RESUMEN
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
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Adyuvantes Inmunológicos/farmacología , Antígenos Virales/inmunología , Candida albicans/química , Mananos/inmunología , Hidróxido de Aluminio/química , Animales , Anticuerpos Neutralizantes/inmunología , Especificidad de Anticuerpos/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Chlorocebus aethiops , Epítopos/inmunología , Inmunidad Innata , Inmunización , Inflamación/patología , Interferones/metabolismo , Lectinas Tipo C/metabolismo , Ligandos , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Senos Paranasales/metabolismo , Subunidades de Proteína/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Solubilidad , Glicoproteína de la Espiga del Coronavirus/metabolismo , Linfocitos T/inmunología , Factor de Transcripción ReIB/metabolismo , Células Vero , beta-Glucanos/metabolismoRESUMEN
Bradykinesia, or slowness of movement, is a defining feature of Parkinson disease (PD) and a major contributor to the negative effects on quality of life associated with this disorder and related conditions. A dominant pathophysiological model of bradykinesia in PD has existed for approximately 30 years and has been the basis for the development of several therapeutic interventions, but accumulating evidence has made this model increasingly untenable. Although more recent models have been proposed, they also appear to be flawed. In this Perspective, I consider the leading prior models of bradykinesia in PD and argue that a more functionally related model is required, one that considers changes that disrupt the fundamental process of accurate information transmission. In doing so, I review emerging evidence of network level functional connectivity changes, information transfer dysfunction and potential motor code transmission error and present a novel model of bradykinesia in PD that incorporates this evidence. I hope that this model may reconcile inconsistencies in its predecessors and encourage further development of therapeutic interventions.
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Hipocinesia , Enfermedad de Parkinson , Humanos , Hipocinesia/fisiopatología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Animales , Modelos Neurológicos , Encéfalo/fisiopatologíaRESUMEN
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
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Plasticidad de la Célula/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Inmunidad , Macrófagos/inmunología , Macrófagos/metabolismo , Infecciones por Respirovirus/etiología , Presentación de Antígeno , Biomarcadores , Susceptibilidad a Enfermedades , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Inmunofenotipificación , Interferón Tipo I/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Especificidad de Órganos/inmunología , Receptores Fc/metabolismo , Infecciones por Respirovirus/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Factores de Transcripción , Virosis/genética , Virosis/inmunología , Virosis/metabolismo , Virosis/virologíaAsunto(s)
Inmunidad Adaptativa , Tolerancia Inmunológica , Inmunidad Innata , Memoria Inmunológica , Inmunidad Adaptativa/inmunología , Animales , Vacuna BCG/inmunología , Diferenciación Celular , Humanos , Tolerancia Inmunológica/inmunología , Inmunidad Innata/inmunología , Memoria Inmunológica/inmunología , VacunaciónRESUMEN
Myocardial infarction, stroke, and sepsis trigger systemic inflammation and organism-wide complications that are difficult to manage. Here, we examined the contribution of macrophages residing in vital organs to the systemic response after these injuries. We generated a comprehensive catalog of changes in macrophage number, origin, and gene expression in the heart, brain, liver, kidney, and lung of mice with myocardial infarction, stroke, or sepsis. Predominantly fueled by heightened local proliferation, tissue macrophage numbers increased systemically. Macrophages in the same organ responded similarly to different injuries by altering expression of tissue-specific gene sets. Preceding myocardial infarction improved survival of subsequent pneumonia due to enhanced bacterial clearance, which was caused by IFNÉ£ priming of alveolar macrophages. Conversely, EGF receptor signaling in macrophages exacerbated inflammatory lung injury. Our data suggest that local injury activates macrophages in remote organs and that targeting macrophages could improve resilience against systemic complications following myocardial infarction, stroke, and sepsis.
