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1.
Mol Cell ; 82(1): 90-105.e13, 2022 01 06.
Artículo en Inglés | MEDLINE | ID: mdl-34942119

RESUMEN

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.


Asunto(s)
Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/metabolismo , Encéfalo/enzimología , Heterocromatina/metabolismo , Discapacidad Intelectual/enzimología , Células-Madre Neurales/enzimología , Neurogénesis , Adolescente , Animales , Antígenos CD , Subunidad Apc7 del Ciclosoma-Complejo Promotor de la Anafase/genética , Conducta Animal , Encéfalo/crecimiento & desarrollo , Cadherinas/genética , Cadherinas/metabolismo , Línea Celular , Niño , Preescolar , Modelos Animales de Enfermedad , Femenino , Heterocromatina/genética , Humanos , Lactante , Discapacidad Intelectual/patología , Discapacidad Intelectual/fisiopatología , Discapacidad Intelectual/psicología , Inteligencia , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitosis , Mutación , Células-Madre Neurales/patología , Proteolisis , Transducción de Señal , Síndrome , Ubiquitinación , Adulto Joven
2.
Nat Rev Mol Cell Biol ; 18(3): 202-210, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28144031

RESUMEN

An emerging body of evidence indicates that post-transcriptional gene regulation relies not only on the sequence of mRNAs but also on their folding into intricate secondary structures and on the chemical modifications of the RNA bases. These features, which are highly dynamic and interdependent, exert direct control over the transcriptome and thereby influence many aspects of cell function. Here, we consider how the coupling of RNA modifications and structures shapes RNA-protein interactions at different steps of the gene expression process.


Asunto(s)
Proteínas/genética , ARN Guía de Kinetoplastida/química , ARN Guía de Kinetoplastida/metabolismo , Conformación de Ácido Nucleico , Biosíntesis de Proteínas , Empalme de Proteína , Proteínas/metabolismo , Estabilidad del ARN , ARN Mensajero/metabolismo
3.
Nature ; 604(7906): 525-533, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35388223

RESUMEN

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.


Asunto(s)
Encéfalo , Longevidad , Estatura , Encéfalo/anatomía & histología , Humanos , Imagen por Resonancia Magnética/métodos , Neuroimagen
4.
PLoS Biol ; 22(3): e3002573, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38547237

RESUMEN

The rising interest and success in deploying inherited microorganisms and cytoplasmic incompatibility (CI) for vector control strategies necessitate an explanation of the CI mechanism. Wolbachia-induced CI manifests in the form of embryonic lethality when sperm from Wolbachia-bearing testes fertilize eggs from uninfected females. Embryos from infected females however survive to sustain the maternally inherited symbiont. Previously in Drosophila melanogaster flies, we demonstrated that CI modifies chromatin integrity in developing sperm to bestow the embryonic lethality. Here, we validate these findings using wMel-transinfected Aedes aegypti mosquitoes released to control vector-borne diseases. Once again, the prophage WO CI proteins, CifA and CifB, target male gametic nuclei to modify chromatin integrity via an aberrant histone-to-protamine transition. Cifs are not detected in the embryo, and thus elicit CI via the nucleoprotein modifications established pre-fertilization. The rescue protein CifA in oogenesis localizes to stem cell, nurse cell, and oocyte nuclei, as well as embryonic DNA during embryogenesis. Discovery of the nuclear targeting Cifs and altered histone-to-protamine transition in both Aedes aegypti mosquitoes and D. melanogaster flies affirm the Host Modification Model of CI is conserved across these host species. The study also newly uncovers the cell biology of Cif proteins in the ovaries, CifA localization in the embryos, and an impaired histone-to-protamine transition during spermiogenesis of any mosquito species. Overall, these sperm modification findings may enable future optimization of CI efficacy in vectors or pests that are refractory to Wolbachia transinfections.


