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1.
Fluids Barriers CNS ; 21(1): 23, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38433215

RESUMO

BACKGROUND: The active transport of molecules into the brain from blood is regulated by receptors, transporters, and other cell surface proteins that are present on the luminal surface of endothelial cells at the blood-brain barrier (BBB). However, proteomic profiling of proteins present on the luminal endothelial cell surface of the BBB has proven challenging due to difficulty in labelling these proteins in a way that allows efficient purification of these relatively low abundance cell surface proteins. METHODS: Here we describe a novel perfusion-based labelling workflow: in vivo glycocapture. This workflow relies on the oxidation of glycans present on the luminal vessel surface via perfusion of a mild oxidizing agent, followed by subsequent isolation of glycoproteins by covalent linkage of their oxidized glycans to hydrazide beads. Mass spectrometry-based identification of the isolated proteins enables high-confidence identification of endothelial cell surface proteins in rats and mice. RESULTS: Using the developed workflow, 347 proteins were identified from the BBB in rat and 224 proteins in mouse, for a total of 395 proteins in both species combined. These proteins included many proteins with transporter activity (73 proteins), cell adhesion proteins (47 proteins), and transmembrane signal receptors (31 proteins). To identify proteins that are enriched in vessels relative to the entire brain, we established a vessel-enrichment score and showed that proteins with a high vessel-enrichment score are involved in vascular development functions, binding to integrins, and cell adhesion. Using publicly-available single-cell RNAseq data, we show that the proteins identified by in vivo glycocapture were more likely to be detected by scRNAseq in endothelial cells than in any other cell type. Furthermore, nearly 50% of the genes encoding cell-surface proteins that were detected by scRNAseq in endothelial cells were also identified by in vivo glycocapture. CONCLUSIONS: The proteins identified by in vivo glycocapture in this work represent the most complete and specific profiling of proteins on the luminal BBB surface to date. The identified proteins reflect possible targets for the development of antibodies to improve the crossing of therapeutic proteins into the brain and will contribute to our further understanding of BBB transport mechanisms.


Assuntos
Barreira Hematoencefálica , Proteoma , Ratos , Camundongos , Animais , Células Endoteliais , Proteômica , Encéfalo , Microvasos , Proteínas de Membrana , Polissacarídeos
2.
BMC Public Health ; 24(1): 561, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388342

RESUMO

BACKGROUND: In the UK, unique and unforeseen factors, including COVID-19, Brexit, and Ukraine-Russia war, have resulted in an unprecedented cost of living crisis, creating a second health emergency. We present, one of the first rapid reviews with the aim of examining the impact of this current crisis, at a population level. We reviewed published literature, as well as grey literature, examining a broad range of physical and mental impacts on health in the short, mid, and long term, identifying those most at risk, impacts on system partners, including emergency services and the third sector, as well as mitigation strategies. METHODS: We conducted a rapid review by searching PubMed, Embase, MEDLINE, and HMIC (2020 to 2023). We searched for grey literature on Google and hand-searched the reports of relevant public health organisations. We included interventional and observational studies that reported outcomes of interventions aimed at mitigating against the impacts of cost of living at a population level. RESULTS: We found that the strongest evidence was for the impact of cold and mouldy homes on respiratory-related infections and respiratory conditions. Those at an increased risk were young children (0-4 years), the elderly (aged 75 and over), as well as those already vulnerable, including those with long-term multimorbidity. Further short-term impacts include an increased risk of physical pain including musculoskeletal and chest pain, and increased risk of enteric infections and malnutrition. In the mid-term, we could see increases in hypertension, transient ischaemic attacks, and myocardial infarctions, and respiratory illnesses. In the long term we could see an increase in mortality and morbidity rates from respiratory and cardiovascular disease, as well as increase rates of suicide and self-harm and infectious disease outcomes. Changes in behaviour are likely particularly around changes in food buying patterns and the ability to heat a home. System partners are also impacted, with voluntary sectors seeing fewer volunteers, an increase in petty crime and theft, alternative heating appliances causing fires, and an increase in burns and burn-related admissions. To mitigate against these impacts, support should be provided, to the most vulnerable, to help increase disposable income, reduce energy bills, and encourage home improvements linked with energy efficiency. Stronger links to bridge voluntary, community, charity and faith groups are needed to help provide additional aid and support. CONCLUSION: Although the CoL crisis affects the entire population, the impacts are exacerbated in those that are most vulnerable, particularly young children, single parents, multigenerational families. More can be done at a community and societal level to support the most vulnerable, and those living with long-term multimorbidity. This review consolidates the current evidence on the impacts of the cost of living crisis and may enable decision makers to target limited resources more effectively.


