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1.
Artigo em Inglês | MEDLINE | ID: mdl-38579238

RESUMO

BACKGROUND: Robotic assisted thoracoscopic surgery facilitates complex pulmonary segmentectomy which offers one-stage diagnostic and therapeutic management of small pulmonary nodules. We aimed to explore the potential advantages of a faster, simplified pathway and earlier diagnosis against the disadvantages of unnecessary morbidity in benign cases. METHODS: In an observational study, patients with small, solitary pulmonary nodules deemed suspicious of malignancy by a multidisciplinary team were offered surgery without a pre or intra operative biopsy. We report our initial experience with robotic assisted thoracoscopic surgery complex segmentectomy (using more than one parenchymal staple line) to preserve as much functioning lung tissue as possible. RESULTS: Over a 4-year period, 245 robotic assisted thoracoscopic surgery complex segmentectomies were performed; 140 right: 105 left. A median of 2 (1-4) segments were removed.There was no in-hospital mortality and no requirement for postoperative ventilation. Complications were reported in 63 (25.7%) cases, of which 36 (57.1%) were hospital-acquired pneumonia.A malignant diagnosis was found in 198 (81%) patients and a benign diagnosis in 47 (19%). The malignant diagnoses included: adenocarcinoma in 136, squamous carcinoma in 31 and carcinoid tumour in 15. The most frequent benign diagnosis was granulomatous inflammation in 18 cases. CONCLUSION: Robotic assisted thoracoscopic surgery complex segmentectomy offers a precise, safe and effective one-stop therapeutic biopsy in incidental and screen detected pulmonary nodules.

2.
J Virol ; : e0019424, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38567950

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10× Genomics Chromium single-cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human monocyte-derived dendritic cells infected with ZIKV at the single-cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN-dependent and -independent genes (the antiviral module). We modeled the ZIKV-specific antiviral state at the protein level, leveraging experimentally derived protein interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per-cell basis with experimental protein interaction data. IMPORTANCE: Zika virus (ZIKV) remains a public health threat given its potential for re-emergence and the detrimental fetal outcomes associated with infection during pregnancy. Understanding the dynamics between ZIKV and its host is critical to understanding ZIKV pathogenesis. Through ZIKV-inclusive single-cell RNA sequencing (scRNA-seq), we demonstrate on the single-cell level the dynamic interplay between ZIKV and the host: the transcriptional program that restricts viral infection and ZIKV-mediated inhibition of that response. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool for gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.

3.
Surg Endosc ; 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38467859

RESUMO

BACKGROUND: Wireless pH monitoring allows for a definitive GERD diagnosis, which is essential for optimal medical or surgical management of the patient. However, there is no guideline recommendation on whether prolonged pH testing (72 or 96 h) provides additional benefit when compared to the standard 48-h testing. We aimed to assess whether prolonged pH monitoring diagnoses more patients with GERD, as well as compare the DeMeester score to acid exposure time as diagnostic criteria for GERD. METHODS: This was a retrospective analysis of consecutive adult patients who underwent wireless esophageal pH monitoring between August 2018 and July 2021. The primary outcome was the additional diagnoses of GERD (predominant acid exposure pattern) in patients who underwent 48-h versus 96-h pH monitoring. Secondary outcomes included comparison of the DeMeester score to acid exposure time and internal agreement between the first and second 48-h blocks of a prolonged 96-h pH study. RESULTS: When comparing 48-h versus 96-h pH testing, the prolonged monitoring group was more likely to have a predominant reflux pattern and thus be diagnosed with definitive GERD by elevated DeMeester score (58.8% vs. 40.8%, p = 0.003) or acid exposure time > 6% (44.7% vs. 32.4%, p = 0.039). For patients who underwent prolonged testing, the results of monitoring beyond 48 h led to a clinically meaningful change in study interpretation in 24.8% of patients. The study data from Days 3 to 4 yielded only a 56.6% agreement with the first 2 days. CONCLUSIONS: In patients undergoing extended pH monitoring, almost half were found to have an abnormal pH study after a normal study on Day 1. An additional 25% of patients had a change in study interpretation by extending the study beyond 48 h. Our findings suggest only 48 h of pH monitoring will miss a diagnosis of GERD in a clinically important number of patients.

