RESUMO
We examined 4- to 11-year-old children's evaluation of six types of lies arranged along a cost-benefit assessment scale factoring both the lie teller and the lie recipient. Children were from three distinct cultural environments: rural Samoa (n = 99), urban China (n = 49), and urban United States (n = 109). Following the simple script of six different stories involving a lie teller and a lie recipient, children were asked to evaluate the character who lied and whether it deserved reward or punishment using a child-friendly Likert scale. From the age when children produce both antisocial and prosocial lies, our results show that their evaluation of lies rests on a cost-benefit analysis of both the lie teller and the lie recipient. Such analysis varies depending on age, type of lie, and the child's cultural environment. In general, Samoan children tended to rate lies more negatively, and they were less differential in their evaluation of the different types of lies compared with both Chinese and U.S. children. We interpret these results as reflecting the differences across cultures in explicit moral teaching and children's relative experience in resource allocation.
Assuntos
Comportamento Infantil , Enganação , Transtorno da Personalidade Antissocial , Criança , Pré-Escolar , China , Análise Custo-Benefício , HumanosRESUMO
d-Glycero-ß-d-manno-heptose 1,7-biphosphate (ß-HBP) is a novel microbial-associated molecular pattern that triggers inflammation and thus has the potential to act as an immune modulator in many therapeutic contexts. To better understand the structure-activity relationship of this molecule, we chemically synthesized analogs of ß-HBP and tested their ability to induce canonical TIFA-dependent inflammation in human embryonic kidney cells (HEK 293T) and colonic epithelial cells (HCT 116). Of the analogs tested, only d-glycero-ß-d-manno-heptose 1-phosphate (ß-HMP) induced TIFA-dependent NF-κB activation and cytokine production in a manner similar to ß-HBP. This finding expands the spectrum of metabolites from the Gram-negative ADP-heptose biosynthesis pathway that can function as innate immune agonists and provides a more readily available agonist of the TIFA-dependent inflammatory pathway that can be easily produced by synthetic methods.
Assuntos
Bactérias Gram-Negativas/fisiologia , Heptoses/imunologia , Imunidade Inata , Fatores Imunológicos/imunologia , Inflamação/imunologia , Manose/imunologia , Moléculas com Motivos Associados a Patógenos/imunologia , Fosfatos/imunologia , Piranos/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células HEK293 , Heptoses/síntese química , Humanos , Imunização , Fatores Imunológicos/síntese química , Inflamação/induzido quimicamente , Manose/síntese química , Fosfatos/síntese química , Piranos/síntese química , Transdução de Sinais , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The neutrophil-specific innate immune receptor CEACAM3 functions as a decoy to capture Gram-negative pathogens, such as Neisseria gonorrhoeae, that exploit CEACAM family members to adhere to the epithelium. Bacterial binding to CEACAM3 results in their efficient engulfment and triggers activation of an nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-dependent inflammatory response by human neutrophils. Herein, we report that CEACAM3 cross-linking is not sufficient for induction of cytokine production and show that the inflammatory response induced by Neisseria gonorrhoeae infection is elicited by an integration of signals from CEACAM3 and toll-like receptors. Using neutrophils from a human CEACAM-expressing mouse line (CEABAC), we use a genetic approach to reveal a molecular bifurcation of the CEACAM3-mediated antimicrobial and inflammatory responses. Ex vivo experiments with CEABAC-Rac2-/- , CEABAC-Bcl10-/- , and CEABAC-Malt1-/- neutrophils indicate that these effectors are not necessary for gonococcal engulfment, yet all 3 effectors contribute to CEACAM3-mediated cytokine production. Interestingly, although Bcl10 and Malt1 are often inextricably linked, Bcl10 enabled synergy between toll-like receptor 4 and CEACAM3, whereas Malt1 did not. Together, these findings reveal an integration of the specific innate immune receptor CEACAM3 into the network of more conventional pattern recognition receptors, providing a mechanism by which the innate immune system can unleash its response to a relentless pathogen.
