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Religious fundamentalism, characterized by rigid adherence to a set of beliefs putatively revealing inerrant truths, is ubiquitous across cultures and has a global impact on society. Understanding the psychological and neurobiological processes producing religious fundamentalism may inform a variety of scientific, sociological, and cultural questions. Research indicates that brain damage can alter religious fundamentalism. However, the precise brain regions involved with these changes remain unknown. Here, we analyzed brain lesions associated with varying levels of religious fundamentalism in two large datasets from independent laboratories. Lesions associated with greater fundamentalism were connected to a specific brain network with nodes in the right orbitofrontal, dorsolateral prefrontal, and inferior parietal lobe. This fundamentalism network was strongly right hemisphere lateralized and highly reproducible across the independent datasets (r = 0.82) with cross-validations between datasets. To explore the relationship of this network to lesions previously studied by our group, we tested for similarities to twenty-one lesion-associated conditions. Lesions associated with confabulation and criminal behavior showed a similar connectivity pattern as lesions associated with greater fundamentalism. Moreover, lesions associated with poststroke pain showed a similar connectivity pattern as lesions associated with lower fundamentalism. These findings are consistent with the current understanding of hemispheric specializations for reasoning and lend insight into previously observed epidemiological associations with fundamentalism, such as cognitive rigidity and outgroup hostility.
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Red Nerviosa , Humanos , Masculino , Femenino , Red Nerviosa/fisiopatología , Red Nerviosa/patología , Persona de Mediana Edad , Encéfalo/fisiopatología , Encéfalo/patología , Adulto , Religión , Imagen por Resonancia Magnética , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , AncianoRESUMEN
BACKGROUND: The American Academy of Orthopaedic Surgeons (AAOS) has developed a clinical practice guideline (CPG) for management of anterior cruciate ligament (ACL) injuries. Primary studies such as randomized controlled trials (RCTs) are cited as evidence for the guidelines. Given the influence that these trials have on patient care, adherence to standardized protocols for conducting and reporting RCTs is essential. PURPOSE: To evaluate the CONSORT (Consolidated Standards of Reporting Trials) Extension for Harms-related reporting of RCTs cited as supporting evidence for the AAOS CPG on the management of ACL tears. STUDY DESIGN: Cross-sectional study. METHODS: The reference section of the AAOS guideline for ACL tears was first screened for RCTs cited in the CPG. Next, each RCT was evaluated for adherence to the CONSORT Extension for Harms checklist. Both identification of RCTs and assessment of adherence were performed in a masked and duplicate process. Descriptive statistics were used to summarize adherence to CONSORT Extension for Harms items. A Pearson correlation test was conducted to assess the relationship between the year of publication and adherence to CONSORT harms reporting. RESULTS: The sample included 113 RCTs, of which 16 (14.2%) were published before the CONSORT Extension for Harms was implemented in 2004. Sample sizes ranged from 24 to 4564 participants, with a mean of 228. None of the included RCTs included all 18 items in the CONSORT Extension for Harms checklist. The mean number of checklist items reported was 4 (of 18; 22.2%). A moderate, positive, and statistically significant correlation was found between the RCT publication year and the adherence with reporting of the CONSORT Extension for Harms (t111 = 3.54; P < .001) (r = 0.32; 95% CI, 0.14-0.47). CONCLUSION: Harms were infrequently reported in RCTs cited as supporting evidence in the AAOS CPG for the management of ACL tears. One encouraging finding was the positive correlation between the year when RCTs were published and how well they adhered to reporting harms. Efforts to improve adverse event reporting are warranted, as RCTs are commonly used to make clinical decisions in orthopaedic surgery.
