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Microvesicles are a heterogeneous group of membrane‐enclosed vesicles that are released from cells into the extracellular space by the outward budding and pinching of the plasma membrane. These vesicles are loaded with multiple selectively sorted proteins and nucleic acids. Although interest in the clinical potential of microvesicles is increasing, there is only limited understanding of different types of microvesicles and the mechanisms involved in their formation. Here, we describe what is presently known about this expanding and complex field of research focusing on the mechanism of biogenesis, cargo loading, and release of microvesicles.

Fast radio bursts (FRBs) are bright millisecond-duration radio bursts at cosmological distances. While young magnetars are the leading source candidate, recent observations suggest that there may be multiple FRB progenitor classes. Here we investigate a potential coincidence between a binary neutron star merger event, GW190425, and a bright, non-repeating FRB event, FRB 20190425A. The FRB is located within the gravitational wave sky localization area, occurred 2.5 h after the gravitational wave event and has a dispersion measure consistent with the distance inferred from gravitational wave parameter estimation. The chance probability of a coincidence between unrelated FRB and gravitational wave events in the searched databases is estimated to be 0.0052 (2.8σ). This potential association is consistent with the theory that the binary neutron star merger left behind a supramassive, highly magnetized compact object, which collapsed to form a black hole after losing angular momentum due to spindown and produced an FRB by ejecting the magnetosphere. If such a physical association is established, the equation of state of the post-merger compact object is likely to be stiff with a Tolman–Oppenheimer–Volkoff non-spinning maximum mass of >2.63−0.23+0.39solarmasses (>2.31−0.08+0.24solarmasses) for a neutron (quark) star remnant.Magnetars are potential sources of fast radio bursts, but are the magnetars that may be created following a binary neutron star merger fast radio burst source? This study of the coincidence between FRB 20190425A and a gravitational wave event finds a weak association.

Tumor cell invasion requires the molecular and physical adaptation of both the cell and its microenvironment. Here we show that tumor cells are able to switch between the use of microvesicles and invadopodia to facilitate invasion through the extracellular matrix. Invadopodia formation accompanies the mesenchymal mode of migration on firm matrices and is facilitated by Rac1 activation. On the other hand, during invasion through compliant and deformable environments, tumor cells adopt an amoeboid phenotype and release microvesicles. Notably, firm matrices do not support microvesicle release, whereas compliant matrices are not conducive to invadopodia biogenesis. Furthermore, Rac1 activation is required for invadopodia function, while its inactivation promotes RhoA activation and actomyosin contractility required for microvesicle shedding. Suppression of RhoA signaling blocks microvesicle formation but enhances the formation of invadopodia. Finally, we describe Rho-mediated pathways involved in microvesicle biogenesis through the regulation of myosin light chain phosphatase. Our findings suggest that the ability of tumor cells to switch between the aforementioned qualitatively distinct modes of invasion may allow for dissemination across different microenvironments.

Breast cancer brain metastases (BCBM) have a 5-20 year latency and account for 30% of mortality; however, mechanisms governing adaptation to the brain microenvironment remain poorly defined. We combine time-course RNA-sequencing of BCBM development with a Drosophila melanogaster genetic screen, and identify Rab11b as a functional mediator of metastatic adaptation. Proteomic analysis reveals that Rab11b controls the cell surface proteome, recycling proteins required for successful interaction with the microenvironment, including integrin β1. Rab11b-mediated control of integrin β1 surface expression allows efficient engagement with the brain ECM, activating mechanotransduction signaling to promote survival. Lipophilic statins prevent membrane association and activity of Rab11b, and we provide proof-of principle that these drugs prevent breast cancer adaptation to the brain microenvironment. Our results identify Rab11b-mediated recycling of integrin β1 as regulating BCBM, and suggest that the recycleome, recycling-based control of the cell surface proteome, is a previously unknown driver of metastatic adaptation and outgrowth. Mechanisms governing adaptation of breast cancer to the brain metastatic microenvironment are unclear. Here, the authors use RNA-sequencing and Drosophila screening to identify Rab11b-mediated endosomal recycling as a unique mechanism for adaptation to a challenging metastatic microenvironment, which can be exploited by repurposing statins.

