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1.
New Phytol ; 238(6): 2685-2697, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36960534

RESUMEN

Fossil discoveries can transform our understanding of plant diversification over time and space. Recently described fossils in many plant families have pushed their known records farther back in time, pointing to alternative scenarios for their origin and spread. Here, we describe two new Eocene fossil berries of the nightshade family (Solanaceae) from the Esmeraldas Formation in Colombia and the Green River Formation in Colorado (USA). The placement of the fossils was assessed using clustering and parsimony analyses based on 10 discrete and five continuous characters, which were also scored in 291 extant taxa. The Colombian fossil grouped with members of the tomatillo subtribe, and the Coloradan fossil aligned with the chili pepper tribe. Along with two previously reported early Eocene fossils from the tomatillo genus, these findings indicate that Solanaceae were distributed at least from southern South America to northwestern North America by the early Eocene. Together with two other recently discovered Eocene berries, these fossils demonstrate that the diverse berry clade and, in turn, the entire nightshade family, is much older and was much more widespread in the past than previously thought.


Asunto(s)
Capsicum , Solanum , Fósiles , Frutas , América del Sur , Filogenia
2.
Rev Med Chil ; 150(8): 1087-1094, 2022 Aug.
Artículo en Español | MEDLINE | ID: mdl-37358157

RESUMEN

In the last decade, medical students stood out as active agents in their training, which implies their involvement in the design, implementation, evaluation, and curricular co-governance. This article describes a model of active undergraduate student participation from 2014 to 2021 and compares the face-to-face and synchronous online modalities, later brought forward by the SARS-COV-2 pandemic. Annually, a call was made to UC School of Medicine undergraduate students to establish the topics and areas to be addressed during self-managed seminars. Then, medical students located in Chile were invited to attend the activity. Psychiatry was established as a priority topic in six out of eight years. Five seminars were conducted, the last two in synchronous online mode. The number of people enrolled in the online modality increased by 251% compared to the face-to-face modality (face-to-face mean = 133 ± 33 SD; online mean = 336 ± 24SD), with no significant differences in rates of attendance between modalities (Odds ratio (OR) = 1,12; 95% CI= 0,82 - 1,55; p = 0,45). The online modality was associated with a higher proportion of enrollees belonging to an institution outside the Metropolitan Region (OR 12,63; 95% CI = 8,64 - 18,46; p < 0,01). The self-managed psychiatry seminars correspond to a model of active undergraduate student participation, with the synchronous online modality representing an opportunity to massify it throughout the national territory.


Asunto(s)
COVID-19 , Educación de Pregrado en Medicina , Psiquiatría , Automanejo , Estudiantes de Medicina , Humanos , SARS-CoV-2
3.
J Phycol ; 57(3): 711-725, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33583038

RESUMEN

Inbreeding, the mating between genetically related individuals, often results in reduced survival and fecundity of offspring, relative to outcrossing. Yet, high inbreeding rates are commonly observed in seaweeds, suggesting compensatory reproductive traits may affect the costs and benefits of the mating system. We experimentally manipulated inbreeding levels in controlled crossing experiments, using gametophytes from 19 populations of Macrocystis pyrifera along its Eastern Pacific coastal distribution (EPC). The objective was to investigate the effects of male-female kinship on female fecundity and fertility, to estimate inbreeding depression in the F1 progeny, and to assess the variability of these effects among different regions and habitats of the EPC. Results revealed that the presence and kinship of males had a significant effect on fecundity and fertility of female gametophytes. Females left alone or in the presence of sibling males express the highest gametophyte size, number, and size of oogonia, suggesting they were able to sense the presence and the identity of their mates before gamete contact. The opposite trend was observed for the production of embryos per female gametes, indicating higher costs of selfing and parthenogenesis than outcrossing on fertility. However, the increased fecundity compensated for the reduced fertility, leading to a stable overall reproductive output. Inbreeding also affected morphological traits of juvenile sporophytes, but not their heatwave tolerance. The male-female kinship effect was stronger in high-latitude populations, suggesting that females from low-latitude marginal populations might have evolved to mate with any male gamete to guarantee reproductive success.