Assuntos
Qualidade Habitacional , Saúde da População , Determinantes Sociais da Saúde , Idoso , Criança , Pré-Escolar , Humanos , União Europeia , Hipertensão , Saúde da População/estatística & dados numéricos , Suicídio , Reino Unido/epidemiologia , Economia , Ambiente Domiciliar , Determinantes Sociais da Saúde/economia , Determinantes Sociais da Saúde/estatística & dados numéricos
3.
PRiMER ; 8: 13, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38406237

RESUMO

Medical educators are expected to disseminate peer-reviewed scholarly work for academic promotion and tenure. However, developing submissions for presentations at national meetings can be confusing and sometimes overwhelming. Awareness and use of some best practices can demystify the process and maximize opportunities for acceptance for a variety of potential submission categories. This article outlines logistical steps and best practices for each stage of the conference submission process that faculty should consider when preparing submissions. These include topic choice, team composition, consideration of different submission types, and strategies for effectively engaging participants.

4.
PLoS One ; 19(2): e0297530, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38324559

RESUMO

Given the increasing prevalence of online data collection, it is important to know how behavioral data obtained online compare to samples collected in the laboratory. This study compares online and in-person measurement of speech perception in older children and adolescents. Speech perception is important for assessment and treatment planning in speech-language pathology; we focus on the American English /ɹ/ sound because of its frequency as a clinical target. Two speech perception tasks were adapted for web presentation using Gorilla: identification of items along a synthetic continuum from rake to wake, and category goodness judgment of English /ɹ/ sounds in words produced by various talkers with and without speech sound disorder. Fifty typical children aged 9-15 completed these tasks online using a standard headset. These data were compared to a previous sample of 98 typical children aged 9-15 who completed the same tasks in the lab setting. For the identification task, participants exhibited smaller boundary widths (suggestive of more acute perception) in the in-person setting relative to the online setting. For the category goodness judgment task, there was no statistically significant effect of modality. The correlation between scores on the two tasks was significant in the online setting but not in the in-person setting, but the difference in correlation strength was not statistically significant. Overall, our findings agree with previous research in suggesting that online and in-person data collection do not yield identical results, but the two contexts tend to support the same broad conclusions. In addition, these results suggest that online data collection can make it easier for researchers connect with a more representative sample of participants.


Assuntos
Percepção da Fala , Transtorno Fonológico , Criança , Humanos , Adolescente , Idioma , Julgamento , Som , Fala
5.
Artigo em Inglês | MEDLINE | ID: mdl-38248544

RESUMO

Homelessness is a pervasive issue in the United States that presents significant challenges to public health. Homeless young adults (HYAs) are at particular risk for increased incidence and severity of depression. Using primary survey data (n = 205) collected in the Phoenix Metropolitan Area, Arizona, from June to August 2022, this study aims to examine the relationship between adverse childhood experiences (ACEs) and depression among HYAs. We adopted the ACEs 10-item scale to measure childhood traumatic experiences, whereas depression was measured by using a PHQ-4 depression scale and diagnosed depression. Regression models were conducted to test the relationships between ACEs and depression outcomes while controlling for the covariates at the individual, interpersonal, and socioeconomic/living environment levels. The average PHQ-4 score was 5.01 (SD = 3.59), and 59.69% of HYAs reported being diagnosed previously with depression. The mean ACEs score was 5.22 out of 10. Other things being equal, for every one unit increase in ACEs scores, the odds of being diagnosed with depression increased by 11.5%, yet it was not statistically significant, while the PHQ-4 score increased by 0.445 (p < 0.001). Overall, HYAs were disproportionately affected by depression. This study elucidates the complex relationship between ACEs and depression among HYAs.


