Aarupnorwood2799

Clathrin-mediated endocytosis (CME) requires energy input from actin polymerization in mechanically challenging conditions. The roles of actin in CME are poorly understood due to inadequate knowledge of actin organization at clathrin-coated structures (CCSs). Using platinum replica electron microscopy of mammalian cells, we show that Arp2/3 complex-dependent branched actin networks, which often emerge from microtubule tips, assemble along the CCS perimeter, lack interaction with the apical clathrin lattice, and have barbed ends oriented toward the CCS. This structure is hardly compatible with the widely held "apical pulling" model describing actin functions in CME. Arp2/3 complex inhibition or epsin knockout produce large flat non-dynamic CCSs, which split into invaginating subdomains upon recovery from Arp2/3 inhibition. Moreover, epsin localization to CCSs depends on Arp2/3 activity. We propose an "edge pushing" model for CME, wherein branched actin polymerization promotes severing and invagination of flat CCSs in an epsin-dependent manner by pushing at the CCS boundary, thus releasing forces opposing the intrinsic curvature of clathrin lattices.Iron-based metal-organic frameworks (MOFs) have aroused extensive concern as prospective photocatalysts for antibiotic (e.g., tetracycline, TC) degradation. However, efficiencies of single and simple Fe-based MOFs still undergo restricted light absorption and weak charge separation. Assembly of different iron-based MOF building blocks into a hybrid MOF@MOF heterostructure reactor could be an encouraging strategy for the effective capture of antibiotics from the aqueous phase. This paper reports a new-style MIL-101(Fe)@MIL-100(Fe) photocatalyst, which was groundbreakingly constructed to realize a double win for boosting the performances of adsorption and photocatalysis. The optical response range, surface open sites, and charge separation efficiency of MIL-101(Fe)@MIL-100(Fe) can be regulated through accurate design and alteration. Attributed to the synergistic effects of double iron-based MOFs, MIL-101(Fe)@MIL-100(Fe) exhibits an excellent photocatalytic activity toward TC degradability compared to MIL-101(Fe) and MIL-100(Fe), which is even superior to those reported previously in the literature. Furthermore, the main active species of •O2- and h+ were proved through trapping tests of the photocatalytic process. Additionally, MIL-101(Fe)@MIL-100(Fe) possesses remarkable stability, maintaining more than 90% initial photocatalytic activity after the fifth cycle. In brief, MIL-101(Fe)@MIL-100(Fe) was highly efficient for TC degradation. Our work offers a new strategy for visible-light photodegradation of TC by exploring the double Fe-based MOF composite.The greatest challenge that limits the application of pyro-catalytic materials is the lack of highly frequent thermal cycling due to the enormous heat capacity of ambient environment, resulting in low pyro-catalytic efficiency. Here, we introduce localized plasmonic heat sources to rapidly yet efficiently heat up pyro-catalytic material itself without wasting energy to raise the surrounding temperature, triggering a significantly expedited pyro-catalytic reaction and enabling multiple pyro-catalytic cycling per unit time. In our work, plasmonic metal/pyro-catalyst composite is fabricated by in situ grown gold nanoparticles on three-dimensional structured coral-like BaTiO3 nanoparticles, which achieves a high hydrogen production rate of 133.1 ± 4.4 μmol·g-1·h-1 under pulsed laser irradiation. We also use theoretical analysis to study the effect of plasmonic local heating on pyro-catalysis. The synergy between plasmonic local heating and pyro-catalysis will bring new opportunities in pyro-catalysis for pollutant treatment, clean energy production, and biological applications.Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.Artificial neural networks have demonstrated superiority over traditional computing architectures in tasks such as pattern classification and learning. However, they do not measure uncertainty in predictions, and hence they can make wrong predictions with high confidence, which can be detrimental for many mission-critical applications. In contrast, Bayesian neural networks (BNNs) naturally include such uncertainty in their model, as the weights are represented by probability distributions (e.g. Gaussian distribution). Here we introduce three-terminal memtransistors based on two-dimensional (2D) materials, which can emulate both probabilistic synapses as well as reconfigurable neurons. The cycle-to-cycle variation in the programming of the 2D memtransistor is exploited to achieve Gaussian random number generator-based synapses, whereas 2D memtransistor based integrated circuits are used to obtain neurons with hyperbolic tangent and sigmoid activation functions. Finally, memtransistor-based synapses and neurons are combined in a crossbar array architecture to realize a BNN accelerator for a data classification task.Cell migration regulates diverse (patho)physiological processes, including cancer metastasis. According to the Osmotic Engine