Tumour-derived microvesicles (TMVs) comprise a class of extracellular vesicles released from tumour cells that are now understood to facilitate communication between the tumour and the surrounding microenvironment. Despite their significance, the regulatory mechanisms governing the trafficking of bioactive cargos to TMVs at the cell surface remain poorly defined. Here we describe a molecular pathway for the delivery of microRNA (miRNA) cargo to nascent TMVs involving the dissociation of a pre-miRNA/Exportin-5 complex from Ran–GTP following nuclear export and its subsequent transfer to a cytoplasmic shuttle comprised of ARF6–GTP and GRP1. As such, ARF6 activation increases the pre-miRNA cargo contained within TMVs through a process that requires the casein kinase 2-mediated phosphorylation of RanGAP1. Furthermore, TMVs were found to contain pre-miRNA processing machinery including Dicer and Argonaute-2, which allow for cell-free pre-miRNA processing within shed vesicles. These findings offer cellular targets to block the loading and processing of pre-miRNAs within TMVs. Clancy et al. delineate a pathway for pre-miRNA delivery into nascent extracellular vesicles released from tumour cells and show that shed vesicles contain machinery allowing cell-free pre-miRNA processing.

Extracellular vesicles and particles have important roles in physiology and disease. Advances in isolation and characterization technologies have enabled the identification of new particles. Supermeres are the newest addition to the rapidly expanding repertoire of the cell secretome, and provide exciting opportunities for clinical translation.

Cells release multiple, distinct forms of extracellular vesicles including structures known as microvesicles, which are known to alter the extracellular environment. Despite growing understanding of microvesicle biogenesis, function and contents, mechanisms regulating cargo delivery and enrichment remain largely unknown. Here we demonstrate that in amoeboid-like invasive tumour cell lines, the v-SNARE, VAMP3, regulates delivery of microvesicle cargo such as the membrane-type 1 matrix metalloprotease (MT1-MMP) to shedding microvesicles. MT1-MMP delivery to nascent microvesicles depends on the association of VAMP3 with the tetraspanin CD9 and facilitates the maintenance of amoeboid cell invasion. VAMP3-shRNA expression depletes shed vesicles of MT1-MMP and decreases cell invasiveness when embedded in cross-linked collagen matrices. Finally, we describe functionally similar microvesicles isolated from bodily fluids of ovarian cancer patients. Together these studies demonstrate the importance of microvesicle cargo sorting in matrix degradation and disease progression. Cells shed various types of vesicles differing in size and content. Here the authors show that cancer cells utilize VAMP3-mediated traffic to deliver MT1-MMP to surface microvesicles and facilitate amoeboid-like cell invasion, with VAMP3-containing vesicles also found in body fluids of cancer patients.

As of 2023, the low-frequency part of the Square Kilometre Array will go online in Australia. It will constitute the largest and most powerful low-frequency radio-astronomical observatory to date, and will facilitate a rich science programme in astronomy and astrophysics. With modest engineering changes, it will also be able to measure cosmic rays via the radio emission from extensive air showers. The extreme antenna density and the homogeneous coverage provided by more than 60,000 antennas within an area of one km2 will push radio detection of cosmic rays in the energy range around 1017 eV to ultimate precision, with superior capabilities in the reconstruction of arrival direction, energy, and an expected depth-of-shower-maximum resolution of < 10 g/cm2.

The lunar technique is a method for maximising the collection area for ultra-high-energy (UHE) cosmic ray and neutrino searches. The method uses either ground-based radio telescopes or lunar orbiters to search for Askaryan emission from particles cascading near the lunar surface. While experiments using the technique have made important advances in the detection of nanosecond-scale pulses, only at the very highest energies has the lunar technique achieved competitive limits. This is expected to change with the advent of the Square Kilometre Array (SKA), the low-frequency component of which (SKA-low) is predicted to be able to detect an unprecedented number of UHE cosmic rays. In this contribution, the status of lunar particle detection is reviewed, with particular attention paid to outstanding theoretical questions, and the technical challenges of using a giant radio array to search for nanosecond pulses. The activities of SKA’s High Energy Cosmic Particles Focus Group are described, as is a roadmap by which this group plans to incorporate this detection mode into SKA-low observations. Estimates for the sensitivity of SKA-low phases 1 and 2 to UHE particles are given, along with the achievable science goals with each stage. Prospects for near-future observations with other instruments are also described.