Assuntos
Experiências Adversas da Infância , Pessoas Mal Alojadas , Humanos , Adulto Jovem , Depressão/epidemiologia , Determinantes Sociais da Saúde , Problemas Sociais
6.
Inflammation ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38289578

RESUMO

Methotrexate (MTX)-induced intestinal mucositis (IM) is a common side effect in cancer treatment that impairs the immune system and gut microbes, resulting in loss of mucosal integrity and gut barrier dysfunction. The quality of life and outcomes of treatment are compromised by IM. The present study was designed to investigate the mucoprotective potential of the benzimidazole derivative N-{4-[2-(4-methoxyphenyl)-1H-benzimidazole-1-sulfonyl] phenyl} acetamide (B8) on MTX-induced IM in mice. IM was induced by a single dose of MTX in mice and assessed by physical manifestations as well as biochemical, oxidative, histological, and inflammatory parameters. B8 (1, 3, 9 mg/kg) significantly reduced diarrhea score, mitigated weight loss, increased feed intake and, survival rate in a dose-dependent manner. Notably, B8 exhibited a mucoprotective effect evident through the mitigation of villus atrophy, crypt hypoplasia, diminished crypt mitotic figures, mucin depletion, and oxidative stress markers (GSH, SOD, MDA, and catalase concentration). Gene expression analysis revealed that B8 downregulated the mRNA expression of tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), IL-1ß, and nuclear factor-κB (NF-κB) and concurrently upregulated IL-10 expression in contrast to the MTX group. Further, B8 significantly improved the luminal microflora profile by augmenting the growth of Lactobacillus spp. and reducing the number of pathogenic bacteria (E. coli). Additionally, the enzyme-linked immunoassay showed that B8 decreased the levels of pro-inflammatory cytokines. Our findings suggest that B8 had mucoprotective effects against MTX-induced IM and could be used as an adjunct in chemotherapy to deter this side effect.

7.
Nat Rev Endocrinol ; 20(2): 111-123, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38049643

RESUMO

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.


Assuntos
Diabetes Mellitus Tipo 2 , Neoplasias da Próstata , Masculino , Adulto , Humanos , Diabetes Mellitus Tipo 2/genética , Puberdade/fisiologia , Maturidade Sexual/fisiologia , Obesidade/genética
8.
Neurosci Biobehav Rev ; 157: 105523, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38142983

RESUMO

The circadian rhythm affects multiple physiological processes, and disruption of the circadian system can be involved in a range of disease-related pathways. The genetic underpinnings of the circadian rhythm have been well-studied in model organisms. Significant progress has been made in understanding how clock genes affect the physiological functions of the nervous system. In addition, circadian timing is becoming a key factor in improving drug efficacy and reducing drug toxicity. The circadian biology of the target cell determines how the organ responds to the drug at a specific time of day, thus regulating pharmacodynamics. The current review brings together recent advances that have begun to unravel the molecular mechanisms of how the circadian clock affects neurophysiological and behavioral processes associated with human brain diseases. We start with a brief description of how the ubiquitous circadian rhythms are regulated at the genetic, cellular, and neural circuit levels, based on knowledge derived from extensive research on model organisms. We then summarize the latest findings from genetic studies of human brain disorders, focusing on the role of human clock gene variants in these diseases. Lastly, we discuss the impact of common dietary factors and medications on human circadian rhythms and advocate for a broader application of the concept of chronomedicine.


Assuntos
Relógios Circadianos , Neurociências , Humanos , Neurofisiologia , Ritmo Circadiano/genética , Relógios Circadianos/genética
9.
PRiMER ; 7: 34, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38149285

RESUMO

Academic promotion, representing achievement of a level of distinction in one's body of work, is an honorable accomplishment in a faculty member's career. External letters of review written by faculty at higher ranks are a critical component of the promotion portfolio. We discuss key considerations for writing external letters. These considerations can be used to mentor this skill for less experienced letter writers. We also highlight how professional societies can aid faculty in developing and strengthening writing and mentoring capabilities for this vital task.

