RESUMO
The initial rise of molecular oxygen (O2) shortly after the Archaean-Proterozoic transition 2.5 billion years ago was more complex than the single step-change once envisioned. Sulfur mass-independent fractionation records suggest that the rise of atmospheric O2 was oscillatory, with multiple returns to an anoxic state until perhaps 2.2 billion years ago1-3. Yet few constraints exist for contemporaneous marine oxygenation dynamics, precluding a holistic understanding of planetary oxygenation. Here we report thallium (Tl) isotope ratio and redox-sensitive element data for marine shales from the Transvaal Supergroup, South Africa. Synchronous with sulfur isotope evidence of atmospheric oxygenation in the same shales3, we found lower authigenic 205Tl/203Tl ratios indicative of widespread manganese oxide burial on an oxygenated seafloor and higher redox-sensitive element abundances consistent with expanded oxygenated waters. Both signatures disappear when the sulfur isotope data indicate a brief return to an anoxic atmospheric state. Our data connect recently identified atmospheric O2 dynamics on early Earth with the marine realm, marking an important turning point in Earth's redox history away from heterogeneous and highly localized 'oasis'-style oxygenation.
Assuntos
Atmosfera , Planeta Terra , Oxigênio , Água do Mar , Atmosfera/química , Sedimentos Geológicos/química , História Antiga , Oceanos e Mares , Oxirredução , Oxigênio/análise , Oxigênio/história , Oxigênio/metabolismo , Água do Mar/química , África do Sul , Isótopos de Enxofre/análise , Tálio/análise , Tálio/químicaRESUMO
Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.
Assuntos
Transformação Celular Neoplásica , Proteína Homóloga a MRE11 , Nucleossomos , Nucleotidiltransferases , Humanos , Proliferação de Células , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Dano ao DNA , Proteína Homóloga a MRE11/metabolismo , Necroptose , Nucleossomos/metabolismo , Nucleotidiltransferases/metabolismo , Radiação Ionizante , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Instabilidade GenômicaRESUMO
Phosphorus is a limiting nutrient that is thought to control oceanic oxygen levels to a large extent1-3. A possible increase in marine phosphorus concentrations during the Ediacaran Period (about 635-539 million years ago) has been proposed as a driver for increasing oxygen levels4-6. However, little is known about the nature and evolution of phosphorus cycling during this time4. Here we use carbonate-associated phosphate (CAP) from six globally distributed sections to reconstruct oceanic phosphorus concentrations during a large negative carbon-isotope excursion-the Shuram excursion (SE)-which co-occurred with global oceanic oxygenation7-9. Our data suggest pulsed increases in oceanic phosphorus concentrations during the falling and rising limbs of the SE. Using a quantitative biogeochemical model, we propose that this observation could be explained by carbon dioxide and phosphorus release from marine organic-matter oxidation primarily by sulfate, with further phosphorus release from carbon-dioxide-driven weathering on land. Collectively, this may have resulted in elevated organic-pyrite burial and ocean oxygenation. Our CAP data also seem to suggest equivalent oceanic phosphorus concentrations under maximum and minimum extents of ocean anoxia across the SE. This observation may reflect decoupled phosphorus and ocean anoxia cycles, as opposed to their coupled nature in the modern ocean. Our findings point to external stimuli such as sulfate weathering rather than internal oceanic phosphorus-oxygen cycling alone as a possible control on oceanic oxygenation in the Ediacaran. In turn, this may help explain the prolonged rise of atmospheric oxygen levels.
Assuntos
Oceanos e Mares , Fósforo , Água do Mar , Atmosfera/química , Dióxido de Carbono/metabolismo , Isótopos de Carbono , Sedimentos Geológicos/química , História Antiga , Hipóxia/metabolismo , Oxigênio/análise , Oxigênio/história , Oxigênio/metabolismo , Fósforo/análise , Fósforo/história , Fósforo/metabolismo , Água do Mar/química , Sulfatos/metabolismo , Carbonatos/análise , Carbonatos/metabolismo , OxirreduçãoRESUMO
Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα, removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities.
