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CONTEXT: Analytic exchange-correlation kernel formulations are of the outermost importance for density functional theory (DFT) perturbation calculations. In this paper, the working equation for the exchange-correlation kernel of the generalized gradient approximation (GGA) for perturbation dependent auxiliary functions is derived and discussed in the framework of auxiliary density functional theory (ADFT). The presented new formulation is extended to the unrestricted approach, too. A comprehensive discussion of the implementation of the GGA ADFT kernel, using either the native exchange-correlation functional implementations in deMon2k or the ones from the LibXC library, is given. Calculations with analytic exchange-correlation kernels are compared to their finite difference counterparts. The obtained results are in quantitative agreement. Nevertheless, analytic GGA ADFT kernel implementations show substantial improvement in the computational performance. Similar results are reported for analytic second derivatives of effective core potential (ECP) and model core potential (MCP) matrix elements when compared to their finite difference counterparts in molecular frequency analyses. METHOD: All calculations are performed in the framework of ADFT as implemented in deMon2k. In the ADFT analytic frequency calculations, auxiliary density perturbation theory was used. The underlying two-center exchange-correlation kernel matrix elements are calculated by numerical integration either with analytic or finite difference kernel expressions. Validation calculations are performed with the VWN and PBE functionals employing DFT-optimized DZVP basis sets in conjunction with automatically generated GEN-A2 auxiliary density function sets. In the (Pt3Cu)n cluster benchmark calculations, the RPBE functional was used. For Pt atoms, the quasi-relativistic LANL2DZ effective core potential with the corresponding valence basis set was employed, whereas for Cu atoms, the all-electron DFT-optimized TZVP basis was applied. The auxiliary density was expanded by the automatically generated GEN-A2* auxiliary function set. We run all benchmark calculations in parallel on 24 cores.
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Objectives: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. Methods: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. Results: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. Conclusion: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.
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OBJECTIVES: To examine drug overdose records in Brazil from 2000 to 2020, analyzing trends over time in overdoses and overall sociodemographic characteristics of the deceased. METHODS: Using data from the Brazilian Mortality Information System (Sistema de Informações sobre Mortalidade), we identified records from 2000-2020 in which the underlying cause-of-death was one of the following codes: X40-X45 (accidental poisoning), X60-X65 (intentional poisoning), or Y10-Y15 (undetermined intentionality poisoning). The Brazilian dataset included 21,410 deaths. We used joinpoint regression analysis to assess changes in trends over time. RESULTS: People who died of drug overdoses in Brazil between 2000 and 2020 had a mean age of 38.91 years; 38.45% were women, and 44.01% were identified as White. Of the overdose deaths, 44.70% were classified as intentional and 32.12% were classified as unintentional. Among the identified drugs, stimulants were the most common class. However, most records did not report which drug was responsible for death. CONCLUSION: Sociodemographic trends in overdose deaths in Brazil must guide country-specific policies. Nevertheless, data collection protocols must be improved, particularly regarding the drug used in overdoses.
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Estimulantes do Sistema Nervoso Central , Overdose de Drogas , Feminino , Humanos , Adulto , Masculino , Brasil/epidemiologiaRESUMO
The random phase approximation of time-dependent auxiliary density functional theory (TDADFT) is rederived from auxiliary density perturbation theory. Our exhaustive validation of TDADFT reveals an upshift of the excitation energies by â¼0.1 eV with respect to standard time-dependent density functional theory. For the computationally efficient implementation of TDADFT, floating point operation optimized three-center electron repulsion integral recurrence relations and their double asymptotic expansions are implemented into the Davidson solver. The computational efficiency of TDADFT is benchmarked with four sets of molecules comprising alkanes, fullerenes, DNA fragments, and zeolites. The results show that TDADFT has a computational scaling between 1.3 and 1.9 with respect to the number of basis functions, which is lower than the scaling of standard time-dependent density functional theory. Due to its computational simplifications, TDADFT is particularly well suited for Born-Oppenheimer molecular dynamics simulations. As illustrative examples, we present the temperature effects on the gas-phase absorption spectra of benzene, naphthalene, and anthracene.
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Simulação de Dinâmica Molecular , Teoria Quântica , Teoria da Densidade Funcional , Elétrons , AlcanosRESUMO
For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.