4.
Front Immunol ; 15: 1353336, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38533502

RESUMO

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative-3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)-that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.


Assuntos
Neoplasias Pulmonares , Proteínas de Membrana , Xantonas , Humanos , Camundongos , Animais , Proteínas de Membrana/metabolismo , Leucócitos Mononucleares/metabolismo , Pulmão/metabolismo
5.
Public Health Nutr ; : 1-25, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38504524

RESUMO

OBJECTIVES: Individuals often use self-directed strategies to manage intake of tempting foods, but what these strategies are and whether they are effective is not well understood. This study assessed the frequency of use and subjective effectiveness of self-directed strategies in relation to BMI and snack intake. DESIGN: A cross-sectional and prospective study with three timepoints (T1: baseline, T2: 3 months, T3: 3 years). At T1, demographics, frequency of use and subjective effectiveness of 41 identified strategies were assessed. At T2 and T3, current weight was reported, and at T2 frequency of snack intake was also recorded. SETTING: Online study in the UK. PARTICIPANTS: Data from N=368 participants (Mage=34.41 years; MBMI=25.06 kg/m2) was used for analysis at T1, N=170 (46.20% of the total sample) at T2 and N=51 (13.59%) at T3. RESULTS: Two strategy factors were identified via principal axis factoring: 1) Diet, exercise, reduction of temptations, and cognitive strategies, and 2) Planning, preparation and eating style. For strategy 1, frequency of use, but not subjective effectiveness, was positively related to BMI at T1. Subjective effectiveness predicted an increase in BMI from T1 and T2 to T3. No relationship to snack intake was found. For strategy 2, frequency of use was negatively related to BMI at T1. Neither frequency of use nor subjective effectiveness were related to changes in BMI over time, but subjective effectiveness was negatively correlated with unhealthy snack intake. CONCLUSION: Self-directed strategies to reduce the intake of tempting foods are not consistently related to BMI or snack intake.

6.
Int Immunol ; 2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38430523

RESUMO

Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche. In this study, we demonstrate that the mesenchymal stromal CXCL12-abundant reticular (CAR) cell population is reduced during acute malaria infection. The reduction of CXCL12 and IL-7 signals in the bone marrow impairs the lymphopoietic niche, leading to the depletion of common lymphoid progenitors, B cell progenitors and mature B cells, including plasma cells in the bone marrow. We found that IFNγ is responsible for the upregulation of Sca1 on CAR cells, yet the decline in CAR cell and B cell populations in the bone marrow is IFNγ-independent. In contrast to the decline in B cell populations, HSCs and multipotent progenitors increased with expansion of myelopoiesis and erythropoiesis, indicating a bias in the differentiation of multipotent progenitors during malaria infection. These findings suggest that malaria may affect host immunity by modulating the bone marrow niche.

