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The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is thus a major goal of contemporary cell biology, with implications for health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and furthermore, through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion.

Approximately one percent of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho family of small GTPases. Through a series of complex biochemical networks, these highly conserved molecular switches control some of the most fundamental processes of cell biology common to all eukaryotes, including morphogenesis, polarity, movement, and cell division. In the first part of this review, we present the best characterized of these biochemical pathways; in the second part, we attempt to integrate these molecular details into a biological context.

Play It Loud celebrates the musical instruments that gave rock and roll its signature sound-from Louis Jordan's alto saxophone and John Lennon's Rickenbacker to the drum set owned by Metallica's Lars Ulrich, Lady Gaga's keytar, and beyond. Seven engrossing essays by veteran music journalists and scholars discuss the technical developments that fostered rock's seductive riffs and driving rhythms, the thrilling innovations musicians have devised to achieve unique effects, and the visual impact their instruments have had. Abundant photographs depict rock's most iconic instruments-including Jerry Lee Lewis's baby grand piano, Chuck Berry's Gibson ES-350T guitar, Bootsy Collins's star-shaped bass, Keith Moon's drum set, and the white Stratocaster Jimi Hendrix played at Woodstock-as works of art in their own right. Produced in collaboration with the Rock & Roll Hall of Fame, this astounding book goes behind the music to offer a rare and in-depth look at the instruments that inspired the musicians and made possible the songs we know and love. Exhibition: The Metropolitan Museum of Art, New York, USA (01.04-15.09.2019); The Rock & Roll Hall of Fame, Cleveland, USA (20.11.2019-13.09.2020). -- Book jacket.

Coordinated directional migration of cells in the mesoderm layer of the early embryo is essential for organization of the body plan. Here we show that mesoderm organization in mouse embryos depends on β-Pix (Arhgef7), a guanine nucleotide exchange factor for Rac1 and Cdc42. As early as E7.5, β-Pix mutants have an abnormally thick mesoderm layer; later, paraxial mesoderm fails to organize into somites. To define the mechanism of action of β-Pix in vivo, we optimize single-cell live-embryo imaging, cell tracking, and volumetric analysis of individual and groups of mesoderm cells. Use of these methods shows that wild-type cells move in the same direction as their neighbors, whereas adjacent β-Pix mutant cells move in random directions. Wild-type mesoderm cells have long polarized filopodia-like protrusions, which are absent in β-Pix mutants. The data indicate that β-Pix-dependent cellular protrusions drive and coordinate collective migration of the mesoderm in vivo. Mesodermal directional cell migration is needed to establish body plan but how this is regulated is unclear. Here, the authors show that loss of the guanine nucleotide exchange factor for Rac1 and Cdc42, β-Pix, at mouse gastrulation disrupts the orderly, collective anterior migration of mesoderm cells due to defective cell protrusions.

Cancer is a disease in which many of the characteristics of normal cell behavior are lost or perturbed. Uncontrolled cell proliferation and inappropriate cell survival are common features of all cancers, but in addition defects in cellular morphogenesis that lead to tissue disruption, the acquisition of inappropriate migratory and invasive characteristics and the generation of genomic instability through defects in mitosis also accompany progression of the disease. This volume is focused on the actin and microtubule cytoskeletons, key players that underpin these cellular processes. Actin and tubulin form highly versatile, dynamic polymers that are capable of organizing cytoplasmic organelles and intracellular compartments, defining cell polarity and generating both pushing and contractile forces. In the cell cycle, these two cytoskeletal structures drive chromosomal separation and cell division. During morphogenesis, they determine cell shape and polarity, and promote stable cell-cell and cell-matrix adhesions through their interactions with cadherins and integrins, respectively. Finally, during cell migration they generate protrusive forces at the front and retraction forces at the rear. These are all aspects of cell behavior than often go awry in cancer. This volume brings together those interested in understanding the contribution of the actin and microtubule cytoskeletons to the cell biology of cancer.

The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive disorder characterised by the clinical triad of megaloblastic anaemia, sensorineural hearing loss and diabetes mellitus (DM) in young patients. We present a case of a young man with type 1 DM who presented with pancytopenia of unclear aetiology, initially attributed to a COVID-19 infection. After obtaining a bone marrow biopsy and pursuing genetic testing, two pathogenic variants of the SLC19A2 gene consistent with TRMA were discovered in this patient. Treatment with 100 mg of thiamine oral supplementation daily led to the complete resolution of his pancytopenia. It is important to consider a genetic cause of pancytopenia in a young person. Early recognition and diagnosis of TRMA can be life-altering given early treatment can reduce insulin requirements and resolve anaemia.

Entosis is a form of epithelial cell cannibalism that is prevalent in human cancer, typically triggered by loss of matrix adhesion. Here, we report an alternative mechanism for entosis in human epithelial cells, driven by mitosis. Mitotic entosis is regulated by Cdc42, which controls mitotic morphology. Cdc42 depletion enhances mitotic deadhesion and rounding, and these biophysical changes, which depend on RhoA activation and are phenocopied by Rap1 inhibition, permit subsequent entosis. Mitotic entosis occurs constitutively in some human cancer cell lines and mitotic index correlates with cell cannibalism in primary human breast tumours. Adherent, wild-type cells can act efficiently as entotic hosts, suggesting that normal epithelia may engulf and kill aberrantly dividing neighbours. Finally, we report that Paclitaxel/taxol promotes mitotic rounding and subsequent entosis, revealing an unconventional activity of this drug. Together, our data uncover an intriguing link between cell division and cannibalism, of significance to both cancer and chemotherapy. For over a century, scientists looking down microscopes at samples from human cancers have noticed cells eating other cells – in other words, cell cannibalism. The causes and mechanisms involved in this unusual process, which is also known as entosis, are not well understood and its relationship to cancer is complex. On one hand, cell cannibalism may promote cancer by providing nutrients for growing tumours and making it more likely that genetic errors will occur. On the other hand, this process may resist cancer by eliminating damaged cells. In the laboratory, cell cannibalism has only been seen in cells that are detached from their surroundings. Cells in the body are typically surrounded and supported by a mesh of proteins called the extracellular matrix. However, within a tumour, cancer cells can often begin to grow without being attached to the matrix, which means that cell cannibalism can occur. A protein called Cdc42 plays a part in how cells attach to each other and to the extracellular matrix, but the role of Cdc42 in controlling entosis had not been previously explored. Durgan et al. initially set out to ask whether Cdc42 was involved in the established process of cell cannibalism, as seen in detached cells. However, the experiments showed that removing Cdc42 from human cells grown in the laboratory had little effect on this method of entosis. Unexpectedly, though, the loss of Cdc42 did enable a different form of cell cannibalism in cells that remained attached to the extracellular matrix, which had not been seen before. This new cannibalism process is linked to cell division, with cells that are dividing or that have recently divided being consumed by neighbours. This form of cell cannibalism is more commonly seen in cancers where the cells divide a lot, and some chemotherapy drugs that interfere with cell division also increase the rate of cell cannibalism. During cell division a group of proteins – including RhoA and myosin – cause cells to become rounder and stiffer. Durgan et al. suggest this allows the dividing cells to force their way inside other cells, the key first stage of entosis. Since cancer cells divide often, this form of cell cannibalism may lead to the cancer cells being destroyed by their healthy neighbours, in a form of “assisted suicide”. This reveals an unexpected link between cell division and cell cannibalism, which is relevant to both cancer and chemotherapy. Future work will explore whether entosis can be used to predict how a cancer will progress in a patient, or how they will respond to a given treatment.