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Diferenciação Sexual , Cromossomo Y , Feminino , Masculino , Animais , Diferenciação Sexual/genética , Cromossomos Sexuais/genética , Cromossomos Sexuais/metabolismo , Caracteres Sexuais , Hormônios Gonadais/metabolismo , Encéfalo/metabolismo , Epigênese Genética , Cromossomo XRESUMO
Background: There is sparse knowledge on overdose deaths resulting from non-benzodiazepines and gabapentinoids usage. We examined overdose death rate across demographics categories and the overdose death trends over time. Methods: Using data from the National Center for Health Statistics (USA), we identified 21,167 persons that died with an overdose ICD code as the underlying cause of death and had a T42.6/T42.7 ICD code, which include gabapentinoids and z-drugs, among their multiple causes of death. The overdose death rate was calculated per 100,000 persons for every year between 2000 and 2018. We used joinpoint regression analyses to assess trends over time. Results: We identified a rise in the proportion of deaths with a T42.6/T42.7 ICD code between 2000 and 2006 (yearly change: +0.06) and between 2006 and 2015 (yearly change: +0.32). From 2000 to 2008, the proportion of deaths with any other T code rose significantly (yearly change: +3.56). Between 2008 and 2018, there was also a significant rise (yearly change: +1.31). From 2000 to 2015, the proportion of deaths with a T42.6/T42.7 ICD code with any other T code rose (yearly change: +2.58). From 2000 to 2015, the proportion of deaths with a T42.6/T42.7 ICD code with a concurrent benzodiazepine T code rose (yearly change: +1.98). From 2000 to 2005, the proportion of alcohol T codes rose non-significantly (yearly change: +0.35). Finally, the proportion of alcohol T codes fell significantly between 2008 and 2018 (yearly change: - 0.74). Interpretation: Deaths due to non-benzodiazepine hypnotics and gabapentinoids increased significantly over the last two decades. Clinicians should not assume that replacing benzodiazepines and opioids with these medications necessarily lowers risk to the patient. Funding: This study was funded by an internal grant from the Columbia University President's Global Innovation Fund (PI: Martins).
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Multiple sclerosis (MS) is an immune-mediated and degenerating disease in which myelin sheaths are damaged as a result of chronic progressive inflammation of the central nervous system. Tibolone [(7α,17α)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-in-3-one], a synthetic estrogenic compound with tissue-specific actions and used for menopausal hormone therapy, shows neuroprotective and antioxidant properties both in vivo and in vitro. In the present study, we analyzed whether tibolone plays a therapeutic role in experimental autoimmune encephalomyelitis (EAE) mice, a commonly used model of MS. Female C57BL/6 mice were induced with the myelin oligodendrocyte glycoprotein MOG35-55 and received s.c. tibolone (0.08 mg kg-1 ) injection every other day from the day of induction until death on the acute phase of the disease. Reactive gliosis, Toll like receptor 4 (TLR4), high mobility group box protein 1 (HMGB1), inflammasome parameters, activated Akt levels and myelin were assessed by a real-time polymerase chain reaction, immunohistochemistry, and western blot analysis. Our findings indicated that, in the EAE spinal cord, tibolone reversed the astrocytic and microglial reaction, and reduced the hyperexpression of TLR4 and HMGB1, as well as NLR family pyrin domain containing 3-caspase 1-interleukin-1ß inflammasome activation. At the same time, tibolone attenuated the Akt/nuclear factor kappa B pathway and limited the white matter demyelination area. Estrogen receptor expression was unaltered with tibolone treatment. Clinically, tibolone improved neurological symptoms without uterine compromise. Overall, our data suggest that tibolone may serve as a promising agent for the attenuation of MS-related inflammation.
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Encefalomielite Autoimune Experimental/tratamento farmacológico , Neurite (Inflamação)/prevenção & controle , Norpregnenos/uso terapêutico , Animais , Modelos Animais de Doenças , Progressão da Doença , Encefalomielite Autoimune Experimental/patologia , Feminino , Inflamação/patologia , Inflamação/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Neurite (Inflamação)/patologia , Fármacos Neuroprotetores/uso terapêutico , Indução de RemissãoRESUMO
Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide. We established hypothalamic neuronal cultures from wild-type or transgenic Four Core Genotypes mice, a model that allows evaluating the effect of sex chromosomes independently of gonadal type. X-linked genes Kdm6a, Eif2s3x and Ddx3x showed higher expression in XX compared to XY neurons, regardless of gonadal sex. Moreover, Kdm6a expression pattern with higher mRNA levels in XX than XY did not change with age at E14, P0, and P60 in hypothalamus or under 17ß-estradiol treatment in culture. Kdm6a pharmacological blockade by GSK-J4 reduced axonal length only in female neurons and decreased the expression of neuritogenic genes Neurod1, Neurod2 and Cdk5r1 in both sexes equally, while a sex-specific effect was observed in Ngn3. Finally, Kdm6a downregulation using siRNA reduced axonal length and Ngn3 expression only in female neurons, abolishing the sex differences observed in control conditions. Altogether, these results point to Kdm6a as a key mediator of the higher axogenesis and Ngn3 expression observed in XX neurons before the critical period of brain masculinization.