Assuntos
Células de Kupffer/citologia , Receptores X do Fígado/genética , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética , Animais , Linhagem da Célula/imunologia , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Células de Kupffer/imunologia , Fígado/citologia , Receptores X do Fígado/metabolismo , Pulmão/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near-infrared spectroscopy in neonates and 6- to 7-month-old infants to investigate the neural substrate supporting NAD learning and detection using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6- to 7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and serve as the foundation for the later engagement of these regions for NAD detection, thus, providing a neural basis for language acquisition.
Assuntos
Encéfalo , Desenvolvimento da Linguagem , Aprendizagem , Espectroscopia de Luz Próxima ao Infravermelho , Humanos , Lactente , Masculino , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Feminino , Encéfalo/fisiologia , Aprendizagem/fisiologia , Recém-Nascido , Mapeamento Encefálico/métodos , Lobo Temporal/fisiologia , Lobo Temporal/diagnóstico por imagem , Idioma , Córtex Pré-Frontal/fisiologiaRESUMO
The rise of atmospheric oxygen fundamentally changed the chemistry of surficial environments and the nature of Earth's habitability1. Early atmospheric oxygenation occurred over a protracted period of extreme climatic instability marked by multiple global glaciations2,3, with the initial rise of oxygen concentration to above 10-5 of the present atmospheric level constrained to about 2.43 billion years ago4,5. Subsequent fluctuations in atmospheric oxygen levels have, however, been reported to have occurred until about 2.32 billion years ago4, which represents the estimated timing of irreversible oxygenation of the atmosphere6,7. Here we report a high-resolution reconstruction of atmospheric and local oceanic redox conditions across the final two glaciations of the early Palaeoproterozoic era, as documented by marine sediments from the Transvaal Supergroup, South Africa. Using multiple sulfur isotope and iron-sulfur-carbon systematics, we demonstrate continued oscillations in atmospheric oxygen levels after about 2.32 billion years ago that are linked to major perturbations in ocean redox chemistry and climate. Oxygen levels thus fluctuated across the threshold of 10-5 of the present atmospheric level for about 200 million years, with permanent atmospheric oxygenation finally arriving with the Lomagundi carbon isotope excursion at about 2.22 billion years ago, some 100 million years later than currently estimated.
Assuntos
Atmosfera/química , Oxigênio/análise , Oxigênio/história , Isótopos de Carbono/análise , Carbonatos/análise , Clima , Ecossistema , Sedimentos Geológicos/química , História Antiga , Oceanos e Mares , Oxirredução , Água do Mar/química , África do Sul , Isótopos de Enxofre/análise , Fatores de TempoRESUMO
The reactivation of developmental genes and pathways during adulthood may contribute to pathogenesis of diseases such as prostate cancer. Analysis of the mechanistic links between development and disease could be exploited to identify signalling pathways leading to disease in the prostate. However, the mechanisms underpinning prostate development require further characterisation to interrogate fully the link between development and disease. Previously, our group developed methods to produce prostate organoids using induced pluripotent stem cells (iPSCs). Here, we show that human iPSCs can be differentiated into prostate organoids using neonatal rat seminal vesicle mesenchyme in vitro. The organoids can be used to study prostate development or modified to study prostate cancer. We also elucidated molecular drivers of prostate induction through RNA-sequencing analyses of the rat urogenital sinus and neonatal seminal vesicles. We identified candidate drivers of prostate development evident in the inductive mesenchyme and epithelium involved with prostate specification. Our top candidates included Spx, Trib3, Snai1, Snai2, Nrg2 and Lrp4. This work lays the foundations for further interrogation of the reactivation of developmental genes in adulthood, leading to prostate disease.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neoplasias da Próstata , Masculino , Humanos , Ratos , Animais , Próstata , Roedores , Sistema Urogenital/fisiologia , Diferenciação Celular/genética , OrganoidesRESUMO
mRNA processing, transport, translation, and ultimately degradation involve a series of dedicated protein complexes that often assemble into large membraneless structures such as stress granules (SGs) and processing bodies (PBs). Here, systematic in vivo proximity-dependent biotinylation (BioID) analysis of 119 human proteins associated with different aspects of mRNA biology uncovers 7424 unique proximity interactions with 1,792 proteins. Classical bait-prey analysis reveals connections of hundreds of proteins to distinct mRNA-associated processes or complexes, including the splicing and transcriptional elongation machineries (protein phosphatase 4) and the CCR4-NOT deadenylase complex (CEP85, RNF219, and KIAA0355). Analysis of correlated patterns between endogenous preys uncovers the spatial organization of RNA regulatory structures and enables the definition of 144 core components of SGs and PBs. We report preexisting contacts between most core SG proteins under normal growth conditions and demonstrate that several core SG proteins (UBAP2L, CSDE1, and PRRC2C) are critical for the formation of microscopically visible SGs.
