulnerabilities and because many tumours exhibitenhanced glucose uptake, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causesgrowth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannoseis taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading tosensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phospho mannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but canbe made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levelscould be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumourtypes.
化学Chemistry
Efficient radical-based light-emitting diodes with doublet emission
双激子高效自由基发光二极管
▲ 作者：Xin Ai、Emrys W. Evans、Shengzhi Dong、Feng Li，et al
▲ 链接：
https://www.nature.com/articles/s41586-018-0695-9
▲ 摘要：
有机发光二极管（OLED）、基于量子点的LED、基于钙钛矿的LED和微LED一直被认为是适用于下一代显示器和主动式照明的轻型和柔性单元。
虽然目前已经有一些基于OLED的高端商业产品，但成本居高不下。
在这里，研究人员演示了自由基OLED的有效作用，它们的发射源是自旋双激子，而不是单激子或三激子。虽然在这些OLED中发射过程仍然允许自旋，但效率限制性被规避。
通过使用发光自由基发射器，研究人员演示了在710纳米的波长下，最大外部量子效率为27%的OLED，这是深红色和红外LED的最高报告值。
▲ Abstract
