RESUMO
We present a global atlas of 4,728 metagenomic samples from mass-transit systems in 60 cities over 3 years, representing the first systematic, worldwide catalog of the urban microbial ecosystem. This atlas provides an annotated, geospatial profile of microbial strains, functional characteristics, antimicrobial resistance (AMR) markers, and genetic elements, including 10,928 viruses, 1,302 bacteria, 2 archaea, and 838,532 CRISPR arrays not found in reference databases. We identified 4,246 known species of urban microorganisms and a consistent set of 31 species found in 97% of samples that were distinct from human commensal organisms. Profiles of AMR genes varied widely in type and density across cities. Cities showed distinct microbial taxonomic signatures that were driven by climate and geographic differences. These results constitute a high-resolution global metagenomic atlas that enables discovery of organisms and genes, highlights potential public health and forensic applications, and provides a culture-independent view of AMR burden in cities.
Assuntos
Farmacorresistência Bacteriana/genética , Metagenômica , Microbiota/genética , População Urbana , Biodiversidade , Bases de Dados Genéticas , HumanosRESUMO
Lysophosphatidic acids (LPAs) evoke nociception and itch in mice and humans. In this study, we assessed the signaling paths. Hydroxychloroquine was injected intradermally to evoke itch in mice, which evoked an increase of LPAs in the skin and in the thalamus, suggesting that peripheral and central LPA receptors (LPARs) were involved in HCQ-evoked pruriception. To unravel the signaling paths, we assessed the localization of candidate genes and itching behavior in knockout models addressing LPAR5, LPAR2, autotaxin/ENPP2 and the lysophospholipid phosphatases, as well as the plasticity-related genes Prg1/LPPR4 and Prg2/LPPR3. LacZ reporter studies and RNAscope revealed LPAR5 in neurons of the dorsal root ganglia (DRGs) and in skin keratinocytes, LPAR2 in cortical and thalamic neurons, and Prg1 in neuronal structures of the dorsal horn, thalamus and SSC. HCQ-evoked scratching behavior was reduced in sensory neuron-specific Advillin-LPAR5-/- mice (peripheral) but increased in LPAR2-/- and Prg1-/- mice (central), and it was not affected by deficiency of glial autotaxin (GFAP-ENPP2-/-) or Prg2 (PRG2-/-). Heat and mechanical nociception were not affected by any of the genotypes. The behavior suggested that HCQ-mediated itch involves the activation of peripheral LPAR5, which was supported by reduced itch upon treatment with an LPAR5 antagonist and autotaxin inhibitor. Further, HCQ-evoked calcium fluxes were reduced in primary sensory neurons of Advillin-LPAR5-/- mice. The results suggest that LPA-mediated itch is primarily mediated via peripheral LPAR5, suggesting that a topical LPAR5 blocker might suppress "non-histaminergic" itch.
Assuntos
Hidroxicloroquina , Camundongos Knockout , Prurido , Receptores de Ácidos Lisofosfatídicos , Animais , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Prurido/induzido quimicamente , Prurido/metabolismo , Prurido/genética , Prurido/tratamento farmacológico , Camundongos , Hidroxicloroquina/farmacologia , Gânglios Espinais/metabolismo , Gânglios Espinais/efeitos dos fármacos , Masculino , Diester Fosfórico Hidrolases/metabolismo , Diester Fosfórico Hidrolases/genética , Lisofosfolipídeos/metabolismo , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacosRESUMO
In this special issue, we invited contributions that critically examined issues of imperialism, colonialism, power, justice, etc. to expand the canon of anticolonial scholarship and critical scholarship in community psychology. Our two objectives were: (1) to build on the canon of anticolonial and critical race scholarship to cultivate an empirical and theoretical body of work and conceptual frameworks about racism and colonialism within the field of community psychology and (2) to unpack the different manifestations of racism in society from the lens of community psychology and reflect on the implications of these varied forms of injustice in the contemporary moment. Rooted in African epistemology and methodology (Martin, 2012), we find the concept of the algorithm to serve as a potent metaphor for the ways in which these oppressive structures operate given the prevalence of algorithms in our daily lives and the algorithm is symbolic of the information age and predictive powers that seem to govern society beyond conscious control. In this sense, imperial algorithms are these structures, patterns, processes, and procedures that perpetuate imperialism. These imperial algorithms manifest as neo-colonialism, surveillance, social engineering, carcerality, reality warping of contemporary racism, health disparities exacerbated by COVID-19, and environmental grids of oppression.
