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1.
Ophthalmol Sci ; 5(1): 100610, 2025.
Artigo em Inglês | MEDLINE | ID: mdl-39386054

RESUMO

Purpose: Lipopolysaccharide (LPS)-type endotoxins are naturally found in the gut microbiota and there is emerging evidence linking gut microbiota and neuroinflammation leading to retinal neurodegeneration. Thinning of the retinal nerve fiber layer (RNFL) is a biomarker of retinal neurodegeneration, and a hallmark of glaucoma, the second leading cause of blindness worldwide. We assessed the association of a blood biomarker of LPS with peripapillary RNFL thickness (RNFLT) and its longitudinal evolution up to 11 years. Design: The Alienor study is a single center prospective population-based cohort study. Subjects: The studied sample of this study includes 1062 eyes of 548 participants receiving ≥1 gradable RNFL measurement. Methods: Plasma esterified 3-hydroxy fatty acids (3-OH FAs) were measured as a proxy of LPS burden. Retinal nerve fiber layer thickness was acquired using spectral-domain OCT imaging every 2 years from 2009 to 2020 (up to 5 visits). Main Outcome Measures: Associations of plasma esterified 3-OH FAs with RNFLT were assessed using linear mixed models. Results: Mean age of the included 548 participants was 82.4 ± 4.3 years and 62.6% were women. Higher plasma esterified 3-OH FAs was significantly associated with thinner RNFLT at baseline (coefficient beta = -1.42 microns for 1 standard deviation-increase in 3-OH FAs, 95% confidence interval [-2.56; -0.28], P = 0.02). This association remained stable after multivariate adjustment for potential confounders. No statistically significant association was found between 3-OH FAs and longitudinal RNFLT change. Conclusions: Higher plasma esterified 3-OH FAs were associated with thinner RNFLT at baseline, indicating an involvement of LPS in the early processes of optic nerve neurodegeneration and highlighting the potential importance of the human microbiota in preserving retinal health. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

2.
Solid State Nucl Magn Reson ; 134: 101971, 2024 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-39357421

RESUMO

Through-space heteronuclear correlation experiments under magic-angle spinning (MAS) conditions can provide unique insights into inter-atomic proximities. In particular, it has been shown that experiments based on two consecutive coherence transfers, 1H → I → 1H, like D-HMQC (dipolar-mediated heteronuclear multiple-quantum correlation), are usually more sensitive for the indirect detection via protons of spin-3/2 quadrupolar nuclei with low gyromagnetic ratio. Nevertheless, the resolution is often decreased by the second-order quadrupolar broadening along the indirect dimension. To circumvent this issue, we incorporate an MQMAS (multiple-quantum MAS) quadrupolar filter into the t1 evolution period of the D-HMQC sequence, which results in a novel pulse sequence called D-HMQC-MQ. The triple-quantum coherences evolving during this filter are excited and reconverted using cosine-modulated long-pulses synchronized with the sample rotation to avoid spinning sidebands in the indirect dimension. The desired coherence transfer pathways during this sequence are selected using two nested cogwheel phase cycles with 56 steps. This high-resolution heteronuclear correlation technique is demonstrated experimentally for the indirect detection via 1H of spin-3/2 isotopes, such as 11B, 23Na and 35Cl, in zinc borate hydrate, NaH2PO4 and l-histidine hydrochloride, respectively. We show that this experiment can be applied at high magnetic fields up to 28.2 T for protons subject to chemical shift anisotropies larger than 20 ppm, provided the MAS frequency is sufficiently stable since the D-HMQC-MQ experiment, like the parent D-HMQC, is sensitive to MAS fluctuations, which can produce t1-noise.

