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1.
Proc Natl Acad Sci U S A ; 121(9): e2309153121, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38386711

RESUMO

The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.


Assuntos
Linfócitos T CD4-Positivos , Células T de Memória , Animais , Camundongos , Memória Imunológica , Memória , Receptores de Interleucina-7 , Transativadores , Antígenos de Diferenciação
2.
Artigo em Inglês | MEDLINE | ID: mdl-38385175

RESUMO

Conduit arterial disease in CKD is an important cause of cardiac complications. Cardiac function in CKD has not been studied in the absence of arterial disease. In an Alport syndrome model bred not to have conduit arterial disease, mice at 225 days of life (dol) had CKD equivalent to human stage 4-5 CKD. PTH and FGF23 levels were one log order elevated, circulating sclerostin was elevated, and renal activin A was strongly induced. Aortic Ca levels were not increased and VSMC transdifferentiation was absent. The CKD mice were not hypertensive, and cardiac hypertrophy was absent. Freshly excised cardiac tissue respirometry (Oroboros) showed ADP-stimulated O2 flux was diminished from 52 to 22 pmol/mg (p=0.044). RNAseq of cardiac tissue from CKD mice revealed significantly decreased levels of cardiac mitochondrial oxidative phosphorylation genes. To examine the effect of activin A signaling, some Alport mice were treated with a monoclonal Ab to activin A or an isotype matched IgG beginning at 75 days of life until euthanasia. Treatment with the Activin A Ab did not affect cardiac oxidative phosphorylation. However, the Activin A antibody was active in the skeleton, disrupting the effect of CKD to stimulate osteoclast number, eroded surfaces and the stimulation of osteoclast-driven remodeling. The data reported here show that cardiac mitochondrial respiration is impaired in CKD in the absence of conduit arterial disease. This is the first report of the direct effect of CKD on cardiac respiration.

3.
Sci Rep ; 14(1): 4952, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418864

RESUMO

To investigate the association between area deprivation index (ADI) and aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Patients aged 40-95 years with severe AS confirmed by echocardiography were included. The 9-digit zip code of patient residence address was used to identify the ADI ranking, based on which patients were divided into 5 groups (with Group E being most deprived). The rates of AV intervention were compared among 5 groups using competing risks analysis, with death as a competing event. We included 1751 patients with severe AS from 2013 to 2018 followed for a median 2.8 (interquartile range, 1.5-4.8) years. The more distressed ADI groups tended to be younger (P = 0.002), female (P < 0.001), and of African American race (P < 0.001), have higher presentation of sepsis (P = 0.031), arrhythmia (P = 0.022), less likely to have previous diagnosis of AS (P < 0.001); and were less likely to undergo AVR (52.5% vs 46.9% vs 46.1% vs 48.9% vs 39.7%, P = 0.023). Using competing risk analysis, the highest ADI group (E) were the least and the lowest ADI group (A) the most likely to undergo AVR (Gray's test, P = 0.025). The association between ADI ranking and AVR rates was influenced by sex and race. Within group analysis, there was significant association between race and AVR (Gray's test, P < 0.001), and between sex and AVR (Gray's test, P < 0.001). Patients with severe AS living in more deprived neighborhoods were less likely to undergo aortic valve interventions, which was influenced by female gender, and African American race.


Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Humanos , Feminino , Estenose da Valva Aórtica/diagnóstico , Implante de Prótese de Valva Cardíaca/efeitos adversos , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Ecocardiografia , Índice de Gravidade de Doença , Estudos Retrospectivos , Resultado do Tratamento , Fatores de Risco
4.
BMJ Open ; 14(2): e075066, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38307538