Asunto(s)
Aedes , Arbovirus , Wolbachia , Animales , Femenino , Masculino , Drosophila melanogaster/genética , Histonas/genética , Mosquitos Vectores , Semen , Drosophila/genética , Cromatina , Protaminas/genética
5.
Biochemistry ; 63(18): 2266-2279, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39189508

RESUMEN

As part of its pathogenesis, Salmonella enterica serovar Typhimurium delivers effector proteins into host cells. One effector is SspH2, a member of the so-called novel E3 ubiquitin ligase family, that interacts with and enhances, NOD1 pro-inflammatory signaling, though the underlying mechanisms are unclear. Here, we report that SspH2 interacts with multiple members of the NLRC family to enhance pro-inflammatory signaling by targeted ubiquitination. We show that SspH2 modulates host innate immunity by interacting with both NOD1 and NOD2 in mammalian epithelial cell culture via the NF-κB pathway. Moreover, purified SspH2 and NOD1 directly interact, where NOD1 potentiates SspH2 E3 ubiquitin ligase activity. Mass spectrometry and mutational analyses identified four key lysine residues in NOD1 that are required for its enhanced activation by SspH2, but not its basal activity. These critical lysine residues are positioned in the same region of NOD1 and define a surface on the receptor that appears to be targeted by SspH2. Overall, this work provides evidence for post-translational modification of NOD1 by ubiquitin and uncovers a unique mechanism of spatially selective ubiquitination to enhance the activation of an archetypal NLR.


Asunto(s)
Proteína Adaptadora de Señalización NOD1 , Salmonella typhimurium , Transducción de Señal , Ubiquitinación , Proteína Adaptadora de Señalización NOD1/metabolismo , Proteína Adaptadora de Señalización NOD1/genética , Humanos , Salmonella typhimurium/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Proteína Adaptadora de Señalización NOD2/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Células HEK293 , Inmunidad Innata , Inflamación/metabolismo , Inflamación/microbiología , FN-kappa B/metabolismo , Infecciones por Salmonella/metabolismo , Infecciones por Salmonella/microbiología , Infecciones por Salmonella/inmunología
6.
Neuropsychol Rev ; 2024 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-38403731

RESUMEN

Over the past decade, research using virtual reality and serious game-based instruments for assessing spatial navigation and spatial memory in at-risk and AD populations has risen. We systematically reviewed the literature since 2012 to identify and evaluate the methodological quality and risk of bias in the analyses of the psychometric properties of VRSG-based instruments. The search was conducted primarily in July-December 2022 and updated in November 2023 in eight major databases. The quality of instrument development and study design were analyzed in all studies. Measurement properties were defined and analyzed according to COSMIN guidelines. A total of 1078 unique records were screened, and following selection criteria, thirty-seven studies were analyzed. From these studies, 30 instruments were identified. Construct and criterion validity were the most reported measurement properties, while structural validity and internal consistency evidence were the least reported. Nineteen studies were deemed very good in construct validity, whereas 11 studies reporting diagnostic accuracy were deemed very good in quality. Limitations regarding theoretical framework and research design requirements were found in most of the studies. VRSG-based instruments are valuable additions to the current diagnostic toolkit for AD. Further research is required to establish the psychometric performance and clinical utility of VRSG-based instruments, particularly the instrument development, content validity, and diagnostic accuracy for preclinical AD screening scenarios. This review provides a straightforward synthesis of the state of the art of VRSG-based instruments and suggests future directions for research.

7.
Phys Rev Lett ; 132(19): 195001, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38804956

RESUMEN

Experiments were performed on laser wakefield acceleration in the highly nonlinear regime. With laser powers P<250 TW and using an initial spot size larger than the matched spot size for guiding, we were able to accelerate electrons to energies E_{max}>2.5 GeV, in fields exceeding 500 GV m^{-1}, with more than 80 pC of charge at energies E>1 GeV. Three-dimensional particle-in-cell simulations show that using an oversized spot delays injection, avoiding beam loss as the wakefield undergoes length oscillation. This enables injected electrons to remain in the regions of highest accelerating fields and leads to a doubling of energy gain as compared to results from using half the focal length with the same laser.