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Racismo , Humanos , Racismo/psicologia , ColonialismoRESUMO
Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.
Assuntos
Feto/patologia , Hidrocefalia/patologia , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Malformações do Sistema Nervoso/patologia , Receptor trkA/metabolismo , Feminino , Feto/metabolismo , Homozigoto , Humanos , Hidrocefalia/etiologia , Hidrocefalia/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Malformações do Sistema Nervoso/etiologia , Malformações do Sistema Nervoso/metabolismo , Linhagem , Receptor trkA/genéticaRESUMO
BACKGROUND: Chemotherapy-induced neuropathic pain (CIPN) describes a pathological pain state that occurs dose-dependently as a side effect and can limit or even impede an effective cancer therapy. Unfortunately, current treatment possibilities for CIPN are remarkably confined and mostly inadequate as CIPN therapeutics themselves consist of low effectiveness and may induce severe side effects, pointing out CIPN as pathological entity with an emerging need for novel treatment targets. Here, we investigated whether the novel and highly specific FKBP51 inhibitor SAFit2 reduces paclitaxel-induced neuropathic pain. METHODS: In this study, we used a well-established multiple low-dose paclitaxel model to investigate analgesic and anti-inflammatory properties of SAFit2. For this purpose, the behavior of the mice was recorded over 14 days and the mouse tissue was then analyzed using biochemical methods. RESULTS: Here, we show that SAFit2 is capable to reduce paclitaxel-induced mechanical hypersensitivity in mice. In addition, we detected that SAFit2 shifts lipid levels in nervous tissue toward an anti-inflammatory and pro-resolving lipid profile that counteracts peripheral sensitization after paclitaxel treatment. Furthermore, SAFit2 reduced the activation of astrocytes and microglia in the spinal cord as well as the levels of pain-mediating chemokines. Its treatment also increased anti-inflammatory cytokines levels in neuronal tissues, ultimately leading to a resolution of neuroinflammation. CONCLUSIONS: In summary, SAFit2 shows antihyperalgesic properties as it ameliorates paclitaxel-induced neuropathic pain by reducing peripheral sensitization and resolving neuroinflammation. Therefore, we consider SAFit2 as a potential novel drug candidate for the treatment of paclitaxel-induced neuropathic pain.
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Neuralgia , Paclitaxel , Camundongos , Animais , Paclitaxel/toxicidade , Doenças Neuroinflamatórias , Gliose/induzido quimicamente , Gliose/tratamento farmacológico , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/prevenção & controle , Lipídeos/efeitos adversosRESUMO
Elimination strategies of chronic hepatitis C virus (HCV) infection aim to optimize the high antiviral potency of direct-acting antivirals (DAAs). Sphingolipids (SLs) constitute bioactive lipid compounds with a remarkable second messenger potential. SL levels associate with responsiveness to interferon treatment in HCV-patients, thus prompting the question whether failure to DAAs can be predicted by the serologic sphingolipidomic profile. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to retrospectively quantify various sphingolipid metabolites in baseline serum samples of 97 chronic HCV patients with DAA failure compared with an age-matched cohort of 95 HCV-patients with sustained virological response (SVR). Sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and sphinganine-1-phosphate (SA1P) serum concentrations were significantly upregulated at baseline in patients with DAA failure compared to patients with SVR. Similarly, GluC24:1Cer baseline levels were significantly upregulated in patients with DAA failure compared to the patients with SVR. However, GluC18Cer serum levels showed decreased baseline levels for patients with DAA failure compared to patients with SVR. In multivariate analysis sphinganine (OR 0.08494, CI 0.07393-0.9759, p = .021223), SA1P (OR 0.9818, CI 0.9653-0.9987, p = .034801), GluCerC18 (OR 1.0683, CI 1.0297-1.1104, p = .000786) and GluCer24:1 (OR 0.9961, CI 0.994-0.998, p = .000294) constituted independent predictors of treatment response. In conclusion, serum sphingolipid concentrations, in particular sphingosine, sphinganine and their derivatives S1P and SA1P as well as glucosylceramides may identify at baseline the minority of HCV patients with DAA failure. Serum sphingolipids could constitute additional biomarkers for national treatment strategies aiming to eliminate HCV infection.