Assuntos
Citoplasma/ultraestrutura , Grânulos Citoplasmáticos/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Transporte/metabolismo , Citoplasma/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Espaço Intracelular , Proteínas/metabolismo , RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Estresse FisiológicoRESUMO
The hippocampus plays a central role as a coordinate system or index of information stored in neocortical loci. Nonetheless, it remains unclear how hippocampal processes integrate with cortical information to facilitate successful memory encoding. Thus, the goal of the current study was to identify specific hippocampal-cortical interactions that support object encoding. We collected fMRI data while 19 human participants (7 female and 12 male) encoded images of real-world objects and tested their memory for object concepts and image exemplars (i.e., conceptual and perceptual memory). Representational similarity analysis revealed robust representations of visual and semantic information in canonical visual (e.g., occipital cortex) and semantic (e.g., angular gyrus) regions in the cortex, but not in the hippocampus. Critically, hippocampal functions modulated the mnemonic impact of cortical representations that are most pertinent to future memory demands, or transfer-appropriate representations Subsequent perceptual memory was best predicted by the strength of visual representations in ventromedial occipital cortex in coordination with hippocampal activity and pattern information during encoding. In parallel, subsequent conceptual memory was best predicted by the strength of semantic representations in left inferior frontal gyrus and angular gyrus in coordination with either hippocampal activity or semantic representational strength during encoding. We found no evidence for transfer-incongruent hippocampal-cortical interactions supporting subsequent memory (i.e., no hippocampal interactions with cortical visual/semantic representations supported conceptual/perceptual memory). Collectively, these results suggest that diverse hippocampal functions flexibly modulate cortical representations of object properties to satisfy distinct future memory demands.Significance Statement The hippocampus is theorized to index pieces of information stored throughout the cortex to support episodic memory. Yet how hippocampal processes integrate with cortical representation of stimulus information remains unclear. Using fMRI, we examined various forms of hippocampal-cortical interactions during object encoding in relation to subsequent performance on conceptual and perceptual memory tests. Our results revealed novel hippocampal-cortical interactions that utilize semantic and visual representations in transfer-appropriate manners: conceptual memory supported by hippocampal modulation of frontoparietal semantic representations, and perceptual memory supported by hippocampal modulation of occipital visual representations. These findings provide important insights into the neural mechanisms underlying the formation of information-rich episodic memory and underscore the value of studying the flexible interplay between brain regions for complex cognition.