10.
Wellcome Open Res ; 8: 413, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37969481

RESUMO

Background: Melioidosis is a bacterial infection which kills an estimated 89,000 people per year in tropical and sub-tropical regions, chiefly affecting the poorest. Diabetes is the primary risk factor, conferring a 12-fold increase in risk. Despite limited funding compared to other neglected tropical diseases, melioidosis vaccine development has generated several candidates for clinical development. CPS-CRM 197/Hcp1 is a promising vaccine candidate developed at the University of Nevada, Reno which is due to enter a Phase I clinical trial in Oxford, UK in 2024. As we move closer to the possibility of field trials of a melioidosis vaccine, it is critical to work in parallel to understand perceptions toward a vaccine among those living where melioidosis rates are high. Reasons for vaccine acceptance versus hesitancy are complex, and include perceived risk of the target disease, concern about side effects, and above all trust in government, scientists, the pharmaceutical industry and other authorities. Methods: We will carry out a qualitative study in Ubon Ratchathani, Thailand, an endemic region for melioidosis, as groundwork for a potential future melioidosis vaccine efficacy study, and in the longer-term vaccine introduction. This study seeks to explore knowledge and attitudes in three main areas; 1) melioidosis disease, 2) vaccines, and 3) participation in clinical vaccine trials. In-depth interviews and focus group discussions will take place in five participant groups of different risks and exposure to melioidosis. Purposive, convenience sampling will be used, also snowball sampling to reach some participant groups. Sample size will be based on participant's experience, to inform the line of enquiries of study, or until data saturation, expecting 66-90 participants across all groups. Discussion: The findings of this study will be written up and published in an open access journal, and will be valuable to inform future design of clinical trials as well as engagement and communications associated with future vaccine rollout.

11.
MethodsX ; 11: 102349, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37680365

RESUMO

Glycoproteins are a particularly interesting subset of the cellular proteome as a high proportion of proteins present on the extracellular cell surface are glycosylated. These cell surface proteins are ideal targets for biologic drug therapies or for diagnostics tests. Here, we describe a modification of the well-described Cell Surface Capture (CSC) method for the selective isolation and identification of cell surface glycoproteins that contain N-linked carbohydrates. This modification, which we refer to as Direct Cell Surface Capture (D-CSC), is based on oxidation of cell surface glycans on intact cells, followed by direct conjugation of the oxidized oligosaccharides to a solid support using hydrazide chemistry, with no biotinylation step. As a proof-of-principle, we applied D-CSC to the analysis of cell surface membrane proteins of three adherent cancer cell lines (A549, OVCAR3, and U87MG) and compared our results to those published using the well-established Cell Surface Capture (CSC) method, demonstrating comparable selectivity for cell surface proteins. •A method enabling the identification of cell surface proteins from cells in culture is described.•Application of this method to profile the cell surface on three different cancer cell lines is included.

12.
J Smok Cessat ; 2023: 9200402, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37766802

RESUMO

Background: Primary care providers play a key role in screening for tobacco use and assessing desire to quit. Tobacco treatment specialists (TTS) are certified in helping patients who desire tobacco cessation. A primary care nurse practitioner within one Midwestern healthcare organization obtained TTS certification and integrated specialized tobacco cessation visits within a primary care clinic from February 2021 to February 2022. Purpose: To determine the efficiency and effectiveness of an integrated TTS-certified nurse practitioner (TTS-NP) in a primary care setting 1-year postimplementation. Method: This program evaluation utilized retrospective electronic health record review and included thirty-three patients. The logic model served as a framework to define efficiency and effectiveness. Results: Patients were referred by a provider (57.6%), nurse (15.2%), or self (27.3). Patients opted for in-person initial visits (81.8%) more than virtual (18.2%). Of a total of 73 scheduled visits, 8 (11%) were no-showed. Patients who self-referred had the lowest no-show rate (5.6%) compared to those referred by a provider (12.8%) or nurse (12.5%). Of the patients included, 87.9% set a goal quit date. Average time until first and second follow-up was 34.6 and 130.4 days after goal quit date. Follow-up was defined as the date of the patient's first message reply to the TTS-NP, or first visit following the goal quit date. A total of 51.9% (n = 14) and 63% (n = 17) reported cessation at the first and second follow-up. TTS-NP visit's cost, independent of any other coverage, was less than other specialty visits in primary care. Conclusion: TTS-NP visits in primary care enabled patients to benefit from lower cost and longitudinal follow-up within a familiar setting. Over half of patients achieved cessation. Results of this program evaluation suggest support for TTS-certified providers in primary care.