Assuntos
Proteína 10 de Linfoma CCL de Células B/genética , Antígeno Carcinoembrionário/imunologia , Gonorreia/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Neisseria gonorrhoeae/imunologia , Neutrófilos/imunologia , Receptor 4 Toll-Like/imunologia , Animais , Antígenos CD/imunologia , Proteína 10 de Linfoma CCL de Células B/imunologia , Moléculas de Adesão Celular/imunologia , Células Cultivadas , Proteínas Ligadas por GPI/imunologia , Gonorreia/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/imunologia , Proteína RAC2 de Ligação ao GTPRESUMO
NKT cells are unconventional T cells that respond to self and microbe-derived lipid and glycolipid Ags presented by the CD1d molecule. Invariant NKT (iNKT) cells influence immune responses in numerous diseases. Although only a few studies have examined their role during intestinal inflammation, it appears that iNKT cells protect from Th1-mediated inflammation but exacerbate Th2-mediated inflammation. Studies using iNKT cell-deficient mice and chemically induced dextran sodium sulfate (DSS) colitis have led to inconsistent results. In this study, we show that CD1d-deficient mice, which lack all NKT cells, harbor an altered intestinal microbiota that is associated with exacerbated intestinal inflammation at steady-state and following DSS treatment. This altered microbiota, characterized by increased abundance of the bacterial phyla Proteobacteria, Deferribacteres, and TM7, among which the mucin-eating Mucispirillum, as well as members of the genus Prevotella and segmented filamentous bacteria, was transmissible upon fecal transplant, along with the procolitogenic phenotype. Our results also demonstrate that this proinflammatory microbiota influences iNKT cell function upon activation during DSS colitis. Collectively, alterations of the microbiota have a major influence on colitis outcome and therefore have to be accounted for in such experimental settings and in studies focusing on iNKT cells.
Assuntos
Colite/imunologia , Colite/microbiologia , Microbioma Gastrointestinal/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Animais , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Transplante de Microbiota Fecal , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/patologia , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/patologia , Prevotella/imunologia , Células Th2/imunologia , Células Th2/patologiaRESUMO
Hypoxia and hypoxia signaling play an integral role in regulating skeletal muscle physiology. Environmental hypoxia and tissue hypoxia in muscles cue for their appropriate physiological response and adaptation, and cause an array of cellular and metabolic changes. In addition, muscle stem cells (satellite cells), exist in a hypoxic state, and this intrinsic hypoxic state correlates with their quiescence and stemness. The mechanisms of hypoxia-mediated regulation of satellite cells and myogenesis are yet to be characterized, and their seemingly contradicting effects reported leave their exact roles somewhat perplexing. This review summarizes the recent findings on the effect of hypoxia and hypoxia signaling on the key aspects of muscle physiology, namely, stem cell maintenance and myogenesis with a particular attention given to distinguish the intrinsic versus local hypoxia in an attempt to better understand their respective regulatory roles and how their relationship affects the overall response. This review further describes their mechanistic links and their possible implications on the relevant pathologies and therapeutics.
Assuntos
Fenômenos Fisiológicos Musculoesqueléticos , Células Satélites de Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Hipóxia/metabolismo , Células Satélites de Músculo Esquelético/metabolismo , Transdução de SinaisRESUMO
Objective: To develop an efficacious and efficient method for treating chronic wounds using "nanosheet" that improves the survival and localization of transplanted cells without prior seeding to optimally derive the regenerative potentials of uncultured stromal vascular fraction (SVF) cells. Approach: We propose a method whereby the wound is covered by uncultured SVF cells using the nanosheet [porous poly(d, l,-lactic acid)] (PDLLA) films) designed to hold cells in a single-cell layer. A chronic wound model was created on 12-month-old db/db mice by inflecting a full-thickness skin excision on their dorsum and was subsequently given either no treatment or a treatment with SVF cells alone (with Tegaderm dressing), nanosheet alone, or nanosheet with SVF cells. Results: The placement of the nanosheet improved the grafted cell retention rate at day 10 timepoint by 5 folds, and the wound area was the smallest in the wounds treated with SVF cells plus nanosheet in comparison to the other groups. Collagen deposition and epidermal growth factor were significantly higher in the wound beds treated with SVF cells with the nanosheet, offering some mechanistic insights. Innovation: Porous poly(d, l,-lactic acid acid) (PDLLA) films or "nanosheet" printed on the nanoscale (1-100 nm in thickness) as a cellular scaffold for cytotherapy for the treatment of chronic wounds. Conclusion: The use of the nanosheet is an effective way to improve the transplanted SVF cell retention and accelerate the overall wound closure.