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Hepatite C Crônica , Hepatite C , Humanos , Hepatite C Crônica/tratamento farmacológico , Antivirais/uso terapêutico , Esfingolipídeos/uso terapêutico , Esfingosina/uso terapêutico , Estudos Retrospectivos , Cromatografia Líquida , Espectrometria de Massas em Tandem , Hepatite C/tratamento farmacológico , Hepacivirus/fisiologia , Resposta Viral Sustentada , BiomarcadoresRESUMO
BACKGROUND: Maladapted endothelial cells (ECs) secrete ENPP2 (ectonucleotide pyrophosphatase/phosphodiesterase 2; autotaxin)-a lysophospholipase D that generates lysophosphatidic acids (LPAs). ENPP2 derived from the arterial wall promotes atherogenic monocyte adhesion induced by generating LPAs, such as arachidonoyl-LPA (LPA20:4), from oxidized lipoproteins. Here, we aimed to determine the role of endothelial ENPP2 in the production of LPAs and atherosclerosis. METHODS: We quantified atherosclerosis in mice harboring loxP-flanked Enpp2 alleles crossed with Apoe-/- mice expressing tamoxifen-inducible Cre recombinase under the control of the EC-specific bone marrow X kinase promoter after 12 weeks of high-fat diet feeding. RESULTS: A tamoxifen-induced EC-specific Enpp2 knockout decreased atherosclerosis, accumulation of lesional macrophages, monocyte adhesion, and expression of endothelial CXCL (C-X-C motif chemokine ligand) 1 in male and female Apoe-/- mice. In vitro, ENPP2 mediated the mildly oxidized LDL (low-density lipoprotein)-induced expression of CXCL1 in aortic ECs by generating LPA20:4, palmitoyl-LPA (LPA16:0), and oleoyl-LPA (LPA18:1). ENPP2 and its activity were detected on the endothelial surface by confocal imaging. The expression of endothelial Enpp2 established a strong correlation between the plasma levels of LPA16:0, stearoyl-LPA (LPA18:0), and LPA18:1 and plaque size and a strong negative correlation between the LPA levels and ENPP2 activity in the plasma. Moreover, endothelial Enpp2 knockout increased the weight of high-fat diet-fed male Apoe-/- mice. CONCLUSIONS: We demonstrated that the expression of ENPP2 in ECs promotes atherosclerosis and endothelial inflammation in a sex-independent manner. This might be due to the generation of LPA20:4, LPA16:0, and LPA18:1 from mildly oxidized lipoproteins on the endothelial surface.
Assuntos
Aterosclerose , Células Endoteliais , Diester Fosfórico Hidrolases , Animais , Aterosclerose/metabolismo , Células Endoteliais/metabolismo , Feminino , Lisofosfolipídeos , Masculino , Camundongos , Camundongos Knockout para ApoE , Diester Fosfórico Hidrolases/genética , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , TamoxifenoRESUMO
BACKGROUND: Infectious agents can reprogram or "train" macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known. OBJECTIVE: We sought to decipher macrophage-trained immunity in allergic asthma. METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation in mice, and an in vitro training setup to analyze persistent changes in macrophage eicosanoid, cytokine, and chemokine production as well as the underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or metabolic flux analysis and liquid chromatography-tandem mass spectrometry analysis, respectively. RESULTS: We found that macrophages differentiated from bone marrow or blood monocyte progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE2, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type 2 imprint, which shifted toward a classical inflammatory training over time. HDM-induced allergic airway inflammation elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl peptide receptor 2-TNF-2-HG-PGE2/PGE2 receptor 2 axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice. CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type 2 airway inflammation and thus represents a target for asthma therapy.