13.
Infect Immun ; 91(10): e0010823, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37725060

RESUMO

Enteric fever, caused by oral infection with typhoidal Salmonella serovars, presents as a non-specific febrile illness preceded by an incubation period of 5 days or more. The enteric fever human challenge model provides a unique opportunity to investigate the innate immune response during this incubation period, and how this response is altered by vaccination with the Vi polysaccharide or conjugate vaccine. We find that on the same day as ingestion of typhoidal Salmonella, there is already evidence of an immune response, with 199 genes upregulated in the peripheral blood transcriptome 12 hours post-challenge (false discovery rate <0.05). Gene sets relating to neutrophils, monocytes, and innate immunity were over-represented (false discovery rate <0.05). Estimating cell proportions from gene expression data suggested a possible increase in activated monocytes 12 hours post-challenge (P = 0.036, paired Wilcoxon signed-rank test). Furthermore, plasma TNF-α rose following exposure (P = 0.011, paired Wilcoxon signed-rank test). There were no significant differences in gene expression (false discovery rate <0.05) in the 12 hours response between those who did and did not subsequently develop clinical or blood culture confirmed enteric fever or between vaccination groups. Together, these results demonstrate early perturbation of the peripheral blood transcriptome after enteric fever challenge and provide initial insight into early mechanisms of protection.


Assuntos
Febre Tifoide , Vacinas Tíficas-Paratíficas , Humanos , Febre Tifoide/prevenção & controle , Salmonella typhi/genética , Vacinas Atenuadas , Vacinação
14.
Community Health Equity Res Policy ; : 2752535X231196415, 2023 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-37635377

RESUMO

The novel Coronavirus (COVID-19) is a highly contagious viral illness that has caused the most significant global health crisis in recent human history. Individuals experiencing homelessness represent one of the more vulnerable populations for COVID-19 infection and morbidity. Amongst individuals experiencing homelessness in Phoenix, a student-led interprofessional organization called Street Medicine Phoenix (SMP) sought to both reduce the risk of COVID-19 transmission and morbidity/mortality related to infection. Through collaborations with the Maricopa County Department of Public Health and various community organizations, SMP developed a format for street-based vaccination clinics. SMP deployed these clinics on numerous occasions to the streets directly surrounding the community homeless shelter, allowing SMP to vaccinate individuals directly in their encampments. Through SMP's efforts starting in February 2021, 400 individuals experiencing homelessness have received at least one COVID-19 vaccine. Challenges encountered included low health literacy, lack of established rapport and trust, low vaccine confidence, difficulty verifying patients' vaccination status, difficulty obtaining sufficient information from patients to create a record in the Arizona State Immunization Information System (ASIIS), monitoring patients post-vaccination, transporting vaccine supplies from encampment to encampment, and lack of patient awareness of the mobile vaccine clinic services. Despite challenges, SMP's outreach efforts have demonstrated the feasibility and importance of mobile public health services to reach homeless encampments, particularly mobile vaccination clinics in response to disease outbreaks, and the necessity of strategic partnerships with community agencies to effectively meet the needs of underserved populations.

15.
J Clin Invest ; 133(16)2023 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-37402153

RESUMO

BACKGROUNDTyphoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODSBulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTSTranscriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSIONThe study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATIONClinicalTrials.gov NCT02324751.


