Myeloid cells are key drivers of physiological responses to pathogen invasion or tissue damage. Members of the C-type lectin receptor (CLR) family stand out among the specialized receptors utilized ...by myeloid cells to orchestrate these responses. CLR ligands include carbohydrate, protein, and lipid components of both pathogens and self, which variably trigger endocytic, phagocytic, proinflammatory, or anti-inflammatory reactions. These varied outcomes rely on a versatile system for CLR signaling that includes tyrosine-based motifs that recruit kinases, phosphatases, or endocytic adaptors as well as nontyrosine-based signals that modulate the activation of other pathways or couple to the uptake machinery. Here, we review the signaling properties of myeloid CLRs and how they impact the role of myeloid cells in innate and adaptive immunity.
Dendritic cells (DCs) prime anti-tumor T cell responses in tumor-draining lymph nodes and can restimulate T effector responses in the tumor site. Thus, in addition to unleashing T cell effector ...activity, current immunotherapies should be directed to boost DC function. Herein, we review the potential function of Flt3L as a tool for cancer immunotherapy. Flt3L is a growth factor that acts in Flt3-expressing multipotent progenitors and common lymphoid progenitors. Despite the broad expression of Flt3 in the hematopoietic progenitors, the main effect of the Flt3/Flt3L axis, revealed by the characterization of mice deficient in these genes, is the generation of conventional DCs (cDCs) and plasmacytoid DCs (pDCs). However, Flt3 signaling through PI3K and mTOR may also affect the function of mature DCs. We recapitulate the use of Flt3L in preclinical studies either as a single agent or in combination with other cancer therapies. We also analyze the use of Flt3L in clinical trials. The strong correlation between type 1 cDC (cDC1) infiltration of human cancers with overall survival in many cancer types suggests the potential use of Flt3L to boost expansion of this DC subset. However, this may need the combination of Flt3L with other immunomodulatory agents to boost cancer immunotherapy.
The amyloid‐forming Aβ peptide is able to interact with metal cations to form very stable complexes that influence fibril formation and contribute to the onset of Alzheimer's disease. Multiple ...structures of peptides derived from Aβ in complex with different metals have been resolved experimentally to provide an atomic‐level description of the metal‐protein interactions. However, Aβ is intrinsically disordered, and hence more amenable to an ensemble description. Molecular dynamics simulations can now reach the timescales needed to generate ensembles for these type of complexes. However, this requires accurate force fields both for the protein and the protein‐metal interactions. Here we use state‐of‐the‐art methods to generate force field parameters for the Zn(II) cations in a set of complexes formed by different Aβ variants and combine them with the Amber99SB*‐ILDN optimized force field. Upon comparison of NMR experiments with the simulation results, further optimized with a Bayesian/Maximum entropy approach, we provide an accurate description of the molecular ensembles for most Aβ‐metal complexes. We find that the resulting conformational ensembles are more heterogeneous than the NMR models deposited in the Protein Data Bank.
Challenge with specific microbial stimuli induces long lasting epigenetic changes in innate immune cells that result in their enhanced response to a second challenge by the same or unrelated ...microbial insult, a process referred to as trained immunity. This opens a new avenue in vaccinology to develop
(TIbV), defined as vaccine formulations that induce training in innate immune cells. Unlike conventional vaccines, which are aimed to elicit only specific responses to vaccine-related antigens, TIbV aim to stimulate broader responses. As trained immunity is generally triggered by pattern recognition receptors (PRRs), TIbV should be formulated with microbial structures containing suitable PRR-ligands. The TIbV concept we describe here may be used for the development of vaccines focused to promote host resistance against a wide spectrum of pathogens. Under the umbrella of trained immunity, a broad protection can be achieved by: (i) increasing the nonspecific effector response of innate immune cells (e.g., monocyte/macrophages) to pathogens, (ii) harnessing the activation state of dendritic cells to enhance adaptive T cell responses to both specific and nonrelated (bystander) antigens. This capacity of TIbV to promote responses beyond their nominal antigens may be particularly useful when conventional vaccines are not available or when multiple coinfections and/or recurrent infections arise in susceptible individuals. As the set of PRR-ligands chosen is essential not only for stimulating trained immunity but also to drive adaptive immunity, the precise design of TIbV will improve with the knowledge on the functional relationship among the different PRRs. While the TIbV concept is emerging, a number of the current anti-infectious vaccines, immunostimulants, and even vaccine adjuvants may already fall in the TIbV category. This may apply to increase immunogenicity of novel vaccine design approaches based on small molecules, like those achieved by reverse vaccinology.
Markov state models (MSMs) have become one of the most important techniques for understanding biomolecular transitions from classical molecular dynamics (MD) simulations. MSMs provide a systematized ...way of accessing the long time kinetics of the system of interest from the short-time scale microscopic transitions observed in simulation trajectories. At the same time, they provide a consistent description of the equilibrium and dynamical properties of the system of interest, and they are ideally suited for comparisons against experiment. A few software packages exist for building MSMs, which have been widely adopted. Here we introduce MasterMSM, a new Python package that uses the master equation formulation of MSMs and provides a number of new algorithms for building and analyzing these models. We demonstrate some of the most distinctive features of the package, including the estimation of rates, definition of core-sets for transition based assignment of states, the estimation of committors and fluxes, and the sensitivity analysis of the emerging networks. The package is available at https://github.com/daviddesancho/MasterMSM.