Assuntos
Asma , Hipersensibilidade , Animais , Dermatophagoides pteronyssinus , Modelos Animais de Doenças , Humanos , Inflamação , Macrófagos , Camundongos , Prostaglandinas E/metabolismo , PyroglyphidaeRESUMO
Microglia, the resident immune cells of the central nervous system, play important roles in brain homeostasis as well as in neuroinflammation, neurodegeneration, neurovascular diseases, and traumatic brain injury. In this context, components of the endocannabinoid (eCB) system have been shown to shift microglia towards an anti-inflammatory activation state. Instead, much less is known about the functional role of the sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P) system in microglia biology. In the present study, we addressed potential crosstalk of the eCB and the S1P systems in BV2 mouse microglia cells challenged with lipopolysaccharide (LPS). We show that URB597, the selective inhibitor of fatty acid amide hydrolase (FAAH)-the main degradative enzyme of the eCB anandamide-prevented LPS-induced production of tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß), and caused the accumulation of anandamide itself and eCB-like molecules such as oleic acid and cis-vaccenic acid ethanolamide, palmitoylethanolamide, and docosahexaenoyl ethanolamide. Furthermore, treatment with JWH133, a selective agonist of the eCB-binding cannabinoid 2 (CB2) receptor, mimicked the anti-inflammatory effects of URB597. Interestingly, LPS induced transcription of both SphK1 and SphK2, and the selective inhibitors of SphK1 (SLP7111228) and SphK2 (SLM6031434) strongly reduced LPS-induced TNFα and IL-1ß production. Thus, the two SphKs were pro-inflammatory in BV2 cells in a non-redundant manner. Most importantly, the inhibition of FAAH by URB597, as well as the activation of CB2 by JWH133, prevented LPS-stimulated transcription of SphK1 and SphK2. These results present SphK1 and SphK2 at the intersection of pro-inflammatory LPS and anti-inflammatory eCB signaling, and suggest the further development of inhibitors of FAAH or SphKs for the treatment of neuroinflammatory diseases.
Assuntos
Endocanabinoides , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/farmacologia , Endocanabinoides/farmacologia , Lipopolissacarídeos/farmacologia , Microglia , Esfingosina/farmacologia , Anti-Inflamatórios/farmacologiaRESUMO
PURPOSE: We compared the diagnostic yield of fetal clinical exome sequencing (fCES) in prospective and retrospective cohorts of pregnancies presenting with anomalies detected using ultrasound. We evaluated factors that led to a higher diagnostic efficiency, such as phenotypic category, clinical characterization, and variant analysis strategy. METHODS: fCES was performed for 303 fetuses (183 ongoing and 120 ended pregnancies, in which chromosomal abnormalities had been excluded) using a trio/duo-based approach and a multistep variant analysis strategy. RESULTS: fCES identified the underlying genetic cause in 13% (24/183) of prospective and 29% (35/120) of retrospective cases. In both cohorts, recessive heterozygous compound genotypes were not rare, and trio and simplex variant analysis strategies were complementary to achieve the highest possible diagnostic rate. Limited prenatal phenotypic information led to interpretation challenges. In 2 prospective cases, in-depth analysis allowed expansion of the spectrum of prenatal presentations for genetic syndromes associated with the SLC17A5 and CHAMP1 genes. CONCLUSION: fCES is diagnostically efficient in fetuses presenting with cerebral, skeletal, urinary, or multiple anomalies. The comparison between the 2 cohorts highlights the importance of providing detailed phenotypic information for better interpretation and prenatal reporting of genetic variants.