Asunto(s)
Macrocystis , Células Germinativas de las Plantas , Endogamia , Reproducción
4.
J Strength Cond Res ; 34(8): 2360-2368, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30052600

RESUMEN

Gouvêa, AL, Martinez, CG, and Kurtenbach, E. Determining maximal muscle strength in mice: validity and reliability of an adapted swimming incremental overload test. J Strength Cond Res 34(8): 2360-2368, 2020-At present, there are no reliable methods to determine maximal muscle strength in small rodents. Here, we established an adapted swimming incremental overload test (SIOT) as an instrument for this purpose. First, to validate the test, BALB/c mice received 20 mg·kg·d of dexamethasone (DEXA group) or water (control group). After 14 days, with a cumulative dose of 120 mg·kg of dexamethasone, the SIOT could detect a decrease of approximately 7% in muscle strength. In addition, this decrease was consistent with a significant reduction in body (above 13.5%) and muscle (approximately 15%) weight in DEXA atrophic animals. To establish the SIOT reliability, another group of animals was evaluated for 5 consecutive days. In this second protocol, the SIOT was executed with an initial load corresponding to 12% of the mouse body weight (BW) fixed to the tail. Increments between 1 and 5% of the BW were added during each attempt to obtain the highest load that was tolerated for a time interval of 5-7 seconds. On the last day, the SIOT reliability test was performed by 2 different raters to obtain the inter-rater reproducibility. The adapted SIOT was shown to be reliable when measured by the same rater (intraclass correlation coefficient [ICC] = 0.939) and by 2 different raters (ICC = 0.830). The Bland-Altman graphical representation did not demonstrate heteroscedastic errors. Therefore, the SIOT proved to be a sensitive and reliable method to measure muscle strength, and it can be applied to small animals in different models of muscle atrophy.


Asunto(s)
Fuerza Muscular/fisiología , Músculo Esquelético/fisiología , Natación/fisiología , Animales , Dexametasona/farmacología , Femenino , Ratones , Ratones Endogámicos BALB C , Fuerza Muscular/efectos de los fármacos , Dinamómetro de Fuerza Muscular , Reproducibilidad de los Resultados
5.
Ann Bot ; 123(3): 451-460, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30212854

RESUMEN

BACKGROUND AND AIMS: The asterids (>80 000 extant species) appear in the fossil record with considerable diversity near the Turonian-Coniacian boundary (~90 Ma; Late Cretaceous) and are strongly represented in the earliest diverging lineage, Cornales. These early asterid representatives have so far been reported from western North America and eastern Asia. In this study, we characterize a new cornalean taxon based on charcoalified fruits from the upper Turonian of eastern North America, a separate landmass from western North America at the time, and identify early palaeobiogeographical patterns of Cornales during the Cretaceous. METHODS: Fossils were studied and imaged using scanning electron microscopy and micro-computed tomography (micro-CT) scanning. To assess the systematic affinities of the fossils, phylogenetic analyses were conducted using maximum parsimony. KEY RESULTS: The charcoalified fruits are represented by tri-locular woody endocarps with dorsal apically opening germination valves. Three septa intersect to form a robust central axis. Endocarp ground tissue consists of two zones: an outer endocarp composed of isodiametric sclereids and an inner endocarp containing circum-locular fibres. Central vasculature is absent; however, there are several small vascular bundles scattered within the septa. Phylogenetic analysis places the new taxon within the extinct genus Eydeia. DISCUSSION: Thick-walled endocarps with apically opening germination valves, no central vascular bundle and one seed per locule are indicative of the order Cornales. Comparative analysis suggests that the fossils represent a new species, Eydeia jerseyensis sp. nov. This new taxon is the first evidence of Cornales in eastern North America during the Cretaceous and provides insights into the palaeobiogeography and initial diversification of the order.