3.
Diagn Interv Imaging ; 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39358155

RESUMO

PURPOSE: The purpose of this study was to compare lung image quality obtained with ultra-high resolution (UHR) spectral photon-counting CT (SPCCT) with that of dual-layer CT (DLCT), at standard and low dose levels using an image quality phantom and an anthropomorphic lung phantom. METHODS: An image quality phantom was scanned using a clinical SPCCT prototype and an 8 cm collimation DLCT from the same manufacturer at 10 mGy. Additional acquisitions at 6 mGy were performed with SPCCT only. Images were reconstructed with dedicated high-frequency reconstruction kernels, slice thickness between 0.58 and 0.67 mm, and matrix between 5122 and 10242 mm, using a hybrid iterative algorithm at level 6. Noise power spectrum (NPS), task-based transfer function (TTF) for iodine and air inserts, and detectability index (d') were assessed for ground-glass and solid nodules of 2 mm to simulate highly detailed lung lesions. Subjective analysis of an anthropomorphic lung phantom was performed by two radiologists using a five-point quality score. RESULTS: At 10 mGy, noise magnitude was reduced by 29.1 % with SPCCT images compared to DLCT images for all parameters (27.1 ± 11.0 [standard deviation (SD)] HU vs. 38.2 ± 1.0 [SD] HU, respectively). At 6 mGy with SPCCT images, noise magnitude was reduced by 8.9 % compared to DLCT images at 10 mGy (34.8 ± 14.1 [SD] HU vs. 38.2 ± 1.0 [SD] HU, respectively). At 10 mGy and 6 mGy, average NPS spatial frequency (fav) was greater for SPCCT images (0.75 ± 0.17 [SD] mm-1) compared to DLCT images at 10 mGy (0.55 ± 0.04 [SD] mm-1) while remaining constant from 10 to 6 mGy. At 10 mGy, TTF at 50 % (f50) was greater for SPCCT images (0.92 ± 0.08 [SD] mm-1) compared to DLCT images (0.67 ± 0.06 [SD] mm-1) for both inserts. At 6 mGy, f50 decreased by 1.1 % for SPCCT images, while remaining greater compared to DLCT images at 10 mGy (0.91 ± 0.06 [SD] mm-1 vs. 0.67 ± 0.06 [SD] mm-1, respectively). At both dose levels, d' were greater for SPCCT images compared to DLCT for all clinical tasks. Subjective analysis performed by two radiologists revealed a greater median image quality for SPCCT (5; Q1, 4; Q3, 5) compared to DLCT images (3; Q1, 3; Q3, 3). CONCLUSION: UHR SPCCT outperforms DLCT in terms of image quality for lung imaging. In addition, UHR SPCCT contributes to a 40 % reduction in radiation dose compared to DLCT.

4.
Pediatr Pulmonol ; 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39360868
5.
PNAS Nexus ; 3(10): pgae399, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39359402

RESUMO

Sea level rise and climate change are shaping present societies, particularly those on oceanic islands. Few historical examples could serve as references for these changes. One such potential model is the Saudeleur Dynasty with its capital Nan Madol on the Pacific Island of Pohnpei. However, the timing of its construction, as well as the dynasty's fluctuations and potential environmental influences, has remained unresolved. Through the analyses of 230Th ages on 171 dates on corals fragments used as building materials and charcoal 14C ages from excavations, 2 major construction phases spanning from the 10th to the 15th century CE can be discerned. The results show that the first phase of the site's construction, spanning the 10th-12th century, marked the dynasty's rise. The second period, spanning from the late 12th to the early 15th century, provides the most substantial evidence for the demise of the island-scale chiefdom and a significant societal reorganization. The phases are centuries earlier than previously believed. With this new evidence, we propose the hypothesis that variations in the El Niño-Southern Oscillation and subsidence-related sea level rise presented major challenges for building and maintaining Nan Madol, and thus, influenced the course of the island's history. This case serves as a compelling example of how adverse climatic conditions can spur investments-in this case, in seawater defense under high sea levels-yet ultimately may contribute to abandonment. It offers lessons for island nations, showcasing coastal resilience in the face of worsening catastrophic events that unfolded over generations.