Assuntos
Exoma , Ultrassonografia Pré-Natal , Proteínas Cromossômicas não Histona , Exoma/genética , Feminino , Feto/anormalidades , Feto/diagnóstico por imagem , Humanos , Fosfoproteínas , Gravidez , Diagnóstico Pré-Natal , Estudos Retrospectivos , Sequenciamento do ExomaRESUMO
Hispanic or Latino (Hispanic) persons with HIV experience disparities in HIV health outcomes compared with some other racial and ethnic groups. A previous report found that the percentages of Hispanic persons who received HIV care, were retained in care, and were virally suppressed were lower than those among non-Hispanic White persons with HIV (1). HIV stigma and discrimination are human rights issues associated with adverse HIV outcomes; eliminating stigma and discrimination among persons with HIV is a national priority*,,§ (2,3). CDC analyzed data from the Medical Monitoring Project (MMP), an annual, cross-sectional study designed to report nationally representative estimates of experiences and outcomes among adults with diagnosed HIV. Data from the 2018-2020 cycles were analyzed to assess self-reported stigma and health care discrimination using adapted versions of validated multi-component scales among 2,690 adult Hispanic persons with HIV in the United States overall and by six characteristics.¶ The median HIV stigma score on a scale of 0-100 was 31.7, with women (35.6) and American Indian or Alaska Native (AI/AN) persons (38.9) reporting the highest scores among Hispanic persons with HIV. HIV stigma was primarily attributed to disclosure concerns (e.g., fearing others will disclose one's HIV status and being careful about who one tells about one's HIV status). Nearly one in four (23%) Hispanic persons with HIV experienced health care discrimination. Health care discrimination was experienced more frequently by Hispanic men (23%) than by Hispanic women (18%) and by Black or African American (Black) Hispanic persons (28%) than by White Hispanic persons (21%). Understanding disparities in experiences of stigma and discrimination is important when designing culturally appropriate interventions to reduce stigma and discrimination.
Assuntos
Infecções por HIV , HIV-1 , Adulto , Negro ou Afro-Americano , Estudos Transversais , Atenção à Saúde , Feminino , Infecções por HIV/diagnóstico , Hispânico ou Latino , Humanos , Masculino , Estados Unidos/epidemiologiaRESUMO
Increasing HIV testing, preexposure prophylaxis (PrEP), and antiretroviral therapy (ART) are pillars of the federal Ending the HIV Epidemic in the U.S. (EHE) initiative, with a goal of decreasing new HIV infections by 90% by 2030.* In response to the COVID-19 pandemic, a national emergency was declared in the United States on March 13, 2020, resulting in the closure of nonessential businesses and most nonemergency health care venues; stay-at-home orders also limited movement within communities (1). As unemployment increased during the pandemic (2), many persons lost employer-sponsored health insurance (3). HIV testing and PrEP prescriptions declined early in the COVID-19 pandemic (4-6); however, the full impact of the pandemic on use of HIV prevention and care services and HIV outcomes is not known. To assess changes in these measures during 2019-2021, quarterly data from two large U.S. commercial laboratories, the IQVIA Real World Data - Longitudinal Prescription Database (IQVIA), and the National HIV Surveillance System (NHSS)§ were analyzed. During quarter 1 (Q1)¶ 2020, a total of 2,471,614 HIV tests were performed, 190,955 persons were prescribed PrEP, and 8,438 persons received a diagnosis of HIV infection. Decreases were observed during quarter 2 (Q2), with 1,682,578 HIV tests performed (32% decrease), 179,280 persons prescribed PrEP (6% decrease), and 6,228 persons receiving an HIV diagnosis (26% decrease). Partial rebounds were observed during quarter 3 (Q3), with 2,325,554 HIV tests performed, 184,320 persons prescribed PrEP, and 7,905 persons receiving an HIV diagnosis. The proportion of persons linked to HIV care, the number who were prescribed ART, and proportion with a suppressed viral load test (<200 copies of HIV RNA per mL) among those tested were stable during the study period. During public health emergencies, delivery of HIV services outside of traditional clinical settings or that use nonclinical delivery models are needed to facilitate access to HIV testing, ART, and PrEP, as well as to support adherence to ART and PrEP medications.