RESUMO

INTRODUCTION: Like many countries, England has a national shortage of registered nurses. Employers strive to retain existing staff, to ease supply pressures. Disproportionate numbers of nurses leave the National Health Services (NHS) both early in their careers, and later, as they near retirement age. Research is needed to understand the job preferences of early-career and late-career nurses working in the NHS, so tailored policies can be developed to better retain these two groups. METHODS AND ANALYSIS: We will collect job preference data for early-career and late-career NHS nurses, respectively using two separate discrete choice experiments (DCEs). Findings from the literature, focus groups, academic experts and stakeholder discussions will be used to identify and select the DCE attributes (ie, job features) and levels. We will generate an orthogonal, fractional factorial design using the experimental software Ngene. The DCEs will be administered through online surveys distributed by the regulator Nursing and Midwifery Council. For each group, we expect to achieve a final sample of 2500 registered NHS nurses working in England. For early-career nurses, eligible participants will be registered nurses who graduated in the preceding 5 years (ie, 2019-2023). Eligible participants for the late-career survey will be registered nurses aged 55 years and above. We will use conditional and mixed logit models to analyse the data. Specifically, study 1 will estimate the job preferences of early-career nurses and the possible trade-offs. Study 2 will estimate the retirement preferences of late-career NHS nurses and the potential trade-offs. ETHICS AND DISSEMINATION: The research protocol was reviewed and approved by the host research organisation Ethics Committees Research Governance (University of Southampton, number 80610) (https://www.southampton.ac.uk/about/governance/regulations-policies/policies/ethics). The results will be disseminated via conference presentations, publications in peer-reviewed journals and annual reports to key stakeholders, the Department of Health and Social Care, and NHS England/Improvement retention leaders. REGISTRATION DETAILS: Registration on OSF http://doi.org/10.17605/OSF.IO/RDN9G.


Assuntos
Enfermeiras e Enfermeiros , Medicina Estatal , Humanos , Grupos Focais , Projetos de Pesquisa , Inglaterra
5.
Neuro Oncol ; 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38285679

RESUMO

BACKGROUND: The aim was to predict survival of glioblastoma at eight months after radiotherapy (a period allowing for completing a typical course of adjuvant temozolomide), by applying deep learning to the first brain MRI after radiotherapy completion. METHODS: Retrospective and prospective data were collected from 206 consecutive glioblastoma, IDH-wildtype patients diagnosed between March 2014-February 2022 across 11 UK centers. Models were trained on 158 retrospective patients from three centers. Holdout test sets were retrospective (n=19; internal validation), and prospective (n=29; external validation from eight distinct centers).Neural network branches for T2-weighted and contrast-enhanced T1-weighted inputs were concatenated to predict survival. A non-imaging branch (demographics/MGMT/treatment data) was also combined with the imaging model. We investigated the influence of individual MR sequences; non-imaging features; and weighted dense blocks pretrained for abnormality detection. RESULTS: The imaging model outperformed the non-imaging model in all test sets (area under the receiver-operating characteristic curve, AUC p=0.038) and performed similarly to a combined imaging/non-imaging model (p>0.05). Imaging, non-imaging, and combined models applied to amalgamated test sets gave AUCs of 0.93, 0.79, and 0.91. Initializing the imaging model with pretrained weights from 10,000s of brain MRIs improved performance considerably (amalgamated test sets without pretraining 0.64; p=0.003). CONCLUSIONS: A deep learning model using MRI images after radiotherapy, reliably and accurately determined survival of glioblastoma. The model serves as a prognostic biomarker identifying patients who will not survive beyond a typical course of adjuvant temozolomide, thereby stratifying patients into those who might require early second-line or clinical trial treatment.

6.
PLoS One ; 19(1): e0297036, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38271381

RESUMO

Previous studies mainly focused on individual-level factors that influence the adoption and usage of mobile technology and social networking sites, with little emphasis paid to the influences of household situations. Using multilevel modelling approach, this study merges household- (n1 = 1,455) and individual-level (n2 = 2,570) data in the U.K. context to investigate (a) whether a household economic capital (HEC) can affect its members' Twitter adoption, (b) whether the influences are mediated by the member's activity variety and self-reported efficacy with mobile technology, and (c) whether the members' traits, including educational level, gross income and residential area, moderate the relationship between HEC and Twitter adoption. Significant direct and indirect associations were discovered between HEC and its members' Twitter adoption. The educational level and gross income of household members moderated the influence of HEC on individuals' Twitter adoption.


