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General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing peptide-binding proteins is challenging, as most peptides do not have defined structures in isolation, and hydrogen bonds must be made to the buried polar groups in the peptide backbone1-3. Here, inspired by natural and re-engineered protein-peptide systems4-11, we set out to design proteins made out of repeating units that bind peptides with repeating sequences, with a one-to-one correspondence between the repeat units of the protein and those of the peptide. We use geometric hashing to identify protein backbones and peptide-docking arrangements that are compatible with bidentate hydrogen bonds between the side chains of the protein and the peptide backbone12. The remainder of the protein sequence is then optimized for folding and peptide binding. We design repeat proteins to bind to six different tripeptide-repeat sequences in polyproline II conformations. The proteins are hyperstable and bind to four to six tandem repeats of their tripeptide targets with nanomolar to picomolar affinities in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including ladders of hydrogen bonds from protein side chains to peptide backbones. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating peptide sequences and for disordered regions of native proteins.
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Peptídeos , Engenharia de Proteínas , Proteínas , Sequência de Aminoácidos , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Proteínas/química , Proteínas/metabolismo , Engenharia de Proteínas/métodos , Ligação de Hidrogênio , Ligação Proteica , Dobramento de Proteína , Conformação ProteicaRESUMO
The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models. In contrast with natural IL-4, Neo-4 is hyperstable and signals exclusively through the type I IL-4 receptor complex, providing previously inaccessible insights into differential IL-4 signaling through type I versus type II receptors. Because of their hyperstability, our computationally designed mimetics can directly incorporate into sophisticated biomaterials that require heat processing, such as three-dimensional-printed scaffolds. Neo-4 should be broadly useful for interrogating IL-4 biology, and the design workflow will inform targeted cytokine therapeutic development.
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Citocinas , Interleucina-4 , Animais , Transdução de SinaisRESUMO
Online citizen science projects such as GalaxyZoo1, Eyewire2 and Phylo3 have proven very successful for data collection, annotation and processing, but for the most part have harnessed human pattern-recognition skills rather than human creativity. An exception is the game EteRNA4, in which game players learn to build new RNA structures by exploring the discrete two-dimensional space of Watson-Crick base pairing possibilities. Building new proteins, however, is a more challenging task to present in a game, as both the representation and evaluation of a protein structure are intrinsically three-dimensional. We posed the challenge of de novo protein design in the online protein-folding game Foldit5. Players were presented with a fully extended peptide chain and challenged to craft a folded protein structure and an amino acid sequence encoding that structure. After many iterations of player design, analysis of the top-scoring solutions and subsequent game improvement, Foldit players can now-starting from an extended polypeptide chain-generate a diversity of protein structures and sequences that encode them in silico. One hundred forty-six Foldit player designs with sequences unrelated to naturally occurring proteins were encoded in synthetic genes; 56 were found to be expressed and soluble in Escherichia coli, and to adopt stable monomeric folded structures in solution. The diversity of these structures is unprecedented in de novo protein design, representing 20 different folds-including a new fold not observed in natural proteins. High-resolution structures were determined for four of the designs, and are nearly identical to the player models. This work makes explicit the considerable implicit knowledge that contributes to success in de novo protein design, and shows that citizen scientists can discover creative new solutions to outstanding scientific challenges such as the protein design problem.
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Ciência do Cidadão/métodos , Criatividade , Engenharia de Proteínas/métodos , Dobramento de Proteína , Automação , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Jogos Experimentais , Modelos Moleculares , Interface Usuário-ComputadorRESUMO
We describe a de novo computational approach for designing proteins that recapitulate the binding sites of natural cytokines, but are otherwise unrelated in topology or amino acid sequence. We use this strategy to design mimics of the central immune cytokine interleukin-2 (IL-2) that bind to the IL-2 receptor ßγc heterodimer (IL-2Rßγc) but have no binding site for IL-2Rα (also called CD25) or IL-15Rα (also known as CD215). The designs are hyper-stable, bind human and mouse IL-2Rßγc with higher affinity than the natural cytokines, and elicit downstream cell signalling independently of IL-2Rα and IL-15Rα. Crystal structures of the optimized design neoleukin-2/15 (Neo-2/15), both alone and in complex with IL-2Rßγc, are very similar to the designed model. Neo-2/15 has superior therapeutic activity to IL-2 in mouse models of melanoma and colon cancer, with reduced toxicity and undetectable immunogenicity. Our strategy for building hyper-stable de novo mimetics could be applied generally to signalling proteins, enabling the creation of superior therapeutic candidates.