Assuntos
Mapeamento Encefálico , Memória Episódica , Humanos , Masculino , Feminino , Hipocampo , Lobo Parietal , Córtex Pré-Frontal , Imageamento por Ressonância MagnéticaRESUMO
When we perceive a scene, our brain processes various types of visual information simultaneously, ranging from sensory features, such as line orientations and colors, to categorical features, such as objects and their arrangements. Whereas the role of sensory and categorical visual representations in predicting subsequent memory has been studied using isolated objects, their impact on memory for complex scenes remains largely unknown. To address this gap, we conducted an fMRI study in which female and male participants encoded pictures of familiar scenes (e.g., an airport picture) and later recalled them, while rating the vividness of their visual recall. Outside the scanner, participants had to distinguish each seen scene from three similar lures (e.g., three airport pictures). We modeled the sensory and categorical visual features of multiple scenes using both early and late layers of a deep convolutional neural network. Then, we applied representational similarity analysis to determine which brain regions represented stimuli in accordance with the sensory and categorical models. We found that categorical, but not sensory, representations predicted subsequent memory. In line with the previous result, only for the categorical model, the average recognition performance of each scene exhibited a positive correlation with the average visual dissimilarity between the item in question and its respective lures. These results strongly suggest that even in memory tests that ostensibly rely solely on visual cues (such as forced-choice visual recognition with similar distractors), memory decisions for scenes may be primarily influenced by categorical rather than sensory representations.
Assuntos
Imageamento por Ressonância Magnética , Reconhecimento Visual de Modelos , Reconhecimento Psicológico , Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Reconhecimento Psicológico/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Estimulação Luminosa/métodos , Percepção Visual/fisiologia , Encéfalo/fisiologia , Encéfalo/diagnóstico por imagem , Rememoração Mental/fisiologia , Mapeamento EncefálicoRESUMO
Humans communicate with small children in unusual and highly conspicuous ways (child-directed communication (CDC)), which enhance social bonding and facilitate language acquisition. CDC-like inputs are also reported for some vocally learning animals, suggesting similar functions in facilitating communicative competence. However, adult great apes, our closest living relatives, rarely signal to their infants, implicating communication surrounding the infant as the main input for infant great apes and early humans. Given cross-cultural variation in the amount and structure of CDC, we suggest that child-surrounding communication (CSC) provides essential compensatory input when CDC is less prevalent-a paramount topic for future studies.
Assuntos
Hominidae , Desenvolvimento da Linguagem , Comunicação Animal , Animais , Comunicação , Humanos , Lactente , AprendizagemRESUMO
Humans are argued to be unique in their ability and motivation to share attention with others about external entities-sharing attention for sharing's sake. Indeed, in humans, using referential gestures declaratively to direct the attention of others toward external objects and events emerges in the first year of life. In contrast, wild great apes seldom use referential gestures, and when they do, it seems to be exclusively for imperative purposes. This apparent species difference has fueled the argument that the motivation and ability to share attention with others is a human-specific trait with important downstream consequences for the evolution of our complex cognition [M. Tomasello, Becoming Human (2019)]. Here, we report evidence of a wild ape showing a conspecific an item of interest. We provide video evidence of an adult female chimpanzee, Fiona, showing a leaf to her mother, Sutherland, in the context of leaf grooming in Kibale Forest, Uganda. We use a dataset of 84 similar leaf-grooming events to explore alternative explanations for the behavior, including food sharing and initiating dyadic grooming or playing. Our observations suggest that in highly specific social conditions, wild chimpanzees, like humans, may use referential showing gestures to direct others' attention to objects simply for the sake of sharing. The difference between humans and our closest living relatives in this regard may be quantitative rather than qualitative, with ramifications for our understanding of the evolution of human social cognition.
Assuntos
Hominidae , Pan troglodytes , Feminino , Humanos , Animais , Gestos , Comunicação Animal , MãesRESUMO
Several recent fMRI studies of episodic and working memory representations converge on the finding that visual information is most strongly represented in occipito-temporal cortex during the encoding phase but in parietal regions during the retrieval phase. It has been suggested that this location shift reflects a change in the content of representations, from predominantly visual during encoding to primarily semantic during retrieval. Yet, direct evidence on the nature of encoding and retrieval representations is lacking. It is also unclear how the representations mediating the encoding-retrieval shift contribute to memory performance. To investigate these two issues, in the current fMRI study, participants encoded pictures (e.g., picture of a cardinal) and later performed a word recognition test (e.g., word "cardinal"). Representational similarity analyses examined how visual (e.g., red color) and semantic representations (e.g., what cardinals eat) support successful encoding and retrieval. These analyses revealed two novel findings. First, successful memory was associated with representational changes in cortical location (from occipito-temporal at encoding to parietal at retrieval) but not with changes in representational content (visual vs. semantic). Thus, the representational encoding-retrieval shift cannot be easily attributed to a change in the nature of representations. Second, in parietal regions, stronger representations predicted encoding failure but retrieval success. This encoding-retrieval "flip" in representations mimics the one previously reported in univariate activation studies. In summary, by answering important questions regarding the content and contributions to the performance of the representations mediating the encoding-retrieval shift, our findings clarify the neural mechanisms of this intriguing phenomenon.