8.
Health Expect ; 27(4): e14136, 2024 08.
Artículo en Inglés | MEDLINE | ID: mdl-38990165

RESUMEN

OBJECTIVES: The purpose of this study was to engage key stakeholders in a health research priority-setting process to identify, prioritize and produce a community-driven list of research questions addressing intersectional issues on mental health and addictions (MHA) in acquired brain injury (ABI). METHODS: A multiphasic health research priority-setting process was co-designed and executed with community-based stakeholders, including researchers, health professionals, clinicians, service providers, representatives from brain injury associations, policy makers and people with lived experience of ABI and MHA, including patients and their family members. Stakeholders' ideas led to the generation of research questions, which were prioritized at a 1-day workshop. RESULTS: Fifty-nine stakeholders participated in the priority-setting activity during the workshop, which resulted in a rank-ordered list of the top 10 questions for research addressing the intersections of ABI and MHA. Questions identified touched on several pressing issues (e.g., opioid crisis, homelessness), encompassed multiple subtypes of ABI (e.g., hypoxic-ischaemic, mild traumatic), and involved different domains (e.g., identification, intervention) of health research. CONCLUSIONS: This community-driven health research priority-setting study identified and prioritized research questions addressing the intersections of ABI and MHA. Researchers and funding agencies should use this list to inform their agendas and address stakeholders' most urgent needs, fostering meaningful improvements to clinical services. PATIENT OR PUBLIC CONTRIBUTION: An 11-person working group comprised of people with lived experience, service providers, researchers, healthcare professionals and other key stakeholders collaboratively developed and informed the scope, design, methodology and interpretation of this study. Over 50 community-based stakeholders contributed to the research priority-setting activity. One co-author is a person with lived experience.


Asunto(s)
Lesiones Encefálicas , Participación de los Interesados , Humanos , Lesiones Encefálicas/terapia , Trastornos Relacionados con Sustancias/terapia , Salud Mental , Prioridades en Salud
9.
BMC Health Serv Res ; 24(1): 881, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39095800

RESUMEN

BACKGROUND: People with acquired brain injury (ABI) may experience concurrent conditions such as, mental health and substance use concerns, that require specialized care. There are services that aim to support people with ABI and these conditions separately; however, little is known about the facilitators and barriers of these services. Therefore, the purpose of this study was to engage stakeholders to investigate the facilitators and barriers of healthcare services for ABI and concurrent issues. METHODS: Semi-structured focus groups were conducted in-person and virtually with people with ABI, caregivers, healthcare professionals, and policy makers during a one-day event in British Columbia, Canada. Manifest content analysis was used with a constructivist perspective to analyze data. RESULTS: 90 participants (including 34 people with ABI) provided insights during 15 simultaneous focus groups. Three categories were identified: (1) complexity of ABI, (2) supports, (3) structure of care. Complexity of ABI outlined the ongoing basic needs after ABI and highlighted the need for public awareness of ABI. Supports outlined healthcare professional and community-based supports. Structure of care described people with ABI needing to meet criteria for support, experiences of navigating through the system and necessity of integrated services. CONCLUSIONS: These findings highlight the facilitators and barriers of healthcare services for ABI and concurrent conditions and provide insights into the changes that may be needed. Doing so can improve the accessibility and quality of ABI healthcare services.


Asunto(s)
Lesiones Encefálicas , Grupos Focales , Accesibilidad a los Servicios de Salud , Investigación Cualitativa , Trastornos Relacionados con Sustancias , Humanos , Trastornos Relacionados con Sustancias/terapia , Femenino , Masculino , Colombia Británica , Persona de Mediana Edad , Adulto , Lesiones Encefálicas/terapia , Trastornos Mentales/terapia , Anciano
10.
J Interprof Care ; 38(3): 469-475, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-36814080