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Desenho de Fármacos , Interleucina-15/imunologia , Interleucina-2/imunologia , Mimetismo Molecular , Receptores de Interleucina-2/agonistas , Receptores de Interleucina-2/imunologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/imunologia , Simulação por Computador , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Interleucina-15/uso terapêutico , Interleucina-2/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Melanoma/tratamento farmacológico , Melanoma/imunologia , Camundongos , Modelos Moleculares , Estabilidade Proteica , Receptores de Interleucina-2/metabolismo , Transdução de Sinais/imunologiaRESUMO
SignificanceScramblases translocate lipids across the lipid bilayer without consumption of ATP, thereby regulating lipid distributions in cellular membranes. Cytosol-to-lumen translocation across the endoplasmic reticulum (ER) membrane is a common process among lipid glycoconjugates involved in posttranslational protein modifications in eukaryotes. These translocations are thought to be mediated by specific ER-resident scramblases, but the identity of these proteins and the underlying molecular mechanisms have been elusive. Here, we show that CLPTM1L, an integral membrane protein with eight putative transmembrane domains, is the major lipid scramblase involved in efficient glycosylphosphatidylinositol biosynthesis in the ER membrane. Our results validate the long-standing hypothesis that lipid scramblases ensure the efficient translocations of lipid glycoconjugates across the ER membrane for protein glycosylation pathways.
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Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Glicosilfosfatidilinositóis , Retículo Endoplasmático/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Lipogênese , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismoRESUMO
BACKGROUND: As overdose deaths continue to rise, public health officials need comprehensive surveillance data to design effective prevention, harm reduction, and treatment strategies. Disparities across race and ethnicity groups, as well as trends in substance use, treatment, or overdose deaths, have been examined individually, but reports rarely compare findings across multiple substances or data sources. OBJECTIVE: To provide a broad assessment of the overdose crisis, we describe trends in substance use, treatment, and overdose mortality across racial and ethnic groups for multiple substances. RESEARCH DESIGN: We conducted a longitudinal, cross-sectional analysis comparing trends. SUBJECTS: We identified self-reported use from the National Survey on Drug Use and Health, substance use treatment admissions from the Treatment Episode Data Set-Admissions, and overdose deaths from the CDC's Multiple Cause of Death files. MEASURES: We measured rates of substance use, treatment, and deaths involving heroin, methamphetamine, and cocaine among United States adults from 2010 to 2019. RESULTS: Heroin, methamphetamine, and cocaine use increased, though not all changes were statistically significant. Treatment admissions indicating heroin and methamphetamine increased while admissions indicating cocaine decreased. Overdose deaths increased among all groups: methamphetamine (257%-1,115%), heroin (211%-577%), and cocaine (88%-259%). Changes in rates of use, treatment, and death for specific substances varied by racial and ethnic group. CONCLUSIONS: Substance use, treatment, and overdose mortality changed considerably, though not always equivalently. Identifying diverging trends in substance-related measures for specific substances and racial and ethnic groups can inform targeted investment in treatment to reduce disparities and respond to emerging changes in the overdose crisis.
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Cocaína , Overdose de Drogas , Metanfetamina , Transtornos Relacionados ao Uso de Substâncias , Adulto , Humanos , Estados Unidos/epidemiologia , Heroína , Analgésicos Opioides , Estudos Transversais , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
BODIPYs have a well-established role in biological sciences as chemosensors and versatile biological markers due to their chemical reactivity, which allows for fine-tuning of their photophysical characteristics. In this work, we combined the unique reactivity of arylazo sulfones with the advantages of a "sunflow" reactor to develop a fast, efficient, and versatile method for the photochemical arylation of BODIPYs and other chromophores. This approach resulted in red-shifted emitting fluorophores due to extended electronic delocalization at the 3- and 5-positions of the BODIPY core. This method represents an advantageous approach for BODIPY functionalization compared to existing strategies.
