The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation and metabolism, and is often deregulated in human ...cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration and cancer. Although mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. This review will summarize recent advances in dissecting the relative contributions of mTORC1 versus mTORC2 in cancer, their role in tumor-associated blood vessels and tumor immunity, and provide an update on mTOR inhibitors.
Trust in Social Relations Schilke, Oliver; Reimann, Martin; Cook, Karen S
Annual review of sociology,
07/2021, Letnik:
47, Številka:
1
Journal Article
Recenzirano
Trust is key to understanding the dynamics of social relations, to the extent that it is often viewed as the glue that holds society together. We review the mounting sociological literature to help ...answer what trust is and where it comes from. To this end, we identify two research streams-on particularized trust and generalized trust, respectively-and propose an integrative framework that bridges these lines of research while also enhancing conceptual precision. This framework provides the springboard for identifying several important avenues for future research, including new investigations into the radius of trust, the intermediate form of categorical trust, and the interrelationships between different forms of trust. This article also calls for more scholarship focusing on the consequences (versus antecedents) of trust, addressing more fully the trustee side of the relation, and employing new empirical methods. Such novel approaches will ensure that trust research will continue to provide important insights into the functioning of modern society in the years to come.
Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of antitumor immune ...responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through MHCs. Although tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen-presenting complex traditionally associated with professional antigen-presenting cells. MHC-II is critical for antigen presentation to CD4
T lymphocytes, whose role in antitumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.
Several advances in recent years have focused increasing attention on the role of the RAF-MEK-ERK1/2 pathway in promoting cell survival. The demonstration that BRAF is a human oncogene mutated at ...high frequency in melanoma, thyroid and colon cancer has provided a pathophysiological context, whilst the description of potent and highly selective inhibitors of BRAF or MEK has allowed a more informed and rational intervention in both normal and tumour cells. In addition, separate studies have uncovered new mechanisms by which the ERK1/2 pathway can control the activity or abundance of members of the BCL-2 protein family to promote cell survival. It is now apparent that various oncogenes co-opt ERK1/2 signalling to de-regulate these BCL-2 proteins and this contributes to, and even underpins, survival signalling in some tumours. New oncogene-targeted therapies allow direct or indirect inhibition of ERK1/2 signalling and can cause quite striking tumour cell death. In other cases, inhibition of the ERK1/2 pathway may be more effective in combination with other conventional and novel therapeutics. Here, we review recent advances in our understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies.
Within the course of a single minute, millions of cells in the human body will undergo programmed cell death in response to physiological or pathological cues. The diminished energetic capacity of an ...apoptotic cell renders the cell incapable of sustaining plasma membrane integrity. Under these circumstances, intracellular contents that might leak into the surrounding tissue microenvironment, a process referred to as secondary necrosis, could induce inflammation and tissue damage. Remarkably, in most cases of physiologically rendered apoptotic cell death, inflammation is avoided because a mechanism to swiftly remove apoptotic cells from the tissue prior to their secondary necrosis becomes activated. This mechanism, referred to as efferocytosis, uses phagocytes to precisely identify and engulf neighboring apoptotic cells. In doing so, efferocytosis mantains tissue homeostasis that would otherwise be disrupted by normal cellular turnover and exacerbated further when the burden of apoptotic cells becomes elevated due to disease or insult. Efferocytosis also supports the resolution of inflammation, restoring tissue homesostasis. The importance of efferocytosis in health and disease underlies the increasing research efforts to understand the mechanisms by which efferocytosis occurs, and how a failure in the efferocytic machinery contributes to diseases, or conversely, how cancers effectively use the existing efferocytic machinery to generate a tumor-tolerant, immunosuppressive tumor microenvironment. We discuss herein the molecular mechanisms of efferocytosis, how the process of efferocytosis might support a tumor ‘wound healing’ phenotype, and efforts to target efferocytosis as an adjunct to existing tumor treatments.
The concentration of radiocarbon (14C) differs between ocean and atmosphere. Radiocarbon determinations from samples which obtained their 14C in the marine environment therefore need a ...marine-specific calibration curve and cannot be calibrated directly against the atmospheric-based IntCal20 curve. This paper presents Marine20, an update to the internationally agreed marine radiocarbon age calibration curve that provides a non-polar global-average marine record of radiocarbon from 0–55 cal kBP and serves as a baseline for regional oceanic variation. Marine20 is intended for calibration of marine radiocarbon samples from non-polar regions; it is not suitable for calibration in polar regions where variability in sea ice extent, ocean upwelling and air-sea gas exchange may have caused larger changes to concentrations of marine radiocarbon. The Marine20 curve is based upon 500 simulations with an ocean/atmosphere/biosphere box-model of the global carbon cycle that has been forced by posterior realizations of our Northern Hemispheric atmospheric IntCal20 14C curve and reconstructed changes in CO2 obtained from ice core data. These forcings enable us to incorporate carbon cycle dynamics and temporal changes in the atmospheric 14C level. The box-model simulations of the global-average marine radiocarbon reservoir age are similar to those of a more complex three-dimensional ocean general circulation model. However, simplicity and speed of the box model allow us to use a Monte Carlo approach to rigorously propagate the uncertainty in both the historic concentration of atmospheric 14C and other key parameters of the carbon cycle through to our final Marine20 calibration curve. This robust propagation of uncertainty is fundamental to providing reliable precision for the radiocarbon age calibration of marine based samples. We make a first step towards deconvolving the contributions of different processes to the total uncertainty; discuss the main differences of Marine20 from the previous age calibration curve Marine13; and identify the limitations of our approach together with key areas for further work. The updated values for ΔR, the regional marine radiocarbon reservoir age corrections required to calibrate against Marine20, can be found at the data base http://calib.org/marine/.