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Lesiones del Ligamento Cruzado Anterior , Adhesión a Directriz , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Lesiones del Ligamento Cruzado Anterior/cirugía , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Estudios Transversales , Reconstrucción del Ligamento Cruzado Anterior , Lista de Verificación , Ortopedia/normasRESUMEN
Nature has evolved diverse electron transport proteins and multiprotein assemblies essential to the generation and transduction of biological energy. However, substantially modifying or adapting these proteins for user-defined applications or to gain fundamental mechanistic insight can be hindered by their inherent complexity. De novo protein design offers an attractive route to stripping away this confounding complexity, enabling us to probe the fundamental workings of these bioenergetic proteins and systems, while providing robust, modular platforms for constructing completely artificial electron-conducting circuitry. Here, we use a set of de novo designed mono-heme and di-heme soluble and membrane proteins to delineate the contributions of electrostatic micro-environments and dielectric properties of the surrounding protein medium on the inter-heme redox cooperativity that we have previously reported. Experimentally, we find that the two heme sites in both the water-soluble and membrane constructs have broadly equivalent redox potentials in isolation, in agreement with Poisson-Boltzmann Continuum Electrostatics calculations. BioDC, a Python program for the estimation of electron transfer energetics and kinetics within multiheme cytochromes, also predicts equivalent heme sites, and reports that burial within the low dielectric environment of the membrane strengthens heme-heme electrostatic coupling. We conclude that redox cooperativity in our diheme cytochromes is largely driven by heme electrostatic coupling and confirm that this effect is greatly strengthened by burial in the membrane. These results demonstrate that while our de novo proteins present minimalist, new-to-nature constructs, they enable the dissection and microscopic examination of processes fundamental to the function of vital, yet complex, bioenergetic assemblies.
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Hemo , Oxidación-Reducción , Hemo/química , Hemo/metabolismo , Solubilidad , Agua/química , Agua/metabolismo , Citocromos/química , Citocromos/metabolismo , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Modelos Moleculares , Electricidad Estática , Ingeniería de ProteínasRESUMEN
This Viewpoint explores a 2023 Biden administration proposal for US agencies to use their march-in rights and the impact this proposed framework could have on drug prices.
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Costos de los Medicamentos , Industria Farmacéutica , Humanos , Costos de los Medicamentos/legislación & jurisprudencia , Industria Farmacéutica/economía , Industria Farmacéutica/legislación & jurisprudencia , Estados Unidos , Gobierno FederalRESUMEN
Given the significant impact of biofilms on human health and material corrosion, research in this field urgently needs more accessible techniques to facilitate the testing of new control agents and general understanding of biofilm biology. Microtiter plates offer a convenient format for standardized evaluations, including high-throughput assays of alternative treatments and molecular modulators. This study introduces a novel Biofilm Analysis Software (BAS) for quantifying biofilms from microtiter plate images. We focused on early biofilm growth stages and compared BAS quantification to common techniques: direct turbidity measurement, intrinsic fluorescence detection linked to pyoverdine production, and standard crystal violet staining which enables image analysis and optical density measurement. We also assessed their sensitivity for detecting subtle growth effects caused by cyclic AMP and gentamicin. Our results show that BAS image analysis is at least as sensitive as the standard method of spectrophotometrically quantifying the crystal violet retained by biofilms. Furthermore, we demonstrated that bacteria adhered after short incubations (from 10 min to 4 h), isolated from planktonic populations by a simple rinse, can be monitored until their growth is detectable by intrinsic fluorescence, BAS analysis, or resolubilized crystal violet. These procedures are widely accessible for many laboratories, including those with limited resources, as they do not require a spectrophotometer or other specialized equipment.
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Biopelículas , Procesamiento de Imagen Asistido por Computador , Programas Informáticos , Biopelículas/crecimiento & desarrollo , Procesamiento de Imagen Asistido por Computador/métodos , Violeta de Genciana , Bacterias/crecimiento & desarrollo , Adhesión Bacteriana , Gentamicinas/farmacologíaRESUMEN
Diisopentyl phthalate (DiPeP) is primarily used as a plasticizer or additive within the production of polyvinyl chloride (PVC), and has many additional industrial applications. Its metabolites were recently found in urinary samples of pregnant women; thus, this substance is of concern as relates to human exposure. Depending upon the nature of the alcohol used in its synthesis, DiPeP may exist either as a mixture consisting of several branched positional isomers, or as a single defined structure. This article investigates the skin sensitization potential and immunomodulatory effects of DiPeP CAS No. 84777-06-0, which is currently marketed and classified as a UVCB substance, by in silico and in vitro methods. Our findings showed an immunomodulatory effect for DiPeP in LPS-induced THP-1 activation assay (increased CD54 expression). In silico predictions using QSAR TOOLBOX 4.5, ToxTree, and VEGA did not identify DiPeP, in the form of a discrete compound, as a skin sensitizer. The keratinocyte activation (Key Event 2 (KE2) of the adverse outcome pathway (AOP) for skin sensitization) was evaluated by two different test methods (HaCaT assay and RHE assay), and results were discordant. While the HaCaT assay showed that DiPeP can activate keratinocytes (increased levels of IL-6, IL-8, IL-1α, and ILA gene expression), in the RHE assay, DiPeP slightly increased IL-6 release. Although inconclusive for KE2, the role of DiPeP in KE3 (dendritic cell activation) was demonstrated by the increased levels of CD54 and IL-8 and TNF-α in THP-1 cells (THP-1 activation assay). Altogether, findings were inconclusive regarding the skin sensitization potential of the UVCB DiPeP-disagreeing with the results of DiPeP in the form of discrete compound (skin sensitizer by the LLNA assay). Additional studies are needed to elucidate the differences between DiPeP isomer forms, and to better understand the applicability domains of non-animal methods in identifying skin sensitization hazards of UVCB substances.