Asunto(s)
Evolución Biológica , Fósiles/anatomía & histología , Magnoliopsida/anatomía & histología , Frutas/anatomía & histología , Frutas/clasificación , Frutas/ultraestructura , Magnoliopsida/clasificación , Magnoliopsida/ultraestructura , Microscopía Electrónica de Rastreo , New Jersey , Filogenia , Microtomografía por Rayos X
6.
Clin Exp Pharmacol Physiol ; 46(6): 513-526, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30834550

RESUMEN

The P2X7 receptor is a ligand-gated purinergic receptor activated by extracellular ATP. The receptor is highly expressed in immune cells and in the brain, and, upon activation, the P2X7 receptor allows a cation flux, leading to the distinct activation of intracellular signalling pathways as the secretion of pro-inflammatory cytokines, and modulation of cell survival. Through these molecular mechanisms, P2X7 is known to play important roles in physiology and pathophysiology of a wide spectrum of diseases, including cancer, inflammatory diseases, neurological, respiratory and more recently cardiovascular diseases. Recent studies demonstrated that the P2X7 could modulate the assembly of the NLRP3 inflammasome, leading to the secretion of pro-inflammatory factors and worsen the cardiac disease phenotypes. This review discusses the critical molecular function of P2X7 in the modulation of the onset, progression and resolution of cardiovascular diseases and analyses the putative future use of P2X7-based therapies that modulate the IL-1ß secretion arm and direct P2X7 antagonists.


Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Miocardio/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Humanos , Antagonistas del Receptor Purinérgico P2X/farmacología , Antagonistas del Receptor Purinérgico P2X/uso terapéutico
7.
Am J Bot ; 104(12): 1857-1866, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-29212767

RESUMEN

PREMISE OF THE STUDY: The plant fossil record for the neotropics is still sparse and temporally discontinuous. The location and description of new fossil material are fundamental for understanding evolutionary and biogeographic patterns of lineages. A new fossil record of Passifloraceae from the late Eocene of Colombia is described in this study. METHODS: Plant fossils were collected from a new locality from the Eocene Esmeraldas Formation. Eighteen fossil seeds were selected, described, and compared with fossil and extant angiosperm seeds based on the literature and herbarium collections. Taxonomic affinities of the fossil seeds within Passifloraceae s.l. were evaluated by comparing morphological characters of the seeds in a phylogenetic context. Stratigraphic information associated with the fossil locality was used to interpret the environment and taphonomic processes associated with fossil deposition. KEY RESULTS: A new seed fossil genus and species, Passifloroidesperma sogamosense gen. and sp. nov., is described and associated with the subfamily Passifloroideae based on the presence of a foveolate seed surface, ruminate endosperm, and a seed coat with prismatic palisade cells. The depositional environment of the locality is described as a floodplain associated with river channels. CONCLUSIONS: A detailed review of the Passifloraceae fossil record indicates that P. sogamosense is the oldest confirmed record of Passifloraceae. Its late Eocene age provides a minimum age that can be used as a calibration point for the crown Passifloroideae node in future dating analyses that together with its neotropical geographic location can shed light on the origin and diversification of the subfamily.


Asunto(s)
Evolución Biológica , Fósiles , Passifloraceae/anatomía & histología , Passifloraceae/clasificación , Colombia , Especificidad de la Especie
8.
Aten Primaria ; 49(4): 233-239, 2017 Apr.
Artículo en Español | MEDLINE | ID: mdl-27914719

RESUMEN

OBJECTIVE: Evaluate the validity and reliability of the knowledge and attitudes of health professionals questionnaire on the Living Will Declaration (LWD) process. DESIGN: Cross-sectional study structured into 3 phases: (i)pilot questionnaire administered with paper to assess losses and adjustment problems; (ii)assessment of the validity and internal reliability, and (iii)assessment of the pre-filtering questionnaire stability (test-retest). LOCATION: Costa del Sol (Malaga) Health Area. January 2014 to April 2015. PARTICIPANTS: Healthcare professionals of the Costa del Sol Primary Care District and the Costa del Sol Health Agency. There were 391 (23.6%) responses, and 100 participated in the stability assessment (83 responses). MAIN MEASUREMENTS: The questionnaire consisted of 2 parts: (i)Knowledge (5 dimensions and 41 items), and (ii)Attitudes (2 dimensions and 17 items). RESULTS: In the pilot study, none of the items lost over 10%. In the evaluation phase of validity and reliability, the questionnaire was reduced to 41 items (29 of knowledge, and 12 of attitudes). In the stability evaluation phase, all items evaluated met the requirement of a kappa higher than 0.2, or had a percentage of absolute agreement exceeding 75%. CONCLUSIONS: The questionnaire will identify the status and areas for improvement in the health care setting, and then will allow an improved culture of LWD process in general population.