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Susceptibilidad a Enfermedades , Macrófagos/inmunología , Macrófagos/metabolismo , Animales , Biomarcadores , Recuento de Células , Susceptibilidad a Enfermedades/inmunología , Receptores ErbB/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Isquemia/etiología , Isquemia/metabolismo , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Células Musculares/inmunología , Células Musculares/metabolismo , Infarto del Miocardio/etiología , Infarto del Miocardio/metabolismo , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Neumonía/etiología , Neumonía/metabolismo , Neumonía/patologíaRESUMEN
Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.
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Acetaldehído/química , Reactivos de Enlaces Cruzados/química , Daño del ADN , Reparación del ADN , Replicación del ADN/fisiología , ADN/química , Etanol/química , Anemia de Fanconi/metabolismo , Animales , Cisplatino/química , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Replicación del ADN/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/metabolismo , Etanol/farmacología , Mutagénesis/efectos de los fármacos , Nucleotidiltransferasas/metabolismo , Mutación Puntual/efectos de los fármacos , Mutación Puntual/genética , Xenopus , Proteínas de Xenopus/metabolismoRESUMEN
The nucleosome remodeling and deacetylase (NuRD) complex modifies nucleosome positioning and chromatin compaction to regulate gene expression. The methyl-CpG-binding domain proteins 2 and 3 (MBD2 and MBD3) play a critical role in complex formation; however, the molecular details of how they interact with other NuRD components have yet to be fully elucidated. We previously showed that an intrinsically disordered region (IDR) of MBD2 is necessary and sufficient to bind to the histone deacetylase core of NuRD. Building on that work, we have measured the inherent structural propensity of the MBD2-IDR using solvent and site-specific paramagnetic relaxation enhancement measurements. We then used the AlphaFold2 machine learning software to generate a model of the complex between MBD2 and the histone deacetylase core of NuRD. This model is remarkably consistent with our previous studies, including the current paramagnetic relaxation enhancement data. The latter suggests that the free MBD2-IDR samples conformations similar to the bound structure. We tested this model of the complex extensively by mutating key contact residues and measuring binding using an intracellular bioluminescent resonance energy transfer assay. Furthermore, we identified protein contacts that, when mutated, disrupted gene silencing by NuRD in a cell model of fetal hemoglobin regulation. Hence, this work provides insights into the formation of NuRD and highlights critical binding pockets that may be targeted to block gene silencing for therapy. Importantly, we show that AlphaFold2 can generate a credible model of a large complex that involves an IDR that folds upon binding.
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Histona Desacetilasas , Nucleosomas , Histona Desacetilasas/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/metabolismo , Silenciador del Gen , Cromatina , Histona Desacetilasa 1/genéticaRESUMEN
During human development, there is a switch in the erythroid compartment at birth that results in silencing of expression of fetal hemoglobin (HbF). Reversal of this silencing has been shown to be effective in overcoming the pathophysiologic defect in sickle cell anemia. Among the many transcription factors and epigenetic effectors that are known to mediate HbF silencing, two of the most potent are BCL11A and MBD2-NuRD. In this report, we present direct evidence that MBD2-NuRD occupies the γ-globin gene promoter in adult erythroid cells and positions a nucleosome there that results in a closed chromatin conformation that prevents binding of the transcriptional activator, NF-Y. We show that the specific isoform, MBD2a, is required for the formation and stable occupancy of this repressor complex that includes BCL11A, MBD2a-NuRD, and the arginine methyltransferase, PRMT5. The methyl cytosine binding preference and the arginine-rich (GR) domain of MBD2a are required for high affinity binding to methylated γ-globin gene proximal promoter DNA sequences. Mutation of the methyl cytosine-binding domain (MBD) of MBD2 results in a variable but consistent loss of γ-globin gene silencing, in support of the importance of promoter methylation. The GR domain of MBD2a is also required for recruitment of PRMT5, which in turn results in placement of the repressive chromatin mark H3K8me2s at the promoter. These findings support a unified model that integrates the respective roles of BCL11A, MBD2a-NuRD, PRMT5, and DNA methylation in HbF silencing.