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Simulación por Computador , Queratinocitos , Ácidos Ftálicos , Humanos , Queratinocitos/efectos de los fármacos , Ácidos Ftálicos/toxicidad , Células HaCaT , Piel/efectos de los fármacos , Piel/inmunología , Piel/metabolismo , Relación Estructura-Actividad Cuantitativa , Plastificantes/toxicidad , Células THP-1 , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Línea CelularRESUMEN
BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.
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Prostatectomía , Neoplasias de la Próstata , Terapia Recuperativa , Humanos , Masculino , Prostatectomía/métodos , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/patología , Anciano , Terapia Recuperativa/métodos , Persona de Mediana Edad , Radioterapia Adyuvante/efectos adversos , Radioterapia Adyuvante/métodos , Antígeno Prostático Específico/sangre , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Clasificación del Tumor , Factores de TiempoRESUMEN
Dust associated with various stellar sources in galaxies at all cosmic epochs remains a controversial topic, particularly whether supernovae play an important role in dust production. We report evidence of dust formation in the cold, dense shell behind the ejecta-circumstellar medium (CSM) interaction in the Type Ia-CSM supernova (SN) 2018evt three years after the explosion, characterized by a rise in mid-infrared emission accompanied by an accelerated decline in the optical radiation of the SN. Such a dust-formation picture is also corroborated by the concurrent evolution of the profiles of the Hα emission line. Our model suggests enhanced CSM dust concentration at increasing distances from the SN as compared to what can be expected from the density profile of the mass loss from a steady stellar wind. By the time of the last mid-infrared observations at day +1,041, a total amount of 1.2 ± 0.2 × 10-2 Mâ of new dust has been formed by SN 2018evt, making SN 2018evt one of the most prolific dust factories among supernovae with evidence of dust formation. The unprecedented witness of the intense production procedure of dust may shed light on the perceptions of dust formation in cosmic history.
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Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.
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Antineoplásicos , Neoplasias , Animales , Ratones , Humanos , Ensayos Antitumor por Modelo de Xenoinjerto , Sistema Inmunológico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Modelos Animales de Enfermedad , Microambiente TumoralRESUMEN
Smoking is the leading cause of preventable death worldwide and remains a critical public health challenge. The burden of disease caused by smoking is disproportionately borne by persons living with mental illness. Public health efforts to address smoking have not historically translated to a significant reduction in smoking prevalence among patients with mental illness. Smoking is a substantial cause of morbidity and mortality among psychiatric patients who smoke at 1.7 to 3.3 times the rate of the general population. Among those with serious mental illness, tobacco-related illness accounts for half of all deaths. Nicotine dependence also interferes with treatment and worsens many psychiatric symptoms. Interventions are underutilized due to persistent misunderstandings regarding tobacco cessation for patients who are mentally ill. Addressing these misunderstandings is crucial in targeting the disparate rates of smoking in this population. Therefore, it is incumbent on psychiatrists to address the outsized effect that smoking has on patients with mental illness.
