Comprehensive Structure and Functional Adaptations of the Yeast Nuclear Pore Complex

Nuclear Pore Complexes (NPCs) mediate the nucleocytoplasmic transport of macromolecules. Here we provide a structure of the yeast NPC in which the inner ring is resolved by cryo-EM at ɑ-helical resolution to show how flexible connectors tie together different structural and functional layers in the spoke. These connectors are targets for phosphorylation and regulated disassembly in cells with an open mitosis. Moreover, some nucleoporin pairs and karyopherins have similar interaction motifs, which suggests an evolutionary and mechanistic link between assembly and transport. We also provide evidence for three major NPC variants that foreshadow functional specializations at the nuclear periphery. Cryo-electron tomography extended these studies to provide a comprehensive model of the in situ NPC with a radially-expanded inner ring. Our model reveals novel features of the central transporter and nuclear basket, suggests a role for the lumenal ring in restricting dilation and highlights the structural plasticity required for transport by the NPC.

Transdermal Delivery Of Macromolecules Using Nanolipid Carriers

: Skin being the largest external organ, offers an enticing procedure for transdermal drug delivery, so the drug needs to rise above the outermost layer of the skin, i.e., stratum corneum. Small molecular drug entities obeying the Lipinski rule, i.e., drugs having a molecular weight less than 500Da, high lipophilicity, and optimum polarity, are favored enough to be used on the skin as therapeutics. Skin's barrier action properties prevent the transport of macromolecules at pre-determined therapeutic rates. Notable advancement in macromolecules' transdermal delivery occurred in recent years. Scientists have opted for liposomes, the use of electroporation or, low-frequency ultrasound techniques. Some of these have shown better delivery of macromolecules at clinically beneficial rates. These physical technologies involve complex mechanisms, which may irreversibly incur skin damage. Majorly, two types of lipid-based formulations, including Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) are widely investigated as a transdermal delivery system. In this review, the concepts, mechanisms, and applications of Nanostructured Lipid Carriers that are considered feasible for transporting macromolecules via transdermal delivery system are thoroughly reviewed and presented along with their clinical perspective.

Durotaxis of passive nanoparticles on elastic membranes

The transport of macromolecules and nanoscopic particles to a target cellular site is a crucial aspect in many physiological processes. This directional motion is generally controlled via active mechanical and chemical processes. Here we show, by means of molecular dynamics simulations and an analytical theory, that completely passive nanoparticles can exhibit directional motion when embedded in non-uniform mechanical environments. Specifically, we study the motion of a passive nanoparticle adhering to a mechanically non-uniform elastic membrane. We observe a non-monotonic affinity of the particle to the membrane as a function of the membrane's rigidity, which results in the particle transport. This transport can be both up or down the rigidity gradient, depending on the absolute values of the rigidities that the gradient spans across. We conclude that rigidity gradients can be used to direct average motion of passive macromolecules and nanoparticles on deformable membranes, resulting in the preferential accumulation of the macromolecules in regions of certain mechanical properties.

DeepRTCP: Predicting ATP-Binding Cassette Transporters Based on 1-Dimensional Convolutional Network

ATP-binding cassette (ABC) transporters can promote cells to absorb nutrients and excrete harmful substances. It plays a vital role in the transmembrane transport of macromolecules. Therefore, the identification of ABC transporters is of great significance for the biological research. This paper will introduce a novel method called DeepRTCP. DeepRTCP uses the deep convolutional neural network and a feature combined of reduced amino acid alphabet based tripeptide composition and PSSM to recognize ABC transporters. We constructed a dataset named ABC_2020. It contains the latest ABC transporters downloaded from Uniprot. We performed 10-fold cross-validation on DeepRTCP, and the average accuracy of DeepRTCP was 95.96%. Compared with the start-of-the-art method for predicting ABC transporters, DeepRTCP improved the accuracy by 9.29%. It is anticipated that DeepRTCP can be used as an effective ABC transporter classifier which provides a reliable guidance for the research of ABC transporters.

Cargo transport through the nuclear pore complex at a glance

ABSTRACTBidirectional transport of macromolecules across the nuclear envelope is a hallmark of eukaryotic cells, in which the genetic material is compartmentalized inside the nucleus. The nuclear pore complex (NPC) is the major gateway to the nucleus and it regulates nucleocytoplasmic transport, which is key to processes including transcriptional regulation and cell cycle control. Accordingly, components of the nuclear transport machinery are often found to be dysregulated or hijacked in diseases. In this Cell Science at a Glance article and accompanying poster, we provide an overview of our current understanding of cargo transport through the NPC, from the basic transport signals and machinery to more emerging aspects, all from a ‘cargo perspective’. Among these, we discuss the transport of large cargoes (>15 nm), as well as the roles of different cargo properties to nuclear transport, from size and number of bound nuclear transport receptors (NTRs), to surface and mechanical properties.

Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe

A functional lymphatic vasculature is essential for tissue fluid homeostasis, immunity, and lipid clearance. Although atherosclerosis has been linked to adventitial lymphangiogenesis, the functionality of aortic lymphatic vessels draining the diseased aorta has never been assessed and the role of lymphatic drainage in atherogenesis is not well understood. We develop a method to measure aortic lymphatic transport of macromolecules and show that it is impaired during atherosclerosis progression, whereas it is ameliorated during lesion regression induced by ezetimibe. Disruption of aortic lymph flow by lymphatic ligation promotes adventitial inflammation and development of atherosclerotic plaque in hypercholesterolemic mice and inhibits ezetimibe-induced atherosclerosis regression. Thus, progression of atherosclerotic plaques may result not only from increased entry of atherogenic factors into the arterial wall but also from reduced lymphatic clearance of these factors as a result of aortic lymph stasis. Our findings suggest that promoting lymphatic drainage might be effective for treating atherosclerosis.