Assuntos
Mapeamento Encefálico , Córtex Cerebral , Imageamento por Ressonância Magnética , Rememoração Mental , Humanos , Masculino , Feminino , Adulto Jovem , Córtex Cerebral/fisiologia , Córtex Cerebral/diagnóstico por imagem , Rememoração Mental/fisiologia , Adulto , Estimulação Luminosa , Reconhecimento Psicológico/fisiologia , Semântica , Reconhecimento Visual de Modelos/fisiologia , AdolescenteRESUMO
Although living and nonliving stimuli are known to rely on distinct brain regions during perception, it is largely unknown if their episodic memory encoding mechanisms differ as well. To investigate this issue, we asked participants to encode object pictures (e.g., a picture of a tiger) and to retrieve them later in response to their names (e.g., word "tiger"). For each of four semantic classes (living-animate, living-inanimate, nonliving-large, and nonliving-small), we examined differences in the similarity in activation patterns (neural pattern similarity [NPS]) for subsequently remembered versus forgotten items. Higher NPS for remembered items suggests an advantage of within-class item similarity, whereas lower NPS for remembered items indicates an advantage for item distinctiveness. We expect NPS within class-specific regions to be higher for remembered than for forgotten items. For example, the parahippocampal cortex has a well-known role in scene processing [Aminoff, E. M., Kveraga, K., & Bar, M. The role of the parahippocampal cortex in cognition. Trends in Cognitive Sciences, 17, 379-390, 2013], and the anterior temporal and inferior frontal gyrus have well-known roles in object processing [Clarke, A., & Tyler, L. K. Object-specific semantic coding in human perirhinal cortex. Journal of Neuroscience, 34, 4766-4775, 2014]. As such, we expect to see higher NPS for remembered items in these regions pertaining to scenes and objects, respectively. Consistent with this hypothesis, in fusiform, parahippocampal, and retrosplenial regions, higher NPS predicted memory for subclasses of nonliving objects, whereas in the left inferior frontal and left retrosplenial regions, lower NPS predicted memory for subclasses of living objects. Taken together, the results support the idea that subsequent memory depends on a balance of similarity and distinctiveness and demonstrate that the neural mechanisms of episodic encoding differ across semantic categories.
RESUMO
Language is unbounded in its generativity, enabling the flexible combination of words into novel sentences. Critically, these constructions are intelligible to others due to our ability to derive a sentence's compositional meaning from the semantic relationships among its components. Some animals also concatenate meaningful calls into compositional-like combinations to communicate more complex information. However, these combinations are structurally highly stereotyped, suggesting a bounded system of holistically perceived signals that impedes the processing of novel variants. Using long-term data and playback experiments on pied babblers, we demonstrate that, despite production stereotypy, they can nevertheless process structurally modified and novel combinations of their calls, demonstrating a capacity for deriving meaning compositionally. Furthermore, differential responses to artificial combinations by fledglings suggest that this compositional sensitivity is acquired ontogenetically. Our findings demonstrate animal combinatorial systems can be flexible at the perceptual level and that such perceptual flexibility may represent a precursor of language-like generativity.