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Trastornos Mentales , Enfermos Mentales , Cese del Hábito de Fumar , Tabaquismo , Humanos , Cese del Hábito de Fumar/psicología , Trastornos Mentales/terapia , Tabaquismo/epidemiología , Tabaquismo/terapia , Tabaquismo/psicología , Prevalencia , PacientesRESUMEN
BACKGROUND: Recommendations within clinical practice guidelines (CPGs) are heavily influenced by results from randomized controlled trials (RCTs). Therefore, it is imperative that all RCT outcomes are reported thoroughly to ensure CPGs are created using accurate information. Here, we evaluate the quality of harms reporting using the CONSORT Extension for Harms in RCTs underpinning recommendations in the American Academy of Orthopedic Surgeons (AAOS) Management of Hip Fractures in Older Adults CPG. METHODS: Each RCT cited as evidence for recommendations in the AAOS Management of Hip Fractures in Older Adults CPG was evaluated using the CONSORT Extension for Harms to determine the quality of harms reporting. Descriptive statistics (frequencies, percentages, 95 % confidence intervals) were used to summarize adherence to CONSORT Harms items. A linear regression model was used to evaluate the CONSORT Harms influence on the quality of reporting over time. RESULTS: Among the 156 RCTs identified, there were a total of 31,848 participants. Most RCTs were conducted at a single center (137; 87.8 %) and in a single-blind manner (130; 83.3 %). Fifty-four (34.6 %) RCTs did not provide funding statements. Trials adequately reported an average of 6.65 out of 18 CONSORT Extension for Harms items (37.0 %). One RCT adequately reported all items, while five reported zero items. Forty-seven RCTs (30.1 %) reported ≥ 50 % of items and 73 (46.8 %) reported ≤ 33.3 % of items. The linear regression model demonstrated no significant increase in mean adherence over time (adjusted R2 = -0.006; p = 0.563). CONCLUSION: Our results highlight inadequate harms reporting among RCTs in the AAOS Management of Hip Fractures in Older Patients CPG. While the CONSORT Harms Extension was intended to enhance reporting, the linear regression model did not demonstrate significant improvements over time.
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Fracturas de Cadera , Cirujanos Ortopédicos , Humanos , Anciano , Ensayos Clínicos Controlados Aleatorios como Asunto , Fracturas de Cadera/cirugíaRESUMEN
Several species of hybrid fruits, such as citrus, grapes, blueberries, apples, tomatoes, and lingonberries among others, have attracted scientific attention in recent years, especially due to their reported antioxidant and anti-inflammatory properties. The bagasse, leaves, bark, and seeds of these hybrid fruits have large amounts of polyphenols, such as flavonoids, which act as potent antioxidants. Several studies have been carried out in cellular models of neurotoxicity of the extract of these fruits, to document the beneficial effects for human health, as well as to prove its antiproliferative effect in cancer cells. In the present review, through a synthesis of existing information in the scientific literature, we demonstrate that hybrid fruits are a source of antioxidant and bioactive compounds, which act in the inhibition of diseases such as cancer, diabetes, and inflammatory and neurodegenerative diseases, and consequently improving human health.
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Persistent pain conditions and sleep disorders are public health problems worldwide. It is widely accepted that sleep disruption increases pain sensitivity; however, the underlying mechanisms are poorly understood. In this study, we used a protocol of 6 hours a day of total sleep deprivation for 3 days in rats to advance the understanding of these mechanisms. We focused on gender differences and the dopaminergic mesocorticolimbic system. The findings demonstrated that sleep restriction (SR) increased pain sensitivity in a similar way in males and females, without inducing a significant stress response. This pronociceptive effect depends on a nucleus accumbens (NAc) neuronal ensemble recruited during SR and on the integrity of the anterior cingulate cortex (ACC). Data on indirect dopaminergic parameters, dopamine transporter glycosylation, and dopamine and cyclic adenosine monophosphate (AMP)-regulated phosphoprotein-32 phosphorylation, as well as dopamine, serotonin, and norepinephrine levels, suggest that dopaminergic function decreases in the NAc and ACC after SR. Complementarily, pharmacological activation of dopamine D2, but not D1 receptors either in the ACC or in the NAc prevents SR from increasing pain sensitivity. The ACC and NAc are the main targets of dopaminergic mesocorticolimbic projections with a key role in pain modulation. This study showed their integrative role in the pronociceptive effect of SR, pointing to dopamine D2 receptors as a potential target for pain management in patients with sleep disorders. These findings narrow the focus of future studies on the mechanisms by which sleep impairment increases pain sensitivity. PERSPECTIVE: This study demonstrates that the pronociceptive effect of SR affects similarly males and females and depends on a NAc neuronal ensemble recruited during SR and on the integrity of the ACC. Findings on dopaminergic function support dopamine D2 receptors as targets for pain management in sleep disorders patients.
