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1.
JAMA Netw Open ; 7(6): e2419245, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38941092

RESUMO

Importance: Significant evidence gaps exist regarding the safety of smoking cessation pharmacotherapies during pregnancy, especially for the risk of congenital malformations. Consequently, professional bodies advise against the use of varenicline and bupropion and recommend caution with nicotine replacement therapy (NRT). Contemporary estimates of the use of smoking cessation pharmacotherapies during pregnancy are lacking. Objective: To quantify the proportion of individuals using prescribed smoking cessation pharmacotherapies during pregnancy and during the first trimester specifically, in 4 countries. Design, Setting, and Participants: This retrospective, population-based cohort study used linked birth records, hospital admission records, and dispensing records of prescribed medications from all pregnancies resulting in birth between 2015 and 2020 in New South Wales, Australia; New Zealand; Norway; and Sweden. Data analyses were conducted in October and November 2023. Exposure: Prescribed smoking cessation pharmacotherapy use (varenicline, NRT, and bupropion) during pregnancy was defined as days' supply overlapping the period from date of conception to childbirth. Main Outcomes and Measures: Prevalence of use among all pregnancies and pregnancies with maternal smoking were calculated. Among women who used a pharmacotherapy, the proportion of women with use during the first trimester of pregnancy was also calculated. Results: Among 1 700 638 pregnancies in 4 countries, 138 033 (8.1%) had maternal smoking and 729 498 (42.9%) were younger than 30 years. The prevalences ranged from 0.02% to 0.14% for varenicline, less than 0.01% to 1.86% for prescribed NRT, and less than 0.01% to 0.07% for bupropion. Among pregnant individuals who smoked, use of pharmacotherapies was up to 10 times higher, with maximum prevalences of 1.25% for varenicline in New South Wales, 11.39% for NRT in New Zealand, and 0.39% for bupropion in New Zealand. Use in the first trimester occurred among more than 90% of individuals using varenicline, approximately 60% among those using NRT, and 80% to 90% among those using bupropion. Conclusions and Relevance: In this cohort study of pregnant individuals in 4 high-income countries, the low prevalence of varenicline and bupropion use during pregnancy and higher prevalence of NRT use aligned with current clinical guidelines. As most use occurred in the first trimester, there is a need for evidence on the risk of congenital malformations for these medications.


Assuntos
Bupropiona , Complicações na Gravidez , Agentes de Cessação do Hábito de Fumar , Abandono do Hábito de Fumar , Dispositivos para o Abandono do Uso de Tabaco , Vareniclina , Humanos , Feminino , Gravidez , Abandono do Hábito de Fumar/estatística & dados numéricos , Abandono do Hábito de Fumar/métodos , Adulto , Estudos Retrospectivos , Agentes de Cessação do Hábito de Fumar/uso terapêutico , Vareniclina/uso terapêutico , Vareniclina/efeitos adversos , Bupropiona/uso terapêutico , Bupropiona/efeitos adversos , Nova Zelândia/epidemiologia , Dispositivos para o Abandono do Uso de Tabaco/estatística & dados numéricos , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Suécia/epidemiologia , New South Wales/epidemiologia , Noruega/epidemiologia , Adulto Jovem , Fumar/epidemiologia , Primeiro Trimestre da Gravidez
2.
J Biol Chem ; 300(7): 107482, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38897567

RESUMO

Siglecs are cell surface receptors whose functions are tied to the binding of their sialoglycan ligands. Recently, we developed an optimized liposome formulation and used it to investigate the binding of human Siglecs (hSiglec) against a panel of gangliosides. Animal models, more specifically murine models, are used to understand human biology; however, species-specific differences can complicate the interpretation of the results. Herein, we used our optimized liposome formulation to dissect the interactions between murine Siglecs (mSiglecs) and gangliosides to assess the appropriateness of mSiglecs as a proxy to better understand the biological roles of hSiglec-ganglioside interactions. Using our optimized liposome formulation, we found that ganglioside binding is generally conserved between mice and humans with mSiglec-1, -E, -F, and -15 binding multiple gangliosides like their human counterparts. However, in contrast to the hSiglecs, we observed little to no binding between the mSiglecs and ganglioside GM1a. Detailed analysis of mSiglec-1 interacting with GM1a and its structural isomer, GM1b, suggests that mSiglec-1 preferentially binds α2-3-linked sialic acids presented from the terminal galactose residue. The ability of mSiglecs to interact or not interact with gangliosides, particularly GM1a, has implications for using mice to study neurodegenerative diseases, infections, and cancer, where interactions between Siglecs and glycolipids have been proposed to modulate these human diseases.