7.
Nat Commun ; 15(1): 8717, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39379373

RESUMO

Type IV pili (T4P) are thin, flexible filaments exposed on the cell surface of gram-negative bacteria and are involved in pathogenesis-related processes, including cell adsorption, biofilm formation, and twitching motility. Bacteriophages often use these filaments as receptors to infect host cells. Here, we describe the identification of a protein that inhibits T4P assembly in Pseudomonas aeruginosa, discovered during a screen for host factors influencing phage infection. We show that expression of PA2560 (renamed PlzR) in P. aeruginosa inhibits adsorption of T4P-dependent phages. PlzR does this by directly binding the T4P chaperone PilZ, which in turn regulates the ATPase PilB and results in disturbed T4P assembly. As the plzR promoter is induced by cyclic di-GMP, PlzR might play a role in coupling T4P function to levels of this second messenger.


Assuntos
Proteínas de Bactérias , Proteínas de Fímbrias , Fímbrias Bacterianas , Pseudomonas aeruginosa , Pseudomonas aeruginosa/metabolismo , Pseudomonas aeruginosa/genética , Fímbrias Bacterianas/metabolismo , Fímbrias Bacterianas/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Fímbrias/metabolismo , Proteínas de Fímbrias/genética , Ligação Proteica , GMP Cíclico/metabolismo , GMP Cíclico/análogos & derivados , Regulação Bacteriana da Expressão Gênica , Regiões Promotoras Genéticas/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Oxirredutases
8.
EBioMedicine ; 108: 105366, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39353280

RESUMO

BACKGROUND: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear. METHODS: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume. FINDINGS: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium. INTERPRETATION: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers. FUNDING: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion.


Assuntos
Artéria Pulmonar , Fumantes , Tomografia Computadorizada por Raios X , Humanos , Masculino , Feminino , Artéria Pulmonar/diagnóstico por imagem , Artéria Pulmonar/patologia , Pessoa de Meia-Idade , Idoso , Tomografia Computadorizada por Raios X/métodos , Doença Pulmonar Obstrutiva Crônica/mortalidade , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Fumar/efeitos adversos , Veias Pulmonares/diagnóstico por imagem , Veias Pulmonares/patologia , Modelos de Riscos Proporcionais
9.
Gen Comp Endocrinol ; 359: 114618, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39368756

RESUMO

As a widely distributed anthropophilic mosquito species and vector of various arboviruses, Aedes aegypti poses a significant threat to human health on a global scale. Investigating mosquito neuropeptides allows us to better understand their physiology. The neuropeptides CCHamide1 (CCHa1) and CCHamide2 (CCHa2) along with their associated G protein-coupled receptors (CCHa1R and CCHa2R) were recently identified and studied across insects. However, expression profiles and physiological roles of CCHamides and their receptors in many other insects, including A. aegypti, remain unclear. This research aimed to quantify and localize the expression of CCHamides along with their receptors and gain insight on their physiological function in the yellow fever mosquito. RT-qPCR analysis revealed transcript abundance of CCHamides and receptors changes over development. Differential expression was also observed in tissues/organs of adult mosquitoes indicating CCHa1 and CCHa2 transcripts are enriched in the midgut, while receptors are expressed across various tissues. CCHamide immunoreactivity was observed in neurons in the brain and ventral nerve cord along with enteroendocrine cells in the posterior midgut adjacent to the midgut-hindgut junction, corroborating their transcript expression profiles. Using different mass spectrometrical approaches, presence of CCHamides were confirmed in the brain of both sexes, including the pars intercerebralis of female mosquitoes, as well as in the gut of adult mosquitoes. For chemical identification of predicted CCHamides, we analyzed brain and gut extracts by ESI-Q Exactive Orbitrap MS and resulting fragmentations confirmed CCHa1 and CCHa2 in brain and midgut samples of both male and female mosquitoes. A heterologous functional assay was used to confirm the specificity and sensitivity of the two CCHamide receptors by assessing their activation in response to diverse mosquito peptides, which confirmed CCHa1 and CCHa2 as natural ligands. Finally, using a capillary feeder (CAFE) bioassay, our results suggest that CCHa2 modulates feeding behaviour in female mosquitoes.