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Depression is a common mood disorder and many patients do not respond to conventional pharmacotherapy or experience a variety of adverse effects. This work proposed that riparin I (RIP I) and riparin II (RIP II) present neuroprotective effects through modulation of astrocytes and microglia, resulting in the reversal of depressive-like behaviors. To verify our hypothesis and clarify the pathways underlying the effect of RIP I and RIP II on neuroinflammation, we used the chronic unpredictable mild stress (CUMS) depression model in mice. Male Swiss mice were exposed to stressors for 28â days. From 15 th to the 22 nd day, the animals received RIP I or RIP II (50â mg/kg) or fluoxetine (FLU, 10â mg/kg) or vehicle, by gavage. On the 29 th day, behavioral tests were performed. Expressions of microglia (ionized calcium-binding adaptor molecule-1 - Iba-1) and astrocyte (glial fibrillary acidic protein - GFAP) markers and levels of cytokines tumor necrosis factor alfa (TNF-α) and interleukin 1 beta (IL-1ß) were measured in the hippocampus. CUMS induced depressive-like behaviors and cognitive impairment, high TNF-α and IL-1ß levels, decreased GFAP, and increased Iba-1 expressions. RIP I and RIP II reversed these alterations. These results contribute to the understanding the mechanisms underlying the antidepressant effect of RIP I and RIP II, which may be related to neuroinflammatory suppression.
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Antidepressivos , Astrócitos , Depressão , Modelos Animais de Doenças , Hipocampo , Microglia , Doenças Neuroinflamatórias , Estresse Psicológico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Camundongos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Depressão/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/complicações , Estresse Psicológico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Fluoxetina/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-1beta/metabolismo , Fármacos Neuroprotetores/farmacologia , Comportamento Animal/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismoRESUMO
In this work, we introduce the Solvate Suite, a comprehensive and modular command-line interface designed for molecular simulation and microsolvation modeling. The suite interfaces with widely used scientific software, streamlining computational experiments for liquid systems through the automated creation of simulation boxes and topology with adjustable simulation parameters. Furthermore, it has features for graphical and statistical analysis of simulated properties and extraction of trajectory configurations with various filters. Additionally, it introduces innovative strategies for microsolvation modeling with a multiscale approach, employing equilibrated dynamics to identify favorable solute-solvent interactions and enabling full cluster optimization for free-energy calculations without imaginary frequency contamination.
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Simulação de Dinâmica Molecular , Software , Solventes , Solventes/química , Termodinâmica , Interface Usuário-ComputadorRESUMO
Biosurfactants are eco-friendly compounds with unique properties and promising potential as sustainable alternatives to chemical surfactants. The current review explores the multifaceted nature of biosurfactant production and applications, highlighting key fermentative parameters and microorganisms able to convert carbon-containing sources into biosurfactants. A spotlight is given on biosurfactants' obstacles in the global market, focusing on production costs and the challenges of large-scale synthesis. Innovative approaches to valorizing agro-industrial waste were discussed, documenting the utilization of lignocellulosic waste, food waste, oily waste, and agro-industrial wastewater in the segment. This strategy strongly contributes to large-scale, cost-effective, and environmentally friendly biosurfactant production, while the recent advances in waste valorization pave the way for a sustainable society.
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Resíduos Industriais , Eliminação de Resíduos , Alimentos , Fermentação , Tensoativos/químicaRESUMO
BACKGROUND: As overdose rates increase for multiple substances, policymakers need to identify geographic patterns of substance-specific deaths. In this study, we describe county-level opioid and psychostimulant overdose patterns and how they correlate with county-level social vulnerability measures. METHODS: A cross-sectional observational study, we used nationwide 2016-2018 restricted access Centers for Disease Prevention and Control county-level mortality files for 1,024 counties. We estimated quartiles of opioid and psychostimulant overdose mortality and provided estimates of their association with county-level Social Vulnerability Index (SVI) percentile. RESULTS: There was high opioid and psychostimulant overdose mortality in the Middle Atlantic, South Atlantic, East North Central, and Mountain regions. The Central US had the lowest opioid and psychostimulant overdose mortality rates. Counties with higher SVI scores (i.e. higher social vulnerability) were significantly more likely to experience high opioid and high psychostimulant overdose (high-high) mortality. A 10-percentile increase in SVI score was associated with a 3.1 percentage point increase in the likelihood of being a high-high county (p < 0.001) in unadjusted models and a 1.5 percentage point increase (p < 0.05) in models adjusting for region. CONCLUSION: Our results illustrated the heterogenous geographic distribution of the growing concurrent opioid and psychostimulant overdose crisis. The substantial regional variation we identified highlights the need for local data to guide policymaking and treatment planning. The association of opioid-psychostimulant overdose mortality with social vulnerability demonstrates the critical need in impacted counties for tailored treatment that addresses the complex medical and social needs of people who use both opioids and psychostimulants.