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COVID-19 , Infecções por HIV , Profilaxia Pré-Exposição , Estados Unidos/epidemiologia , Humanos , COVID-19/epidemiologia , Pandemias , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Teste de HIVRESUMO
HIV testing is a core strategy for the Ending the HIV Epidemic in the U.S. (EHE) initiative, which has the aim of reducing new HIV infections by at least 90% by 2030.* During 2016-2017, jurisdictions with the highest HIV diagnosis rates were those with higher prevalences of HIV testing; past-year HIV testing was higher among persons who reported recent HIV risk behaviors compared with those who did not report these risks (1). During 2020-2021, the COVID-19 pandemic disrupted health care delivery, including HIV testing in part because many persons avoided services to comply with COVID-19 risk mitigation efforts (2). In addition, public health departments redirected some sexual health services to COVID-19-related activities. CDC analyzed data from four national data collection systems to assess the numbers of HIV tests performed and HIV infections diagnosed in the United States in the years before (2019) and during (2020) the COVID-19 pandemic. In 2020, HIV diagnoses reported to CDC decreased by 17% compared with those reported in 2019. This decrease was preceded by decreases in HIV testing during the same period, particularly among priority populations including Black or African American (Black) gay men, Hispanic or Latino (Hispanic) gay men, bisexual men, other men who have sex with men (MSM), and transgender persons in CDC-funded jurisdictions. To compensate for testing and diagnoses missed during the COVID-19 pandemic and to accelerate the EHE initiative, CDC encourages partnerships among federal organizations, state and local health departments, community-based organizations, and health care systems to increase access to HIV testing services, including strategies such as self-testing and routine opt-out screening in health care settings.
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COVID-19 , Infecções por HIV , Minorias Sexuais e de Gênero , COVID-19/diagnóstico , COVID-19/epidemiologia , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Teste de HIV , Homossexualidade Masculina , Humanos , Masculino , Pandemias/prevenção & controle , Estados Unidos/epidemiologiaRESUMO
Recent studies suggest that synaptic lysophosphatidic acids (LPAs) augment glutamate-dependent cortical excitability and sensory information processing in mice and humans via presynaptic LPAR2 activation. Here, we studied the consequences of LPAR2 deletion or antagonism on various aspects of cognition using a set of behavioral and electrophysiological analyses. Hippocampal neuronal network activity was decreased in middle-aged LPAR2-/- mice, whereas hippocampal long-term potentiation (LTP) was increased suggesting cognitive advantages of LPAR2-/- mice. In line with the lower excitability, RNAseq studies revealed reduced transcription of neuronal activity markers in the dentate gyrus of the hippocampus in naïve LPAR2-/- mice, including ARC, FOS, FOSB, NR4A, NPAS4 and EGR2. LPAR2-/- mice behaved similarly to wild-type controls in maze tests of spatial or social learning and memory but showed faster and accurate responses in a 5-choice serial reaction touchscreen task requiring high attention and fast spatial discrimination. In IntelliCage learning experiments, LPAR2-/- were less active during daytime but normally active at night, and showed higher accuracy and attention to LED cues during active times. Overall, they maintained equal or superior licking success with fewer trials. Pharmacological block of the LPAR2 receptor recapitulated the LPAR2-/- phenotype, which was characterized by economic corner usage, stronger daytime resting behavior and higher proportions of correct trials. We conclude that LPAR2 stabilizes neuronal network excitability upon aging and allows for more efficient use of resting periods, better memory consolidation and better performance in tasks requiring high selective attention. Therapeutic LPAR2 antagonism may alleviate aging-associated cognitive dysfunctions.