7.
Proc Natl Acad Sci U S A ; 121(6): e2300644120, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38306481

RESUMO

It is unclear how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to the strong but ineffective inflammatory response that characterizes severe Coronavirus disease 2019 (COVID-19), with amplified immune activation in diverse cell types, including cells without angiotensin-converting enzyme 2 receptors necessary for infection. Proteolytic degradation of SARS-CoV-2 virions is a milestone in host viral clearance, but the impact of remnant viral peptide fragments from high viral loads is not known. Here, we examine the inflammatory capacity of fragmented viral components from the perspective of supramolecular self-organization in the infected host environment. Interestingly, a machine learning analysis to SARS-CoV-2 proteome reveals sequence motifs that mimic host antimicrobial peptides (xenoAMPs), especially highly cationic human cathelicidin LL-37 capable of augmenting inflammation. Such xenoAMPs are strongly enriched in SARS-CoV-2 relative to low-pathogenicity coronaviruses. Moreover, xenoAMPs from SARS-CoV-2 but not low-pathogenicity homologs assemble double-stranded RNA (dsRNA) into nanocrystalline complexes with lattice constants commensurate with the steric size of Toll-like receptor (TLR)-3 and therefore capable of multivalent binding. Such complexes amplify cytokine secretion in diverse uninfected cell types in culture (epithelial cells, endothelial cells, keratinocytes, monocytes, and macrophages), similar to cathelicidin's role in rheumatoid arthritis and lupus. The induced transcriptome matches well with the global gene expression pattern in COVID-19, despite using <0.3% of the viral proteome. Delivery of these complexes to uninfected mice boosts plasma interleukin-6 and CXCL1 levels as observed in COVID-19 patients.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Animais , Camundongos , Células Endoteliais , Proteoma , Peptídeos
8.
Curr Opin Pediatr ; 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38411588

RESUMO

PURPOSE OF REVIEW: There is expanding evidence for point-of-care ultrasound (POCUS) use in pediatric emergency medicine - this review highlights the benefits and challenges in the clinical integration of high-yield POCUS applications. Specifically, it will delve into POCUS applications during resuscitations, controversies of Focused Assessment with Sonography for Trauma (FAST) in pediatric trauma, POCUS-guided procedures, and examples of clinical pathways where POCUS can expedite definitive care. RECENT FINDINGS: POCUS can enhance diagnostic accuracy and aid in management of pediatric patients in shock and help identify reversible causes during cardiac arrest. The use of the FAST in pediatric blunt abdominal trauma remains nuanced - its proper use requires an integration with clinical findings and an appreciation of its limitations. POCUS has been shown to enhance safety and efficacy of procedures such as nerve blocks, incision & drainage, and intravenous access. Integrating POCUS into pathways for conditions such as intussusception and testicular torsion expedites downstream care. SUMMARY: POCUS enhances diagnostic efficiency and management in pediatric patients arriving at the ED with undifferentiated shock, cardiac arrest, or trauma. Additionally, POCUS improves procedural success and safety, and is integral to clinical pathways for expediting definitive care for various pediatric emergencies. Future research should continue to focus on the impact of POCUS on patient outcomes, ensuring user competency, and the expansion of POCUS into diverse settings.

9.
Nat Biotechnol ; 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38168986

RESUMO

Spatial transcriptomics (ST) has demonstrated enormous potential for generating intricate molecular maps of cells within tissues. Here we present iStar, a method based on hierarchical image feature extraction that integrates ST data and high-resolution histology images to predict spatial gene expression with super-resolution. Our method enhances gene expression resolution to near-single-cell levels in ST and enables gene expression prediction in tissue sections where only histology images are available.

10.
Mol Metab ; 80: 101880, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38218536

RESUMO

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition. Myostatin and Activin A are TGFß-like ligands that signal via the activin type II receptors (ActRII) to antagonize muscle growth. Pre-clinical and clinical studies demonstrate that ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In this manuscript, we test the hypothesis that combined ActRII blockade and GLP-1 receptor agonism will preserve muscle mass, leading to improvements in skeletomuscular and metabolic function and enhanced fat loss. METHODS: In this study, we explore the therapeutic potential of bimagrumab, a monoclonal antibody against ActRII, to modify body composition alone and during weight loss induced by GLP-1 receptor agonist semaglutide in diet-induced obese mice. Mechanistically, we define the specific role of the anabolic kinase Akt in mediating the hypertrophic muscle effects of ActRII inhibition in vivo. RESULTS: Treatment of obese mice with bimagrumab induced a ∼10 % increase in lean mass while simultaneously decreasing fat mass. Daily treatment of obese mice with semaglutide potently decreased body weight; this included a significant decrease in both muscle and fat mass. Combination treatment with bimagrumab and semaglutide led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake. Treatment with both drugs was associated with improved metabolic outcomes, and increased lean mass was associated with improved exercise performance. Deletion of both Akt isoforms in skeletal muscle modestly reduced, but did not prevent, muscle hypertrophy driven by ActRII inhibition. CONCLUSIONS: Collectively, these data demonstrate that blockade of ActRII signaling improves body composition and metabolic parameters during calorie deficit driven by GLP-1 receptor agonism and demonstrate the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling.