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Estimulantes do Sistema Nervoso Central , Overdose de Drogas , Overdose de Opiáceos , Transtornos Relacionados ao Uso de Opioides , Humanos , Analgésicos Opioides/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Estudos Transversais , Overdose de Drogas/prevenção & controle , Estimulantes do Sistema Nervoso Central/uso terapêutico , Overdose de Opiáceos/tratamento farmacológicoRESUMO
PURPOSE: Based on the tripod concept of load distribution, our study aimed to evaluate whether a slight extension of first metatarsal (M1) that may occur after the Lapidus procedure (LP) could alter the radiographic measurements of the hindfoot and influence clinical and functional outcomes. METHODS: Twenty-five patients (27 feet) were reviewed. Hindfoot radiographic analysis was based on seven measurements. Clinical and functional outcomes were evaluated with self-reported questionnaires. Transfer metatarsalgia was also assessed. Correlation analysis was performed according to variations of the studied variables. RESULTS: The average extension of the M1 was 4.26 degrees (p < 0.001). None of the hindfoot radiographic measurements changed significantly (p = 0.13, p = 0.50, p = 0.19, p = 0.70, p = 0.11, p = 0.36, p = 0.83). Patients improved on most questionnaires (p < 0.001). None presented transfer metatarsalgia. No correlation between M1 extension and clinical and functional outcomes was found. CONCLUSION: Possibly there is a tolerance of M1 extension in which it does not alter the radiographic measurements of the hindfoot, overload the lesser metatarsals, or compromise clinical and functional outcomes.
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Hallux Valgus , Ossos do Metatarso , Metatarsalgia , Humanos , Ossos do Metatarso/diagnóstico por imagem , Ossos do Metatarso/cirurgia , Hallux Valgus/diagnóstico por imagem , Radiografia , Metatarsalgia/diagnóstico por imagem , Metatarsalgia/etiologia , Metatarsalgia/cirurgiaRESUMO
Immune response to biomaterials, which is intimately related to their surface properties, can produce chronic inflammation and fibrosis, leading to implant failure. This study investigated the development of magnetic nanoparticles coated with silica and incorporating the anti-inflammatory drug naproxen, aimed at multifunctional biomedical applications. The synthesized nanoparticles were characterized using various techniques that confirmed the presence of magnetite and the formation of a silica-rich bioactive glass (BG) layer. In vitro studies demonstrated that the nanoparticles exhibited bioactive properties, forming an apatite surface layer when immersed in simulated body fluid, and biocompatibility with bone cells, with good viability and alkaline phosphatase activity. Naproxen, either free or encapsulated, reduced nitric oxide production, an inflammatory marker, while the BG coating alone did not show anti-inflammatory effects in this study. Overall, the magnetic nanoparticles coated with BG and naproxen showed promise for biomedical applications, especially anti-inflammatory activity in macrophages and in the bone field, due to their biocompatibility, bioactivity, and osteogenic potential.
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Materiais Revestidos Biocompatíveis , Vidro , Nanopartículas de Magnetita , Naproxeno , Naproxeno/farmacologia , Naproxeno/química , Vidro/química , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Nanopartículas de Magnetita/química , Animais , Camundongos , Humanos , Óxido Nítrico/metabolismo , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Dióxido de Silício/química , Sobrevivência Celular/efeitos dos fármacos , Células RAW 264.7 , Osteogênese/efeitos dos fármacosRESUMO
Pollution by microplastics (MPs) in mangroves is a growing concern, given its potential ecological and human health impacts. The characteristics of microplastic pollution and a risk assessment of MPs in the Amazon region's coastal sediments are still insufficient, and information about MP pollution in the benthic component of the mangrove ecosystem is lacking. We analyzed MP concentrations in the surface sediment of 9 stations in three tidal channels along the Ajuruteua Peninsula connected to the Caeté River estuary, aiming to assess the hazard level on the environment based on the Pollution Load Index (PLI). Raman and Fourier transform infrared spectroscopy determined the MP's chemical composition. The results showed that the abundance of sediment MPs ranged from 100 to 1200 items kg-1, with an average of 433 ± 261.6 items kg-1. The MPs were mainly composed of transparent and blue fragments and fibers, ranging in size from 100 to 5000 µm. Six types of polymers were identified, including alkyd varnish (AV), resin dispersion (RD), chlorinated polyethylene (CPE), polyethylene-polypropylene (PE-PP), low-density polyethylene (LDPE), and hostaperm blue (HB). Hydrodynamic processes within estuaries and tidal channels play a crucial role in explaining the concentrations found, as circulation determines the pattern of sediment deposition and the particles adhered to it. PLI risk assessment showed that all sampling sites were at hazard level I: a low level of contamination in the mangrove sediments. However, a more comprehensive and systematic monitoring campaign is needed to expand our knowledge about pollution and contamination by MPs in Amazon mangrove areas.
