mTORC1 activity is supported by spatial association with focal adhesions

The mammalian target of rapamycin complex 1 (mTORC1) integrates mitogenic and stress signals to control growth and metabolism. Activation of mTORC1 by amino acids and growth factors involves recruitment of the complex to the lysosomal membrane and is further supported by lysosome distribution to the cell periphery. Here, we show that translocation of lysosomes toward the cell periphery brings mTORC1 into proximity with focal adhesions (FAs). We demonstrate that FAs constitute discrete plasma membrane hubs mediating growth factor signaling and amino acid input into the cell. FAs, as well as the translocation of lysosome-bound mTORC1 to their vicinity, contribute to both peripheral and intracellular mTORC1 activity. Conversely, lysosomal distribution to the cell periphery is dispensable for the activation of mTORC1 constitutively targeted to FAs. This study advances our understanding of spatial mTORC1 regulation by demonstrating that the localization of mTORC1 to FAs is both necessary and sufficient for its activation by growth-promoting stimuli.     

Computational analyses reveal spatial relationships between nuclear pore complexes and specific lamins

Nuclear lamin isoforms form fibrous meshworks associated with nuclear pore complexes (NPCs). Using datasets prepared from subpixel and segmentation analyses of 3D–structured illumination microscopy images of WT and lamin isoform knockout mouse embryo fibroblasts, we determined with high precision the spatial association of NPCs with specific lamin isoform fibers. These relationships are retained in the enlarged lamin meshworks of Lmna^−/− and Lmnb1^−/− fibroblast nuclei. Cryo-ET observations reveal that the lamin filaments composing the fibers contact the nucleoplasmic ring of NPCs. Knockdown of the ring-associated nucleoporin ELYS induces NPC clusters that exclude lamin A/C fibers but include LB1 and LB2 fibers. Knockdown of the nucleoporin TPR or NUP153 alters the arrangement of lamin fibers and NPCs. Evidence that the number of NPCs is regulated by specific lamin isoforms is presented. Overall the results demonstrate that lamin isoforms and nucleoporins act together to maintain the normal organization of lamin meshworks and NPCs within the nuclear envelope.     

Evolution of herbs: key to the conundrum might be tolerance not avoidance

草本植物的进化：解决难题的关键在于忍耐而非逃避 木本植物延续了其祖先被子植物的生长形态,而草本植物则不断地从中进化演变。虽然关于驱动草本植物习性进化的因素已有许多假设,但是通过舍弃地上生物质从而避免冬季冻害的能力常常被认为是促使其进化的主要力量。然而,鉴于草本植物在反复干扰中依旧能够轻松存活,我们提出了不可预测的干扰可能比季节性霜冻更为重要的假设。我们通过比较草本植物和木本植物应对3种模拟干扰(容易预测的冬季冰冻、不易预测的春季冰冻和食草作用)的能力来验证这一假设。通过比较20种不同植物在同质园实验中的表现,我们评估了这些干扰对植物死亡和再生方面的影响。研究结果表明,在冬季冰冻条件下,比起木本植物,草本植物在存活率上并没有优势。在不易预测的春季冰冻条件下,草本植物比木本植物的存活率更高。而在模拟食草作用的条件下,草本植物的这种生存优势更大。在不可预测的条件下,草本植物相较于木本植物的生存优势表明,草本植物的生长形式可能是对不可预测的干扰的适应,这种逆境忍耐通过其损失地上生物质也能够生存的能力得以实现。因此,哺乳动物的食草行为或火灾等原因或许最有可能是木本植物向草本植物过渡的因素。     

SARS-CoV-2 tropism,entry, replication,and propagation: Considerations for drug discovery and development

Since the initial report of the novel Coronavirus Disease 2019 (COVID-19) emanating from Wuhan, China, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread globally. While the effects of SARS-CoV-2 infection are not completely understood, there appears to be a wide spectrum of disease ranging from mild symptoms to severe respiratory distress, hospitalization, and mortality. There are no Food and Drug Administration (FDA)-approved treatments for COVID-19 aside from remdesivir; early efforts to identify efficacious therapeutics for COVID-19 have mainly focused on drug repurposing screens to identify compounds with antiviral activity against SARS-CoV-2 in cellular infection systems. These screens have yielded intriguing hits, but the use of nonhuman immortalized cell lines derived from non-pulmonary or gastrointestinal origins poses any number of questions in predicting the physiological and pathological relevance of these potential interventions. While our knowledge of this novel virus continues to evolve, our current understanding of the key molecular and cellular interactions involved in SARS-CoV-2 infection is discussed in order to provide a framework for developing the most appropriate in vitro toolbox to support current and future drug discovery efforts.