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Dopamina , Núcleo Accumbens , Humanos , Masculino , Ratas , Animales , Núcleo Accumbens/fisiología , Dopamina/farmacología , Giro del Cíngulo , Dolor , Privación de Sueño/complicacionesRESUMEN
Brazil has great biodiversity, and the Amazon biome stands out for a variety of native fruits with high economic and nutritional potential. Murici (Byrsonima crassifolia) and taperebá (Spondias mombin) are sources of vitamins, minerals, and phytochemicals with potential health benefits. Because of the bioactive potential of these Brazilian fruits, this review aims to gather the most current existing knowledge about their botanical, nutritional, and phytochemical properties, because the presence of several bioactive compounds may bring promising strategies to the prevention and treatment of several diseases. The search was conducted of the LILACS, MEDLINE, PubMed, and Science Direct databases, considering articles published between 2010 and 2023. The compiled results showed that these fruits, their leaves, and seeds have great antioxidant activity and are a good source of phytochemicals, especially phenolic compounds. In vitro and in vivo studies indicate that these bioactive compounds have several health benefits related to the prevention or treatment of diseases, including antioxidant effects; anti-inflammatory effects; and antidiabetic, antidepressant, neuroprotective, antiproliferative, anticancer, hypolipemic, cardioprotective, gastroprotective, hepatoprotective, and nephroprotective effects, and they are particularly related to the reduction of damage from oxidative stress. This review highlights the potential of these fruits as functional foods and for therapeutic purposes. However, it is recommended to conduct more studies on the identification and quantification of phytochemicals present in these fruits and studies in humans to better understand the mechanisms of action related to their effects and to understand the interaction of these compounds with the human body, as well as to prove the safety and efficacy of these compounds on health.
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Anacardiaceae , Antioxidantes , Animales , Humanos , Antioxidantes/farmacología , Antioxidantes/análisis , Fitoquímicos/farmacología , Fitoquímicos/análisis , Anacardiaceae/química , Frutas/química , Técnicas de Cultivo de CélulaRESUMEN
OBJECTIVES: This study used hydrogen nuclear magnetic resonance spectroscopy for the first time to examine differences in the metabolomic profile of stifle joint synovial fluid from dogs with cranial cruciate ligament rupture with and without meniscal injuries, in order to identify biomarkers of meniscal injury. Identifying a biomarker of meniscal injury could then ultimately be used to design a minimally invasive diagnostic test for meniscal injuries in dogs. MATERIALS AND METHODS: Stifle joint synovial fluid was collected from dogs undergoing stifle joint surgery or arthrocentesis for lameness investigations. We used multi-variate statistical analysis using principal component analysis and univariate statistical analysis using one-way analysis of variance and analysis of co-variance to identify differences in the metabolomic profile between dogs with cranial cruciate ligament rupture and meniscal injury, cranial cruciate ligament rupture without meniscal injury, and neither cranial cruciate ligament rupture nor meniscal injury, taking into consideration clinical variables. RESULTS: A total of 154 samples of canine synovial fluid were included in the study. Sixty-four metabolites were annotated to the hydrogen nuclear magnetic resonance spectroscopy spectra. Six spectral regions were found to be significantly altered (false discovery rate adjusted P-value <0.05) between groups with cranial cruciate ligament rupture with and without meniscal injury, including three attributed to nuclear magnetic resonance mobile lipids [mobile lipid -CH3 (P=0.016), mobile lipid -n(CH3 )3 (P=0.017), mobile unsaturated lipid (P=0.031)]. CLINICAL SIGNIFICANCE: We identified an increase in nuclear magnetic resonance mobile lipids in the synovial fluid of dogs with meniscal injury which are of interest as potential biomarkers of meniscal injury.
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Lesiones del Ligamento Cruzado Anterior , Enfermedades de los Perros , Perros , Animales , Ligamento Cruzado Anterior/patología , Ligamento Cruzado Anterior/cirugía , Meniscos Tibiales/cirugía , Lesiones del Ligamento Cruzado Anterior/diagnóstico por imagen , Lesiones del Ligamento Cruzado Anterior/veterinaria , Rotura/veterinaria , Rotura/cirugía , Biomarcadores , Rodilla de Cuadrúpedos , Hidrógeno , Lípidos , Enfermedades de los Perros/diagnóstico , Enfermedades de los Perros/patologíaRESUMEN
The tunable design of protein redox potentials promises to open a range of applications in biotechnology and catalysis. Here, we introduce a method to calculate redox potential changes by combining fluctuation relations with molecular dynamics simulations. It involves the simulation of reduced and oxidized states, followed by the instantaneous conversion between them. Energy differences introduced by the perturbations are obtained using the Kubo-Onsager approach. Using a detailed fluctuation relation coupled with Bayesian inference, these are postprocessed into estimates for the redox potentials in an efficient manner. This new method, denoted MD + CB, is tested on a de novo four-helix bundle heme protein (the m4D2 "maquette") and five designed mutants, including some mutants characterized experimentally in this work. The MD + CB approach is found to perform reliably, giving redox potential shifts with reasonably good correlation (0.85) to the experimental values for the mutants. The MD + CB approach also compares well with redox potential shift predictions using a continuum electrostatic method. The estimation method employed within the MD + CB approach is straightforwardly transferable to standard equilibrium MD simulations and holds promise for redox protein engineering and design applications.