10.
Mol Psychiatry ; 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39406996

RESUMO

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

11.
JMIR Mhealth Uhealth ; 12: e50745, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39401131

RESUMO

Background: Although at the base of the pyramid-shaped organization of the Rwandan health system, community health workers (CHWs) are central to the community-based management of disease outbreaks. Objective: This mixed methods study aimed to explore the feasibility, acceptability, satisfaction, and challenges of a mobile health (mHealth) tool for community-based COVID-19 screening in Rwanda. Methods: Two urban (Gasabo and Nyarugenge) and 2 rural (Rusizi and Kirehe) districts in Rwanda participated in the project (smartphone app for COVID-19 screening). A mixed methods approach was used to inform the feasibility (awareness and expectation), acceptability (use and perceived benefits), satisfaction, and challenges of the mHealth intervention. At the end of the project, CHWs were asked to complete a quantitative questionnaire on the use of and satisfaction with the app. Then, in-depth interviews and focus group discussions were organized with CHWs. A content analysis was performed on the transcripts. Results: Overall, 383 CHWs were recruited and trained; 378 CHWs participated in the study. The mean age of CHWs was 36.7 (SD 6.6) to 45.3 (SD 9.9) years and most were women (237/378, 62.7%). More than 7000 people were registered with the use of the app and 20% were referred to a local COVID-19 testing facility. According to CHW reporting, the median number of people screened by each CHW ranged from 152 (IQR 70-276) for Nyarugenge to 24 (IQR 16-90) for Rusizi. COVID-19 positivity rates were higher in urban than rural districts: more than half of the CHWs in Gasabo reported a confirmed positive case versus only 2.4% for Kirehe and 15.4% for Rusizi. Despite the app being a novel tool, CHWs were well aware of the use of such a tool and had appropriate expectations. Acceptability and satisfaction were very high, with differences between urban and rural districts. Satisfaction was higher in Nyarugenge (72.8/100) and Gasabo (80.7/100) than in Kirehe (61.6/100) and Rusizi (64.5/100). More than 80% of the CHWs were willing to continue using the e-ASCov app, with the exception of CHWs in Kirehe (56.7%). The app was perceived as a tool to generate information on COVID-19, inform on the status of the pandemic, and help curb the spread of the pandemic in Rwanda. CHWs were satisfied with the app at all stages of its implementation in their districts. Conclusions: In this proof-of-concept study, a smartphone app for screening COVID-19 was useful as an mHealth tool to be used by CHWs, with the potential to increase health system efficiency in an epidemic context. The context should be analyzed for generalization on a country-wide scale, both in case of an epidemic and to take into account certain conditions at the community level. Information is needed on the conditions of generalization and transferability of this type of app to other health conditions so that CHWs can be given their full place in a pyramidal health system.


Assuntos
COVID-19 , Agentes Comunitários de Saúde , Estudos de Viabilidade , Programas de Rastreamento , Aplicativos Móveis , Humanos , Ruanda/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , COVID-19/diagnóstico , Feminino , Masculino , Adulto , Programas de Rastreamento/métodos , Programas de Rastreamento/estatística & dados numéricos , Aplicativos Móveis/estatística & dados numéricos , Pessoa de Meia-Idade , Telemedicina , Inquéritos e Questionários , Pesquisa Qualitativa , Grupos Focais , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/psicologia
12.
BMJ Open ; 14(10): e086723, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39401964