Assuntos
Mídias Sociais , Humanos , Análise Multinível , Características da Família , Renda , Escolaridade
8.
J Immunol ; 212(4): 586-595, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38149929

RESUMO

Following viral infection, CD4+ T cell differentiation is tightly regulated by cytokines and TCR signals. Although most activated CD4+ T cells express IL-2Rα after lymphocytic choriomeningtis virus infection, by day 3 postinfection, only half of activated T cells maintain expression. IL-2Rα at this time point distinguishes precursors for terminally differentiated Th1 cells (IL-2Rαhi) from precursors for Tfh cells and memory T cells (IL-2Rαlo) and is linked to strong TCR signals. In this study, we test whether TCR-dependent IL-2 links the TCR to CD4+ T cell differentiation. We employ a mixture of anti-IL-2 Abs to neutralize IL-2 throughout the primary CD4+ T cell response to lymphocytic choriomeningitis virus infection in mice or only after the establishment of lineage-committed effector cells (day 3 postinfection). We report that IL-2 signals drive the formation of Th1 precursor cells in the early stages of the immune response and sustain Th1 responses during its later stages (after day 3). Effector-stage IL-2 also shapes the composition and function of resulting CD4+ memory T cells. Although IL-2 has been shown previously to drive Th1 differentiation by reducing the activity of the transcriptional repressor TCF-1, we found that sustained IL-2 signals were still required to drive optimal Th1 differentiation even in the absence of TCF-1. Therefore, we concluded that IL-2 plays a central role throughout the effector phase in regulating the balance between Th1 and Tfh effector and memory cells via mechanisms that are both dependent and independent of its role in modulating TCF-1 activity.


Assuntos
Interleucina-2 , Células Th1 , Animais , Camundongos , Linfócitos T CD4-Positivos , Diferenciação Celular , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2 , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T
9.
Cell Genom ; 3(12): 100426, 2023 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-38116120

RESUMO

Acute myeloid leukemia (AML) and myeloid neoplasms develop through acquisition of somatic mutations that confer mutation-specific fitness advantages to hematopoietic stem and progenitor cells. However, our understanding of mutational effects remains limited to the resolution attainable within immunophenotypically and clinically accessible bulk cell populations. To decipher heterogeneous cellular fitness to preleukemic mutational perturbations, we performed single-cell RNA sequencing of eight different mouse models with driver mutations of myeloid malignancies, generating 269,048 single-cell profiles. Our analysis infers mutation-driven perturbations in cell abundance, cellular lineage fate, cellular metabolism, and gene expression at the continuous resolution, pinpointing cell populations with transcriptional alterations associated with differentiation bias. We further develop an 11-gene scoring system (Stem11) on the basis of preleukemic transcriptional signatures that predicts AML patient outcomes. Our results demonstrate that a single-cell-resolution deep characterization of preleukemic biology has the potential to enhance our understanding of AML heterogeneity and inform more effective risk stratification strategies.

10.
Elife ; 122023 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-38113081

RESUMO

Neurons coordinate their activity to produce an astonishing variety of motor behaviors. Our present understanding of motor control has grown rapidly thanks to new methods for recording and analyzing populations of many individual neurons over time. In contrast, current methods for recording the nervous system's actual motor output - the activation of muscle fibers by motor neurons - typically cannot detect the individual electrical events produced by muscle fibers during natural behaviors and scale poorly across species and muscle groups. Here we present a novel class of electrode devices ('Myomatrix arrays') that record muscle activity at unprecedented resolution across muscles and behaviors. High-density, flexible electrode arrays allow for stable recordings from the muscle fibers activated by a single motor neuron, called a 'motor unit,' during natural behaviors in many species, including mice, rats, primates, songbirds, frogs, and insects. This technology therefore allows the nervous system's motor output to be monitored in unprecedented detail during complex behaviors across species and muscle morphologies. We anticipate that this technology will allow rapid advances in understanding the neural control of behavior and identifying pathologies of the motor system.


Assuntos
Neurônios Motores , Primatas , Ratos , Camundongos , Animais , Neurônios Motores/fisiologia , Eletrodos , Fibras Musculares Esqueléticas
11.
bioRxiv ; 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38014190

