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PHOTO (COLOR): Voluntary declarations in submitted manuscripts can describe gender balance in study samples, for example. "These [manuscript] statements might arguably only be done by those who already understand the importance of equity, diversity, and inclusion", Roessler said. [Extracted from the article]

MAP: This map of a developing liver shows single cells as dots, color coded by cell type. In 2016, drawing on technologies that enable researchers to routinely study individual cells, a group of 90 scientists from the around the world launched the Human Cell Atlas (HCA), which aims to catalog how cells operate in different tissues. [Extracted from the article]

The MCU ensures that proliferating cells produce the ATP required to progress through the cell cycle. [ABSTRACT FROM AUTHOR]

No holds barred for antitumor attack: Epstein-Barr virus (EBV) is a common pathogen that contributes to the development of several cancers, which can be difficult to treat. γδ-T cells have innate activity and have been proposed as a cancer immunotherapy, but they have been difficult to apply, particularly because they have to be individually prepared for each patient. To overcome the hurdles associated with whole γδ-T cell–based therapy, Wang et al. isolated exosomes from a subtype of activated γδ-T cells, which contained multiple immunostimulatory molecules and cell death–inducing ligands. These exosomes were effective against multiple mouse models of EBV-associated cancers and did not require customized preparation unlike cell-based therapies. Treatment of life-threatening Epstein-Barr virus (EBV)–associated tumors remains a great challenge, especially for patients with relapsed or refractory disease. Here, we found that exosomes derived from phosphoantigen-expanded Vδ2-T cells (Vδ2-T-Exos) contained death-inducing ligands (FasL and TRAIL), an activating receptor for natural killer (NK) cells (NKG2D), immunostimulatory ligands (CD80 and CD86), and antigen-presenting molecules (MHC class I and II). Vδ2-T-Exos targeted and efficiently killed EBV-associated tumor cells through FasL and TRAIL pathways and promoted EBV antigen–specific CD4 and CD8 T cell expansion. Administration of Vδ2-T-Exos effectively controlled EBV-associated tumors in Rag2−/−γc−/− and humanized mice. Because expanding Vδ2-T cells and preparing autologous Vδ2-T-Exos from cancer patients ex vivo in large scale is challenging, we explored the antitumor activity of allogeneic Vδ2-T-Exos in humanized mouse cancer models. Here, we found that allogeneic Vδ2-T-Exos had more effective antitumor activity than autologous Vδ2-T-Exos in humanized mice; the allogeneic Vδ2-T-Exos increased the infiltration of T cells into tumor tissues and induced more robust CD4 and CD8 T cell–mediated antitumor immunity. Compared with exosomes derived from NK cells (NK-Exos) with direct cytotoxic antitumor activity or dendritic cells (DC-Exos) that induced T cell antitumor responses, Vδ2-T-Exos directly killed tumor cells and induced T cell–mediated antitumor response, thus resulting in more effective control of EBV-associated tumors. This study provided proof of concept for the strategy of using Vδ2-T-Exos, especially allogeneic Vδ2-T-Exos, to treat EBV-associated tumors. [ABSTRACT FROM AUTHOR]