Assuntos
Receptores de Activinas Tipo II , Anticorpos Monoclonais Humanizados , Receptor do Peptídeo Semelhante ao Glucagon 1 , Obesidade , Proteínas Proto-Oncogênicas c-akt , Redução de Peso , Animais , Camundongos , Receptores de Activinas Tipo II/antagonistas & inibidores , Receptores de Activinas Tipo II/metabolismo , Ativinas/metabolismo , Anticorpos Bloqueadores/metabolismo , Anticorpos Bloqueadores/farmacologia , Anticorpos Bloqueadores/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Hipertrofia/metabolismo , Camundongos Obesos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Anticorpos Monoclonais Humanizados/administração & dosagem , Obesidade/tratamento farmacológico
11.
Diagn Pathol ; 19(1): 21, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38268039

RESUMO

BACKGROUND: Chronic myeloid leukemia (CML) is characterized by the presence of BCR::ABL1 fusion gene resulting from a reciprocal translocation, t(9;22)(q34;q11.2), leading to prominent granulocytic proliferation. The majority of patients initially present in chronic phase (CP), which may progress to advanced CML with predominantly granulocytic phenotypes in the absence of proper treatment or response to tyrosine kinase inhibitors (TKIs). We present an exceptionally rare case in which an erythroid variant emerged from a CML patient resistant to multiple TKIs. This variant is characterized by the detection of t(9;22) BCR::ABL1 fusion in erythroid precursors at various maturation stages and the absence of granulocytic progenitor hyperplasia typically seen in classical CML. CASE PRESENTATION: A 33-year-old female with CP-CML had received multiple TKI therapies since her initial diagnosis in 2015. Due to intolerable side effects and inconsistent adherence, she exhibited an inadequate response and developed new-onset pancytopenia. Bone marrow (BM) biopsy specimen revealed a hypercellular marrow with significant erythroid hyperplasia (90% of marrow cellularity) and a reversed myeloid-to-erythroid (M: E) ratio of 1:10. Both erythroid and myeloid cells displayed progressive maturation without dysplasia or excess blasts. Chromosomal analysis identified t(9;22) (q34;q11.2) in 19 out of 20 metaphase cells. BCR::ABL1 fusion transcript (p210 isoform) was confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and next-generation sequencing (NGS). Notably, no additional pathogenic cytogenetic abnormalities or ABL1 kinase domain mutations were detected. Here, we report the first published case of an erythroid variant emerging in a CML patient resistant to multiple TKIs-a distinct entity from the erythroid blast crisis evolving from CML. CONCLUSION: The erythroid variant of CML is distinguished by the presence of t(9;22) (q34;q11.2) BCR::ABL1 in predominant erythroid precursors at different stages of maturation. In a myeloid neoplasm showing predominant erythroid hyperplasia without typical CML features, it is vital to correlate morphology and t(9;22) BCR::ABL1 cytogenetic testing for accurate diagnosis, and to prevent confusion with PEL transformation in CML.