5.
J Hosp Med ; 19(7): 616-618, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38528713

RESUMO

GUIDELINE TITLE: IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections RELEASE DATE: October 2, 2023 PRIOR VERSION: March 16, 2020 DEVELOPER: IWGDF Editorial Board FUNDING SOURCE: International Working Group on the Diabetic Foot (IWGDF), Infectious Diseases Society of America (IDSA) TARGET POPULATION: Adults with suspected or confirmed diabetes-related foot infections.


Assuntos
Pé Diabético , Médicos Hospitalares , Humanos , Pé Diabético/diagnóstico , Pé Diabético/terapia , Guias de Prática Clínica como Assunto , Antibacterianos/uso terapêutico
6.
Pest Manag Sci ; 80(7): 3612-3619, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38451019

RESUMO

BACKGROUND: The two-spotted spider mite Tetranychus urticae causes significant damage to ornamental, cotton, sugarcane and horticultural crops in Australia. It has a long history of developing resistance to many acaricides including bifenazate. A mutation in the conserved cd1- and ef-helices of the Qo pocket of cytochrome b is recognized as the primary mechanism of bifenazate resistance. To investigate the resistance mechanisms against bifenazate in Australian two-spotted spider mite, we sequenced the complete mitochondrion genome of five mite strains including a susceptible and bifenazate-resistant strain. RESULTS: We identified a novel mutation D252N in the G126S background at cytochrome b being the cause of bifenazate resistance in a bifenazate-resistant strain, Bram. We validated the role of this mutation combination by reciprocal crosses between a bifenazate resistant and susceptible strain. By doing these crosses we confirmed the pattern of inheritance was maternal. Additionally, mitochondrial heteroplasmy was not observed by single mite genotyping of the mutations in cytb in a known bifenazate-resistant strain Bram. The phylogenetic analysis with the complete mitochondrion genome sequences revealed that Australian two-spotted spider mite strains are closely related to the green form of T. urticae found in China. CONCLUSIONS: The novel mutation D252N found in the cytochrome b in the G126S background was revealed to be the main cause of bifenazate resistance in the Australian T. urticae strain Bram. © 2024 Society of Chemical Industry.


Assuntos
Acaricidas , Citocromos b , Tetranychidae , Animais , Tetranychidae/genética , Tetranychidae/efeitos dos fármacos , Citocromos b/genética , Acaricidas/farmacologia , Mutação , Resistência a Medicamentos/genética , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/metabolismo , Filogenia , Feminino , Carbamatos , Hidrazinas
7.
Med J Aust ; 220(7): 372-378, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38514449

RESUMO

OBJECTIVE: To assess the impact of the Health Care Homes (HCH) primary health care initiative on quality of care and patient outcomes. DESIGN, SETTING: Quasi-experimental, matched cohort study; analysis of general practice data extracts and linked administrative data from ten Australian primary health networks, 1 October 2017 - 30 June 2021. PARTICIPANTS: People with chronic health conditions (practice data extracts: 9811; linked administrative data: 10 682) enrolled in the HCH 1 October 2017 - 30 June 2019; comparison groups of patients receiving usual care (1:1 propensity score-matched). INTERVENTION: Participants were involved in shared care planning, provided enhanced access to team care, and encouraged to seek chronic condition care at the HCH practice where they were enrolled. Participating practices received bundled payments based on clinical risk tier. MAIN OUTCOME MEASURES: Access to care, processes of care, diabetes-related outcomes, hospital service use, risk of death. RESULTS: During the first twelve months after enrolment, the mean numbers of general practitioner encounters (rate ratio, 1.14; 95% confidence interval [CI], 1.11-1.17) and Medicare Benefits Schedule claims for allied health services (rate ratio, 1.28; 95% CI, 1.24-1.33) were higher for the HCH than the usual care group. Annual influenza vaccinations (relative risk, 1.20; 95% CI, 1.17-1.22) and measurements of blood pressure (relative risk, 1.09; 95% CI, 1.08-1.11), blood lipids (relative risk, 1.19; 95% CI, 1.16-1.21), glycated haemoglobin (relative risk, 1.06; 95% CI, 1.03-1.08), and kidney function (relative risk, 1.13; 95% CI, 1.11-1.15) were more likely in the HCH than the usual care group during the twelve months after enrolment. Similar rate ratios and relative risks applied in the second year. The numbers of emergency department presentations (rate ratio, 1.09; 95% CI, 1.02-1.18) and emergency admissions (rate ratio, 1.13; 95% CI, 1.04-1.22) were higher for the HCH group during the first year; other differences in hospital use were not statistically significant. Differences in glycaemic and blood pressure control in people with diabetes in the second year were not statistically significant. By 30 June 2021, 689 people in the HCH group (6.5%) and 646 in the usual care group (6.1%) had died (hazard ratio, 1.07; 95% CI, 0.96-1.20). CONCLUSIONS: The HCH program was associated with greater access to care and improved processes of care for people with chronic diseases, but not changes in diabetes-related outcomes, most measures of hospital use, or risk of death.