Taming tonic signaling: Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) is an effective therapy for select lymphomas. The potency of this therapy can be limited by antigen-independent (tonic) signaling, which promotes progressive CAR-T cell inactivation. Fisher et al. used mass cytometry to analyze CAR-T cells and found that the process of increasing αβ T cell numbers during CAR-T cell production (expansion) was sufficient to increase tonic signaling in αβ T cells. In contrast, expansion of γδT cells did not alter their basal activity. When these cells were engineered to express a chimeric costimulatory receptor, they specifically recognized transformed, but not healthy, myeloid cell targets. These data demonstrate a strategy for engineering specific antitumor responses free of the complications associated with tonic signaling. Despite the benefits of chimeric antigen receptor (CAR)–T cell therapies against lymphoid malignancies, responses in solid tumors have been more limited and off-target toxicities have been more marked. Among the possible design limitations of CAR-T cells for cancer are unwanted tonic (antigen-independent) signaling and off-target activation. Efforts to overcome these hurdles have been blunted by a lack of mechanistic understanding. Here, we showed that single-cell analysis with time course mass cytometry provided a rapid means of assessing CAR-T cell activation. We compared signal transduction in expanded T cells to that in T cells transduced to express second-generation CARs and found that cell expansion enhanced the response to stimulation. However, expansion also induced tonic signaling and reduced network plasticity, which were associated with expression of the T cell exhaustion markers PD-1 and TIM-3. Because this was most evident in pathways downstream of CD3ζ, we performed similar analyses on γδT cells that expressed chimeric costimulatory receptors (CCRs) lacking CD3ζ but containing DAP10 stimulatory domains. These CCR-γδT cells did not exhibit tonic signaling but were efficiently activated and mounted cytotoxic responses in the presence of CCR-specific stimuli or cognate leukemic cells. Single-cell signaling analysis enabled detailed characterization of CAR-T and CCR-T cell activation to better understand their functional activities. Furthermore, we demonstrated that CCR-γδT cells may offer the potential to avoid on-target, off-tumor toxicity and allo-reactivity in the context of myeloid malignancies. [ABSTRACT FROM AUTHOR]

The article discusses a research paper on the mechanism in mammalian cells for forming the autophagosomal membrane. It references a study by Tsuboyama et al., published within the issue of "Science". It discusses the implications of the study to the mechanism in mammalian cells for forming the autophagosomal membrane, and the action of two ubiquitin-like protein conjugation systems.

Fat triggers metastasis: In melanoma patient samples, tumors appear to grow in a lateral, proliferative phase within the upper epidermal layer of the skin but switch to a vertical, invasive phase when they grow into the deeper layers where adipose (fat) exists. Golan et al. examined cocultures of melanoma cells and adipocytes and identified a direct role for fat cells in this metastatic switch. The authors found that adipocytes secreted cytokines that signaled through their receptors on melanoma cells to repress the expression of a microRNA that promotes proliferative and suppresses invasive phenotypes. The microRNA also represses the expression of a receptor for the growth factor TGF-β, which is implicated in metastatic disease and abundant in the dermal layer. Blocking TGF-β signaling prevented the invasive switch in cultured melanoma cells and, therefore, may suppress metastasis in patients. Transforming growth factor–β (TGF-β) superfamily members are critical signals in tissue homeostasis and pathogenesis. Melanoma grows in the epidermis and invades the dermis before metastasizing. This disease progression is accompanied by increased sensitivity to microenvironmental TGF-β. Here, we found that skin fat cells (adipocytes) promoted metastatic initiation by sensitizing melanoma cells to TGF-β. Analysis of melanoma clinical samples revealed that adipocytes, usually located in the deeper hypodermis layer, were present in the upper dermis layer within proximity to in situ melanoma cells, an observation that correlated with disease aggressiveness. In a coculture system, adipocytes secreted the cytokines IL-6 and TNF-α, which induced a proliferative-to-invasive phenotypic switch in melanoma cells by repressing the expression of the microRNA miR-211. In a xenograft model, miR-211 exhibited a dual role in melanoma progression, promoting cell proliferation while inhibiting metastatic spread. Bioinformatics and molecular analyses indicated that miR-211 directly targeted and repressed the translation of TGFBR1 mRNA, which encodes the type I TGF-β receptor. Hence, through this axis of cytokine-mediated repression of miR-211, adipocytes increased the abundance of the TGF-β receptor in melanoma cells, thereby enhancing cellular responsiveness to TGF-β ligands. The induction of TGF-β signaling, in turn, resulted in a proliferative-to-invasive phenotypic switch in cultured melanoma cells. Pharmacological inhibition of TGF-β prevented these effects. Our findings further reveal a molecular link between fat cells and metastatic progression in melanoma that might be therapeutically targeted in patients. [ABSTRACT FROM AUTHOR]