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Monitoramento Ambiental , Sedimentos Geológicos , Microplásticos , Microplásticos/análise , Microplásticos/toxicidade , Brasil , Medição de Risco , Sedimentos Geológicos/química , Sedimentos Geológicos/análise , Áreas Alagadas , Poluentes Químicos da Água/análiseRESUMO
Xylazine-associated wounds are a distinct, novel clinical entity characterized by co-occurrence with substance use, progressive necrosis of skin, muscle, tendon, and bone, and slow healing. In Philadelphia, the specter of limb loss, stigma, and shame has hung over hospital-based care for xylazine-associated wounds among people who use drugs (PWUD) and kept many people away from engaging in care. Continued engagement in harm reduction wound care nursing, however, offers an opportunity for PWUD to address their wounds and their fears with members of the medical world. In the absence of established best practices, harm reduction's model of risk-reductive care offers a way forward for patients and practitioners alike. Here, "harm reduction" describes an ethic of practical, trauma-informed, patient-centered care. It is this integration of harm reduction into medicine and public health that effectively promotes the safety, survival, and recovery of PWUD across all spectrums of drug use habits and housing stability.
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Mobile herbicides have a high potential for groundwater contamination. An alternative to decrease the mobility of herbicides is to apply materials with high sorbent capacity to the soil, such as biochars. The objective of this research was to evaluate the effect of eucalyptus, rice hull, and native bamboo biochar amendments on sorption and desorption of hexazinone, metribuzin, and quinclorac in a tropical soil. The sorption-desorption was evaluated using the batch equilibrium method at five concentrations of hexazinone, metribuzin, and quinclorac. Soil was amended with eucalyptus, rice hull, and native bamboo biochar at a rate of 0 (control-unamended) and 1% (w w-1), corresponding to 0 and 12 t ha-1, respectively. The amount of sorbed herbicides in the unamended soil followed the decreasing order: quinclorac (65.9%) > metribuzin (21.4%) > hexazinone (16.0%). Native bamboo biochar provided the highest sorption compared to rice hull and eucalyptus biochar-amended soils for the three herbicides. The amount of desorbed herbicides in the unamended soil followed the decreasing order: metribuzin (18.35%) > hexazinone (15.9%) > quinclorac (15.1%). Addition of native bamboo biochar provided the lowest desorption among the biochar amendments for the three herbicides. In conclusion, the biochars differently affect the sorption and desorption of hexazinone, metribuzin, and quinclorac mobile herbicides in a tropical soil. The addition of eucalyptus, rice hull, and native bamboo biochars is a good alternative to increase the sorption of hexazinone, metribuzin, and quinclorac, thus, reducing mobility and availability of these herbicides to nontarget organisms in soil.
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Eucalyptus , Herbicidas , Oryza , Quinolinas , Sasa , Poluentes do Solo , Triazinas , Carvão Vegetal , Solo , Adsorção , Monitoramento Ambiental , Herbicidas/análise , Poluentes do Solo/análiseRESUMO
The emergence of novel variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) underscores the need to investigate alternative approaches to prevent infection and treat patients with coronavirus disease 2019. Here, we report the preclinical efficacy of NL-CVX1, a de novo decoy that blocks virus entry into cells by binding with nanomolar affinity and high specificity to the receptor-binding domain of the SARS-CoV-2 spike protein. Using a transgenic mouse model of SARS-CoV-2 infection, we showed that a single prophylactic intranasal dose of NL-CVX1 conferred complete protection from severe disease following SARS-CoV-2 infection. Multiple therapeutic administrations of NL-CVX1 also protected mice from succumbing to infection. Finally, we showed that infected mice treated with NL-CVX1 developed both anti-SARS-CoV-2 antibodies and memory T cells and were protected against reinfection a month after treatment. Overall, these observations suggest NL-CVX1 is a promising therapeutic candidate for preventing and treating severe SARS-CoV-2 infections.