Assuntos
Diabetes Mellitus , Programas Nacionais de Saúde , Humanos , Idoso , Estudos de Coortes , Pontuação de Propensão , Austrália , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapia , Doença Crônica , Atenção à Saúde
9.
Plant Dis ; 108(7): 1959-1963, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38277650

RESUMO

Puccinia coronata f. sp. avenae (Pca) is an important foliar pathogen of oat which causes crown rust disease. The virulence profile of 48 Pca isolates derived from different locations in Australia was characterized using a collection of oat lines often utilized in rust surveys in the United States and Australia. This analysis indicates that Pca populations in Eastern Australia are broadly virulent, which contrasts with the population in Western Australia (WA). Several oat lines/Pc genes are effective against all rust samples collected from WA, suggesting they may provide useful resistance in this region if deployed in combination. We identified 19 lines from the United States oat differential set that display disease resistance to Pca in WA, with some in agreement with previous rust survey reports. We adopted the 10-letter nomenclature system to define oat crown rust races in Australia and compare the frequency of those virulence traits to published data from the United States. Based on this nomenclature, 42 unique races were detected among the 48 isolates, reflecting the high diversity of virulence phenotypes for Pca in Australia. Nevertheless, the Pca population in the United States is substantially more broadly virulent than that of Australia. Close examination of resistance profiles for the oat differential set lines after infection with Pca supports hypotheses of allelism or redundancy among Pc genes or the presence of several resistance genes in some oat differential lines. These findings illustrate the need to deconvolute the oat differential set using molecular tools.[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Assuntos
Avena , Doenças das Plantas , Puccinia , Avena/microbiologia , Doenças das Plantas/microbiologia , Austrália , Virulência/genética , Puccinia/patogenicidade , Puccinia/genética , Resistência à Doença/genética , Estados Unidos , Basidiomycota/genética , Basidiomycota/patogenicidade , Basidiomycota/fisiologia
10.
Biochem Pharmacol ; 221: 116032, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38281601

RESUMO

Repeated sublethal hypoxia exposure induces brain inflammation and affects the initiation and progression of cognitive dysfunction. Experiments from the current study showed that hypoxic exposure downregulates PKA/CREB signaling, which is restored by forskolin (FSK), an adenylate cyclase activator, in both Neuro2a (N2a) cells and zebrafish brain. FSK significantly protected N2a cells from hypoxia-induced cell death and neurite shrinkage. Intraperitoneal administration of FSK for 5 days on zebrafish additionally led to significant recovery from hypoxia-induced social interaction impairment and learning and memory (L/M) deficit. FSK suppressed hypoxia-induced neuroinflammation, as indicated by the observed decrease in NF-κB activation and GFAP expression. We further investigated the potential effect of FSK on O-GlcNAcylation changes induced by hypoxia. Intriguingly FSK induced marked upregulation of the protein level of O-GlcNAc transferase catalyzing addition of the GlcNAc group to target proteins, accompanied by elevated O-GlcNAcylation of nucleocytoplasmic proteins. The hypoxia-induced O-GlcNAcylation decrease in the brain of zebrafish was considerably restored following FSK treatment. Based on the collective results, we propose that FSK rescues hypoxia-induced cognitive dysfunction, potentially through regulation of HBP/O-GlcNAc cycling.


Assuntos
Disfunção Cognitiva , Peixe-Zebra , Animais , Colforsina/farmacologia , Cognição , Hipóxia/complicações , Transtornos da Memória
11.
Clin Oncol (R Coll Radiol) ; 36(1): e11-e19, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37973477

RESUMO

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.


Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/patologia , Estradiol , Antagonistas de Androgênios/uso terapêutico , Androgênios , Qualidade de Vida , Estrogênios , Testosterona
12.
Pest Manag Sci ; 80(3): 1510-1522, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37953499

RESUMO

BACKGROUND: Fall armyworm (FAW), Spodoptera frugiperda, is a highly polyphagous crop pest that has spread over the world rapidly and invaded Australia in 2020. Globally, FAW has been reported to be resistant to several insecticides permitted in Australia. Timely resistance diagnosis is critical for integrated pest management-based control of FAW in Australia. RESULTS: We developed a multi-amplicon panel by next-generation sequencing (multiamplicon-seq) to identify known insecticide resistance mutations in Australian FAW with high throughput and low cost. The panel included nine known mutations causing insecticide resistance in FAW and four gene mutations causing insecticide resistance in several insect species, not yet reported in FAW. We sequenced 36 plates (96-well) in one MiSeq flow cell with easy sequencing library preparation. We found that Australian FAW carried a very high proportion of the F290V mutation in the acetylcholinesterase (AChE) gene that causes resistance to organophosphate and carbamate insecticides. Furthermore, FAW has a GABA-activated chloride channel mutation, A301Q in the RDL gene. The sequencing-based platform provided evidence of a duplication in the AChE gene. Here several single nucleotide polymorphisms (SNPs) within the 476-bp amplicon of the AChE gene demonstrated 100% heterozygosity across samples and some individuals carried two haplotypes with the F290V mutation. CONCLUSION: Molecular surveillance by multiamplicon-seq will increase capacity for early detection and future resistance monitoring in highly dispersed Australian FAW. It can provide timely resistance information and has the potential to play an important role in the resistance management of FAW. © 2023 Society of Chemical Industry.


Assuntos
Inseticidas , Humanos , Animais , Inseticidas/farmacologia , Spodoptera , Resistência a Inseticidas/genética , Acetilcolinesterase , Austrália , Sequenciamento de Nucleotídeos em Larga Escala , Larva
13.
Phytopathology ; 114(6): 1356-1365, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38114076

RESUMO

Puccinia coronata f. sp. avenae is the causal agent of the disease known as crown rust, which represents a bottleneck in oat production worldwide. Characterization of pathogen populations often involves race (pathotype) assignments using differential sets, which are not uniform across countries. This study compared the virulence profiles of 25 P. coronata f. sp. avenae isolates from Australia using two host differential sets, one from Australia and one from the United States. These differential sets were also genotyped using diversity arrays technology sequencing technology. Phenotypic and genotypic discrepancies were detected on 8 out of 29 common lines between the two sets, indicating that pathogen race assignments based on those lines are not comparable. To further investigate molecular markers that could assist in the stacking of rust resistance genes important for Australia, four published Pc91-linked markers were validated across the differential sets and then screened across a collection of 150 oat cultivars. Drover, Aladdin, and Volta were identified as putative carriers of the Pc91 locus. This is the first report to confirm that the cultivar Volta carries Pc91 and demonstrates the value of implementing molecular markers to characterize materials in breeding pools of oat. Overall, our findings highlight the necessity of examining seed stocks using pedigree and molecular markers to ensure seed uniformity and bring robustness to surveillance methodologies. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.


Assuntos
Avena , Resistência à Doença , Genótipo , Doenças das Plantas , Puccinia , Avena/microbiologia , Avena/genética , Doenças das Plantas/microbiologia , Resistência à Doença/genética , Austrália , Puccinia/genética , Fenótipo , Virulência/genética , Estados Unidos , Marcadores Genéticos/genética , Basidiomycota/genética , Basidiomycota/fisiologia
14.
Fungal Biol ; 127(12): 1484-1490, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-38097322

RESUMO

The genus Elsinoe includes many aggressive plant pathogens that infect various economically important agricultural, horticultural and forestry plants. Significant diseases include citrus scab caused by E. fawcettii and E. australis, grapevine spot anthracnose by E. ampelina, and the emerging Eucalyptus scab and shoot malformation disease caused by the recently described E. necatrix. Despite their importance as plant pathogens, little is known regarding the biology of many Elsinoe spp. To gain insights into the reproductive biology of these fungi, we characterized the mating-type loci of seven species using whole genome sequence data. Results showed that the MAT1 locus organization and its flanking genes is relatively conserved in most cases. All seven species manifested a typical heterothallic mating system characterized by having either the MAT1-1 or MAT1-2 idiomorph present in an isolate. These idiomorphs were defined by the MAT1-1-1 or the MAT1-2-1 gene, respectively. A unique MAT1-1 idiomorph containing a truncated MAT1-2-1 gene, and a MAT1-1-1 gene, was identified in E. necatrix and E. fawcettii genomes. Additionally, two idiomorph-specific proteins were found in the MAT1-1 and MAT1-2 idiomorphs of E. australis. Universal mating-type markers confirmed heterothallism across 21 Elsinoe spp., are poised to advance future studies regarding the biology of these fungi.