Asunto(s)
Actitud del Personal de Salud , Conocimientos, Actitudes y Práctica en Salud , Voluntad en Vida , Autoinforme , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados
9.
J Sci Food Agric ; 96(7): 2410-7, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26219432

RESUMEN

BACKGROUND: Agrobacterium sp. IFO 13140 cells were immobilized on a loofa sponge and used to produce curdlan over five successive cycles. The interaction between microbial cells and the loofa sponge as well as the produced curdlan were characterized by Fourier transform infrared-attenuated total reflectance (FTIR-ATR) spectrometry. The purity of the curdlan was also evaluated. The storage stability of the immobilized cells was assessed and the produced curdlan was used in a functional yogurt formulation. RESULTS: The average curdlan production by immobilized cells was 17.84 g L(-1) . The presence of the microorganism in the sponge was confirmed and did not cause alterations in the matrix, and the chemical structure of the curdlan was the same as that of commercial curdlan. The purity of both was similar. The immobilized cells remained active after 300 days of storage at -18 °C. The use of the produced curdlan in a functional yogurt resulted in a product with lower syneresis. CONCLUSION: A large number of cells physically adhered to the surface of loofa sponge fibers, and its use as an immobilization matrix to produce curdlan was effective. The use of the produced curdlan in yogurt allowed the development of a more stable product. © 2015 Society of Chemical Industry.


Asunto(s)
Agrobacterium/metabolismo , Manipulación de Alimentos/métodos , Luffa/química , Yogur , beta-Glucanos/metabolismo , Agrobacterium/química , Biopolímeros , Células Inmovilizadas , beta-Glucanos/química
10.
Am J Bot ; 102(2): 273-89, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25667080

RESUMEN

PREMISE OF THE STUDY: Documented fossil floras in the neotropics are sparse, yet their records provide evidence on the spatial and temporal occurrence of taxa, allowing for testing of biogeographical and diversification scenarios on individual lineages. A new fossil Piper from the Late Cretaceous of Colombia is described here, and its importance for assessing diversification patterns in the genus is addressed. METHODS: Leaf architecture of 32 fossil leaf compressions from the Guaduas Formation was compared with that of 294 extant angiosperm species. The phylogenetic position of the fossil named Piper margaritae sp. nov. was established based on leaf traits and a molecular scaffold of Piper. The age of the fossil was independently used as a calibration point for divergence time estimations. KEY RESULTS: Natural affinities of P. margaritae to the Schilleria clade of Piper indicate that the genus occurred in tropical America by the Late Cretaceous. Estimates of age divergence and lineage accumulation reveal that most of the extant diversity of the genus accrued during the last ∼30 Myr. CONCLUSIONS: The recent radiation of Piper is coeval with both the Andean uplift and the emergence of Central America, which have been proposed as important drivers of diversity. This pattern could exemplify a recurrent theme among many neotropical plant lineages.


Asunto(s)
Fósiles , Fenotipo , Filogenia , Piper/genética , Hojas de la Planta/anatomía & histología , Clima Tropical , Colombia , Especificidad de la Especie
11.
Bioprocess Biosyst Eng ; 38(6): 1055-63, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25561345

RESUMEN

Cyclodextrin glycosyltransferase (CGTase) catalyzes starch conversion into cyclic or linear oligosaccharides, important industrial products for the complexation of non-polar substances. In this work, conditions to increase CGTase production from Bacillus circulans strain DF 9R were optimized by two systems. On one hand, free cells were grown in batch fermentation experiments to optimize aeration and pH. The highest activity (1.47 ± 0.21 U ml(-1)) was achieved after 48 h of growth, aeration of 1.5 vvm and pH regulated to 7.6. On the other hand, bacterial cells were immobilized on loofa and synthetic sponge, and used for CGTase production in a semi-continuous process. An initial biomass of 30 mg of lyophilized cells and an immobilization time of 24 h with loofa or synthetic sponge were enough to achieve increased production of CGTase: 0.91 ± 0.10 and 0.95 ± 0.11 U ml(-1), respectively. Sponges with immobilized bacteria were reused in 12 successive cycles. Besides, in our conditions, CGTase was not adsorbed onto the supports used for immobilization, which ensured the total recovery of the enzyme from the culture medium. The two CGTase production processes studied showed similar productivity and could be potentially scaled up.