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Enzima de Conversão de Angiotensina 2 , COVID-19 , Animais , Humanos , Camundongos , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/prevenção & controle , Camundongos Transgênicos , SARS-CoV-2 , Glicoproteína da Espícula de CoronavírusRESUMO
ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Salivary biomarkers of oxidative stress in children with dental caries: Systematic review and meta-analysis doi:10.1016/j.archoralbio.2022.105432. SOURCE OF FUNDING: CAPES (Coordination for the improvement of higher education, National Council of Technological and Scientific Development), Finace code 001. TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data.
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Antioxidantes , Biomarcadores , Cárie Dentária , Estresse Oxidativo , Saliva , Criança , Humanos , Saliva/química , Revisões Sistemáticas como Assunto , Metanálise como AssuntoRESUMO
OBJECTIVES: Engagement in guideline-recommended sexually transmitted infection (STI) care is fundamental to ending the STI epidemic in the USA. However, the US 2021-2025 STI National Strategic Plan and STI surveillance reports do not include a framework to measure quality STI care delivery. This study developed and applied an STI Care Continuum that can be used across settings to improve STI care quality, assess adherence to guideline-recommended care and standardise the measurement of progress towards National Strategic goals. METHODS: Review of the Centers for Disease Control and Prevention STI Treatment guidelines identified seven distinct steps of STI care for gonorrhoea, chlamydia and syphilis: (1) STI testing indication, (2) STI test completion, (3) HIV testing, (4) STI diagnosis, (5) partner services, (6) STI treatment and (7) STI retesting. Steps 1-4, 6 and 7 for gonorrhoea and/or chlamydia (GC/CT) were measured among females aged 16-17 years with a clinic visit at an academic paediatric primary care network in 2019. We used Youth Risk Behavior Surveillance Survey data to estimate step 1, and electronic health record data for steps 2, 3, 4, 6 and 7. RESULTS: Among 5484 female patients aged 16-17 years, an estimated 44% had an STI testing indication. Among those patients, 17% were tested for HIV, of whom none tested positive, and 43% were tested for GC/CT, 19% of whom were diagnosed with GC/CT. Of these patients, 91% received treatment within 2 weeks and 67% were retested within 6 weeks to 1 year after diagnosis. On retesting, 40% were diagnosed with recurrent GC/CT. CONCLUSIONS: Local application of an STI Care Continuum identified STI testing, retesting and HIV testing as areas for improvement. The development of an STI Care Continuum identified novel measures for monitoring progress towards National Strategic indicators. Similar methods can be applied across jurisdictions to target resources, standardise data collection and reporting and improve STI care quality.
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Infecções por Chlamydia , Chlamydia , Gonorreia , Infecções por HIV , Infecções Sexualmente Transmissíveis , Humanos , Adolescente , Feminino , Criança , Gonorreia/diagnóstico , Gonorreia/epidemiologia , Gonorreia/terapia , Philadelphia , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/terapia , Qualidade da Assistência à Saúde , Atenção Primária à Saúde , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por Chlamydia/diagnóstico , Infecções por Chlamydia/tratamento farmacológico , Infecções por Chlamydia/epidemiologiaRESUMO
Astrocytes play multiple important roles in brain physiology. However, depending on the stimuli, astrocytes may exacerbate inflammatory reactions, contributing to the development and progression of neurological diseases. Therefore, therapies targeting astrocytes represent a promising area for the development of new brain drugs. Thiazolidinones are heterocyclic compounds that have a sulfur and nitrogen atom and a carbonyl group in the ring and represent a class of compounds of great scientific interest due to their pharmacological properties. The aim of this study was to investigate the effect of 3-(3-(diethylamino)propyl)-2-(4-(methylthio)phenyl)thiazolidin-4-one (DS27) on cell proliferation and morphology, oxidative stress parameters, activity of the enzymes ectonucleotidases and acetylcholinesterase (AChE) and interleukin 6 (IL-6) levels in primary astrocyte cultures treated with lipopolysaccharide (LPS), to model neuroinflammation. The astrocyte culture was exposed to LPS (10 µg/ml) for 3 h and subsequently treated with compound DS27 for 24 and 48 h (concentrations ranging to 10-100 µM). LPS induced an increase in astrocyte proliferation, AChE activity, IL-6 levels, oxidative damage, ATP and ADP and a reduction in AMP hydrolysis in rat primary astrocyte cultures. DS27 treatment was effective in reversing these alterations induced by LPS. Our findings demonstrated that DS27 is able to modulate cholinergic and purinergic signaling, redox status, and the levels of pro-inflammatory cytokines in LPS-induced astrocyte damage. These glioprotective effects of DS27 may be very important for improving neuroinflammation, which is associated with many brain diseases.