RESUMO

INTRODUCTION: There are limited global data on ectopic pregnancy (EP) and molar pregnancy (MP), making it important to understand their epidemiology and management across different regions. Our study aimed to describe their prevalence for both conditions, severity of their complications and management among women in selected health facilities across 17 countries in Africa and Latin America and the Caribbean (LAC). METHODS: This is a secondary analysis of the WHO multi-country survey on abortion. Data were collected from 280 healthcare facilities across 11 countries in Africa and 6 in LAC. Sociodemographic information, signs and symptoms, management and clinical outcomes were extracted from medical records. Facility-level data on post-abortion care (PAC) capabilities were also collected, and facilities were classified accordingly. χ2 or Fisher's exact tests were used to compare categorical data. RESULTS: The total number of women with EP and MP across both regions was 9.9% (2 415/24 424) where EP accounted for 7.8% (1 904/24 424) and MP for 2.1% (511/24 424). EP presented a higher severity of complications than MP. At admission, 49.8% of EP had signs of peritoneal irritation. The most common surgical management for EP was laparotomy (87.2%) and for MP, uterine evacuation (89.8%). Facilities with higher scores in infrastructure and capability to provide PAC more frequently provided minimal invasive management using methotrexate/other medical treatment (34.9%) and laparoscopy (5.1%). CONCLUSION: In Africa and LAC, EP and MP cause significant maternal morbidity and mortality. The disparity in the provision of good quality care highlights the need to strengthen the implementation of evidence-based recommendations in the clinical and surgical management of EP and MP.


Assuntos
Aborto Induzido , Mola Hidatiforme , Gravidez Ectópica , Humanos , Feminino , Gravidez , América Latina/epidemiologia , África/epidemiologia , Região do Caribe/epidemiologia , Estudos Transversais , Adulto , Prevalência , Gravidez Ectópica/epidemiologia , Gravidez Ectópica/terapia , Aborto Induzido/estatística & dados numéricos , Mola Hidatiforme/epidemiologia , Mola Hidatiforme/terapia , Mola Hidatiforme/cirurgia , Adulto Jovem , Adolescente
13.
BMC Med Educ ; 24(1): 1144, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39402543

RESUMO

BACKGROUND: The undergraduate medical training programme is demanding and rigorous. This underlines the importance of a peer mentorship strategy to improve the well-being, self-determination, school connectedness, and performance of struggling medical and nursing students. This study is aimed at identifying struggling medical and nursing students using two cumulative continuous assessment test (CAT) scores, assess their subjective vitality and school engagement and evaluate the impact of the peer mentorship intervention on them. METHODS: The study will adopt a mixed-methods approach and will be conducted in the medical colleges of Nnamdi Azikiwe University, Awka, Nigeria, and the University of Rwanda. Three instruments will be used: The subjective Vitality Scale (SVS), the University Student Engagement Inventory (USEI), and the academic records of the students before and after the commencement of the intervention programme. The consenting least-performing medical and nursing students identified by their low CAT scores (below 45%) in basic medical sciences will be selected for study in each institution. The outcome measures will include students' CAT scores, subjective vitality, and school engagement scores. The data will be analysed both quantitatively and qualitatively. Thematic content analysis will be adopted in the analysis of the responses generated from the focus group discussion. The mean ± standard deviation or median and interquartile range statistic will be adopted for the quantitative data. DISCUSSION: Given the paucity of data on struggling medical and nursing students in Nigeria and Rwanda, this research was designed to help in exploring evidence-based interventions to improve and prevent poor subjective well-being of struggling students. The study is expected to fill these knowledge gaps. TRIAL REGISTRATION: Pan African Clinical Trial registry, PACTR202405546896613, registration date: 27th May, 2024. This proposal has been supported by grant 1R25TW011217 from the US National Institutes of Health (NIH)/Fogarty International Center (FIC) which also includes co-funds from the U.S. Department of State's Office of the U.S. Global AIDS Coordinator and Health Diplomacy (S/GAC) and the President's Emergency Plan for AIDS Relief (PEPFAR) to the African Forum for Research and Education in Health (AFREhealth). The Grant Principal Investigators are Profs. Nelson K.Sewankambo (contact PI), Prisca Adejumo, Jean Bisimwa Nachega, Fatima Suleman.