Assuntos
Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Neurônios/metabolismo , Receptores de Ácidos Lisofosfatídicos/metabolismo , Envelhecimento , Animais , Encéfalo/metabolismo , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Cromatografia Líquida de Alta Pressão , Giro Denteado/metabolismo , Análise Discriminante , Família de Proteínas EGF/deficiência , Família de Proteínas EGF/genética , Feminino , Fígado/metabolismo , Potenciação de Longa Duração , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Componente Principal , Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores , Receptores de Ácidos Lisofosfatídicos/deficiência , Receptores de Ácidos Lisofosfatídicos/genética , Espectrometria de Massas em TandemRESUMO
The tension on the supply of surgical and FFP2 masks during the first wave of the COVID-19 pandemic leads to study the potential reuse of these masks. As washing is easily adaptable at home, this treatment solution was retained. In this work, thirty-six references of surgical masks and four FFP2 masks were tested without being worn or washed and after several washing cycles. The results highlighted a great heterogeneity of performances depending on the mask trademarks, both for surgical masks and FFP2. The quality of the meltblown and spunbond layers and the presence/absence of electrostatic charges at the fiber surface are put forward to explain the variability of results, both on differential pressures and filtration efficiencies. The differential pressure and the particle filtration efficiency of the washed masks were maintained up to 10 washing cycles and met the standard requirements. However, an immersion in water with a detergent induces an efficiency decrease for submicronic particles. This lower performance, constant after the first washing cycle, can be explained by the loss of electrostatic charges during the washing cycle. The modifications of surface properties after washing also lead to a loss of the hydrophobic behavior of type IIR surgical masks, which can therefore no more be considered as resistant to blood projections.
RESUMO
BACKGROUND: Cardiovascular diseases like stroke cause changes to sphingolipid mediators like sphingosine 1-phosphate (S1P) or its ceramide analogs, which bear the potential to either alleviate or exacerbate the neurological damage. Therefore, the precise identification of alterations within the sphingolipidome during ischemic stroke (IS) and hemorrhagic transformation (HT) harbors a putative therapeutic potential to orchestrate local and systemic immunomodulatory processes. Due to the scarcity of research in this field, we aimed to characterize the sphingolipidome in IS and HT. METHODS: C57BL/6 mice underwent middle cerebral artery occlusion (MCAO) and specimens of the peri-infarct tissue were taken for sphingolipid profiling. RESULTS: Ischemic stroke resulted in reduced S1P whilst ceramides were elevated six hours post ischemia onset. However, these differences were nearly revoked at 24 hours post ischemia onset. Moreover, the topmost S1P and ceramide levels were linked to the presence of HT after MCAO. In this study we show the characterization of the sphingolipidomic landscape of the peri-infarct tissue after ischemic stroke and HT. Especially, highest values of S1P, C 18 lactosylceramide, C 18 glucosylceramide, and C 24:1 ceramide were nearly entirely expressed by mice with HT. CONCLUSIONS: Our results warrant further investigations into the immunomodulatory consequences of altered sphingolipid species for the development of HT after IS.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Camundongos Endogâmicos C57BL , Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/complicações , Modelos Animais de Doenças , Esfingolipídeos/uso terapêutico , Ceramidas/uso terapêuticoRESUMO
BACKGROUND: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD. OBJECTIVE: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD. METHODS: Transcriptional, metabolic, and lipid mediator profiles in macrophages from patients with N-ERD and healthy controls were assessed by RNA sequencing, Seahorse assays, and LC-MS/MS. Metabolites in nasal lining fluid, sputum, and plasma from patients with N-ERD (n = 15) and healthy individuals (n = 10) were quantified by targeted metabolomics analyses. Genome-wide methylomics were deployed to define epigenetic mechanisms of macrophage reprogramming in N-ERD. RESULTS: This study shows that N-ERD monocytes/macrophages exhibit an overall reduction in DNA methylation, aberrant metabolic profiles, and an increased expression of chemokines, indicative of a persistent proinflammatory activation. Differentially methylated regions in N-ERD macrophages included genes involved in chemokine signaling and acylcarnitine metabolism. Acylcarnitines were increased in macrophages, sputum, nasal lining fluid, and plasma of patients with N-ERD. On inflammatory challenge, N-ERD macrophages produced increased levels of acylcarnitines, proinflammatory arachidonic acid metabolites, cytokines, and chemokines as compared to healthy macrophages. CONCLUSIONS: Together, these findings decipher a proinflammatory metabolic and epigenetic reprogramming of macrophages in N-ERD.
Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Asma/imunologia , Macrófagos/imunologia , Pólipos Nasais/imunologia , Anti-Inflamatórios não Esteroides/imunologia , Asma/induzido quimicamente , Humanos , Memória Imunológica/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Pólipos Nasais/induzido quimicamenteRESUMO
To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.