Assuntos
Ascomicetos , Genes Fúngicos Tipo Acasalamento , Ascomicetos/genética , Reprodução/genética
15.
Nat Prod Res ; : 1-7, 2023 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-37865971

RESUMO

One new prenyl flavanone (1), (2S)-8-prenyl-5,6-dihydroxy-7-methoxyflavanone, and one new diarylbutanol (2), (7'S)-3'-hydroxy-linderagatin-A, were isolated from the stem bark of Uvaria siamensis (Annonaceae), along with five known compounds, eriodictyol (3), quercetin (4), paprazine (5), N-trans-caffeoyltyramine (6), and N-trans-feruloyltyramine (7). Their structures were determined through extensive spectroscopic analyses and comparison with the literature. The α-glucosidase inhibitory potential of 1-7 was evaluated. Compound 6 showed the highest inhibitory activity against α-glucosidase and exhibited superior potency compared to the positive control, with an IC50 value of 0.12 µM.

16.
Nat Commun ; 14(1): 5237, 2023 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-37640713

RESUMO

Cellular glycosylation is characterized by chemical complexity and heterogeneity, which is challenging to reproduce synthetically. Here we show chemoenzymatic synthesis on phage to produce a genetically-encoded liquid glycan array (LiGA) of complex type N-glycans. Implementing the approach involved by ligating an azide-containing sialylglycosyl-asparagine to phage functionalized with 50-1000 copies of dibenzocyclooctyne. The resulting intermediate can be trimmed by glycosidases and extended by glycosyltransferases yielding a phage library with different N-glycans. Post-reaction analysis by MALDI-TOF MS allows rigorous characterization of N-glycan structure and mean density, which are both encoded in the phage DNA. Use of this LiGA with fifteen glycan-binding proteins, including CD22 or DC-SIGN on cells, reveals optimal structure/density combinations for recognition. Injection of the LiGA into mice identifies glycoconjugates with structures and avidity necessary for enrichment in specific organs. This work provides a quantitative evaluation of the interaction of complex N-glycans with GBPs in vitro and in vivo.


Assuntos
Asparagina , Bacteriófagos , Animais , Camundongos , Glicosilação , Azidas , Biblioteca Gênica
17.
In Vivo ; 37(5): 2155-2160, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37652493

RESUMO

BACKGROUND/AIM: The aim of this study was to evaluate the safety and efficacy of AFree oral spray, in combination with Standard of Care, in treating mild to moderate COVID-19 patients. This was an open-label, single-blinded, and controlled randomized clinical trial. PATIENTS AND METHODS: The study involved 1,252 patients, who were randomly assigned to either the control or study group, with 626 patients in each group. Patients in the control group were treated with Standard of Care recommended by the Ministry of Health of Vietnam, while patients in the study group received AFree oral spray in addition to Standard of Care for a period of 10 days. The clinical progression and outcomes of both groups were compared. RESULTS: The results showed that the proportion of patients with clinical symptoms on the 5th, 7th and 10th days were significantly lower in the study group (45.05%, 3.19% and 0%, respectively) compared to the control group (86.10%, 67.73% and 22.84%, respectively). Additionally, the rate of Real-time PCR test positivity for COVID-19 was significantly lower in the study group compared to the control group on the 4th, 7th, and 10th days (82.75% vs. 98.72%, 9.27% vs. 92.97%, and 1.12% vs. 50.48%, respectively). Furthermore, no side effects or complications related to AFree oral spray were recorded in the study group. CONCLUSION: The use of AFree oral spray resulted in significant improvements in clinical symptoms, recovery time, and viral clearance in COVID-19 patients with mild to moderate symptoms. This therapy has been shown to be safe and can be used as an adjuvant treatment for COVID-19 as well as other respiratory viral infections.