Assuntos
Febre Tifoide , Vacinas Tíficas-Paratíficas , Adulto , Humanos , Polissacarídeos Bacterianos/genética , Receptores de Antígenos de Linfócitos B , Salmonella typhi/genética , Febre Tifoide/prevenção & controle , Vacinas Tíficas-Paratíficas/genética , Vacinação
16.
Front Immunol ; 14: 1182556, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37122746

RESUMO

Liposomes composed of sulfated lactosyl archaeol (SLA) have been shown to be a safe and effective vaccine adjuvant with a multitude of antigens in preclinical studies. In particular, SLA-adjuvanted SARS-CoV-2 subunit vaccines based on trimeric spike protein antigens were shown to be immunogenic and efficacious in mice and hamsters. With the continued emergence of SARS-CoV-2 variants, we sought to evaluate next-generation vaccine formulations with an updated antigenic identity. This was of particular interest for the widespread Omicron variant, given the abundance of mutations and structural changes observed within its spike protein compared to other variants. An updated version of our resistin-trimerized SmT1 corresponding to the B.1.1.529 variant was successfully generated in our Chinese Hamster Ovary (CHO) cell-based antigen production platform and characterized, revealing some differences in protein profile and ACE2 binding affinity as compared to reference strain-based SmT1. We next evaluated this Omicron-based spike antigen for its immunogenicity and ability to generate robust antigen-specific immune responses when paired with SLA liposomes or AddaS03 (a mimetic of the AS03 oil-in-water emulsion adjuvant system found in commercialized SARS-CoV-2 protein vaccines). Immunization of mice with vaccine formulations containing this updated antigen with either adjuvant stimulated neutralizing antibody responses favouring Omicron over the reference strain. Cell-mediated responses, which play an important role in the neutralization of intracellular infections, were induced to a much higher degree with the SLA adjuvant relative to the AddaS03-adjuvanted formulations. As such, updated vaccines that are better capable of targeting towards SARS-CoV-2 variants can be generated through an optimized combination of antigen and adjuvant components.


Assuntos
Adjuvantes de Vacinas , COVID-19 , Cricetinae , Animais , Camundongos , SARS-CoV-2 , Glicolipídeos , Sulfatos , Células CHO , Lipossomos , Glicoproteína da Espícula de Coronavírus/genética , COVID-19/prevenção & controle , Cricetulus , Imunidade Celular , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Archaea , Vacinas contra COVID-19
17.
BMJ Open ; 13(5): e068966, 2023 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-37225278

RESUMO

INTRODUCTION: This is the first efficacy study of an oral live attenuated vaccine against Salmonella Paratyphi A using a human challenge model of paratyphoid infection. S. Paratyphi A is responsible for 3.3 million cases of enteric fever every year, with over 19 000 deaths. Although improvements to sanitation and access to clean water are vital to reduce the burden of this condition, vaccination offers a cost-effective, medium-term solution. Efficacy trials of potential S. Paratyphi vaccine candidates in the field are unlikely to be feasible given the large number of participants required. Human challenge models therefore offer a unique, cost-effective solution to test efficacy of such vaccines. METHODS AND ANALYSIS: This is an observer-blind, randomised, placebo-controlled trial phase I/II of the oral live-attenuated vaccine against S. Paratyphi A, CVD 1902. Volunteers will be randomised 1:1 to receive two doses of CVD 1902 or placebo, 14 days apart. One month following second vaccination all volunteers will ingest S. Paratyphi A bacteria with a bicarbonate buffer solution. They will be reviewed daily in the following 14 days and diagnosed with paratyphoid infection if the predefined microbiological or clinical diagnostic criteria are met. All participants will be treated with antibiotics on diagnosis, or at day 14 postchallenge if not diagnosed. The vaccine efficacy will be determined by comparing the relative attack rate, that is, the proportion of those diagnosed with paratyphoid infection, in the vaccine and placebo groups. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the Berkshire Medical Research Ethics Committee (REC ref 21/SC/0330). The results will be disseminated via publication in a peer-reviewed journal and presentation at international conferences. TRIAL REGISTRATION NUMBER: ISRCTN15485902.