RESUMO

Paleogenomics has expanded our knowledge of human evolutionary history. Since the 2020s, the study of ancient DNA has increased its focus on reconstructing the recent past. However, the accuracy of paleogenomic methods in answering questions of historical and archaeological importance amidst the increased demographic complexity and decreased genetic differentiation within the historical period remains an open question. We used two simulation approaches to evaluate the limitations and behavior of commonly used methods, qpAdm and the f3-statistic, on admixture inference. The first is based on branch-length data simulated from four simple demographic models of varying complexities and configurations. The second, an analysis of Eurasian history composed of 59 populations using whole-genome data modified with ancient DNA conditions such as SNP ascertainment, data missingness, and pseudo-haploidization. We show that under conditions resembling historical populations, qpAdm can identify a small candidate set of true sources and populations closely related to them. However, in typical ancient DNA conditions, qpAdm is unable to further distinguish between them, limiting its utility for resolving fine-scaled hypotheses. Notably, we find that complex gene-flow histories generally lead to improvements in the performance of qpAdm and observe no bias in the estimation of admixture weights. We offer a heuristic for admixture inference that incorporates admixture weight estimate and P-values of qpAdm models, and f3-statistics to enhance the power to distinguish between multiple plausible candidates. Finally, we highlight the future potential of qpAdm through whole-genome branch-length f2-statistics, demonstrating the improved demographic inference that could be achieved with advancements in f-statistic estimations.

12.
Cureus ; 15(10): e47284, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38021991

RESUMO

Background Residents from diverse specialties perform clinical rotations in the emergency department (ED). There is little research about the value of the ED rotation for them. Objectives We sought to determine the learning objectives of non-EM residents (NEMRs) in the ED, the effectiveness of the rotation, and the highest-yield components of their experience. Methods From 2017-2019, we surveyed NEMR on their pre-rotation learning objectives and their comfort level with 15 common ED presentations/procedures before and after the rotation. We assessed how well their objectives were met, the highest-yield components of their rotation, and opportunities for improvement. Results We collected responses from 56 (47%) pre-rotation and 61 (51%) post-rotation residents over a two-year period. The five most commonly cited learning goals were: management of acutely ill patients, triage skills, procedural competence, and ultrasound. Seventy-eight percent (78%) of residents reported their learning goals were moderately to very well met during their rotation. NEMRs' level of comfort improved in all the commonly encountered clinical experiences in the ED in a statistically significant manner. They cited on-shift teaching by attending physicians and senior EM residents as the most valuable learning resource. Conclusion NEMR from diverse medical and surgical specialties could identify specific learning objectives for their EM rotation with common themes, and the majority felt their educational goals were met. They gained comfort with the management and triage of all the assessed common ED conditions. By collecting and defining their specific needs and goals, we are better equipped to improve the quality and value of the rotation.

13.
bioRxiv ; 2023 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-37904998

RESUMO

Although a broad range of methods exists for reconstructing population history from genome-wide single nucleotide polymorphism data, just a few methods gained popularity in archaeogenetics: principal component analysis (PCA); ADMIXTURE, an algorithm that models individuals as mixtures of multiple ancestral sources represented by actual or inferred populations; formal tests for admixture such as f3-statistics and D/f4-statistics; and qpAdm, a tool for fitting two-component and more complex admixture models to groups or individuals. Despite their popularity in archaeogenetics, which is explained by modest computational requirements and ability to analyze data of various types and qualities, protocols relying on qpAdm that screen numerous alternative models of varying complexity and find "fitting" models (often considering both estimated admixture proportions and p-values as a composite criterion of model fit) remain untested on complex simulated population histories in the form of admixture graphs of random topology. We analyzed genotype data extracted from such simulations and tested various types of high-throughput qpAdm protocols ("rotating" and "non-rotating", with or without temporal stratification of target groups and proxy ancestry sources, and with or without a "model competition" step). We caution that high-throughput qpAdm protocols may be inappropriate for exploratory analyses in poorly studied regions/periods since their false discovery rates varied between 12% and 68% depending on the details of the protocol and on the amount and quality of simulated data (i.e., >12% of fitting two-way admixture models imply gene flows that were not simulated). We demonstrate that for reducing false discovery rates of qpAdm protocols to nearly 0% it is advisable to use large SNP sets with low missing data rates, the rotating qpAdm protocol with a strictly enforced rule that target groups do not pre-date their proxy sources, and an unsupervised ADMIXTURE analysis as a way to verify feasible qpAdm models. Our study has a number of limitations: for instance, these recommendations depend on the assumption that the underlying genetic history is a complex admixture graph and not a stepping-stone model.