Combined patient and animal model studies implicate microbiota-triggered TH17 cells as disease drivers and therapeutic targets in periodontitis. Probing periodontitis pathology: Periodontitis is a common inflammatory disease that can lead to bone loss. Dutzan et al. used a mouse model of ligature-induced periodontitis and samples from patients to demonstrate that TH17 cells drive disease. People naturally deficient in TH17 cells were less likely to develop periodontitis. These pathogenic cells were dependent on the microbiome, and targeting TH17 cells with a small-molecule inhibitor dampened inflammation and bone loss in mice. Their results reveal mechanisms behind the immunopathology and could lead to effective treatments for this disease. Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, we demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Our study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis. [ABSTRACT FROM AUTHOR]

Phase separation advocates hold that proteins and other molecules self-organize into denser structures inside cells, like oil drops forming in water. The results spurred Tjian, McSwiggen, Mir, and Xavier Darzacq, a cell biologist who co-directs the UC Berkeley lab with Tjian, to scrutinize the phase separation literature. Tjian and colleagues also chastised researchers for often assuming the protein concentration in a cell is high enough to trigger phase separation, instead of actually measuring it. Mir, who has been skeptical of much of the evidence for phase separation, agrees that the field seems to be moving away from the "everything is phase separation" stage to a more nuanced discussion of the formation and functions of condensates. [Extracted from the article]

New method to edit cell's "powerhouse" DNA could help study variety of genetic diseases PHOTO (COLOR): A new genome editing tool brings together two halves of a bacterial toxin (yellow) at targeted points on the DNA double helix to fix mutations. They also hope to improve editing efficiency and reduce off-target edits so that mtDNA base editing can eventually be tested in humans. [Extracted from the article]

PHOTO (COLOR): To slay the larger cancer cell they are attached to, the two smaller killer T cells release protein bombs. Whether killer T cells just squirt out granzymes and perforin or rely on specialized structures to transport the lethal molecules to the target cell has not been clear. However, he cautions that the authors have not demonstrated whether killer T cells make and then release SMAPs or release the components, which then assemble into SMAPs at the target. [Extracted from the article]

Highlights from the article: With the DNA-snipping CRISPR genome-editing system, they cut one of the antibody genes in mouse B cells. After the inserted gene settled into position in the sliced DNA, it began to work, and the B cells churned out the RSV-targeting antibody. The B cell approach might allow researchers to harness these antibodies and thus provide protection against HIV infection.

Exosomes containing the adaptor ASC spread NLRP3 inflammasome activation between cells after manganese exposure. Exosomes transfer inflammasome activation: Chronic occupational exposure to manganese is associated with the development of Parkinson's disease. Sarkar et al. found that exposure of primed microglial cells or mice to manganese increased NLRP3 inflammasome expression and activation. Manganese caused mitochondrial dysfunction in treated microglial cells and stimulated their release of exosomes containing the inflammasome adaptor protein ASC. The effects of manganese on inflammasome activation were sensitive to reduced endocytosis and transferable by exposure of cells to purified exosomes from ASC-sufficient cells. Similarly, serum exosomes from welders contained more ASC and were more inflammatory than those from normal donors, suggesting that occupational manganese exposure may increase systemic inflammasome activation due to exosome-mediated transfer of ASC. Chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases. Divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In this study, we examined whether Mn2+ activates the multiprotein NLRP3 inflammasome complex to promote neuroinflammation. Exposing activated mouse microglial cells to Mn2+ substantially augmented NLRP3 abundance, caspase-1 cleavage, and maturation of the inflammatory cytokine interleukin-1β (IL-1β). Exposure of mice to Mn2+ had similar effects in brain microglial cells. Furthermore, Mn2+ impaired mitochondrial ATP generation, basal respiratory rate, and spare capacity in microglial cells. These data suggest that Mn-induced mitochondrial defects drove the inflammasome signal amplification. We found that Mn induced cell-to-cell transfer of the inflammasome adaptor protein ASC in exosomes. Furthermore, primed microglial cells exposed to exosomes from Mn-treated mice released more IL-1β than did cells exposed to exosomes from control-treated animals. We also observed that welders exposed to manganese-containing fumes had plasma exosomes that contained more ASC than did those from a matched control group. Together, these results suggest that the divalent metal manganese acts as a key amplifier of NLRP3 inflammasome signaling and exosomal ASC release. [ABSTRACT FROM AUTHOR]