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Hemoglobina Fetal , gamma-Globinas , Adulto , Recién Nacido , Humanos , Genes Reguladores , Factores de Transcripción , Cromatina , Citosina , Proteína-Arginina N-Metiltransferasas , Proteínas de Unión al ADNRESUMEN
A long-standing question in vision science is how the three cone photoreceptor types-long (L), medium (M), and short (S) wavelength sensitive-combine to generate our perception of color. Hue perception can be described along two opponent axes: red-green and blue-yellow. Psychophysical measurements of color appearance indicate that the cone inputs to the red-green and blue-yellow opponent axes are M vs. L + S and L vs. M + S, respectively. However, the "cardinal directions of color space" revealed by psychophysical measurements of color detection thresholds following adaptation are L vs. M and S vs. L + M. These cardinal directions match the most common cone-opponent retinal ganglion cells (RGCs) in the primate retina. Accordingly, the cone opponency necessary for color appearance is thought to be established in the cortex. While neurons with the appropriate M vs. L + S and L vs. M + S opponency have been reported in the retina and lateral geniculate nucleus, their existence continues to be debated. Resolving this long-standing debate is necessary because a complete account of the cone opponency in the retinal output is critical for understanding how downstream neural circuits process color. Here, we performed adaptive optics calcium imaging to noninvasively measure foveal RGC light responses in the living Macaca fascicularis eye. We confirm the presence of L vs. M + S and M vs. L + S neurons with noncardinal cone opponency and demonstrate that cone-opponent signals in the retinal output are more diverse than classically thought.
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Percepción de Color , Fóvea Central , Células Fotorreceptoras Retinianas Conos , Células Ganglionares de la Retina , Animales , Células Ganglionares de la Retina/fisiología , Células Fotorreceptoras Retinianas Conos/fisiología , Fóvea Central/fisiología , Percepción de Color/fisiología , Estimulación Luminosa/métodos , Masculino , Femenino , Macaca fascicularisRESUMEN
During the COVID-19 pandemic, the American Heart Association created a new 2024 Impact Goal with health equity at its core, in recognition of the increasing health disparities in our country and the overwhelming evidence of the damaging effect of structural racism on cardiovascular and stroke health. Concurrent with the announcement of the new Impact Goal was the release of an American Heart Association presidential advisory on structural racism, recognizing racism as a fundamental driver of health disparities and directing the American Heart Association to advance antiracist strategies regarding science, business operations, leadership, quality improvement, and advocacy. This policy statement builds on the call to action put forth in our presidential advisory, discussing specific opportunities to leverage public policy in promoting overall well-being and rectifying those long-standing structural barriers that impede the progress that we need and seek for the health of all communities. Although this policy statement discusses difficult aspects of our past, it is meant to provide a forward-looking blueprint that can be embraced by a broad spectrum of stakeholders who share the association's commitment to addressing structural racism and realizing true health equity.
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Equidad en Salud , Racismo , Estados Unidos , Humanos , Racismo Sistemático , American Heart Association , Pandemias/prevención & control , Racismo/prevención & control , Política PúblicaRESUMEN
BACKGROUND: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management. METHODS: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed). FINDINGS: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported. INTERPRETATION: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients. FUNDING: Swing Therapeutics.