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Genes Ligados ao Cromossomo X/genética , Histona Desmetilases/genética , Histonas/genética , Hipotálamo/fisiologia , Neurônios/fisiologia , Diferenciação Sexual/genética , Animais , Axônios/fisiologia , Feminino , Masculino , Camundongos , Proteínas do Tecido Nervoso/genética , Caracteres SexuaisRESUMO
Objetivo. Describir la evidencia disponible sobre la trans-misión por Covid-19 e infecciones respiratorias agudas simi-lares al Covid-19 en espacios públicos abiertos. Material y métodos. La búsqueda incluyó 4 926 artículos en inglés de los años 2000 a 2020. Seis investigadores revisaron el título y el resumen de los artículos de Embase y PubMed; dos inves-tigadores revisaron los de medRxiv. Todos los investigadores revisaron textos completos y otros resolvieron las discre-pancias. Resultados. De los 21 artículos seleccionados, se observó que la presencia de virus en superficies públicas, aguas residuales y áreas exteriores no fue indicativa de trans-misión. No obstante, se observó que el uso de cubrebocas, el lavado de manos, el distanciamiento social, no asistir a eventos masivos y la movilidad individual a espacios públicos podría ayudar a reducir el riesgo de transmisión. Conclusión. Esta información podría coadyuvar a generar recomendaciones en salud pública, sin embargo, es recomendable actualizar esta revisión conforme avance la evidencia científica.
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COVID-19/transmissão , Infecções Respiratórias/transmissão , Doença Aguda , HumanosRESUMO
Resumen: Objetivo: Describir la evidencia disponible sobre la transmisión por Covid-19 e infecciones respiratorias agudas similares al Covid-19 en espacios públicos abiertos. Material y métodos: La búsqueda incluyó 4 926 artículos en inglés de los años 2000 a 2020. Seis investigadores revisaron el título y el resumen de los artículos de Embase y PubMed; dos investigadores revisaron los de medRxiv. Todos los investigadores revisaron textos completos y otros resolvieron las discrepancias. Resultados: De los 21 artículos seleccionados, se observó que la presencia de virus en superficies públicas, aguas residuales y áreas exteriores no fue indicativa de transmisión. No obstante, se observó que el uso de cubrebocas, el lavado de manos, el distanciamiento social, no asistir a eventos masivos y la movilidad individual a espacios públicos podría ayudar a reducir el riesgo de transmisión. Conclusión: Esta información podría coadyuvar a generar recomendaciones en salud pública, sin embargo, es recomendable actualizar esta revisión conforme avance la evidencia científica.
Abstract: Objective: To describe the available evidence on the transmission of Covid-19 or similar acute respiratory infections in open, public spaces. Materials and methods: Our search included 4 926 articles in English from 2000 to 2020. Six researchers reviewed the title and abstracts from Embase and PubMed databases, and two researchers reviewed medRxiv database. All reviewed full texts and others resolved the discrepancies. Results: A total of 21 articles were selected. The presence of the SARS-CoV-2 virus on public surfaces, sewage, and outdoor areas was not indicative of transmission. Nevertheless, we observed that applying preventive measures such as the use of face masks, hand washing, social distancing, restricting attendance to massive events, and reducing people's mobility to public spaces may reduce the risk of transmission. Conclusions: This information could help to generate public health recommendations. However, we advise updating this review as new evidence is generated.
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Tibolone (TIB), a selective tissue estrogenic activity regulator (STEAR) in clinical use by postmenopausal women, activates hormonal receptors in a tissue-specific manner. Estrogenic activity is present mostly in the brain, vagina, and bone, while the inactive forms predominate in the endometrium and breast. Conflicting literature on TIB's actions has been observed. While it has benefits for vasomotor symptoms, bone demineralization, and sexual health, a higher relative risk of hormone-sensitive cancer has been reported. In the brain, TIB can improve mood and cognition, neuroinflammation, and reactive gliosis. This review aims to discuss the systemic effects of TIB on peri- and post-menopausal women and its role in the brain. We suggest that TIB is a hormonal therapy with promising neuroprotective properties.