Assuntos
Doenças da Medula Óssea , Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Feminino , Humanos , Adulto , Hiperplasia , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Biópsia
12.
ACS Nano ; 18(3): 1907-1920, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38190607

RESUMO

Bacterial photodynamic inactivation based on the combined actions of photosensitizers, light, and oxygen presents a promising alternative for eliminating bacteria compared to conventional water disinfection methods. However, a significant challenge in this approach is the inability to retrieve photosensitizers after phototreatment, posing potential adverse environmental impacts. Additionally, conventional photosensitizers often exhibit limited photostability and photodynamic efficiency. This study addresses these challenges by employing an aggregation-induced emission (AIE) photosensitizer, iron oxide magnetic nanoparticles (Fe3O4 MNPs), and Pluronic F127 to fabricate AIE magnetic nanoparticles (AIE MNPs). AIE MNPs not only exhibit fluorescence imaging capabilities and superior photosensitizing ability but also demonstrate broad-spectrum bactericidal activities against both Gram-positive and Gram-negative bacteria. The controlled release of TPA-Py-PhMe and magnetic characteristics of the AIE MNPs facilitate reuse and recycling for multiple cycles of bacterial inactivation in water. Our findings contribute valuable insights into developing environmentally friendly disinfectants, emphasizing the full potential of AIE photosensitizers in photodynamic inactivation beyond biomedical applications.


Assuntos
Nanopartículas de Magnetita , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Antibacterianos , Bactérias Gram-Negativas , Bactérias Gram-Positivas
13.
Gastrointest Endosc ; 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38272274

RESUMO

BACKGROUND AND AIMS: Randomized controlled trials (RCTs) have reported that artificial intelligence (AI) improves endoscopic polyp detection. Different methodologies, namely parallel and tandem designs, have been employed to evaluate the efficacy of AI-assisted colonoscopy in RCTs. Systematic reviews and meta-analyses have reported a pooled effect that includes both study designs. However, it is unclear whether there are inconsistencies in the reported results of these two designs. Here, we aimed to determine whether study characteristics moderate between-trial differences in outcomes when evaluating the effectiveness of AI-assisted polyp detection. METHODS: A systematic search of Ovid MEDLINE, EMBASE, Cochrane Central, Web of Science, and IEEE Xplore was performed through March 1, 2023 for RCTs comparing AI-assisted colonoscopy with routine high-definition colonoscopy in polyp detection. Primary outcome of interest was the impact of study type on adenoma detection rate (ADR). Secondary outcomes included the impact of study type on adenomas per colonoscopy (APC) and withdrawal time, as well as the impact of geographical location, AI system, and endoscopist experience on ADR. Pooled event analysis was performed using a random effects model. RESULTS: Twenty-four RCTs involving 17413 colonoscopies (8680 AI assisted, 8733 non-AI assisted) were included. AI-assisted colonoscopy improved overall ADR; RR 1.24 [1.17-1.31], I2=53%, p<0.001. Tandem studies collectively demonstrated improved ADR in AI-aided colonoscopies (RR 1.18 [95% CI 1.08-1.30], I2=0%, p<0.001), as did parallel studies (RR 1.26 [1.17-1.35], I2=62%, p<0.001), with no statistical subgroup difference between study design. Both tandem and parallel study designs revealed improvement in APC in AI-aided colonoscopies, but this improvement was more marked among tandem studies (p<0.001). AI assistance significantly increased withdrawal times for parallel (p=0.002), but not tandem studies. ADR improvement was more marked among studies conducted in Asia compared to Europe and North America in a subgroup analysis (p=0.007). Type of AI system used or endoscopist experience did not impact overall improvement in ADR. CONCLUSIONS: Either parallel or tandem study design can capture the improvement in ADR resulting from the use of AI-assisted polyp detection systems. Tandem studies powered to detect differences in endoscopic performance through paired comparison may be a resource-efficient method of evaluating new AI-assisted technologies.