Dendritic cells (DCs) control innate and adaptive immunity by patrolling tissues to gather antigens and danger signals derived from microbes and tissue. Subsequently, DCs integrate those ...environmental cues, orchestrate immunity or tolerance, and regulate tissue homeostasis. Recent advances in the field of immunometabolism highlight the notion that immune cells markedly alter cellular metabolic pathways during differentiation or upon activation, which has important implications on their functionality. Previous studies showed that active oxidative phosphorylation in mitochondria is associated with immature or tolerogenic DCs, while increased glycolysis upon pathogen sensing can promote immunogenic DC functions. However, new results in the last years suggest that regulation of DC metabolism in steady state, after immunogenic activation and during tolerance in different pathophysiological settings, may be more complex. Moreover, ontogenically distinct DC subsets show different functional specializations to control T cell responses. It is, thus, relevant how metabolism influences DC differentiation and plasticity, and what potential metabolic differences exist among DC subsets. Better understanding of the emerging connection between metabolic adaptions and functional DC specification will likely allow the development of therapeutic strategies to manipulate immune responses.
FeFe hydrogenases are the most efficient H2 -producing enzymes. However, inactivation by O2 remains an obstacle that prevents them being used in many biotechnological devices. Here, we combine ...electrochemistry, site-directed mutagenesis, molecular dynamics and quantum chemical calculations to uncover the molecular mechanism of O2 diffusion within the enzyme and its reactions at the active site. We propose that the partial reversibility of the reaction with O2 results from the four-electron reduction of O2 to water. The third electron/proton transfer step is the bottleneck for water production, competing with formation of a highly reactive OH radical and hydroxylated cysteine. The rapid delivery of electrons and protons to the active site is therefore crucial to prevent the accumulation of these aggressive species during prolonged O2 exposure. These findings should provide important clues for the design of hydrogenase mutants with increased resistance to oxidative damage.
Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil ...emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources. CXCL1 was produced mainly by TNF-stimulated endothelial cells (ECs) and pericytes and supported luminal and sub-EC neutrophil crawling. Conversely, neutrophils were the main producers of CXCL2, and this chemokine was critical for correct breaching of endothelial junctions. This pro-migratory activity of CXCL2 depended on the atypical chemokine receptor 1 (ACKR1), which is enriched within endothelial junctions. Transmigrating neutrophils promoted a self-guided migration response through EC junctions, creating a junctional chemokine “depot” in the form of ACKR1-presented CXCL2 that enabled efficient unidirectional luminal-to-abluminal migration. Thus, CXCL1 and CXCL2 act in a sequential manner to guide neutrophils through venular walls as governed by their distinct cellular sources.
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•The CXCR2 ligands CXCL1 and CXCL2 play distinct roles in neutrophil diapedesis•Endothelial cell (EC)- and pericyte-derived CXCL1 mediate neutrophil crawling•CXCL2 is neutrophil derived and is retained at EC junctions by ACKR1•ACKR1-CXCL2 axis is critical for unidirectional paracellular neutrophil TEM in vivo
Girbl et al. find that sequential interactions with the chemokines CXCL1 and CXCL2 guide neutrophil crawling and subsequent migration through venular walls during inflammation. Transmigrating neutrophils promoted unidirectional luminal-to-abluminal migration by depositing CXCL2 on the chemokine receptor ACKR1 at endothelial junctions, providing a paradigm of self-guided migration.
The goal of successful anti-tumoural immunity is the development of long-term protective immunity to prevent relapse. Infiltration of tumours with CD8
T cells with a resident memory (Trm) phenotype ...correlates with improved survival. However, the interplay of circulating CD8
T cells and Trm cells remains poorly explored in tumour immunity. Using different vaccination strategies that fine-tune the generation of Trm cells or circulating memory T cells, here we show that, while both subsets are sufficient for anti-tumour immunity, the presence of Trm cells improves anti-tumour efficacy. Transferred central memory T cells (Tcm) generate Trm cells following viral infection or tumour challenge. Anti-PD-1 treatment promotes infiltration of transferred Tcm cells within tumours, improving anti-tumour immunity. Moreover, Batf3-dependent dendritic cells are essential for reactivation of circulating memory anti-tumour response. Our findings show the plasticity, collaboration and requirements for reactivation of memory CD8
T cells subsets needed for optimal tumour vaccination and immunotherapy.
This study aimed to assess country-specific evidence of physical and non-physical acts of workplace violence towards nurses working in the health sector in 5 European countries, and then to identify ...reasons for not reporting violence experienced at work.
This retrospective cross-sectional study was conducted in 5 participating countries (Poland, the Czech Republic, the Slovak Republic, Turkey, and Spain). All registered nurses working in selected healthcare settings for at least 1 year were invited to participate in the study. A questionnaire adapted from the
, developed jointly by the International Labour Office, the International Council of Nurses, the World Health Organization and Public Services International, was used. The selection of healthcare settings and the distribution of the questionnaire were conducted according to the recommendations of the questionnaire authors.
In total, 1089 nurses submitted completed questionnaires which could be included in the study. Of these, 54% stated that they had been exposed to non-physical violence and 20% had been exposed to physical violent acts. A total of 15% of the surveyed nurses experienced both forms of workplace violence. In addition, 18% of the respondents confirmed having witnessed physical violence in their workplace. The most common perpetrators were patients and patients' relatives. In about 70% of these cases, no actions were taken after the act of violence to investigate its causes. About half of the study group did not report workplace violence as they believed it was useless or not important. The most common consequences of workplace violence included being "superalert" or watchful and on guard.
Nurses internationally are both victims of and witnesses to workplace violence. Workplace violence is often seen by nurses as an occupational hazard and, as such, it remains not reported. The first step in preventing workplace violence is not only to acknowledge its existence but also to ensure the appropriate reporting of violent acts. Int J Occup Med Environ Health. 2020;33(3):325-38.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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