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Fibromialgia , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Terapia de Aceptación y Compromiso/métodos , Terapia Cognitivo-Conductual/métodos , Fibromialgia/terapia , Teléfono Inteligente , Resultado del Tratamiento , Salud DigitalRESUMEN
BACKGROUND: Anti-inflammatory therapy with long-term colchicine prevented vascular recurrence in coronary disease. Unlike coronary disease, which is typically caused by atherosclerosis, ischaemic stroke is caused by diverse mechanisms including atherosclerosis and small vessel disease or is frequently due to an unknown cause. We aimed to investigate the hypothesis that long-term colchicine would reduce recurrent events after ischaemic stroke. METHODS: We did a randomised, parallel-group, open-label, blinded endpoint assessed trial comparing long-term colchicine (0·5 mg orally per day) plus guideline-based usual care with usual care only. Hospital-based patients with non-severe, non-cardioembolic ischaemic stroke or high-risk transient ischaemic attack were eligible. The primary endpoint was a composite of first fatal or non-fatal recurrent ischaemic stroke, myocardial infarction, cardiac arrest, or hospitalisation (defined as an admission to an inpatient unit or a visit to an emergency department that resulted in at least a 24 h stay [or a change in calendar date if the hospital admission or discharge times were not available]) for unstable angina. The p value for significance was 0·048 to adjust for two prespecified interim analyses conducted by the data monitoring committee, for which the steering committee and trial investigators remained blinded. The trial was registered at ClinicalTrials.gov (NCT02898610) and is completed. FINDINGS: 3154 patients were randomly assigned between Dec 19, 2016, and Nov 21, 2022, with the last follow-up on Jan 31, 2024. The trial finished before the anticipated number of outcomes was accrued (367 outcomes planned) due to budget constraints attributable to the COVID-19 pandemic. Ten patients withdrew consent for analysis of their data, leaving 3144 patients in the intention-to-treat analysis: 1569 (colchicine and usual care) and 1575 (usual care alone). A primary endpoint occurred in 338 patients, 153 (9·8%) of 1569 patients allocated to colchicine and usual care and 185 (11·7%) of 1575 patients allocated to usual care alone (incidence rates 3·32 vs 3·92 per 100 person-years, hazard ratio 0·84; 95% CI 0·68-1·05, p=0·12). Although no between-group difference in C-reactive protein (CRP) was observed at baseline, patients treated with colchicine had lower CRP at 28 days and at 1, 2, and 3 years (p<0·05 for all timepoints). The rates of serious adverse events were similar in both groups. INTERPRETATION: Although no statistically significant benefit was observed on the primary intention-to-treat analysis, the findings provide new evidence supporting the rationale for anti-inflammatory therapy in further randomised trials. FUNDING: Health Research Board Ireland, Deutsche Forschungsgemeinschaft (German Research Foundation), and Fonds Wetenschappelijk Onderzoek Vlaanderen (Research Foundation Flanders), Belgium.
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Colchicina , Accidente Cerebrovascular Isquémico , Prevención Secundaria , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Colchicina/administración & dosificación , Colchicina/uso terapéutico , Hospitalización/estadística & datos numéricos , Ataque Isquémico Transitorio/prevención & control , Ataque Isquémico Transitorio/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/prevención & control , Infarto del Miocardio/prevención & control , Recurrencia , Prevención Secundaria/métodos , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
Dectin-1 is a well-characterized C-type lectin receptor involved in anti-fungal immunity through the recognition of polysaccharides; however, molecular mechanisms and outcomes initiated through self-recognition have not been fully understood. Here, we purified a water-soluble fraction from mouse liver that acts as a Dectin-1 agonist. To address the physiological relevance of this recognition, we utilized sterile liver inflammation models. The CCl4-induced hepatitis model showed that Dectin-1 deficiency led to reduced inflammation through decreased inflammatory cell infiltration and lower pro-inflammatory cytokine levels. Moreover, in a NASH model induced by streptozotocin and a high-fat diet, hepatic inflammation and fibrosis were ameliorated in Dectin-1-deficient mice. The Dectin-1 agonist activity was increased in the water-soluble fraction from NASH mice, suggesting a potential pathogenic cycle between Dectin-1 activation and hepatitis progression. In vivo administration of the fraction into mice induced hepatic inflammation. These results highlight a role of self-recognition through Dectin-1 that triggers hepatic innate immune responses and contributes to the exacerbation of inflammation in pathogenic settings. Thus, the blockade of this axis may provide a therapeutic option for liver inflammatory diseases.
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Hepatitis , Lectinas Tipo C , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Inflamación/metabolismo , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico/inmunología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , AguaRESUMEN
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.