RESUMEN

Bedside interdisciplinary rounds (IDR) improve teamwork, communication, and collaborative culture in inpatient settings. Implementation of bedside IDR in academic settings depends on engagement from resident physicians; however, little is known about their knowledge and preferences related to bedside IDR. The goal of this program was to identify medical resident perceptions about bedside IDR and to engage resident physicians in the design, implementation, and assessment of bedside IDR in an academic setting. This is a pre-post mixed methods survey assessing resident physicians' perceptions surrounding a stakeholder-informed bedside IDR quality improvement project. Resident physicians in the University of Colorado Internal Medicine Residency Program (n = 77 pre-implementation survey responses from 179 eligible participants - response rate 43%) were recruited via e-mail to participate in surveys assessing perceptions surrounding the inclusion of interprofessional team members, timing, and preferred structure of bedside IDR. A bedside IDR structure was created based on input from resident and attending physicians, patients, nurses, care coordinators, pharmacists, social workers, and rehabilitation specialists. This rounding structure was implemented on acute care wards in June 2019 at a large academic regional VA hospital in Aurora, CO. Resident physicians were surveyed post implementation (n = 58 post-implementation responses from 141 eligible participants - response rate 41%) about interprofessional input, timing, and satisfaction with bedside IDR. The pre-implementation survey revealed several important resident needs during bedside IDR. Post-implementation survey results revealed high overall satisfaction with bedside IDR among residents, improved perceived efficiency of rounds, preserved quality of education, and value added by interprofessional input. Results also suggested areas for future improvement including timeliness of rounds and enhanced systems-based teaching. This project successfully engaged residents as stakeholders in system-level interprofessional change by incorporating their values and preferences into a bedside IDR framework.


Asunto(s)
Internado y Residencia , Médicos , Rondas de Enseñanza , Humanos , Relaciones Interprofesionales , Cuidados Críticos , Actitud del Personal de Salud , Grupo de Atención al Paciente
11.
Clin Infect Dis ; 76(11): 2007-2009, 2023 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-36869697

RESUMEN

This retrospective cohort study was performed to compare clinical outcomes between patients with Staphylococcus aureus bacteremia who received an early versus late infectious disease consultation. Early consultation resulted in significantly greater adherence to quality care indicators and shorter hospital stays.


Asunto(s)
Bacteriemia , Enfermedades Transmisibles , Infecciones Estafilocócicas , Humanos , Staphylococcus aureus , Estudios Retrospectivos , Resultado del Tratamiento , Enfermedades Transmisibles/tratamiento farmacológico , Bacteriemia/diagnóstico , Bacteriemia/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Derivación y Consulta , Antibacterianos/uso terapéutico
12.
Hum Brain Mapp ; 44(16): 5238-5293, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-36537283

RESUMEN

We propose a unique, minimal assumption, approach based on variance analyses (compared with standard approaches) to investigate genetic influence on individual differences on the functional connectivity of the brain using 65 monozygotic and 65 dizygotic healthy young adult twin pairs' low-frequency oscillation resting state functional Magnetic Resonance Imaging (fMRI) data from the Human Connectome Project. Overall, we found high number of genetically-influenced functional (GIF) connections involving posterior to posterior brain regions (occipital/temporal/parietal) implicated in low-level processes such as vision, perception, motion, categorization, dorsal/ventral stream visuospatial, and long-term memory processes, as well as high number across midline brain regions (cingulate) implicated in attentional processes, and emotional responses to pain. We found low number of GIF connections involving anterior to anterior/posterior brain regions (frontofrontal > frontoparietal, frontotemporal, frontooccipital) implicated in high-level processes such as working memory, reasoning, emotional judgment, language, and action planning. We found very low number of GIF connections involving subcortical/noncortical networks such as basal ganglia, thalamus, brainstem, and cerebellum. In terms of sex-specific individual differences, individual differences in males were more genetically influenced while individual differences in females were more environmentally influenced in terms of the interplay of interactions of Task positive networks (brain regions involved in various task-oriented processes and attending to and interacting with environment), extended Default Mode Network (a central brain hub for various processes such as internal monitoring, rumination, and evaluation of self and others), primary sensorimotor systems (vision, audition, somatosensory, and motor systems), and subcortical/noncortical networks. There were >8.5-19.1 times more GIF connections in males than females. These preliminary (young adult cohort-specific) findings suggest that individual differences in the resting state brain may be more genetically influenced in males and more environmentally influenced in females; furthermore, standard approaches may suggest that it is more substantially nonadditive genetics, rather than additive genetics, which contribute to the differences in sex-specific individual differences based on this young adult (male and female) specific cohort. Finally, considering the preliminary cohort-specific results, based on standard approaches, environmental influences on individual differences may be substantially greater than that of genetics, for either sex, frontally and brain-wide. [Correction added on 10 May 2023, after first online publication: added: functional Magnetic Resonance Imaging. Added: individual differences in, twice. Added statement between furthermore … based on standard approaches.].