Assuntos
COVID-19 , Humanos , Estudos Prospectivos , Sprays Orais , SARS-CoV-2 , Saúde Pública , Progressão da Doença , Resultado do Tratamento
18.
Anal Chem ; 95(29): 10903-10912, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37439544

RESUMO

Application of the prostate-specific antigen (PSA) test, which measures PSA levels in blood, is standard in prostate cancer (PCa) screening. However, because PSA levels may be elevated for reasons other than PCa, it leads to high rates of misdiagnosis and overtreatment. Recently, alteration in the N-glycan sialylation of PSA, specifically increased levels of α2-3-linked N-acetylneuraminic acid (α2-3-Neu5Ac or α2-3-sialic acid), was identified as a potential biomarker for clinically significant PCa. Here, we introduce a robust top-down native mass spectrometry (MS) approach, performed using a combination of α2-3-Neu5Ac-specific and nonspecific neuraminidases and employing center-of-mass monitoring (CoMMon), for quantifying the levels of α2-3-Neu5Ac as a fraction of total N-linked Neu5Ac present on PSA extracted from blood serum. To illustrate the potential of the assay for clinical diagnosis and disease staging of PCa, the percentages of α2-3-Neu5Ac on PSA (%α23PSA) in the serum of low-grade (International Society of Urological Pathology Grade Group/GG1), intermediate-grade (GG2), and high-grade (GG3,4,5) PCa individuals were measured. We observed a high sensitivity (85.5%) and specificity (84.6%) for discrimination of GG1 from clinically significant GG2-5 patients when using a %α23PSA test cut-off of 28.0%. Our results establish that the %α23PSA in blood serum PSA, which can be precisely measured in a non-invasive manner with our dual neuraminidase native MS/CoMMon assay, can discriminate between clinically significant PCa (GG2-5) and low-grade PCa (GG1). Such discrimination has not been previously achieved and represents an important clinical need. This assay could greatly improve the standard PSA test and serve as a valuable PCa diagnostic tool.


Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Ácido N-Acetilneuramínico , Neoplasias da Próstata/patologia , Biomarcadores , Biópsia Líquida , Biópsia
19.
Sci Adv ; 9(28): eadg6638, 2023 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-37450594

RESUMO

Membrane technologies that enable the efficient purification of impaired water sources are needed to address growing water scarcity. However, state-of-the-art engineered membranes are constrained by a universal, deleterious trade-off where membranes with high water permeability lack selectivity. Current membranes also poorly remove low-molecular weight neutral solutes and are vulnerable to degradation from oxidants used in water treatment. We report a water desalination technology that uses applied pressure to drive vapor transport through membranes with an entrapped air layer. Since separation occurs due to a gas-liquid phase change, near-complete rejection of dissolved solutes including sodium chloride, boron, urea, and N-nitrosodimethylamine is observed. Membranes fabricated with sub-200-nm-thick air layers showed water permeabilities that exceed those of commercial membranes without sacrificing salt rejection. We also find the air-trapping membranes tolerate exposure to chlorine and ozone oxidants. The results advance our understanding of evaporation behavior and facilitate high-throughput ultraselective separations.


Assuntos
Destilação , Purificação da Água , Permeabilidade , Gases , Purificação da Água/métodos , Membranas Artificiais
20.
ACS Cent Sci ; 9(7): 1374-1387, 2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37521792

RESUMO

Native mass spectrometry (nMS) screening of natural glycan libraries against glycan-binding proteins (GBPs) is a powerful tool for ligand discovery. However, as the glycan concentrations are unknown, affinities cannot be measured directly from natural libraries. Here, we introduce Concentration-Independent (COIN)-nMS, which enables quantitative screening of natural glycan libraries by exploiting slow mixing of solutions inside a nanoflow electrospray ionization emitter. The affinities (Kd) of detected GBP-glycan interactions are determined, simultaneously, from nMS analysis of their time-dependent relative abundance changes. We establish the reliability of COIN-nMS using interactions between purified glycans and GBPs with known Kd values. We also demonstrate the implementation of COIN-nMS using the catch-and-release (CaR)-nMS assay for glycosylated GBPs. The COIN-CaR-nMS results obtained for plant, fungal, viral, and human lectins with natural libraries containing hundreds of N-glycans and glycopeptides highlight the assay's versatility for discovering new ligands, precisely measuring their affinities, and uncovering "fine" specificities. Notably, the COIN-CaR-nMS results clarify the sialoglycan binding properties of the SARS-CoV-2 receptor binding domain and establish the recognition of monosialylated hybrid and biantennary N-glycans. Moreover, pharmacological depletion of host complex N-glycans reduces both pseudotyped virions and SARS-CoV-2 cell entry, suggesting that complex N-glycans may serve as attachment factors.

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