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Eccema , Trasplante de Células Madre Hematopoyéticas , Síndrome de Wiskott-Aldrich , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Proteína del Síndrome de Wiskott-Aldrich/genética , Células Madre Hematopoyéticas/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Terapia Genética/métodos , Eccema/etiología , Eccema/metabolismo , Eccema/terapiaRESUMEN
Protected areas (PAs) are a cornerstone of global conservation and central to international plans to minimize global extinctions. During the coming century, global ecosystem destruction and fragmentation associated with increased human population and economic activity could make the long-term survival of most terrestrial vertebrates even more dependent on PAs. However, the capacity of the current global PA network to sustain species for the long term is unknown. Here, we explore this question for all nonvolant terrestrial mammals for which we found sufficient data, â¼4,000 species. We first estimate the potential population size of each such mammal species in each PA and then use three different criteria to estimate if solely the current global network of PAs might be sufficient for their long-term survival. Our analyses suggest that current PAs may fail to provide robust protection for about half the species analyzed, including most species currently listed as threatened with extinction and a third of species not currently listed as threatened. Hundreds of mammal species appear to have no viable protected populations. Underprotected species were found across all body sizes, taxonomic groups, and geographic regions. Large-bodied mammals, endemic species, and those in high-biodiversity tropical regions were particularly poorly protected by existing PAs. As new international biodiversity targets are formulated, our results suggest that the global network of PAs must be greatly expanded and most importantly that PAs must be located in diverse regions that encompass species not currently protected and must be large enough to ensure that protected species can persist for the long term.
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Conservación de los Recursos Naturales , Mamíferos , Animales , Biodiversidad , Extinción Biológica , HumanosRESUMEN
The interaction between the Candida albicans cell wall and pattern recognition receptors is crucial for the initiation of host immune responses which, ultimately, contribute to the clearance of this pathogenic fungus. In the present study, we investigate the ability of C. albicans mannans to modulate immune response and induce innate immune memory (also termed trained immunity). Using mutants of C. albicans that are defective in, or lack mannosyl residues, we show that alterations in the mannosylation of the C. albicans cell wall affect the innate cytokine response and strongly reduce the secretion of T cell-derived cytokines. Subsequently, we demonstrate that the branching of N-linked mannan, but not O-linked mannan, is essential to potentiate the induction of trained immunity, a process mediated by Dectin-2. In conclusion, N-linked mannan is needed, in addition to ß-glucans, for an effective induction of trained immunity by C. albicans.
RESUMEN
The photoreceptor outer segment (OS) is the phototransductive organelle in the vertebrate retina. OS tips are regularly ingested and degraded by the adjacent retinal pigment epithelium (RPE), offsetting the addition of new disk membrane at the base of the OS. This catabolic role of the RPE is essential for photoreceptor health, with defects in ingestion or degradation underlying different forms of retinal degeneration and blindness. Although proteins required for OS tip ingestion have been identified, spatiotemporal analysis of the ingestion process in live RPE cells is lacking; hence, the literature reflects no common understanding of the cellular mechanisms that affect ingestion. We imaged live RPE cells from mice (both sexes) to elucidate the ingestion events in real time. Our imaging revealed roles for f-actin dynamics and specific dynamic localizations of two BAR (Bin-Amphiphysin-Rvs) proteins, FBP17 and AMPH1-BAR, in shaping the RPE apical membrane as it surrounds the OS tip. Completion of ingestion was observed to occur by scission of the OS tip from the remainder of the OS, with a transient concentration of f-actin forming around the site of imminent scission. Actin dynamics were also required for regulating the size of the ingested OS tip, and the time course of the overall ingestion process. The size of the ingested tip is consistent with the term "phagocytosis." However, phagocytosis usually refers to engulfment of an entire particle or cell, whereas our observations of OS tip scission indicate a process that is more specifically described as "trogocytosis," in which one cell "nibbles" another cell.SIGNIFICANCE STATEMENT The ingestion of the photoreceptor outer segment (OS) tips by the retinal pigment epithelium (RPE) is a dynamic cellular process that has fascinated scientists for 60 years. Yet its molecular mechanisms had not been addressed in living cells. We developed a live-cell imaging approach to investigate OS tip ingestion, and focused on the dynamic participation of actin filaments and membrane-shaping BAR proteins. We observed scission of OS tips for the first time, and were able to monitor local changes in protein concentration preceding, during, and following scission. Our approach revealed that actin filaments were concentrated at the site of OS scission and were required for regulating the size of the ingested OS tip and the time course of the ingestion process.