Power decreases trust in social exchange Schilke, Oliver; Reimann, Martin; Cook, Karen S.
Proceedings of the National Academy of Sciences - PNAS,
10/2015, Letnik:
112, Številka:
42
Journal Article
Recenzirano
Odprti dostop
How does lacking vs. possessing power in a social exchange affect people’s trust in their exchange partner? An answer to this question has broad implications for a number of exchange settings in ...which dependence plays an important role. Here, we report on a series of experiments in which we manipulated participants’ power position in terms of structural dependence and observed their trust perceptions and behaviors. Over a variety of different experimental paradigms and measures, we find that more powerful actors place less trust in others than less powerful actors do. Our results contradict predictions by rational actor models, which assume that low-power individuals are able to anticipate that a more powerful exchange partner will place little value on the relationship with them, thus tends to behave opportunistically, and consequently cannot be trusted. Conversely, our results support predictions by motivated cognition theory, which posits that low-power individuals want their exchange partner to be trustworthy and then act according to that desire. Mediation analyses show that, consistent with the motivated cognition account, having low power increases individuals’ hope and, in turn, their perceptions of their exchange partners’ benevolence, which ultimately leads them to trust.
A complete characterization of the inkjet printing process using metallic nanoparticle inks on a paper substrate for microwave frequencies up to 12.5 GHz as well as its application to low-cost, high ...gain and wideband antenna design are demonstrated in this work. Laser and heat sintering of metallic nanoparticles are compared on paper substrate for the first time which demonstrate immense cost and time benefits of laser sintering. The antennas fabricated using the characterized process include a Vivaldi for the UWB band which exhibits a significantly higher gain of up to 8 dBi as compared to the currently published inkjet printed antennas, and a novel slow-wave log periodic dipole array which employs a new miniaturization technique to show 20% width reduction.
Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum. Approaches aimed at intrinsic cellular immunity in the tumor microenvironment are less ...understood, but are of intense interest, based on their ability to induce tumor cell apoptosis while orchestrating innate and adaptive immune responses against tumor antigens. The intrinsic immune response is initiated by ancient, highly conserved intracellular proteins that detect viral infection. For example, the RIG-I-like receptors (RLRs), a family of related RNA helicases, detect viral oligonucleotide patterns of certain RNA viruses. RLR activation induces immunogenic cell death of virally infected cells, accompanied by increased inflammatory cytokine production, antigen presentation, and antigen-directed immunity against virus antigens. Approaches aimed at non-infectious RIG-I activation in cancers are being tested as a treatment option, with the goal of inducing immunogenic tumor cell death, stimulating production of pro-inflammatory cytokines, enhancing tumor neoantigen presentation, and potently increasing cytotoxic activity of tumor infiltrating lymphocytes. These studies are finding success in several pre-clinical models, and are entering early phases of clinical trial. Here, we review pre-clinical studies of RLR agonists, including the successes and challenges currently faced RLR agonists on the path to clinical translation.
Detection of human wastewater contamination in recreational waters is of critical importance to regulators due to the risks posed to public health. To identify such risks, human wastewater-associated ...microbial source tracking (MST) markers have been developed. At present, however, a greater understanding of the suitability of these markers for the detection of diluted human wastewater in environmental waters is necessary to predict risk. Here, we compared the process limit of detection (PLOD) and process limit of quantification (PLOQ) of six human wastewater-associated MST markers (
HF183 HF183,
H8 EC H8,
, human adenovirus HAdV, human polyomavirus HPyV, and pepper mild mottle virus PMMoV) in relation to a fecal indicator bacterium (FIB),
sp. 23S rRNA (ENT 23S), and three enteric viruses (human adenovirus serotypes 40/41 HAdV 40/41, human norovirus HNoV, and human enterovirus EV) in beach water samples seeded with raw and secondary-treated wastewater. Among the six MST markers tested, HF183 was the most sensitive measure of human fecal pollution and was quantifiable up to dilutions of 10
and 10
for beach water samples seeded with raw and secondary-treated wastewater, respectively. Other markers and enteric viruses were detected at various dilutions (10
to 10
). These MST markers, FIB, and enteric viruses were then quantified in beach water (
= 12) and sand samples (
= 12) from South East Queensland (SEQ), Australia, to estimate the levels of human fecal pollution. Of the 12 sites examined, beach water and sand samples from several sites had quantifiable concentrations of HF183 and PMMoV markers. Overall, our results indicate that while HF183 is the most sensitive measure of human fecal pollution, it should be used in conjunction with a conferring viral marker to avoid overestimating the risk of gastrointestinal illness.
MST is an effective tool to help utilities and regulators improve recreational water quality around the globe. Human fecal pollution poses significant public health risks compared to animal fecal pollution. Several human wastewater-associated markers have been developed and used for MST field studies. However, a head-to-head comparison in terms of their performance to detect diluted human fecal pollution in recreational water is lacking. In this study, we cross-compared the performance of six human wastewater-associated markers in relation to FIB and enteric viruses in beach water samples seeded with raw and secondary-treated wastewater. The results of this study will provide guidance to regulators and utilities on the appropriate application of MST markers for tracking the sources of human fecal pollution in environmental waters and confer human health risks.
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