Assuntos
Idioma , Vocalização Animal , Animais , Passeriformes/fisiologia , Percepção AuditivaRESUMO
BACKGROUND: Fundamentally defined by an imbalance in energy consumption and energy expenditure, obesity is a significant risk factor of several musculoskeletal conditions including osteoarthritis (OA). High-fat diets and sedentary lifestyle leads to increased adiposity resulting in systemic inflammation due to the endocrine properties of adipose tissue producing inflammatory cytokines and adipokines. We previously showed serum levels of specific adipokines are associated with biomarkers of bone remodelling and cartilage volume loss in knee OA patients. Whilst more recently we find the metabolic consequence of obesity drives the enrichment of pro-inflammatory fibroblast subsets within joint synovial tissues in obese individuals compared to those of BMI defined 'health weight'. As such this present study identifies obesity-associated genes in OA joint tissues which are conserved across species and conditions. METHODS: The study utilised 6 publicly available bulk and single-cell transcriptomic datasets from human and mice studies downloaded from Gene Expression Omnibus (GEO). Machine learning models were employed to model and statistically test datasets for conserved gene expression profiles. Identified genes were validated in OA tissues from obese and healthy weight individuals using quantitative PCR method (N = 38). Obese and healthy-weight patients were categorised by BMI > 30 and BMI between 18 and 24.9 respectively. Informed consent was obtained from all study participants who were scheduled to undergo elective arthroplasty. RESULTS: Principal component analysis (PCA) was used to investigate the variations between classes of mouse and human data which confirmed variation between obese and healthy populations. Differential gene expression analysis filtered on adjusted p-values of p < 0.05, identified differentially expressed genes (DEGs) in mouse and human datasets. DEGs were analysed further using area under curve (AUC) which identified 12 genes. Pathway enrichment analysis suggests these genes were involved in the biosynthesis and elongation of fatty acids and the transport, oxidation, and catabolic processing of lipids. qPCR validation found the majority of genes showed a tendency to be upregulated in joint tissues from obese participants. Three validated genes, IGFBP2 (p = 0.0363), DOK6 (0.0451) and CASP1 (0.0412) were found to be significantly different in obese joint tissues compared to lean-weight joint tissues. CONCLUSIONS: The present study has employed machine learning models across several published obesity datasets to identify obesity-associated genes which are validated in joint tissues from OA. These results suggest obesity-associated genes are conserved across conditions and may be fundamental in accelerating disease in obese individuals. Whilst further validations and additional conditions remain to be tested in this model, identifying obesity-associated genes in this way may serve as a global aid for patient stratification giving rise to the potential of targeted therapeutic interventions in such patient subpopulations.
Assuntos
Obesidade , Transcriptoma , Humanos , Obesidade/genética , Obesidade/complicações , Obesidade/metabolismo , Animais , Camundongos , Transcriptoma/genética , Especificidade da Espécie , Perfilação da Expressão Gênica , Análise de Componente Principal , Aprendizado de Máquina , Regulação da Expressão Gênica , Masculino , FemininoRESUMO
OBJECTIVE: Synovitis is a widely accepted sign of osteoarthritis (OA), characterised by tissue hyperplasia, where increased infiltration of immune cells and proliferation of resident fibroblasts adopt a pro-inflammatory phenotype, and increased the production of pro-inflammatory mediators that are capable of sensitising and activating sensory nociceptors, which innervate the joint tissues. As such, it is important to understand the cellular composition of synovium and their involvement in pain sensitisation to better inform the development of effective analgesics. METHODS: Studies investigating pain sensitisation in OA with a focus on immune cells and fibroblasts were identified using PubMed, Web of Science and SCOPUS. RESULTS: In this review, we comprehensively assess the evidence that cellular crosstalk between resident immune cells or synovial fibroblasts with joint nociceptors in inflamed OA synovium contributes to peripheral pain sensitisation. Moreover, we explore whether the elucidation of common mechanisms identified in similar joint conditions may inform the development of more effective analgesics specifically targeting OA joint pain. CONCLUSION: The concept of local environment and cellular crosstalk within the inflammatory synovium as a driver of nociceptive joint pain presents a compelling opportunity for future research and therapeutic advancements.