14.
Nat Commun ; 15(1): 788, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38278785

RESUMO

In neurodegenerative diseases, polymorphism and supramolecular assembly of ß-sheet amyloids are implicated in many different etiologies and may adopt either a left- or right-handed supramolecular chirality. Yet, the underlying principles of how sequence regulates supramolecular chirality remains unknown. Here, we characterize the sequence specificity of the central core of amyloid-ß 42 and design derivatives which enable chirality inversion at biologically relevant temperatures. We further find that C-terminal modifications can tune the energy barrier of a left-to-right chiral inversion. Leveraging this design principle, we demonstrate how temperature-triggered chiral inversion of peptides hosting therapeutic payloads modulates the dosed release of an anticancer drug. These results suggest a generalizable approach for fine-tuning supramolecular chirality that can be applied in developing treatments to regulate amyloid morphology in neurodegeneration as well as in other disease states.


Assuntos
Peptídeos beta-Amiloides , Amiloide , Amiloide/química , Temperatura
15.
bioRxiv ; 2024 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-38293140

RESUMO

Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10x Genomics Chromium single cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human moDCs infected with ZIKV at the single cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN dependent and independent genes (antiviral module). We modeled the ZIKV specific antiviral state at the protein level leveraging experimentally derived protein-interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per cell basis with experimental protein interaction data. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool to gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.

16.
Sex Transm Dis ; 51(1): 54-60, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37889944

RESUMO

BACKGROUND: Over 30,000 mpox cases were reported during the 2022 mpox outbreak with many cases occurring among gay, bisexual and other men who have sex with men (MSM). Decreases in U.S. mpox cases were likely accelerated by a combination of vaccination and modifications to sexual behaviors associated with mpox virus transmission. We assessed reports of sexual behavior change among participants receiving mpox vaccination in Washington, DC. METHODS: During August to October 2022, 711 adults aged ≥18 years receiving mpox vaccination at two public health clinics in Washington, DC completed a self-administered questionnaire that asked whether sexual behaviors changed since learning about mpox. We calculated the frequency and percentages of participants reporting an increase, decrease, or no change in 4 of these behaviors by demographic, clinical, and behavioral characteristics with 95% confidence intervals. RESULTS: Overall, between 46% and 61% of participants reported a decrease in sexual behaviors associated with mpox virus transmission, 39% to 54% reported no change in these behaviors, and <1% reported an increase. Approximately 61% reported decreases in one-time sexual encounters (95% confidence interval [CI], 56.8%-64.7%), 54.3% reduced numbers of sex partners (95% CI, 50.4%-58.0%), 53.4% decreased sex via a dating app or sex venue (95% CI, 49.7%-58.0%), and 45.6% reported less group sex (95% CI, 40.4%-50.9%). Reported decreases in these behaviors were higher for MSM than women; in non-Hispanic Black than non-Hispanic White participants; and in participants with human immunodeficiency virus than participants without human immunodeficiency virus. CONCLUSIONS: Most participants receiving mpox vaccination reported decreasing sexual behaviors associated with mpox virus transmission, including groups disproportionately affected by the outbreak.


Assuntos
Minorias Sexuais e de Gênero , Vacina Antivariólica , Adulto , Masculino , Feminino , Humanos , Adolescente , Homossexualidade Masculina , Vírus da Varíola dos Macacos , District of Columbia/epidemiologia , Comportamento Sexual
17.
Sex Transm Dis ; 51(1): 47-53, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37921836

RESUMO

BACKGROUND: More than 30,000 mpox cases have been confirmed in the United States since May 2022. Mpox cases have disproportionally occurred among adult gay, bisexual, and other men who have sex with men; transgender persons; and Black and Hispanic/Latino persons. We examined knowledge, attitudes, and practices regarding mpox vaccination among adults presenting for vaccination to inform prevention efforts. METHODS: We collected mixed-methods data from a convenience sample of adults presenting for JYNNEOS vaccination at 3 DC Health mpox vaccine clinics during August-October 2022. Survey and interview topics included knowledge about mpox symptoms and vaccine protection, beliefs about vaccine access, and trusted sources of information. RESULTS: In total, 352 participants completed self-administered surveys and 62 participants completed an in-depth interview. Three main themes emerged from survey and interview data. First, most participants had a general understanding about mpox, but gaps remained in comprehensive understanding about mpox symptoms, modes of transmission, vaccine protection, personal risk, and vaccine dosing strategies. Second, participants had high trust in public health agencies. Third, participants wanted more equitable and less stigmatizing access to mpox vaccine services. CONCLUSIONS: Nonstigmatizing, inclusive, and clear communication from trusted sources, including public health agencies, is needed to address mpox knowledge gaps and increase vaccine access and uptake in affected communities. Mpox outreach efforts should continue innovative approaches, including person-level risk assessment tools, to address community needs.