14.
bioRxiv ; 2023 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-37873189

RESUMO

Adaptive immune resistance (AIR) is a protective process used by cancer to escape elimination by CD8+ T cells. Inhibition of immune checkpoints PD-1 and CTLA-4 specifically target Interferon-gamma (IFNγ)-driven AIR. AIR begins at the plasma membrane where tumor cell-intrinsic cytokine signaling is initiated. Thus, plasma membrane remodeling by endomembrane trafficking could regulate AIR. Herein we report that the trafficking protein ADP-Ribosylation Factor 6 (ARF6) is critical for IFNγ-driven AIR. ARF6 prevents transport of the receptor to the lysosome, augmenting IFNγR expression, tumor intrinsic IFNγ signaling and downstream expression of immunosuppressive genes. In murine melanoma, loss of ARF6 causes resistance to immune checkpoint blockade (ICB). Likewise, low expression of ARF6 in patient tumors correlates with inferior outcomes with ICB. Our data provide new mechanistic insights into tumor immune escape, defined by ARF6-dependent AIR, and support that ARF6-dependent endomembrane trafficking of the IFNγ receptor influences outcomes of ICB.

16.
Polymers (Basel) ; 15(19)2023 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-37835919

RESUMO

This study investigates the density of states and structural characteristics of helical homopolymers. Comprising repeating identical units, the model enables the exploration of complex behaviors arising from a simple, yet generalized, set of potentials. Utilizing microcanonical analysis, transitions between helical structures are identified and categorized. Through a systematic comparison of results under varying conditions, we develop a nuanced understanding of the system's general behavior. A two-dimensional plot illustrates the relative distribution of different structural types, effectively showcasing their prevalence. The findings of this study substantially advance our understanding of the density of states and structural transformations of helical homopolymers across a range of conditions. Additionally, the prevalence plot offers valuable insights into the occurrence of suppressed intermediate states, particularly in models featuring stiff helix segments. This research significantly enhances our understanding of the complex interactions governing helix bundling phenomena within the context of helical homopolymers.

17.
Mol Ecol Resour ; 23(8): 1823-1840, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37712846

RESUMO

In-solution hybridisation enrichment of genetic variation is a valuable methodology in human paleogenomics. It allows enrichment of endogenous DNA by targeting genetic markers that are comparable between sequencing libraries. Many studies have used the 1240k reagent-which enriches 1,237,207 genome-wide SNPs-since 2015, though access was restricted. In 2021, Twist Biosciences and Daicel Arbor Biosciences independently released commercial kits that enabled all researchers to perform enrichments for the same 1240 k SNPs. We used the Daicel Arbor Biosciences Prime Plus kit to enrich 132 ancient samples from three continents. We identified a systematic assay bias that increases genetic similarity between enriched samples and that cannot be explained by batch effects. We present the impact of the bias on population genetics inferences (e.g. Principal Components Analysis, ƒ-statistics) and genetic relatedness (READ). We compare the Prime Plus bias to that previously reported of the legacy 1240k enrichment assay. In ƒ-statistics, we find that all Prime-Plus-generated data exhibit artefactual excess shared drift, such that within-continent relationships cannot be correctly determined. The bias is more subtle in READ, though interpretation of the results can still be misleading in specific contexts. We expect the bias may affect analyses we have not yet tested. Our observations support previously reported concerns for the integration of different data types in paleogenomics. We also caution that technological solutions to generate 1240k data necessitate a thorough validation process before their adoption in the paleogenomic community.

18.
bioRxiv ; 2023 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-37693425

RESUMO

Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection/immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.

19.
J Clin Med ; 12(18)2023 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-37762875

RESUMO

Microvascular obstruction (MVO) is a recognised phenomenon following mechanical reperfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI). Invasive and non-invasive modalities to detect and measure the extent of MVO vary in their accuracy, suggesting that this phenomenon may reflect a spectrum of pathophysiological changes at the level of coronary microcirculation. The importance of detecting MVO lies in the observation that its presence adds incremental risk to patients following STEMI treatment. This increased risk is associated with adverse cardiac remodelling seen on cardiac imaging, increased infarct size, and worse patient outcomes. This review provides an outline of the pathophysiology, clinical implications, and prognosis of MVO in STEMI. It describes historic and novel pharmacological and non-pharmacological therapies to address this phenomenon in conjunction with primary PCI.

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