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Encéfalo/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Menopausa/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Norpregnenos/farmacologia , Encéfalo/imunologia , Encéfalo/metabolismo , Moduladores de Receptor Estrogênico/efeitos adversos , Feminino , Humanos , Menopausa/imunologia , Menopausa/metabolismo , Norpregnenos/efeitos adversosRESUMO
Hypothalamic neurons show sex differences in neuritogenesis, female neurons have longer axons and higher levels of the neuritogenic factor neurogenin 3 (Ngn3) than male neurons in vitro. Moreover, the effect of 17-ß-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the "four core genotypes" mouse model, in which the factors of "gonadal sex" and "sex chromosome complement" are dissociated. We showed that sex differences in neurite outgrowth are determined by sex chromosome complement (XX > XY). Moreover, E2 increased the mRNA expression of Ngn3 and axonal length only in XY neurons. ERα/ß expressions are regulated by sex chromosome complement; however, E2-effect on Ngn3 expression in XY neurons was only fully reproduced by PPT, a specific ligand of ERα, and prevented by MPP, a specific antagonist of ERα. Together our data indicate that sex chromosomes regulate early development of hypothalamic neurons by orchestrating not only sex differences in neuritogenesis, but also regulating the effect of E2 on Ngn3 expression through activation of ERα in hypothalamic neurons.
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Axônios , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Estradiol/fisiologia , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Neurônios/metabolismo , Cromossomos Sexuais , Animais , Feminino , Masculino , CamundongosRESUMO
Sensation seeking has been proposed as a risk factor for gambling and gambling problems; however, existing evidence for a relationship between sensation seeking and gambling behaviors is inconclusive and data are lacking for emerging adults and racial and ethnic minorities. In this longitudinal study, we explored the association between developmental trajectories of sensation seeking in childhood and adolescence and gambling and gambling problems in early adulthood in individuals of Puerto Rican origin. Gambling data were collected during 2014-2018 from a subsample of participants in the Boricua Youth Study who were recruited in the South Bronx of New York City and in San Juan and Caguas, Puerto Rico. Sensation seeking was measured using a 10-item instrument modified from the scale created by Russo et al. for use in children as young as 5 years old. Developmental trajectories of age-adjusted sensation seeking were created using growth mixture models. Gambling and gambling problems were assessed based on the Canadian Adolescent Gambling Inventory (CAGI) Version 1.09. Data were analyzed using descriptive methods and multivariable logistic regression. Individuals in the high sensation-seeking class had lower adjusted odds of past-year gambling (OR = .36; 95% confidence interval [.14, .92]) than did those in the normative sensation-seeking class, whereas no differences were observed for individuals in the low and accelerated classes. No relationship was found between sensation seeking and past-year gambling problems. Given the severe consequences of early initiation of gambling and gambling problems, other early life risk factors and alternative hypotheses for the elevated prevalence of gambling problems in young adults and racial and ethnic minority populations should be explored. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
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Comportamento Infantil , Jogo de Azar/etnologia , Hispânico ou Latino/estatística & dados numéricos , Adolescente , Comportamento do Adolescente , Adulto , Criança , Pré-Escolar , Etnicidade , Feminino , Jogo de Azar/epidemiologia , Hispânico ou Latino/psicologia , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Grupos Minoritários , Cidade de Nova Iorque/epidemiologia , Prevalência , Porto Rico/etnologia , Fatores de Risco , Sensação , Adulto JovemRESUMO
The high concentrations of free fatty acids as a consequence of obesity and being overweight have become risk factors for the development of different diseases, including neurodegenerative ailments. Free fatty acids are strongly related to inflammatory events, causing cellular and tissue alterations in the brain, including cell death, deficits in neurogenesis and gliogenesis, and cognitive decline. It has been reported that people with a high body mass index have a higher risk of suffering from Alzheimer's disease. Hormones such as oestradiol not only have beneficial effects on brain tissue, but also exert some adverse effects on peripheral tissues, including the ovary and breast. For this reason, some studies have evaluated the protective effect of oestrogen receptor (ER) agonists with more specific tissue activities, such as the neuroactive steroid tibolone. Activation of ERs positively affects the expression of pro-survival factors and cell signalling pathways, thus promoting cell survival. This review aims to discuss the relationship between lipotoxicity and the development of neurodegenerative diseases. We also elaborate on the cellular and molecular mechanisms involved in neuroprotection induced by oestrogens.