Assuntos
Minorias Sexuais e de Gênero , Vacina Antivariólica , Adulto , Masculino , Humanos , District of Columbia , Conhecimentos, Atitudes e Prática em Saúde , Homossexualidade Masculina , Vacinação
18.
Nat Biotechnol ; 42(2): 190-191, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37231264
19.
J Pharm Sci ; 113(3): 587-595, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38103687

RESUMO

Dengue presents a major public health concern in over 100 countries due to the absence of an effective vaccine and antiviral therapy against all four dengue virus (DENV) serotypes. Several antiviral peptides were previously reported to inhibit at least three or all four DENV serotypes. Chemical modifications such as d-amino acid substitutions, polyethylene glycol (PEG)ylation, and cyclization could be applied to peptides to improve their biological activities and stability in serum. The PEGylated peptide 3 (PEG-P3) was identified to be the most promising antiviral candidate as it demonstrated good inhibitory effects against all four DENV serotypes during the pre- and post-infection stages, Based on the RP-HPLC and LC/MS analysis, peptide 4 was identified to be more stable in human serum than peptide 3, with 78.9 % and 41.6 % of the peptides remaining after 72 h of incubation in human serum, respectively. Both peptides were also able to retain their antiviral activities against specific DENV serotypes after 72 h incubation in human serum. PEG-P3 was found to be more stable than the unmodified peptide 3 with 89.4 % of PEG-P3 remaining in the human serum after 72 h of incubation. PEG-P3 was able to retain its inhibitory effects against DENV-1 to 4 after 72 h of incubation in human serum. This study provided insights into the antiviral activities and stabilities of the unmodified and chemically modified peptides in human serum.


Assuntos
Vírus da Dengue , Dengue , Humanos , Dengue/tratamento farmacológico , Sorogrupo , Peptídeos/química , Antivirais/uso terapêutico
20.
Virology ; 589: 109941, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37984152

RESUMO

The hand, food, and mouth disease (HFMD) is primarily caused by Enterovirus A71 (EV-A71). EV-A71 outbreaks in the Asia Pacific have been associated with severe neurological disease and high fatalities. Currently, there are no FDA-approved antivirals for the treatment of EV-A71 infections. In this study, the SP81 peptide, derived from the VP1 capsid protein of EV-A71 was shown to be a promising antiviral candidate for the treatment of EV-A71 infections. SP81 peptide was non-toxic to RD cells up to 45 µM, with a half-maximal cytotoxic concentration (CC50) of 90.32 µM. SP81 peptide exerted antiviral effects during the pre- and post-infection stages with 50% inhibitory concentrations (IC50) of 4.529 µM and 1.192 µM, respectively. Direct virus inactivation of EV-A71 by the SP81 peptide was also observed with an IC50 of 8.076 µM. Additionally, the SP81 peptide exhibited direct virus inactivation of EV-A71 at 95% upon the addition of the SP81 peptide within 5 min. This study showed that the SP81 peptide exhibited significant inhibition of EV-A71 and could serve as a promising antiviral agent for further clinical development against EV-A71 infections.


Assuntos
Enterovirus Humano A , Infecções por Enterovirus , Enterovirus , Doença de Mão, Pé e Boca , Humanos , Infecções por Enterovirus/tratamento farmacológico , Peptídeos/farmacologia , Antígenos Virais , Antivirais/farmacologia
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