Asunto(s)
Bacillus/enzimología , Fermentación , Glucosiltransferasas/biosíntesis , Animales , Biomasa , Reactores Biológicos , Concentración de Iones de Hidrógeno , Poríferos
12.
Bioprocess Biosyst Eng ; 38(7): 1291-301, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25656697

RESUMEN

This study aimed to improve the yield of cyclodextrins (CDs) production in repetitive batches. An innovative ultrafiltration system was used to remove the inhibitory products that accumulated in the medium and to recover the enzyme. The assays were performed with the CGTase from Bacillus firmus strain 37 in purified, semi-purified, and crude extract forms. Maltodextrin (10% w/v) and corn starch (5% w/v) were used as substrates. After eight repetitive 24-h batches, the yield of ß-CD obtained with the purified enzyme and the corn starch substrate was 0.54 mmol/L/h, which was 36% greater than that observed with the 10% maltodextrin substrate. The crude CGTase extract with the corn starch substrate showed a productivity of 0.38 mmol/L/h, which was 29% lower than using the purified enzyme and the corn starch substrate but 7% higher than using the purified enzyme and the maltodextrin substrate. The crude extract, assayed with the corn starch substrate in the presence of 10% ethanol reached 0.43 mmol/L/h productivity, which was 12% higher compared to the assay without ethanol. The semi-purified enzyme was assayed with the corn starch substrate in the presence of 10% ethanol for eight batches lasting 12 h and an excellent selectivity for the ß-CD was obtained, reaching a mean percentage of 96.0%. Therefore, this ultrafiltration system enabled several batches of CD production, with efficient removal of products inhibitory to the CGTase and recovery of the enzyme. The possibility of industrial application of this system is promising.


Asunto(s)
Bacillus/enzimología , Ciclodextrinas/biosíntesis , Glucosiltransferasas/metabolismo , Ultrafiltración/instrumentación , Especificidad por Sustrato
13.
Molecules ; 20(5): 7957-73, 2015 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-25946555

RESUMEN

Curdlan production by Agrobacterium sp. IFO13140 immobilized on loofa sponge, alginate and loofa sponge with alginate was investigated. There was no statistically-significant difference in curdlan production when the microorganism was immobilized in different matrices. The loofa sponge was chosen because of its practical application and economy and because it provides a high stability through its continued use. The best conditions for immobilization on loofa sponge were 50 mg of cell, 200 rpm and 72 h of incubation, which provided a curdlan production 1.50-times higher than that obtained by free cells. The higher volumetric productivity was achieved by immobilized cells (0.09 g/L/h) at 150 rpm. The operating stability was evaluated, and until the fourth cycle, immobilized cells retained 87.40% of the production of the first cycle. The immobilized cells remained active after 300 days of storage at 4 °C. The results of this study demonstrate success in immobilizing cells for curdlan biosynthesis, making the process potentially suitable for industrial scale-up. Additional studies may show a possible contribution to the reduction of operating costs.


Asunto(s)
Agrobacterium/metabolismo , Células Inmovilizadas/metabolismo , Luffa/metabolismo , Luffa/microbiología , Poríferos/metabolismo , beta-Glucanos/metabolismo , Animales , Temperatura
14.
Aten Primaria ; 47(8): 514-22, 2015 Oct.
Artículo en Español | MEDLINE | ID: mdl-25555491