Asunto(s)
Encéfalo , Conectoma , Femenino , Humanos , Masculino , Adulto Joven , Ganglios Basales , Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Mapeo Encefálico , Conectoma/métodos , Imagen por Resonancia Magnética , Red Nerviosa/fisiología , Tálamo , Gemelos Dicigóticos
13.
Bioconjug Chem ; 34(8): 1447-1458, 2023 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-37458383

RESUMEN

The influenza A virus causes substantial morbidity and mortality worldwide every year and poses a constant threat of an emergent pandemic. Seasonal influenza vaccination strategies fail to provide complete protection against infection due to antigenic drift and shift. A universal vaccine targeting a conserved influenza epitope could substantially improve current vaccination strategies. The ectodomain of the matrix 2 protein (M2e) of influenza is a highly conserved epitope between virus strains but is also poorly immunogenic. Administration of M2e and the immunostimulatory stimulator of interferon genes (STING) agonist 3'3'-cyclic guanosine-adenosine monophosphate (cGAMP) encapsulated in microparticles made of acetalated dextran (Ace-DEX) has previously been shown to be effective for increasing the immunogenicity of M2e, primarily through T-cell-mediated responses. Here, the immunogenicity of Ace-DEX MPs delivering M2e was further improved by conjugating the M2e peptide to the particle surface in an effort to affect B-cell responses more directly. Conjugated or encapsulated M2e co-administered with Ace-DEX MPs containing cGAMP were used to vaccinate mice, and it was shown that two or three vaccinations could fully protect against a lethal influenza challenge, while only the surface-conjugated antigen constructs could provide some protection against lethal challenge with only one vaccination. Additionally, the use of a reducible linker augmented the T-cell response to the antigen. These results show the utility of conjugating M2e to the surface of a particle carrier to increase its immunogenicity for use as the antigen in a universal influenza vaccine.


Asunto(s)
Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Animales , Ratones , Humanos , Gripe Humana/prevención & control , Dextranos/química , Epítopos , Ratones Endogámicos BALB C , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/genética , Anticuerpos Antivirales
14.
Mol Pharm ; 20(9): 4687-4697, 2023 09 04.
Artículo en Inglés | MEDLINE | ID: mdl-37603310

RESUMEN

Current seasonal influenza vaccines are limited in that they need to be reformulated every year in order to account for the constant mutation of the virus. Hemagglutinin (HA) immunogens have been developed using a computationally optimized broadly reactive antigen (COBRA) methodology, which are able to elicit an antibody response that neutralizes antigenically distinct influenza strains; however, subunit proteins are not immunogenic enough on their own to generate a substantial immune response. Due to this, different delivery strategies and adjuvants can be used to improve immunogenicity. Recently, we reported a new coordination polymer composed of the dipeptide carnosine and zinc (ZnCar) that is able to deliver protein antigens along with CpG to generate a potent immune response. In the present work, ZnCar was used to deliver the COBRA HA immunogen Y2 and the adjuvant CpG. We incorporated Y2 into ZnCar using two different methods to assess which would be the most immunogenic. Mice vaccinated with Y2 and CpG complexed with ZnCar showed an improved humoral and cellular response when compared to mice vaccinated with soluble Y2 and CpG. Further, we demonstrate in vitro that when Y2 and CpG are coordinated with ZnCar, they are protected from degradation at 40 °C for 3 months or 24 °C for 6 months. Overall, ZnCar shows promise as a delivery vehicle for subunit vaccines, given its superior immunogenicity and in vitro storage stability.