Assuntos
Azoximetano/efeitos adversos , Neoplasias Associadas a Colite/patologia , Neoplasias do Colo/patologia , Sulfato de Dextrana/efeitos adversos , Esfingosina N-Aciltransferase/genética , Linfócitos T/metabolismo , Animais , Neoplasias Associadas a Colite/induzido quimicamente , Neoplasias Associadas a Colite/genética , Neoplasias Associadas a Colite/imunologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Células Jurkat , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Especificidade de Órgãos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Carga TumoralRESUMO
AIMS: Parkinson's disease (PD) is frequently associated with a prodromal sensory neuropathy manifesting with sensory loss and chronic pain. We have recently shown that PD-associated sensory neuropathy in patients is associated with high levels of glucosylceramides. Here, we assessed the underlying pathology and mechanisms in Pink1-/- SNCAA53T double mutant mice. METHODS: We studied nociceptive and olfactory behaviour and the neuropathology of dorsal root ganglia (DRGs), including ultrastructure, mitochondrial respiration, transcriptomes, outgrowth and calcium currents of primary neurons, and tissue ceramides and sphingolipids before the onset of a PD-like disease that spontaneously develops in Pink1-/- SNCAA53T double mutant mice beyond 15 months of age. RESULTS: Similar to PD patients, Pink1-/- SNCAA53T mice developed a progressive prodromal sensory neuropathy with a loss of thermal sensitivity starting as early as 4 months of age. In analogy to human plasma, lipid analyses revealed an accumulation of glucosylceramides (GlcCer) in the DRGs and sciatic nerves, which was associated with pathological mitochondria, impairment of mitochondrial respiration, and deregulation of transient receptor potential channels (TRPV and TRPA) at mRNA, protein and functional levels in DRGs. Direct exposure of DRG neurons to GlcCer caused transient hyperexcitability, followed by a premature decline of the viability of sensory neurons cultures upon repeated GlcCer application. CONCLUSIONS: The results suggest that pathological GlcCer contribute to prodromal sensory disease in PD mice via mitochondrial damage and calcium channel hyperexcitability. GlcCer-associated sensory neuron pathology might be amenable to GlcCer lowering therapeutic strategies.
Assuntos
Mutação/genética , Doença de Parkinson/genética , Proteínas Quinases/genética , alfa-Sinucleína/genética , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios/patologia , Doença de Parkinson/patologia , Transtornos Parkinsonianos/genética , Transtornos Parkinsonianos/patologia , Proteínas Quinases/deficiência , alfa-Sinucleína/metabolismoRESUMO
Sphingosine 1-phosphate (S1P) signaling influences numerous cell biological mechanisms such as differentiation, proliferation, survival, migration, and angiogenesis. Intriguingly, our current knowledge is based solely on the role of S1P with an 18-carbon long-chain base length, S1P d18:1. Depending on the composition of the first and rate-limiting enzyme of the sphingolipid de novo metabolism, the serine palmitoyltransferase, other chain lengths have been described in vivo. While cells are also able to produce S1P d20:1, its abundance and function remains elusive so far. Our experiments are highlighting the role of S1P d20:1 in the mouse central nervous system (CNS) and human glioblastoma. We show here that S1P d20:1 and its precursors are detectable in both healthy mouse CNS-tissue and human glioblastoma. On the functional level, we focused our work on one particular, well-characterized pathway, the induction of cyclooxygenase (COX)-2 expression via the S1P receptor 2 (S1P2 ). Intriguingly, S1P d20:1 only fairly induces COX-2 expression and can block the S1P d18:1-induced COX-2 expression mediated via S1P2 activation in the human glioblastoma cell line LN229. This data indicates that S1P d20:1 might act as an endogenous modulator of S1P signaling via a partial agonism at the S1P2 receptor. While our findings might stimulate further research on the relevance of long-chain base lengths in sphingolipid signaling, the metabolism of S1P d20:1 has to be considered as an integral part of S1P signaling pathways in vivo.