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BECLIN1 is a well-established regulator of autophagy, a process essential for mammalian survival. It functions in conjunction with other proteins to form Class III Phosphoinositide 3-Kinase (PI3K) complexes to generate phosphorylated phosphatidylinositol (PtdIns), lipids essential for not only autophagy but other membrane trafficking processes. Over the years, studies have elucidated the structural, biophysical, and biochemical properties of BECLIN1, which have shed light on how this protein functions to allosterically regulate these critical processes of autophagy and membrane trafficking. Here, we review these findings and how BECLIN1’s diverse protein interactome regulates it, as well as its impact on organismal physiology.

Perforin is a key protein of the vertebrate immune system. Secreted by cytotoxic lymphocytes as soluble monomers, perforin can self-assemble into oligomeric pores of 10–20 nm inner diameter in the membranes of virus-infected and cancerous cells. These large pores facilitate the entry of pro-apoptotic granzymes, thereby rapidly killing the target cell. To elucidate the pathways of perforin pore assembly, we carried out real-time atomic force microscopy and electron microscopy studies. Our experiments reveal that the pore assembly proceeds via a membrane-bound prepore intermediate state, typically consisting of up to approximately eight loosely but irreversibly assembled monomeric subunits. These short oligomers convert to more closely packed membrane nanopore assemblies, which can subsequently recruit additional prepore oligomers to grow the pore size. Perforin monomers self-assemble into pre-pores that first insert into the membrane and then recruit additional subunits to grow in size.

Endothelial cells are integral components of all vasculature within complex organisms. As they line the blood vessel wall, endothelial cells are constantly exposed to a variety of molecular factors and shear force that can induce cellular damage and stress. However, how endothelial cells are removed or eliminate unwanted cellular contents, remains unclear. The generation of large extracellular vesicles (EVs) has emerged as a key mechanism for the removal of cellular waste from cells that are dying or stressed. Here, we used intravital microscopy of the bone marrow to directly measure the kinetics of EV formation from endothelial cells in vivo under homoeostatic and malignant conditions. These large EVs are mitochondria-rich, expose the ‘eat me’ signal phosphatidylserine, and can interact with immune cell populations as a potential clearance mechanism. Elevated levels of circulating EVs correlates with degradation of the bone marrow vasculature caused by acute myeloid leukaemia. Together, our study provides in vivo spatio-temporal characterization of EV formation in the murine vasculature and suggests that circulating, large endothelial cell-derived EVs can provide a snapshot of vascular damage at distal sites. The extrusion of large extracellular vesicles is an important mechanism that facilitates cell-to-cell communication and maintains homoeostasis. Here, Atkin-Smith et al. use intravital microscopy to directly visualize the formation of large extracellular vesicles in bone marrow.

This essay employs the \"Korean War minor\" as a methodological lens to demonstrate the need for more Asian Americanist critique at the intersection of American childhood studies and empire studies. While scholars have shown how children and children's culture were central to advancing US Cold War policy at home and abroad, this body of research largely neglects to interrogate the centrality of whiteness to dominant constructions of children/childhood. Attending to childhood as a technology of racist, patriarchal, imperial power, I elucidate how the biopolitics of the Korean War produce juvenile Asian-raced and gendered bodies at the precarious boundaries of childhood, as not quite children but, rather, childlike . I grapple, in particular, with how to reclaim the \"girl\" from US military archives, as the rubric of the \"boy-mascot\" and \"camptown woman\" overdetermine and constrain how the girl is allowed to come into view. I develop and enact this decolonial practice of reclaiming the Korean War minor through an analysis of Nora Okja Keller's Fox Girl , a novel that is particularly invested in narrating the camptown girl into being. Fox Girl directs attention to the limits of a politics of childhood innocence and prompts a generative reconceptualization of childhood in relation to justice.