RESUMEN

OBJECTIVE: To identify the underlying interests of the Living Will Declaration (LWD) process and to determine the consensus, using a questionnaire, of the knowledge and attitudes of health professionals. DESIGN: A study was performed in two phases using a Delphi technique with a Rand method. 1. Dimensions proposed: generation of ideas and their subsequent prioritizing; 2. Proposal and prioritizing of items grouped into blocks of Knowledge and Attitudes, developed between August 2012 and January 2013. SETTING: The work was carried out by initial telephone contact with panellists, and then later by the panellists belonged to the Andalusia Public Health System. PARTICIPANTS: The criteria for selecting the eight components of the panel were knowledge and experience in the field of the freedom of the patient in Andalusia. RESULTS: The Knowledge identified included: 1 A) Legal and general aspects; 2 A) A conceptual definition; 3 A) Standardised LWD documents: 4 A) Practical experience; 5 A) Procedure and registering of the LWDs. The second block included Attitudes: 1 B) Attitudes of the professional in the application of LWDs in clinical practice, and 2 B) Attitudes of the professional in «complex¼ ethical scenarios The 7 panellists who finally took part proposed 165 items. After applying the prioritizing criteria, scores, and scenario selection, 58 (35.2%) items were identified as suitable scenarios. CONCLUSIONS: The proposed questionnaire included wide parcels of concepts and contents that, once validated, will help to measure the training interventions carried out on health professionals in order to improve knowledge and attitudes on the subject of LWDs.


Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Personal de Salud , Voluntad en Vida , Humanos , Encuestas y Cuestionarios
15.
Radiol Case Rep ; 19(7): 2650-2653, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38645950

RESUMEN

Acute calcific longus colli tendinitis is a differential diagnosis of neck pain. Typical presentation consists in a triad of symptoms including acute onset neck pain, neck stiffness and odynophagia. Computed tomography (CT) is the gold standard for acute calcific longus colli tendinitis diagnosis and the main radiological findings include prevertebral soft tissue swelling and the presence of amorphous calcifications. The case involves a 39-year-old female who presented to the emergency department with acute unilateral cervical pain that resulted in acute calcific longus colli tendinitis.

16.
Curr Med Chem ; 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38584539

RESUMEN

The COVID-19 pandemic significantly impacted the global populace, resulting in a staggering number of deaths across the globe. New approaches and biomarkers to evaluate disease progression are crucial for improving disease management. In this context, serum proteomics has emerged as a promising tool for identifying molecular alterations related to COVID-19. This work carried out a bibliometric evaluation of the current status and trends of studies applying serum proteomics to COVID-19 subjects. The search was performed using Web of Science and Scopus databases, and the results were analyzed in VOSviewer software. The investigation was limited to articles published between January 2020 and February 2023. The analysis found 48 articles, primarily experimental studies. China is the most influential country in this field, followed by the USA. The co-occurrence analysis performed by VOSviewer showed 170 keywords, of which 9 reached the occurrence threshold and were divided into two groups. The most cited words were related to biomarker identification and the use of proteomics for diagnosing and treating COVID-19. The most cited proteins include those classically associated with the immune system (IgG, IgM, interleukins, CXCL, CCL, MCP, CRP) and SAA1, SAA1, ApoA-1, TTR (prealbumin), SerpinA and ITIH4. Other studies have validated the predictive value of these serum markers and have the potential to improve the management of COVID-19 patients. The findings highlighted in this bibliometric study can help the researchers design new projects to enhance our understanding of the complex interplay between SARS-CoV-2 and host immunity.

17.
bioRxiv ; 2024 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-38798587

RESUMEN

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and the lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints. However, the underlying immune alterations that enhance immunopathology in MtD remain unclear, constituting a key gap in knowledge that complicates treatment and increases mortality in this population. Here we employ in vitro and in vivo approaches to clarify the molecular and cellular basis for innate immune hyperactivity in models of polymerase gamma (Polg)-related MtD. We reveal that type I interferon (IFN-I)-mediated upregulation of caspase-11 and guanylate-binding proteins (GBPs) increase macrophage sensing of the opportunistic microbe Pseudomonas aeruginosa (PA) in Polg mutant mice. Furthermore, we show that excessive macrophage cytokine secretion and pyroptotic cell death contribute to lung inflammation and morbidity after infection with PA. Our work sheds new light on innate immune dysregulation in MtD and reveals potential targets for limiting infection- and inflammation-related complications in Polg-related MtD.