Assuntos
Doenças Cardiovasculares , Salmonella paratyphi A , Humanos , Adulto , Vacinas Atenuadas , Voluntários Saudáveis , Voluntários , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase I como Assunto
18.
Front Endocrinol (Lausanne) ; 14: 983670, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37033219

RESUMO

Introduction: Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. Methods: In this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice) to examine the effect on sexual responsiveness. Results: MC4R knockout mice were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. These changes were independent of body weight. Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. Discussion: These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.


Assuntos
Lordose , Receptor Tipo 4 de Melanocortina , Masculino , Camundongos , Animais , Feminino , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Lordose/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Neurônios/metabolismo , Camundongos Knockout , Melanocortinas/metabolismo , Proteínas Repressoras , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
19.
J Speech Lang Hear Res ; 66(4): 1252-1273, 2023 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-36930986

RESUMO

PURPOSE: This study collected measures of auditory-perceptual and oral somatosensory acuity in typically developing children and adolescents aged 9-15 years. We aimed to establish reference data that can be used as a point of comparison for individuals with residual speech sound disorder (RSSD), especially for RSSD affecting American English rhotics. We examined concurrent validity between tasks and hypothesized that performance on at least some tasks would show a significant association with age, reflecting ongoing refinement of sensory function in later childhood. We also tested for an inverse relationship between performance on auditory and somatosensory tasks, which would support the hypothesis of a trade-off between sensory domains. METHOD: Ninety-eight children completed three auditory-perceptual tasks (identification and discrimination of stimuli from a "rake"-"wake" continuum and category goodness judgment for naturally produced words containing rhotics) and three oral somatosensory tasks (bite block with auditory masking, oral stereognosis, and articulatory awareness, which involved explicit judgments of relative tongue position for different speech sounds). Pairwise associations were examined between tasks within each domain and between task performance and age. Composite measures of auditory-perceptual and somatosensory functions were used to investigate the possibility of a sensory trade-off. RESULTS: Statistically significant associations were observed between the identification and discrimination tasks and the bite block and articulatory awareness tasks. In addition, significant associations with age were found for the category goodness and bite block tasks. There was no statistically significant evidence of a trade-off between auditory-perceptual and somatosensory domains. CONCLUSIONS: This study provided a multidimensional characterization of speech-related sensory function in older children/adolescents. Complete materials to administer all experimental tasks have been shared, along with measures of central tendency and dispersion for scores in two subgroups of age. Ultimately, we hope to apply this information to make customized treatment recommendations for children with RSSD based on sensory profiles.


Assuntos
Apraxias , Percepção da Fala , Adolescente , Humanos , Criança , Fala , Fonética , Estimulação Acústica , Sensação
20.
Nat Struct Mol Biol ; 30(6): 841-852, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36928458

RESUMO

Leucine-rich repeat-containing protein 8 (LRRC8) family members form volume-regulated anion channels activated by hypoosmotic cell swelling. LRRC8 channels are ubiquitously expressed in vertebrate cells as heteromeric assemblies of LRRC8A (SWELL1) and LRRC8B-E subunits. Channels of different subunit composition have distinct properties that explain the functional diversity of LRRC8 currents across cell types. However, the basis for heteromeric LRRC8 channel assembly and function is unknown. Here we leverage a fiducial-tagging strategy to determine single-particle cryo-EM structures of heterohexameric LRRC8A:C channels in multiple conformations. Compared to homomers, LRRC8A:C channels show pronounced differences in architecture due to heterotypic LRR interactions that displace subunits away from the conduction axis and poise the channel for activation. Structures and functional studies further reveal that lipids embedded in the channel pore block ion conduction in the closed state. These results provide insight into determinants for heteromeric LRRC8 channel assembly, activity and gating by lipids.


Assuntos
Lipídeos , Proteínas de Membrana , Proteínas de Membrana/metabolismo , Ânions/metabolismo
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