Diverse pathogenic agents often utilize overlapping host networks and hub proteins within these networks represent attractive targets for broad-spectrum drugs. Using bacterial toxins, we describe a new approach for discovering broad-spectrum therapies capable of inhibiting host proteins that mediate multiple pathogenic pathways. This approach can be widely used, as it combines genetic-based target identification with cell survival-based and protein function-based multiplex drug screens and concurrently discovers therapeutic compounds and their protein targets. Using B-lymphoblastoid cells derived from the HapMap Project cohort of persons of African, European and Asian ancestry we identified host caspases as hub proteins that mediate the lethality of multiple pathogenic agents. We discovered that an approved drug, Bithionol, inhibits host caspases and also reduces the detrimental effects of anthrax lethal toxin, diphtheria toxin, cholera toxin, Pseudomonas aeruginosa exotoxin A, Botulinum neurotoxin, ricin and Zika virus. Our study reveals the practicality of identifying host proteins that mediate multiple disease pathways and discovering broad-spectrum therapies that target these hub proteins.

The major limitations of pathogen-directed therapies are the emergence of drug-resistance and their narrow spectrum of coverage. A recently applied approach directs therapies against host proteins exploited by pathogens in order to circumvent these limitations. However, host-oriented drugs leave the pathogens unaffected and may result in continued pathogen dissemination. In this study we aimed to discover drugs that could simultaneously cross-inhibit pathogenic agents, as well as the host proteins that mediate their lethality. We observed that many pathogenic and host-assisting proteins belong to the same functional class. In doing so we targeted a protease component of anthrax toxin as well as host proteases exploited by this toxin. We identified two approved drugs, ascorbic acid 6-palmitate and salmon sperm protamine, that effectively inhibited anthrax cytotoxic protease and demonstrated that they also block proteolytic activities of host furin, cathepsin B, and caspases that mediate toxin’s lethality in cells. We demonstrated that these drugs are broad-spectrum and reduce cellular sensitivity to other bacterial toxins that require the same host proteases. This approach should be generally applicable to the discovery of simultaneous pathogen and host-targeting inhibitors of many additional pathogenic agents.

Autophagy-related genes have been closely associated with intestinal homeostasis. BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrate autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice leads to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibit extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells display morphological abnormalities. Deletion of the autophagy regulator, ATG7, fails to elicit similar effects, suggesting additional novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice show E-CADHERIN mislocalisation associated with abnormalities in the endocytic trafficking pathway. This provides a mechanism linking endocytic trafficking mediated by BECLIN1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has important implications for our understanding of intestinal pathophysiology. Deletion of BECLIN1 in mice leads to fatal intestinal disruption and compromised gut barrier integrity. This study establishes that BECLIN1 is essential for intestinal homeostasis and uncovers its role in endocytic trafficking in this process.

This essay explores the violence and viability of kawaii, a Japanese \"cute\" aesthetic, for theorizing Asian American feminism. Critics point out kawaii's embeddedness in visual commodity culture and global racial capitalism, denouncing the multivalent forms of objectification that Asian cutification entails and invites. Through an analysis of the anime Madoka Magica and Ruth Ozeki's novel A Tale for the Time Being, this essay demonstrates how the invocation of kawaii need not be read as a simple resignation to structural inequities. Both works harness this feminized cute aesthetic to speak to the social and economic precarity of the contemporary neoliberal moment and to imagine alternative models of ethicopolitical collectivity that can better accommodate those forms and feelings of precarity.

This essay reflects on the critical possibilities and stakes of (re)imagining Asian/America as a multispecies formation by analyzing Larissa Lai’s novel, Salt Fish Girl, alongside sybil unrest, her collaborative poem with Rita Wong. Through mobilizing speculative and spectacularized images of the Asian girl, respectively, both texts press us to confront linked human-nonhuman histories of racialization and gendered violence/exploitation. The novel conjures stinky multispecies assemblages that disrupt the knowledge-power structures of Orientalism, while the poem literally stages the assembling of multiple authorial bodies and cultivates transgressive ecological frames of vision. This essay engages these works to theorize expanded ecofeminist models of ethico-political collectivity for Asian American studies.