RESUMO
Spinal surgeries are increasingly performed in the United States, but complication rates can be unacceptably high at up to 26%. Consequently, plastic surgeons (PS) are sometimes recruited by spine surgeons (SS) for intraoperative assistance with soft tissue closures. An electronic multidatabase literature search was systematically conducted to determine whether spinal wound closure performed by PS minimizes postoperative wound healing complications when compared to closure by SS (neurosurgical or orthopedic), with the hypothesis that closures by PS minimizes incidence of complications. All published studies involving patients who underwent posterior spinal surgery with closure by PS or SS at index spine surgery were identified. Filtering by exclusion criteria identified 10 studies, 4 of which were comparative in nature and included both closures by PS and SS. Of these 4, none reported significant differences in postoperative outcomes between the groups. Across all studies, PS were involved in cases with higher baseline risk for wound complications and greater comorbidity burden. Closures by PS were significantly more likely to have had prior chemotherapy in 2 of the 4 (50%) studies (P = 0.014, P < 0.001) and radiation in 3 of the 4 (75%) studies (P < 0.001, P < 0.01, P < 0.001). In conclusion, closures by PS are frequently performed in higher risk cases, and use of PS in these closures may normalize the risk of wound complications to that of the normal risk cohort, though the overall level of evidence of the published literature is low.
Assuntos
Complicações Pós-Operatórias , Infecção da Ferida Cirúrgica , Humanos , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Infecção da Ferida Cirúrgica/epidemiologia , Procedimentos Neurocirúrgicos/efeitos adversos , Procedimentos Neurocirúrgicos/métodos , Coluna Vertebral/cirurgia , Procedimentos de Cirurgia Plástica/métodos , Técnicas de Fechamento de Ferimentos , Cirurgia Plástica/métodosRESUMO
It is increasingly recognized that cigarette smoke (CS) exposure increases the incidence and severity of acute respiratory distress syndrome (ARDS) in critical ill humans and animals. However, the mechanism(s) is not well understood. This study aims to investigate mechanism underlying the priming effect of CS on Pseudomonas aeruginosa-triggered acute lung injury, by using pre-clinic animal models and genetically modified mice. We demonstrated that CS impaired P. aeruginosa-induced mitophagy flux, promoted p62 accumulation, and exacerbated P. aeruginosa-triggered mitochondrial damage and NLRP3 inflammasome activation in alveolar macrophages; an effect associated with increased acute lung injury and mortality. Pharmacological inhibition of caspase-1, a component of inflammasome, attenuated CS primed P. aeruginosa-triggered acute lung injury and improved animal survival. Global or myeloid-specific knockout of IL-1ß, a downstream component of inflammasome activation, also attenuated CS primed P. aeruginosa-triggered acute lung injury. Our results suggest that NLRP3 inflammasome activation is an important mechanism for CS primed P. aeruginosa-triggered acute lung injury. (total words: 155).
Assuntos
Lesão Pulmonar Aguda , Fumar Cigarros , Humanos , Camundongos , Animais , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Pseudomonas aeruginosa , Lesão Pulmonar Aguda/induzido quimicamente , Camundongos Endogâmicos C57BLRESUMO
There are a plethora of cognitive sequelae in addition to neglect and extinction that arise with unilateral right hemispheric stroke (RHS). Cognitive deficits following non-dominant (right) hemisphere stroke are common with unilateral neglect and extinction being the most recognized examples. The severity of RHS is usually underestimated by the National Institutes of Health Stroke Scale (NIHSS), which in terms of lateralized right hemisphere cognitive deficits, tests only for visual inattention/extinction. They account for 2 out of 42 total possible points. Additional neuropsychiatric sequelae include but are not limited to deficiencies in affective prosody comprehension and production (aprosodias), understanding and expressing facial emotions, empathy, recognition of familiar faces, anxiety, mania, apathy, and psychosis. These sequelae have a profound impact on patients' quality of life; affecting communication, interpersonal relationships, and the ability to fulfill social roles. They also pose additional challenges to recovery. There is presently a gap in the literature regarding a cohesive overview of the significant cognitive sequelae following RHS. This paper serves as a narrative survey of the current understanding of the subject, with particular emphasis on neuropsychiatric poststroke syndromes not predominantly associated with left hemisphere lesions (LHL), bilateral lesions, hemiplegia, or paralysis. A more comprehensive understanding of the neuropsychological consequences of RHS extending beyond the typical associations of unilateral neglect and extinction may have important implications for clinical practice, including the ways in which clinicians approach diagnostics, treatment, and rehabilitation.