Asunto(s)
Carnosina , Vacunas contra la Influenza , Gripe Humana , Animales , Ratones , Humanos , Adyuvantes Inmunológicos , Adyuvantes Farmacéuticos , Polímeros
15.
J Immunol ; 206(9): 2015-2028, 2021 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-33820855

RESUMEN

The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-ß. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.


Asunto(s)
Micropartículas Derivadas de Células/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Interferón Tipo I/inmunología , Proteínas de la Membrana/inmunología , Nucleótidos Cíclicos/inmunología , Transducción de Señal/inmunología , Animales , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/prevención & control , Femenino , Humanos , Interferón Tipo I/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Proteínas de la Membrana/agonistas , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Noqueados , Nucleótidos Cíclicos/administración & dosificación , Nucleótidos Cíclicos/metabolismo , Transducción de Señal/efectos de los fármacos
17.
Memory ; 31(2): 297-314, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36475538

RESUMEN

ABSTRACTThis study compares semantic and phonological interference vulnerability across the full range of learning processes. Method: 43 controls aged 61-88 underwent a neuropsychological examination, French adaptation of the LASSI-L, and an experimental phonological test, the TIP-A. Paired sample t-tests, factorial ANOVA and hierarchical regressions were conducted, psychometric properties were calculated. Results: TIP-A efficiently generated phonological interference between concurrent word lists and was associated with short-term memory, unlike LASSI-L. On LASSI-L, proactive interference was higher than retroactive interference; the opposite pattern was found on TIP-A. Memory performance was better explained by age in the semantic than in the phonological task. Age was not associated with interference vulnerability. Intrusions and false recognition were associated with cognitive functioning regardless of age, particularly in the semantic context. Conclusion: To our knowledge, this is the first study to assess phonological and semantic interference using homologous concurrent word list tasks, and not a working memory build-up or DRM paradigm. The pattern obtained illustrates the weak initial memory trace in a phonological context and results are discussed according to depth-of-processing and dual-process theories. Similar paradigms could be studied among various pathologies for a better understanding of generalised interference vulnerability vs. specific semantic or phonological impairment.


Asunto(s)
Envejecimiento , Semántica , Humanos , Aprendizaje , Memoria a Corto Plazo , Cognición
18.
J Dairy Sci ; 106(2): 1110-1129, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36494224

RESUMEN

Genomic selection increases accuracy and decreases generation interval, accelerating genetic changes in populations. Assumptions of genetic improvement must be addressed to quantify the magnitude and direction of change. Genetic trends of US dairy cattle breeds were examined to determine the genetic gain since the implementation of genomic evaluations in 2009. Inbreeding levels and generation intervals were also investigated. Breeds included Ayrshire, Brown Swiss, Guernsey, Holstein (HO), and Jersey (JE), which were characterized by the evaluation breed the animal received. Mean genomic predicted breeding values (PBV¯) were analyzed per year to calculate genetic trends for bulls and cows. The data set contained 154,008 bulls and 33,022,242 cows born since 1975. Breakpoints were estimated using linear regression, and nonlinear regression was used to fit the piecewise model for the small sample number in some years. Generation intervals and inbreeding levels were also investigated since 1975. Milk, fat, and protein yields, somatic cell score, productive life, daughter pregnancy rate, and livability PBV¯ were documented. In 2017, 100% of bulls in this data set were genotyped. The percentage of genotyped cows has increased 23 percentage points since 2010. Overall, production traits have increased steadily over time, as expected. The HO and JE breeds have benefited most from genomics, with up to 192% increase in genetic gain since 2009. Due to the low number of observations, trends for Ayrshire, Brown Swiss, and Guernsey are difficult to infer from. Trends in fertility are most substantial; particularly, most breeds are trending downwards and daughter pregnancy rate for JE has been decreasing steadily since 1975 for bulls and cows. Levels of genomic inbreeding are increasing in HO bulls and cows. In 2017, genomic inbreeding levels were 12.7% for bulls and 7.9% for cows. A suggestion to control this is to include the genomic inbreeding coefficient with a negative weight to the selection index of bulls with high future genomic inbreeding levels. For sires of bulls, the current generation intervals are 2.2 yr in HO, 3.2 in JE, 4.4 in Brown Swiss, 5.1 in Ayrshire, and 4.3 in Guernsey. The number of colored breed bulls in the United States is currently at an extremely low level, and this number will only increase with a market incentive or additional breed association involvement. Increased education and extension could be beneficial to increase knowledge about inbreeding levels, use of genomics and genetic improvement, and genetic diversity in the genomic selection era.