Model, polarization of NHE1 at the leading edge of confined cells facilitates water uptake, cell protrusion and motility. The physiological relevance of the Osmotic Engine Model and the identity of molecules mediating cell rear shrinkage remain elusive. Here, we demonstrate that NHE1 and SWELL1 preferentially polarize at the cell leading and trailing edges, respectively, mediate cell volume regulation, cell dissemination from spheroids and confined migration. SWELL1 polarization confers migration direction and efficiency, as predicted mathematically and determined experimentally via optogenetic spatiotemporal regulation. Optogenetic RhoA activation at the cell front triggers SWELL1 re-distribution and migration direction reversal in SWELL1-expressing, but not SWELL1-knockdown, cells. Efficient cell reversal also requires Cdc42, which controls NHE1 repolarization. Dual NHE1/SWELL1 knockdown inhibits breast cancer cell extravasation and metastasis in vivo, thereby illustrating the physiological significance of the Osmotic Engine Model.Mitoribosomes of green algae display a great structural divergence from their tracheophyte relatives, with fragmentation of both rRNA and proteins as a defining feature. Here, we report a 2.9 Å resolution structure of the mitoribosome from the alga Polytomella magna harbouring a reduced rRNA split into 13 fragments. We found that the rRNA contains a non-canonical reduced form of the 5S, as well as a permutation of the LSU domain I. The mt-5S rRNA is stabilised by mL40 that is also found in mitoribosomes lacking the 5S, which suggests an evolutionary pathway. Through comparison to other ribosomes with fragmented rRNAs, we observe that the pattern is shared across large evolutionary distances, and between cellular compartments, indicating an evolutionary convergence and supporting the concept of a primordial fragmented ribosome. On the protein level, eleven peripherally associated HEAT-repeat proteins are involved in the binding of 3' rRNA termini, and the structure features a prominent pseudo-trimer of one of them (mL116). Finally, in the exit tunnel, mL128 constricts the tunnel width of the vestibular area, and mL105, a homolog of a membrane targeting component mediates contacts with an inner membrane bound insertase. Together, the structural analysis provides insight into the evolution of the ribosomal machinery in mitochondria.Magnetite-apatite deposits are important sources of iron and other metals. A prominent example are the magnetite lavas at the El Laco volcano, Northern Chile. Their formation processes remain debated. Here, we test the genetic hypothesis that an Fe-rich melt separated from silicate magma and ascended along collapse-related fractures. We complement recent analyses with thermodynamic modelling to corroborate Fe-Si liquid immiscibility evident in melt inclusions at El Laco and present viscometry of Fe- and Si-rich melts to assess the time and length scales of immiscible liquid separation. Using a rock deformation model, we demonstrate that volcano collapse can form failure zones extending towards the edifice flanks along which the ore liquid ascends towards extrusion driven by vapour exsolution despite its high density. Our results support the proposed magmatic genesis for the El Laco deposits. Geochemical and textural similarities indicate magnetite-apatite deposits elsewhere form by similar processes.Macromolecular association is crucial to many fields in biomedical sciences, including drug development, gene editing, and diagnostics. In particular, protein-protein association and dissociation rate constants are typically determined using surface plasmon resonance systems, which require costly instrumentation and cumbersome procedures (e.g., blocking, washing, and separation). Herein, we demonstrate that protein-binding constants can be readily determined using a real-time biosensing platform facilitated by graphene oxide-modified microwell plates and fluorophore-labeled proteins, where the fluorescent probes remain highly fluorescent during protein association, whereas fluorescent bioprobes that are not associated with their counterparts are quenched by graphene oxide. Binding data of three pairs of proteins were systematically determined employing this single-step platform and compared with those data reported by the suppliers or the literature, suggesting that this approach is comparable and consistent with the existing ones. Such pairs include (i) human immunoglobulin G (H-IgG)-fluorophore-labeled anti-H-IgG, (ii) prostate-specific antigen (PSA)-quantum dot-labeled anti-PSA, and (iii) anti-RBD-fluorophore-labeled SARS-CoV-2 spike receptor-binding domain recombinant protein. tetrathiomolybdate chemical structure We also offer an open-source software that automatically determines the binding kinetics constants of proteins. This Technical Note introduces a simple, yet effective, platform to determine relevant information on protein kinetics, which can be performed using a microwell plate reader and economical materials like graphene oxide. We foresee a new generation of diagnostics based on our affordable protein kinetics analysis.