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Actinas , Epitelio Pigmentado de la Retina , Masculino , Femenino , Ratones , Animales , Epitelio Pigmentado de la Retina/metabolismo , Actinas/metabolismo , Fagocitosis/fisiología , Citoesqueleto de Actina/metabolismo , Ingestión de AlimentosRESUMEN
The rod photoreceptor synapse is the first synapse of dim-light vision and one of the most complex in the mammalian CNS. The components of its unique structure, a presynaptic ribbon and a single synaptic invagination enclosing several postsynaptic processes, have been identified, but disagreements about their organization remain. Here, we have used EM tomography to generate high-resolution images of 3-D volumes of the rod synapse from the female domestic cat. We have resolved the synaptic ribbon as a single structure, with a single arciform density, indicating the presence of one long site of transmitter release. The organization of the postsynaptic processes, which has been difficult to resolve with past methods, appears as a tetrad arrangement of two horizontal cell and two rod bipolar cell processes. Retinal detachment severely disrupts this organization. After 7 d, EM tomography reveals withdrawal of rod bipolar dendrites from most spherules; fragmentation of synaptic ribbons, which lose their tight association with the presynaptic membrane; and loss of the highly branched telodendria of the horizontal cell axon terminals. After detachment, the hilus, the opening through which postsynaptic processes enter the invagination, enlarges, exposing the normally sequestered environment within the invagination to the extracellular space of the outer plexiform layer. Our use of EM tomography provides the most accurate description to date of the complex rod synapse and details changes it undergoes during outer segment degeneration. These changes would be expected to disrupt the flow of information in the rod pathway.SIGNIFICANCE STATEMENT Ribbon-type synapses transmit the first electrical signals of vision and hearing. Despite their crucial role in sensory physiology, the three-dimensional ultrastructure of these synapses, especially the complex organization of the rod photoreceptor synapse, is not well understood. We used EM tomography to obtain 3-D imaging at nanoscale resolution to help resolve the organization of rod synapses in normal and detached retinas. This approach has enabled us to show that in the normal retina a single ribbon and arciform density oppose a tetrad of postsynaptic processes. In addition, it enabled us to provide a 3-D perspective of the ultrastructural changes that occur in response to retinal detachment.
Asunto(s)
Desprendimiento de Retina , Femenino , Animales , Gatos , Microscopía Electrónica , Sinapsis/metabolismo , Retina/ultraestructura , Células Bipolares de la Retina , Células Fotorreceptoras Retinianas Bastones/ultraestructura , MamíferosRESUMEN
There is increasing recognition of the public health importance of snakebite envenoming. Worldwide annual incidence is likely to be 5 million bites, with mortality exceeding 150 000 deaths, and the resulting physical and psychological morbidity leads to substantial social and economic repercussions. Prevention through community education by trained health workers is the most effective and economically viable strategy for reducing risk of bites and envenoming. Clinical challenges to effective treatment are most substantial in rural areas of low-resource settings, where snakebites are most common. Classic skills of history taking, physical examination, and use of affordable point-of-care tests should be followed by monitoring of evolving local and systemic envenoming. Despite the profusion of new ideas for interventions, hyperimmune equine or ovine plasma-derived antivenoms remain the only specific treatment for snakebite envenoming. The enormous interspecies and intraspecies complexity and diversity of snake venoms, revealed by modern venomics, demands a radical redesign of many current antivenoms.