Assuntos
Educação de Graduação em Medicina , Mentores , Grupo Associado , Estudantes de Medicina , Estudantes de Enfermagem , Humanos , Nigéria , Estudantes de Enfermagem/psicologia , Estudantes de Medicina/psicologia , Ruanda , Desempenho Acadêmico , Masculino , Feminino
15.
Small ; : e2406794, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39402783

RESUMO

Hexagonal boron nitride (h-BN) bubbles are of significant interest to micro-scale hydrogen storage thanks to their ability to confine hydrogen gas molecules. Previous reports of h-BN bubble creation from grown h-BN films require electron beams under vacuum, making integrating with other experimental setups for hydrogen production impractical. Therefore, in this study, the formation of h-BN bubbles is demonstrated in a 20 nm h-BN film grown on a sapphire substrate with a 213 nm UV laser beam. Using atomic force microscopy, it is shown that longer illumination time induces larger h-BN bubbles up to 20 µm with higher density. It is also demonstrated that h-BN bubbles do not collapse for more than 6 months after their creation. The internal pressure and gravimetric storage capacity of h-BN bubbles are reported. A maximum internal pressure of 41 MPa and a gravimetric storage capacity of 6% are obtained. These findings show that h-BN bubbles can be a promising system for long-term hydrogen storage.

16.
Nat Commun ; 15(1): 8497, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39353896

RESUMO

Positron Emission Tomography (PET) ligands have advanced Alzheimer's disease (AD) diagnosis and treatment. Using autoradiography and cryo-EM, we identify AD brain tissue with elevated tau burden, purify filaments, and determine the structure of second-generation high avidity PET ligand MK-6240 at 2.31 Å resolution, which bound at a 1:1 ratio within the cleft of tau paired-helical filament (PHF), engaging with glutamine 351, lysine 353, and isoleucine 360. This information elucidates the basis of MK-6240 PET in quantifying PHF deposits in AD and may facilitate the structure-based design of superior ligands against tau amyloids.


Assuntos
Doença de Alzheimer , Microscopia Crioeletrônica , Tomografia por Emissão de Pósitrons , Proteínas tau , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Proteínas tau/metabolismo , Proteínas tau/química , Proteínas tau/ultraestrutura , Tomografia por Emissão de Pósitrons/métodos , Humanos , Microscopia Crioeletrônica/métodos , Ligantes , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Autorradiografia , Feminino , Masculino , Carbolinas
17.
Biomacromolecules ; 25(10): 6555-6569, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39351822

RESUMO

Alginates are marine polysaccharides known for their ability to selectively bind calcium ions and form hydrogels. They are widely used in biomedical applications but are challenging to produce as nanogels. Here we introduce a self-assembly route to create stable alginate-based nanogels under near-equilibrium conditions. Guluronate (G) blocks, which interact with divalent cations such as Ca2+, Ba2+, and Sr2+, were extracted from alginates and covalently linked through their reducing end to the reducing end of dextran (Dex) chains, forming linear block copolymers that self-assemble into micellar nanogels with a core-corona structure in the presence of these ions. Real-time dynamic light scattering (DLS) and small-angle neutron scattering (SANS) were used to study the self-assembly mechanism of the copolymer during dialysis against divalent ions. For the G12-b-Dex51 copolymer, we achieved spherical micelles with an 8 nm radius and an aggregation number of around 20. Although the type of divalent cation affected micelle stability, it did not influence their size. Micellar nanogels are dynamic structures, capable of ion exchange, and can disassemble with chelating agents like ethylenediamine tetraacetic acid (EDTA).


Assuntos
Alginatos , Micelas , Nanogéis , Alginatos/química , Nanogéis/química , Hidrogéis/química , Cátions Bivalentes/química , Dextranos/química , Polietilenoglicóis/química , Polietilenoimina/química , Ácidos Hexurônicos
18.
J Int Med Res ; 52(10): 3000605241289284, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39387192