18.
Sci Rep ; 14(1): 712, 2024 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-38184672

RESUMEN

SARS-CoV-2 receptor binding domain (RBD) mediates viral entry into human cells through its interaction with angiotensin converting enzyme 2 (ACE2). Most neutralizing antibodies elicited by infection or vaccination target this domain. Such a functional relevance, together with large RBD sequence variability arising during viral spreading, point to the need of exploring the complex landscape of interactions between RBD-derived variants, ACE2 and antibodies. The current work was aimed at developing a simple platform to do so. Biologically active and antigenic Wuhan-Hu-1 RBD, as well as mutated RBD variants found in nature, were successfully displayed on filamentous phages. Mutational scanning confirmed the global plasticity of the receptor binding motif within RBD, highlighted residues playing a critical role in receptor binding, and identified mutations strengthening the interaction. The ability of vaccine-induced antibodies to inhibit ACE2 binding of many mutated RBD variants, albeit at different extents, was shown. Amino acid replacements which could compromise such inhibitory potential were underscored. The expansion of our approach could be the starting point for a large-scale phage-based exploration of diversity within RBD of SARS-CoV-2 and related coronaviruses, useful to understand structure-function relationships, to engineer RBD proteins, and to anticipate changes to watch during viral evolution.


Asunto(s)
Bacteriófagos , COVID-19 , Humanos , Enzima Convertidora de Angiotensina 2 , SARS-CoV-2/genética , Anticuerpos Neutralizantes , Anticuerpos Antivirales
19.
Commun Biol ; 6(1): 828, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37558752

RESUMEN

Interleukin-2 (IL-2) engineered versions, with biased immunological functions, have emerged from yeast display and rational design. Here we reshaped the human IL-2 interface with the IL-2 receptor beta chain through the screening of phage-displayed libraries. Multiple beta super-binders were obtained, having increased receptor binding ability and improved developability profiles. Selected variants exhibit an accumulation of negatively charged residues at the interface, which provides a better electrostatic complementarity to the beta chain, and faster association kinetics. These findings point to mechanistic differences with the already reported superkines, characterized by a conformational switch due to the rearrangement of the hydrophobic core. The molecular bases of the favourable developability profile were tracked to a single residue: L92. Recombinant Fc-fusion proteins including our variants are superior to those based on H9 superkine in terms of expression levels in mammalian cells, aggregation resistance, stability, in vivo enhancement of immune effector responses, and anti-tumour effect.


Asunto(s)
Evolución Molecular Dirigida , Subunidad beta del Receptor de Interleucina-2 , Interleucina-2 , Biblioteca de Péptidos , Humanos , Subunidad beta del Receptor de Interleucina-2/química , Interleucina-2/química , Interleucina-2/genética , Interleucina-2/metabolismo , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Evolución Molecular Dirigida/métodos , Dominios Proteicos , Animales , Ratones , Línea Celular Tumoral
20.
Front Public Health ; 10: 805774, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35252091

RESUMEN

Although suicide is considered a major preventable cause of mortality worldwide, we do not have effective strategies to prevent it. Lithium has been consistently associated with lowering risk of suicide. This effect could occur at very low concentrations, such as trace doses of lithium in tap water. Several ecological studies and recent meta-analysis have suggested an inverse association between lithium in water and suicide in the general population, with a lack of knowledge of clinically significant side effects. This paper is aimed as a proposal to discuss the addition of lithium to drinking water to decrease the suicide rate. For this, we review the evidence available, use previous experiences, such as water fluoridation to prevent dental caries, and discuss the complexity involved in such a public policy. Considering the limited data available and the controversies contained in this proposal, we suggest that a consensus on lithium concentration in water is needed, where the suicide rates start to reduce, as happened with water fluoridation. This measure will require to develop community-controlled trials with strict monitoring of any side effects, where democratic procedures would constitute one of the most appropriate ways to validate its implementation according to the reality of each community.


Asunto(s)
Caries Dental , Agua Potable , Prevención del Suicidio , Humanos , Litio/análisis , Política Pública
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