Assuntos
Fibroblastos , Osteoartrite , Membrana Sinovial , Sinovite , Humanos , Fibroblastos/metabolismo , Osteoartrite/fisiopatologia , Artralgia/fisiopatologia , Imunomodulação , Dor Nociceptiva/fisiopatologia , Animais , Nociceptores/fisiologiaRESUMO
BACKGROUND: Before 2016, patients with isolated synchronous colorectal peritoneal metastases (PMCRC) diagnosed in expert centers had a higher odds of undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) and better overall survival (OS) than those diagnosed in referring centers. Nationwide efforts were initiated to increase awareness and improve referral networks. METHODS: This nationwide study aimed to evaluate whether the between-center differences in odds of undergoing CRS-HIPEC and OS have reduced since these national efforts were initiated. All patients with isolated synchronous PMCRC diagnosed between 2009 and 2021 were identified from the Netherlands Cancer Registry. Associations between hospital of diagnosis and the odds of undergoing CRS-HIPEC, as well as OS, were assessed using multilevel multivariable regression analyses for two periods (2009-2015 and 2016-2021). RESULTS: In total, 3948 patients were included. The percentage of patients undergoing CRS-HIPEC increased from 17.2% in 2009-2015 (25.4% in expert centers, 16.5% in referring centers), to 23.4% in 2016-2021 (30.2% in expert centers, 22.6% in referring centers). In 2009-2015, compared with diagnosis in a referring center, diagnosis in a HIPEC center showed a higher odds of undergoing CRS-HIPEC (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02-2.67) and better survival (hazard ratio [HR] 0.80, 95% CI 0.66-0.96). In 2016-2021, there were no differences in the odds of undergoing CRS-HIPEC between patients diagnosed in HIPEC centers versus referring centers (OR 1.27, 95% CI 0.76-2.13) and survival (HR 1.00, 95% CI 0.76-1.32). CONCLUSION: Previously observed differences in odds of undergoing CRS-HIPEC were no longer present. Increased awareness and the harmonization of treatment for PMCRC may have contributed to equal access to care and a similar chance of survival at a national level.
Assuntos
Neoplasias Colorretais , Procedimentos Cirúrgicos de Citorredução , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Peritoneais , Humanos , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/mortalidade , Procedimentos Cirúrgicos de Citorredução/mortalidade , Masculino , Feminino , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Neoplasias Colorretais/mortalidade , Pessoa de Meia-Idade , Taxa de Sobrevida , Terapia Combinada , Idoso , Prognóstico , Seguimentos , Países Baixos , Acessibilidade aos Serviços de Saúde , Sistema de Registros , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
This Letter describes, to the best of our knowledge, a new approach to flow tagging, nitric oxide (NO) Ionization Induced Flow Tagging and Imaging (NiiFTI), and presents the first experimental demonstration for single-shot velocimetry in a near Mach 6 hypersonic flow at 250 kHz. The mean velocity of 860 m/s was measured with a single-shot standard deviation of as low as 3.4 m/s and mean velocity uncertainty of 5.5 m/s. NiiFTI is characterized by a long fluorescence lifetime of nitrogen with 1e decay of approximately 50 µs measured in air. The method relies on a single nanosecond laser combined with a high-speed camera, creating an opportunity for the utilization of a typical nitric oxide (NO) laser-induced fluorescence (LIF) experimental setup with minor modifications as well as pulse-burst lasers (PBLs) for ultrahigh repetition rates.
RESUMO
The arbitrary relationship between signifier and signified is one of the features responsible for language's extreme lability, adaptability, and expressiveness. Understanding this arbitrariness and its emergence is essential in any account of the evolution of language. To shed light on the phylogeny of the phenomenon, comparative data examining the relationship between signal form and function in the communication systems of non-humans is central. Here we report the results of a study on the production and usage the whistle-high hoot call combination (W + HH) from two distant populations of wild bonobos (Pan paniscus): Lui Kotale, DRC, and Kokolopori, DRC. We find that the context in which bonobos produce the W + HHs varies systematically between populations. Our results suggest that variation in W + HH production may represent an example of signal-adjustment optionality, a key component of arbitrariness.