RESUMO

Thrust manipulation is one of the most commonly used techniques for managing musculoskeletal pain in clinical practice. This involves the application of a high-velocity, low-amplitude force directed to the joints with the intent of achieving joint cavitation. This current case report describes a female in her mid-20s who presented with excessive bilateral and involuntary hand muscle contractions after bilateral thrust manipulation. Dystonia appeared both at rest and during voluntary movements but was aggravated by actions such as finger flexion or spreading and disappeared during sleep. A diagnosis of complex regional pain syndrome (CRPS) type I combined with dystonia was made. Prednisolone administered between 2 and 5 weeks after symptom onset significantly reduced CRPS symptoms, but intramuscular botulinum toxin injection 5 weeks after symptom onset was ineffective at controlling her symptoms. Seven weeks after symptom onset, the patient was administered 2 mg trihexyphenidyl oral twice a day, 2.5 mg diazepam oral twice a day and 5 mg baclofen oral three times a day for 1 month and this significantly reduced dystonia, but complete resolution was not achieved. Clinicians should be aware that dystonia is a rare complication of thrust manipulation.


Assuntos
Baclofeno , Distonia , Mãos , Humanos , Feminino , Mãos/fisiopatologia , Adulto , Distonia/tratamento farmacológico , Distonia/etiologia , Distonia/diagnóstico , Distonia/fisiopatologia , Baclofeno/uso terapêutico , Baclofeno/administração & dosagem , Triexifenidil/uso terapêutico , Diazepam/uso terapêutico , Diazepam/administração & dosagem , Prednisolona/uso terapêutico , Prednisolona/administração & dosagem , Manipulações Musculoesqueléticas/métodos
19.
Database (Oxford) ; 20242024 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-39395187

RESUMO

Nonsense variations, characterized by premature termination codons, play a major role in human genetic diseases as well as in cancer susceptibility. Despite their high prevalence, effective therapeutic strategies targeting premature termination codons remain a challenge. To understand and explore the intricate mechanisms involved, we developed StopKB, a comprehensive knowledgebase aggregating data from multiple sources on nonsense variations, associated genes, diseases, and phenotypes. StopKB identifies 637 317 unique nonsense variations, distributed across 18 022 human genes and linked to 3206 diseases and 7765 phenotypes. Notably, ∼32% of these variations are classified as nonsense-mediated mRNA decay-insensitive, potentially representing suitable targets for nonsense suppression therapies. We also provide an interactive web interface to facilitate efficient and intuitive data exploration, enabling researchers and clinicians to navigate the complex landscape of nonsense variations. StopKB represents a valuable resource for advancing research in precision medicine and more specifically, the development of targeted therapeutic interventions for genetic diseases associated with nonsense variations. Database URL: https://lbgi.fr/stopkb/.


Assuntos
Códon sem Sentido , Bases de Dados Genéticas , Bases de Conhecimento , Humanos , Códon sem Sentido/genética , Degradação do RNAm Mediada por Códon sem Sentido , Fenótipo
20.
Nat Prod Res ; : 1-9, 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39401069

RESUMO

A new saponin namely diosgeninoside (25 R-spirost-5-en-3-O-[ß-D-glucopyranosyl (1→2) - ß-D-glucuronic acid]) and a new fatty acid betacic acid: (Z)-8(S*),9(S*),10(R*)-trihydroxy-11-octadecenoic acid together with six known compounds: N-trans-coumaroyl tyramine, ergosta-7,22-dien-3ß,5α,6ß-triol, ß-sitosterol, and ß-sitosterol-3-O-ß-D-glucopyranoside, L-threitol and soya-cerebroside I were isolated from the methanolic extract of Solanum betaceum. The structures were elucidated by interpretation of their 1D and 2D NMR spectra and spectrometric data. The methanolic extract, the EtOAc and n-BuOH fractions, and several isolated compounds were tested for antibacterial activity against four bacteria (Staphylococcus aureus; Staphylococcus epidermidis; Escherichia coli; and Pseudomonas aeruginosa). The methanolic extract and the EtOAc fraction showed moderate activity against Staphylococcus aureus and Pseudomonas aeruginosa with MIC value of 128 µg/mL. Compound 1 showed moderate activity against Staphylococcus aureus with MIC value of 64 µg/mL.

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