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Hemo , Simulación de Dinámica Molecular , Secuencia de Aminoácidos , Teorema de Bayes , Estructura Secundaria de Proteína , Hemo/química , Proteínas/química , Oxidación-ReducciónRESUMEN
There are few reports of Trypanosoma in snakes, as well as little information about its pathogenicity in these animals. Thus, the present study aimed to characterize Trypanosoma found in Boa constrictor snakes, to verify the influence of the parasitism on hematological and clinical biochemistry parameters, and to perform a phylogenetic study of the isolates. Blood samples from sixty-one boas were analyzed for the presence of trypanosomatids and by hematological and clinical biochemistry assays. The flagellates that were found in this analysis were used for cell culture, morphometry, and molecular analysis. Later, molecular typing phylogenetic studies were performed. Nine positive animals (14.75%) were identified by microscopy analysis. The hematological results showed that parasitized animals presented significantly lower levels of packed cell volume, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. In the leukogram, eosinophils and heterophils counts were higher in parasitized animals. Considering the molecular analyses, the isolates presented a higher identity of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the 18S small subunit ribosomal RNA (SSU rRNA) gene fragments with Trypanosoma serpentis. The phylogenetic tree, using the GAPDH, clustered all isolates with T. serpentis and Trypanosoma cascavelli. This is the first description of T. serpentis parasitizing boas and of the clinical changes caused by trypanosomatid infection in snakes.
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Boidae , Trypanosoma , Animales , Boidae/genética , Filogenia , ADN Ribosómico/genética , ARN Ribosómico 18S/genética , Serpientes , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , ADN ProtozoarioRESUMEN
The Construction File (CF) specification establishes a standardized interface for molecular biology operations, laying a foundation for automation and enhanced efficiency in experiment design. It is implemented across three distinct software projects: PyDNA_CF_Simulator, a Python project featuring a ChatGPT plugin for interactive parsing and simulating experiments; ConstructionFileSimulator, a field-tested Java project that showcases 'Experiment' objects expressed as flat files; and C6-Tools, a JavaScript project integrated with Google Sheets via Apps Script, providing a user-friendly interface for authoring and simulation of CF. The CF specification not only standardizes and modularizes molecular biology operations but also promotes collaboration, automation, and reuse, significantly reducing potential errors. The potential integration of CF with artificial intelligence, particularly GPT-4, suggests innovative automation strategies for synthetic biology. While challenges such as token limits, data storage, and biosecurity remain, proposed solutions promise a way forward in harnessing AI for experiment design. This shift from human-driven design to AI-assisted workflows, steered by high-level objectives, charts a potential future path in synthetic biology, envisioning an environment where complexities are managed more effectively.
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Inteligencia Artificial , Biología Sintética , Humanos , Programas Informáticos , Simulación por Computador , AutomatizaciónRESUMEN
BACKGROUND: With increasing sports medicine content on social media, we sought to identify the top sports medicine influencers on X (formerly Twitter) and analyse their common characteristics. METHODS: X influence scores for "Sports Medicine" were collected in November 2021 from Right Relevance. Accounts were then screened in a blind, duplicate manner for personal and X profile characteristics. RESULTS: Physical therapists/physiotherapists made up 48% of the top sports science and medicine influencers. Locations in the U.S. and U.K. were listed for half of the influencers. The mean h-index was 30.2 (95% CI = [24.8-35.6]) with a median of 22.0 (range = 1-101). Most individuals reported multiple practice settings (63%), with 60% associated with an academic setting. Professional (62%) and Olympic (49%) level athletics were most frequently mentioned, with soccer (48%) and rugby (30%) as the most common sports. Among 76 profiles with URLs, most were linked to personal websites (57.9%). CONCLUSION: The top influencers on X consisted of accredited sports science and medicine professionals across various locations and occupations, providing ample networking and collaboration opportunities. The relatively high h-index in this study suggests sports science and medicine influencers on X are notable contributors to academic literature.
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INTRODUCTION: Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live-attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients. METHODS: Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included. RESULTS: We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤ .0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft-versus-host disease (GVHD) did not affect the compliance with measles (p = .08) or YF vaccination (p = .7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p < .0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination. CONCLUSION: A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem.