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Survival requires the selection of appropriate behaviour in response to threats, and dysregulated defensive reactions are associated with psychiatric illnesses such as post-traumatic stress and panic disorder1. Threat-induced behaviours, including freezing and flight, are controlled by neuronal circuits in the central amygdala (CeA)2; however, the source of neuronal excitation of the CeA that contributes to high-intensity defensive responses is unknown. Here we used a combination of neuroanatomical mapping, in vivo calcium imaging, functional manipulations and electrophysiology to characterize a previously unknown projection from the dorsal peduncular (DP) prefrontal cortex to the CeA. DP-to-CeA neurons are glutamatergic and specifically target the medial CeA, the main amygdalar output nucleus mediating conditioned responses to threat. Using a behavioural paradigm that elicits both conditioned freezing and flight, we found that CeA-projecting DP neurons are activated by high-intensity threats in a context-dependent manner. Functional manipulations revealed that the DP-to-CeA pathway is necessary and sufficient for both avoidance behaviour and flight. Furthermore, we found that DP neurons synapse onto neurons within the medial CeA that project to midbrain flight centres. These results elucidate a non-canonical top-down pathway regulating defensive responses.
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Reacción de Prevención , Núcleo Amigdalino Central , Vías Nerviosas , Neuronas , Reacción de Prevención/fisiología , Núcleo Amigdalino Central/citología , Núcleo Amigdalino Central/fisiología , Neuronas/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Fármacos actuantes sobre Aminoácidos Excitadores/farmacología , Ácido Glutámico/metabolismo , Vías Nerviosas/fisiología , Calcio/análisis , Electrofisiología , Puente/citología , Puente/fisiologíaRESUMEN
Current vaccine efforts to combat SARS-CoV-2 are focused on the whole spike protein administered as mRNA, viral vector, or protein subunit. However, the SARS-CoV-2 receptor-binding domain (RBD) is the immunodominant portion of the spike protein, accounting for 90% of serum neutralizing activity. In this study, we constructed several versions of RBD and together with aluminum hydroxide or DDA (dimethyldioctadecylammonium bromide)/TDB (d-(+)-trehalose 6,6'-dibehenate) adjuvant evaluated immunogenicity in mice. We generated human angiotensin-converting enzyme 2 knock-in mice to evaluate vaccine efficacy in vivo following viral challenge. We found that 1) subdomain (SD)1 was essential for the RBD to elicit maximal immunogenicity; 2) RBDSD1 produced in mammalian HEK cells elicited better immunogenicity than did protein produced in insect or yeast cells; 3) RBDSD1 combined with the CD4 Th1 adjuvant DDA/TDB produced higher neutralizing Ab responses and stronger CD4 T cell responses than did aluminum hydroxide; 4) addition of monomeric human Fc receptor to RBDSD1 (RBDSD1Fc) significantly enhanced immunogenicity and neutralizing Ab titers; 5) the Beta version of RBDSD1Fc provided a broad range of cross-neutralization to multiple antigenic variants of concern, including Omicron; and 6) the Beta version of RBDSD1Fc with DDA/TDB provided complete protection against virus challenge in the knock-in mouse model. Thus, we have identified an optimized RBD-based subunit vaccine suitable for clinical trials.
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COVID-19 , Vacunas Virales , Humanos , Animales , Ratones , SARS-CoV-2 , Vacunas contra la COVID-19 , Hidróxido de Aluminio , Glicoproteína de la Espiga del Coronavirus , Vacunas de Subunidad , Anticuerpos Antivirales , Anticuerpos Neutralizantes , MamíferosRESUMEN
An efficient approach for 1,2-difunctionalization of aromatic olefins and the synthesis of functionalized 1,4-diols monoethers has been established via a photoinduced three-component reaction of an α-alkoxycarboxylic acid, an aromatic olefin, and an aldehyde. The reaction proceeds by photoinduced oxidative decarboxylation of the carboxylic acid followed by the addition of the α-alkoxyalkyl radical to the olefin, one-electron reduction of the addition radical, and the nucleophilic attack of the resulting carbanion to the aldehyde. Besides the convenient one-pot protocol of the three-component reaction, this method offers several other advantages, including good functional group tolerance for the three substrates, gentle reaction conditions, and ease of scaling up. The reaction mechanism has been investigated through free radical trapping experiment and isotope labeling experiments.
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BACKGROUND: The design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design. METHODS: PVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-|1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies. RESULTS: Overall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes. CONCLUSIONS: A flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development. TRIAL REGISTRATION: NCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).
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Miositis Osificante , Osificación Heterotópica , Humanos , Miositis Osificante/tratamiento farmacológico , Osificación Heterotópica/tratamiento farmacológico , Estudios Prospectivos , Enfermedades Raras , Ensayos Clínicos Controlados Aleatorios como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).
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Acondroplasia/tratamiento farmacológico , Crecimiento/efectos de los fármacos , Péptido Natriurético Tipo-C/análogos & derivados , Osteogénesis/efectos de los fármacos , Acondroplasia/fisiopatología , Adolescente , Biomarcadores/análisis , Estatura/efectos de los fármacos , Niño , Preescolar , Colágeno/sangre , GMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Femenino , Gráficos de Crecimiento , Humanos , Inyecciones Subcutáneas , Masculino , Péptido Natriurético Tipo-C/administración & dosificación , Péptido Natriurético Tipo-C/efectos adversos , Péptido Natriurético Tipo-C/uso terapéuticoRESUMEN
PURPOSE: We report the first prospective, international, natural history study of the ultra-rare genetic disorder fibrodysplasia ossificans progressiva (FOP). FOP is characterized by painful, recurrent flare-ups, and disabling, cumulative heterotopic ossification (HO) in soft tissues. METHODS: Individuals aged ≤65 years with classical FOP (ACVR1R206H variant) were assessed at baseline and over 36 months. RESULTS: In total, 114 individuals participated; 33 completed the study (mean follow up: 26.8 months). Median age was 15.0 (range: 4-56) years; 54.4% were male. During the study, 82 (71.9%) individuals reported 229 flare-ups (upper back: 17.9%, hip: 14.8%, shoulder: 10.9%). After 84 days, 14 of 52 (26.9%) imaged flare-ups had new HO at the flare-up site (mean new HO volume: 28.8 × 103 mm3). Mean baseline low-dose whole-body computed tomography (excluding head) HO volume was 314.4 × 103 mm3; lowest at 2 to <8 years (68.8 × 103 mm3) and increasing by age (25-65 years: 575.2 × 103 mm3). The mean annualized volume of new HO was 23.6 × 103 mm3/year; highest at 8 to <15 and 15 to <25 years (21.9 × 103 and 41.5 × 103 mm3/year, respectively) and lowest at 25 to 65 years (4.6 × 103 mm3/year). CONCLUSION: Results from individuals receiving standard care for up to 3 years in this natural history study show the debilitating effect and progressive nature of FOP cross-sectionally and longitudinally, with greatest progression during childhood and early adulthood.
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Miositis Osificante , Osificación Heterotópica , Adolescente , Adulto , Femenino , Humanos , Masculino , Miositis Osificante/diagnóstico por imagen , Miositis Osificante/epidemiología , Osificación Heterotópica/diagnóstico por imagen , Osificación Heterotópica/genética , Dolor , Estudios Prospectivos , Preescolar , Niño , Adulto Joven , Persona de Mediana EdadRESUMEN
PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.
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Acondroplasia , Niño , Masculino , Femenino , Humanos , Preescolar , Estudios Prospectivos , Acondroplasia/epidemiología , Acondroplasia/genética , Acondroplasia/diagnóstico , EstaturaRESUMEN
After the March 2020 declaration of the COVID-19 pandemic in the United States, an analysis of provider ordering data from the federally funded Vaccines for Children program found a substantial decrease in routine pediatric vaccine ordering (1), and data from New York City and Michigan indicated sharp declines in routine childhood vaccine administration in these areas (2,3). In November 2020, CDC interim guidance stated that routine vaccination of children and adolescents should remain an essential preventive service during the COVID-19 pandemic (4,5). To further understand the impact of the pandemic on routine childhood and adolescent vaccination, vaccine administration data during March-September 2020 from 10 U.S. jurisdictions with high-performing* immunization information systems were assessed. Fewer administered doses of routine childhood and adolescent vaccines were recorded in all 10 jurisdictions during March-September 2020 compared with those recorded during the same period in 2018 and 2019. The number of vaccine doses administered substantially declined during March-May 2020, when many jurisdictions enacted stay-at-home orders. After many jurisdictions lifted these orders, the number of vaccine doses administered during June-September 2020 approached prepandemic baseline levels, but did not increase to the level that would have been necessary to catch up children who did not receive routine vaccinations on time. This lag in catch-up vaccination might pose a serious public health threat that would result in vaccine-preventable disease outbreaks, especially in schools that have reopened for in-person learning. During the past few decades, the United States has achieved a substantial reduction in the prevalence of vaccine-preventable diseases driven in large part to the ongoing administration of routinely recommended pediatric vaccines. These efforts need to continue even during the COVID-19 pandemic to reduce the morbidity and mortality from vaccine-preventable diseases. Health care providers should assess the vaccination status of all pediatric patients, including adolescents, and contact those who are behind schedule to ensure that all children are fully vaccinated.
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COVID-19/epidemiología , Pandemias , Vacunación/estadística & datos numéricos , Vacunas/administración & dosificación , Adolescente , Niño , Preescolar , Humanos , Lactante , Estados Unidos/epidemiologíaRESUMEN
Influenza causes considerable morbidity and mortality in the United States. Between 2010 and 2020, an estimated 9-41 million cases resulted in 140,000-710,000 hospitalizations and 12,000-52,000 deaths annually (1). As the United States enters the 2021-22 influenza season, the potential impact of influenza illnesses is of concern given that influenza season will again coincide with the ongoing COVID-19 pandemic, which could further strain overburdened health care systems. The Advisory Committee on Immunization Practices (ACIP) recommends routine annual influenza vaccination for the 2021-22 influenza season for all persons aged ≥6 months who have no contraindications (2). To assess the potential impact of the COVID-19 pandemic on influenza vaccination coverage, the percentage change between administration of at least 1 dose of influenza vaccine during September-December 2020 was compared with the average administered in the corresponding periods in 2018 and 2019. The data analyzed were reported from 11 U.S. jurisdictions with high-performing state immunization information systems.* Overall, influenza vaccine administration was 9.0% higher in 2020 compared with the average in 2018 and 2019, combined. However, in 2020, the number of influenza vaccine doses administered to children aged 6-23 months and children aged 2-4 years, was 13.9% and 11.9% lower, respectively than the average for each age group in 2018 and 2019. Strategic efforts are needed to ensure high influenza vaccination coverage among all age groups, especially children aged 6 months-4 years who are not yet eligible to receive a COVID-19 vaccine. Administration of influenza vaccine and a COVID-19 vaccine among eligible populations is especially important to reduce the potential strain that influenza and COVID-19 cases could place on health care systems already overburdened by COVID-19.
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COVID-19/epidemiología , Vacunas contra la Influenza/administración & dosificación , Pandemias , Vacunación/estadística & datos numéricos , Adolescente , Adulto , Comités Consultivos , Anciano , Centers for Disease Control and Prevention, U.S. , Niño , Preescolar , Humanos , Inmunización/normas , Lactante , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Persona de Mediana Edad , Estaciones del Año , Estados Unidos/epidemiología , Adulto JovenRESUMEN
PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.
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Enfermedades Autoinmunes/epidemiología , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/complicaciones , Histona Demetilasas/genética , Proteínas de Neoplasias/genética , Enfermedades de Inmunodeficiencia Primaria/epidemiología , Enfermedades Vestibulares/complicaciones , Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/inmunología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , Prevalencia , Sistema de Registros , Índice de Severidad de la Enfermedad , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/inmunología , Adulto JovenRESUMEN
Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.
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Anomalías Múltiples/genética , Proteínas de Unión al ADN/genética , Cara/anomalías , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/fisiopatología , Proteínas de Neoplasias/genética , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/fisiopatología , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/fisiopatología , Adolescente , Estatura , Índice de Masa Corporal , Peso Corporal , Niño , Preescolar , Cara/fisiopatología , Femenino , Gráficos de Crecimiento , Enfermedades Hematológicas/diagnóstico , Histona Demetilasas/genética , Humanos , Masculino , Mutación/genética , Enfermedades Vestibulares/diagnósticoRESUMEN
The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P < 0.001), and was significantly associated with decreased HGA clearance (CLHGA ) (P < 0.001) and FEHGA (P < 0.001). CLHGA and FEHGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasising the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration.
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Alcaptonuria/metabolismo , Tasa de Filtración Glomerular , Ácido Homogentísico/metabolismo , Riñón/metabolismo , Ocronosis/etiología , Adulto , Alcaptonuria/fisiopatología , Estudios de Casos y Controles , Creatinina/metabolismo , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Ocronosis/fisiopatología , Fenilalanina/metabolismo , Factores Sexuales , Tirosina/metabolismoRESUMEN
CONTEXT: The methanol extracts from Hippeastrum reticulatum (L'Hér.) Herb. (Amaryllidaceae) (HR) display acetylcholinesterase inhibitory (AChEI) activity. OBJECTIVE: AChEI of alkaloids isolated from HR bulbs and the ameliorating effects of the alkaloid fraction (AHR) on memory and cognitive dysfunction in scopolamine-treated mice were investigated. MATERIALS AND METHODS: Alkaloids were isolated by column chromatography and identified by spectroscopy. AChEI was evaluated using the modified Ellman's method. Sixty Swiss male mice were randomly divided into six groups, received samples for 15 days. Normal group received saline, scopolamine-treated group scopolamine (1.5 mg/kg, intraperitoneal injection). Test groups received AHR (5, 10 and 15 mg/kg, per os) and positive control group donepezil (5 mg/kg, per os), administered 1 h before the test, scopolamine was injected 30 min prior to testing. The cognitive-enhancing activity of AHR against scopolamine-induced memory impairments was investigated using Y-maze, the novel object recognition test (NORT) and the Morris water maze (MWM) test. RESULTS: Seven alkaloids were isolated for the first time from the genus Hippeastrum: trans-dihydronarciclasine (1), N-chloromethylnarcissidinium (2), narciprimin (3), narciclasine-4-O-ß-d-xylopyranoside (4), N-methyltyramine (5), 3ß,11α-dihydroxy-1,2-dehydrocrinane (6) and brunsvigine (7); three are new compounds (2, 5, 6). Among them, 2-3 and 5-6 showed AChEI in vitro with IC50 values of 29.1, 46.4, 70.1 and 104.5 µg/mL, respectively. The anti-AChEI of 2, 5 and 6 are reported for the first time. In in vivo test, AHR (15 mg/kg) significantly increased in spontaneous alternation performance in the Y-maze test (p < 0.01), it significantly increased the time spent exploring the novel object (p < 0.05) comparison with scopolamine-treated group. The administration of AHR at doses 10 and 15 mg/kg significantly decreased escapes latency and swimming distance to the platform on day 6 compared to these in day 1 (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: AHR could be a potential candidate of future trials for treatment of memory and cognitive dysfunction in Alzheimer's disease.
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Alcaloides/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Amaryllidaceae/química , Extractos Vegetales/farmacología , Alcaloides/administración & dosificación , Alcaloides/aislamiento & purificación , Animales , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/aislamiento & purificación , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Donepezilo/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Ratones , Extractos Vegetales/administración & dosificación , Reconocimiento en Psicología , Escopolamina , Aprendizaje Espacial/efectos de los fármacosRESUMEN
Snakes and conspecific faces are quickly and efficiently detected in primates. Because the medial prefrontal cortex (mPFC) has been implicated in attentional allocation to biologically relevant stimuli, we hypothesized that it might also be highly responsive to snakes and conspecific faces. In this study, neuronal responses in the monkey mPFC were recorded, while monkeys discriminated 8 categories of visual stimuli. Here, we show that the monkey mPFC neuronal responses to snakes and conspecific faces were unique. First, the ratios of the neurons that responded strongly to snakes and monkey faces were greater than those of the neurons that responded strongly to the other stimuli. Second, mPFC neurons responded stronger and faster to snakes and monkey faces than the other categories of stimuli. Third, neuronal responses to snakes were unaffected by low-pass filtering of the images. Finally, activity patterns of responsive mPFC neurons discriminated snakes from the other stimuli in the second 50 ms period and monkey faces in the third period after stimulus onset. These response features indicate that the mPFC processes fast and coarse visual information of snakes and monkey faces, and support the hypothesis that snakes and social environments have shaped the primate visual system over evolutionary time.
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Macaca/fisiología , Reconocimiento Visual de Modelos/fisiología , Corteza Prefrontal/fisiología , Serpientes , Animales , Cara , Femenino , MasculinoRESUMEN
Streptavidin (SA), and other related proteins, has been isolated from a wide range of organisms, including bacteria, fungi, frogs, fish, and birds. Although their original function is not well understood, they have found an important place in biotechnology based on their unique ability to bind biotin molecules with high affinity and specificity. The SA-biotin interaction is robust and easy to incorporate into different designs, and as such, it is used when reliable molecule interaction is needed under poorly controlled experimental conditions. There are continued efforts to engineer these proteins to modulate their size, valency, and affinity, since the optimum molecular properties vary depending on individual applications. This review will describe recent developments in streptavidin engineering to meet these requirements, including those that form novel oligomeric states, e.g., a monomer, have fewer functional biotin-binding sites, or bind biotin with reduced affinity. We also examine various reported applications of both natural or engineered SA constructs in cell biology, biochemistry, genetics, synthetic chemistry, cancer therapy, drug delivery, and nanotechnology to illustrate the breadth of modern science that is advanced by the endogenous and engineered SA-biotin interactions.
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Biotecnología/métodos , Biotina/metabolismo , Ingeniería de Proteínas/métodos , Estreptavidina/química , Sitios de Unión , Sistemas CRISPR-Cas , Tratamiento Basado en Trasplante de Células y Tejidos , Cinética , Nanotecnología , Unión ProteicaRESUMEN
Purpose. To investigate the knowledge, attitude, and practice of surgeons toward introducing novel surgical techniques in Egypt, Palestine, and Vietnam. Summary Background Data. Despite the recent advances in modern surgical care and its role in advancing the quality and the length of lives, surgery in the developing world has stagnated or even regressed. Methods. A survey was undertaken among the surgeons in 9 hospitals belonging to the 3 countries. Questions were categorized into knowledge, attitude, and practice questions. Meta-analyses were performed to estimate the event rate and compare between knowledge and practice, senior and junior surgeons. Results. A total of 244 responses, with a response rate of 79.7%, were included in the analysis. Regarding knowledge and attitude, the results were satisfactory except that only 55.8% of surgeons appraised their level of education and 43.3% wanted to earn money from the novel procedure. There was a significant difference between knowledge and practice regarding getting informed consent from the patients (P = .024), discussing the novelty of the procedure (P < .001), discussing the alternative procedures (P < .001), discussing the surgeons' experience and level of skills (P < .001), discussing the risk of the new procedure (P < .001), and monitoring the outcomes after the new procedure (P < .001). Conclusions. Most surgeons have sufficient knowledge and are motivated regarding adopting novel surgical techniques in order to provide the best care for the patients. However, there was a gap between knowledge and practice. Training programs and evidence-based guidelines regarding the introduction of novel surgical techniques are needed to overcome these challenges.
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Difusión de Innovaciones , Conocimientos, Actitudes y Práctica en Salud , Cirujanos/psicología , Procedimientos Quirúrgicos Operativos/tendencias , Adulto , Estudios Transversales , Egipto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medio Oriente , Encuestas y Cuestionarios , VietnamRESUMEN
Motivation: Multiple sequence alignment (MSA) is commonly used to analyze sets of homologous protein or DNA sequences. This has lead to the development of many methods and packages for MSA over the past 30 years. Being able to compare different methods has been problematic and has relied on gold standard benchmark datasets of 'true' alignments or on MSA simulations. A number of protein benchmark datasets have been produced which rely on a combination of manual alignment and/or automated superposition of protein structures. These are either restricted to very small MSAs with few sequences or require manual alignment which can be subjective. In both cases, it remains very difficult to properly test MSAs of more than a few dozen sequences. PREFAB and HomFam both rely on using a small subset of sequences of known structure and do not fairly test the quality of a full MSA. Results: In this paper we describe QuanTest, a fully automated and highly scalable test system for protein MSAs which is based on using secondary structure prediction accuracy (SSPA) to measure alignment quality. This is based on the assumption that better MSAs will give more accurate secondary structure predictions when we include sequences of known structure. SSPA measures the quality of an entire alignment however, not just the accuracy on a handful of selected sequences. It can be scaled to alignments of any size but here we demonstrate its use on alignments of either 200 or 1000 sequences. This allows the testing of slow accurate programs as well as faster, less accurate ones. We show that the scores from QuanTest are highly correlated with existing benchmark scores. We also validate the method by comparing a wide range of MSA alignment options and by including different levels of mis-alignment into MSA, and examining the effects on the scores. Availability and Implementation: QuanTest is available from http://www.bioinf.ucd.ie/download/QuanTest.tgz. Contact: quan.le@ucd.ie. Supplementary information: Supplementary data are available at Bioinformatics online.
Asunto(s)
Estructura Secundaria de Proteína , Alineación de Secuencia/métodos , Análisis de Secuencia de Proteína/métodos , Programas Informáticos , Algoritmos , Secuencia de Aminoácidos , Benchmarking , Biología Computacional/métodos , Exactitud de los Datos , Alineación de Secuencia/normas , Análisis de Secuencia de Proteína/normasRESUMEN
OBJECTIVE: The aim of this work was to assess baseline serum levels of established biomarkers related to inflammation and oxidative stress in samples from alkaptonuric subjects enrolled in SONIA1 (n = 40) and SONIA2 (n = 138) clinical trials (DevelopAKUre project). METHODS: Baseline serum levels of Serum Amyloid A (SAA), IL-6, IL-1ß, TNFα, CRP, cathepsin D (CATD), IL-1ra, and MMP-3 were determined through commercial ELISA assays. Chitotriosidase activity was assessed through a fluorimetric method. Advanced Oxidation Protein Products (AOPP) were determined by spectrophotometry. Thiols, S-thiolated proteins and Protein Thiolation Index (PTI) were determined by spectrophotometry and HPLC. Patients' quality of life was assessed through validated questionnaires. RESULTS: We found that SAA serum levels were significantly increased compared to reference threshold in 57.5% and 86% of SONIA1 and SONIA2 samples, respectively. Similarly, chitotriosidase activity was above the reference threshold in half of SONIA2 samples, whereas CRP levels were increased only in a minority of samples. CATD, IL-1ß, IL-6, TNFα, MMP-3, AOPP, thiols, S-thiolated protein and PTI showed no statistically significant differences from control population. We provided evidence that alkaptonuric patients presenting with significantly higher SAA, chitotriosidase activity and PTI reported more often a decreased quality of life. This suggests that worsening of symptoms in alkaptonuria (AKU) is paralleled by increased inflammation and oxidative stress, which might play a role in disease progression. CONCLUSIONS: Monitoring of SAA may be suggested in AKU to evaluate inflammation. Though further evidence is needed, SAA, chitotriosidase activity and PTI might be proposed as disease activity markers in AKU.
Asunto(s)
Alcaptonuria/sangre , Inflamación/sangre , Estrés Oxidativo , Adulto , Productos Avanzados de Oxidación de Proteínas/sangre , Alcaptonuria/metabolismo , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Catepsina D/sangre , Femenino , Hexosaminidasas/sangre , Humanos , Inflamación/metabolismo , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Metaloproteinasa 3 de la Matriz/sangre , Persona de Mediana Edad , Proteína Amiloide A Sérica/análisis , Compuestos de Sulfhidrilo/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto JovenRESUMEN
0D/2D heterojunctions, especially quantum dots (QDs)/nanosheets (NSs) have attracted significant attention for use of photoexcited electrons/holes due to their high charge mobility. Herein, unprecedent heterojunctions of vanadate (AgVO3 , BiVO4 , InVO4 and CuV2 O6 ) QDs/graphitic carbon nitride (g-C3 N4 ) NSs exhibiting multiple unique advances beyond traditional 0D/2D composites have been developed. The photoactive contribution, up-conversion absorption, and nitrogen coordinating sites of g-C3 N4 NSs, highly dispersed vanadate nanocrystals, as well as the strong coupling and band alignment between them lead to superior visible-light-driven photoelectrochemical (PEC) and photocatalytic performance, competing with the best reported photocatalysts. This work is expected to provide a new concept to construct multifunctional 0D/2D nanocomposites for a large variety of opto-electronic applications, not limited in photocatalysis.
RESUMEN
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.