Assuntos
Cérebro , Transtornos da Percepção , Acidente Vascular Cerebral , Lateralidade Funcional , Hemiplegia , Humanos , Testes Neuropsicológicos , Transtornos da Percepção/etiologia , Qualidade de Vida , Acidente Vascular Cerebral/complicaçõesRESUMO
The innate immune system is the first line of defense against invasive fungal infections. As a consequence, many successful fungal pathogens have evolved elegant strategies to interact with host immune cells. For example, Candida albicans undergoes a morphogenetic switch coupled to cell wall remodeling upon phagocytosis by macrophages and then induces macrophage pyroptosis, an inflammatory cell death program. To elucidate the genetic circuitry through which C. albicans orchestrates this host response, we performed the first large-scale analysis of C. albicans interactions with mammalian immune cells. We identified 98 C. albicans genes that enable macrophage pyroptosis without influencing fungal cell morphology in the macrophage, including specific determinants of cell wall biogenesis and the Hog1 signaling cascade. Using these mutated genes, we discovered that defects in the activation of pyroptosis affect immune cell recruitment during infection. Examining host circuitry required for pyroptosis in response to C. albicans infection, we discovered that inflammasome priming and activation can be decoupled. Finally, we observed that apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization can occur prior to phagolysosomal rupture by C. albicans hyphae, demonstrating that phagolysosomal rupture is not the inflammasome activating signal. Taking the data together, this work defines genes that enable fungal cell wall remodeling and activation of macrophage pyroptosis independently of effects on morphogenesis and identifies macrophage signaling components that are required for pyroptosis in response to C. albicans infection.IMPORTANCECandida albicans is a natural member of the human mucosal microbiota that can also cause superficial infections and life-threatening systemic infections, both of which are characterized by inflammation. Host defense relies mainly on the ingestion and destruction of C. albicans by innate immune cells, such as macrophages and neutrophils. Although some C. albicans cells are killed by macrophages, most undergo a morphological change and escape by inducing macrophage pyroptosis. Here, we investigated the C. albicans genes and host factors that promote macrophage pyroptosis in response to intracellular fungi. This work provides a foundation for understanding how host immune cells interact with C. albicans and may lead to effective strategies to modulate inflammation induced by fungal infections.
Assuntos
Candida albicans/genética , Genes Fúngicos , Interações Hospedeiro-Patógeno , Macrófagos/microbiologia , Piroptose , Animais , Candida albicans/patogenicidade , Feminino , Ensaios de Triagem em Larga Escala , Evasão da Resposta Imune , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , FagocitoseRESUMO
Intestinal epithelial cells (IECs) act as sentinels for incoming pathogens. Cytosol-invasive bacteria, such as Shigella flexneri, trigger a robust pro-inflammatory nuclear factor κB (NF-κB) response from IECs that is believed to depend entirely on the peptidoglycan sensor NOD1. We found that, during Shigella infection, the TRAF-interacting forkhead-associated protein A (TIFA)-dependent cytosolic surveillance pathway, which senses the bacterial metabolite heptose-1,7-bisphosphate (HBP), functions after NOD1 to detect bacteria replicating free in the host cytosol. Whereas NOD1 mediated a transient burst of NF-κB activation during bacterial entry, TIFA sensed HBP released during bacterial replication, assembling into large signaling complexes to drive a dynamic inflammatory response that reflected the rate of intracellular bacterial proliferation. Strikingly, IECs lacking TIFA were unable to discriminate between proliferating and stagnant intracellular bacteria, despite the NOD1/2 pathways being intact. Our results define TIFA as a rheostat for intracellular bacterial replication, escalating the immune response to invasive Gram-negative bacteria that exploit the host cytosol for growth.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Citosol/metabolismo , Imunidade Inata , Espaço Intracelular/microbiologia , Shigella flexneri/crescimento & desenvolvimento , Transdução de Sinais , Células HeLa , Humanos , Proteína Adaptadora de Sinalização NOD1/metabolismo , Fosfatos/metabolismo , Vacúolos/metabolismoRESUMO
d-glycero-ß-d-manno-heptose 1,7-biphosphate (HBP) is an enzymatic intermediate in the biosynthesis of the heptose component of lipopolysaccharide (LPS), and was recently revealed to be a pathogen-associated molecular pattern (PAMP) that allows detection of Gram-negative bacteria by the mammalian immune system. Cellular detection of HBP depends upon its stimulation of a cascade that leads to the phosphorylation and assembly of the TRAF-interacting with forkhead-associated domain protein A (TIFA), which activates the transcription factor NF-κB. In this note, an alternate chemical synthesis of HBP is described and its biological activity is established, providing pure material for further assessing and exploiting the biological activity of this compound.