Asunto(s)
Genoma , Selección Genética , Embarazo , Femenino , Bovinos/genética , Animales , Masculino , Estados Unidos , Genotipo , Endogamia , Genómica , Fenotipo
19.
Ophthalmic Plast Reconstr Surg ; 39(2): e40-e43, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36700847

RESUMEN

The authors present the case of a middle-aged woman with subacute progressive swelling of the OD associated with pain and severely limited duction in all gazes. MRI demonstrated a ~3 cm circumscribed mass in the extraconal space, which displaced and distorted the globe and impinged upon ocular adnexa. She underwent lateral orbitotomy with bone osteotomy to remove the mass, and subsequent histopathologic examination showed woven bone set within a fibrotic background, microscopic features of fibrous dysplasia. Fibrous dysplasia is characterized by abnormal scar-like bony proliferation, typically within a preexisting structure of the skeletal system. To the authors' knowledge, this represents the first example of fibrous dysplasia presenting as an orbital mass unconnected to the craniofacial skeleton.


Asunto(s)
Displasia Fibrosa Ósea , Enfermedades Orbitales , Persona de Mediana Edad , Femenino , Humanos , Enfermedades Orbitales/cirugía , Órbita/cirugía , Osteotomía , Imagen por Resonancia Magnética
20.
J Environ Manage ; 344: 118780, 2023 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-37611345

RESUMEN

Methane (CH4) emissions from landfills are a major contributor to global greenhouse gas emissions. Compost-based biocovers offer a viable approach to reduce CH4 emissions from landfills; however, the effectiveness in climates with varying temperatures is not well understood. The methane removal performances of two compost-based biocover materials (food and yard waste compost) were examined under different temperature conditions using laboratory column experiments. A reactive transport model was used to simulate the experimental results to develop a better quantitative understanding of the effect of temperature on overall methane removal efficiency. As expected, experimental results indicated that the oxidation rate was influenced by temperature, as it was reduced when the temperature decreased from 22 °C to 8 °C. However, some oxidation was observed at a lower temperature, which was confirmed by CO2 concentrations above the initial level and the observed temperatures above the exposure temperature along the height of biocover column. Furthermore, results showed that when the compost-based materials were subjected to 8 °C and then increased to 22 °C, methane oxidation within the material recovered quickly and returned to similar oxidation rates as observed before the temperature was reduced, suggesting that compost-based biocovers may not be affected by cyclic temperature variations when used in colder climates. Methane oxidation capacity was limited by the maximum oxidation rate, the biocover porosity, and the gas saturation profile that affects residence time and overall methane oxidation in the columns. The model results show that the CH4 oxidation rate was reduced by one order of magnitude when the temperature decreased from 22 °C to 8 °C. Therefore, the calculated Q10 values were 4.19 and 5.18 for the food and yard waste compost, respectively. Overall, compost-based landfill biocovers, such as food and yard waste compost, are capable of mitigate CH4 emissions from old and small landfills under different temperature conditions.


Asunto(s)
Compostaje , Temperatura , Clima , Clima Frío , Metano
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