Design, synthesis, and biological evaluation of new thalidomide–donepezil hybrids as neuroprotective agents targeting cholinesterases and neuroinflammation

A new series of eight multifunctional thalidomide–donepezil hybrids were synthesized based on the multi target-directed ligand strategy and evaluated as potential neuroprotective, cholinesterase inhibitors and anti neuroinflammatory agents against neurodegenerative diseases. A molecular hybridization approach was used for structural design by combining the N-benzylpiperidine pharmacophore of donepezil and the isoindoline 1,3-dione fragment from the thalidomide structure. The most promising compound, PQM-189 (3g), showed good AChE inhibitory activity with an IC50 value of 3.15 μM, which was predicted by docking studies as interacting with the enzyme in the same orientation observed in the AChE–donepezil complex and a similar profile of interaction. Additionally, compound 3g significantly decreased iNOS and IL-1β levels by 43% and 39%, respectively, after 24 h of incubation with lipopolysaccharide. In vivo data confirmed the ability of 3g to prevent locomotor impairment and changes in feeding behavior elicited by lipopolysaccharide. Moreover, the PAMPA assay evidenced adequate blood–brain barrier and gastrointestinal tract permeabilities with an Fa value of 69.8%. Altogether, these biological data suggest that compound 3g can treat the inflammatory process and oxidative stress resulting from the overexpression of iNOS and therefore the increase in reactive nitrogen species, and regulate the release of pro-inflammatory cytokines such as IL-1β. In this regard, compound PQM-189 (3g) was revealed to be a promising neuroprotective and anti-neuroinflammatory agent with an innovative thalidomide–donepezil-based hybrid molecular architectur

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Diretrizes Brasileiras de Medidas da Pressão Arterial Dentro e Fora do Consultório – 2023

Hypertension is one of the primary modifiable risk factors for morbidity and mortality worldwide, being a major risk factor for coronary artery disease, stroke, and kidney failure. Furthermore, it is highly prevalent, affecting more than one-third of the global population. Blood pressure measurement is a MANDATORY procedure in any medical care setting and is carried out by various healthcare professionals. However, it is still commonly performed without the necessary technical care. Since the diagnosis relies on blood pressure measurement, it is clear how important it is to handle the techniques, methods, and equipment used in its execution with care. It should be emphasized that once the diagnosis is made, all short-term, medium-term, and long-term investigations and treatments are based on the results of blood pressure measurement. Therefore, improper techniques and/or equipment can lead to incorrect diagnoses, either underestimating or overestimating values, resulting in inappropriate actions and significant health and economic losses for individuals and nations. Once the correct diagnosis is made, as knowledge of the importance of proper treatment advances, with the adoption of more detailed normal values and careful treatment objectives towards achieving stricter blood pressure goals, the importance of precision in blood pressure measurement is also reinforced. Blood pressure measurement (described below) is usually performed using the traditional method, the so-called casual or office measurement. Over time, alternatives have been added to it, through the use of semi-automatic or automatic devices by the patients themselves, in waiting rooms or outside the office, in their own homes, or in public spaces. A step further was taken with the use of semi-automatic devices equipped with memory that allow sequential measurements outside the office (ABPM; or HBPM) and other automatic devices that allow programmed measurements over longer periods (HBPM). Some aspects of blood pressure measurement can interfere with obtaining reliable results and, consequently, cause harm in decision-making. These include the importance of using average values, the variation in blood pressure during the day, and short-term variability. These aspects have encouraged the performance of a greater number of measurements in various situations, and different guidelines have advocated the use of equipment that promotes these actions. Devices that perform HBPM or ABPM, which, in addition to allowing greater precision, when used together, detect white coat hypertension (WCH), masked hypertension (MH), sleep blood pressure alterations, and resistant hypertension (RHT) (defined in Chapter 2 of this guideline), are gaining more and more importance. Taking these details into account, we must emphasize that information related to diagnosis, classification, and goal setting is still based on office blood pressure measurement, and for this reason, all attention must be given to the proper execution of this procedure.La hipertensión arterial (HTA) es uno de los principales factores de riesgo modificables para la morbilidad y mortalidad en todo el mundo, siendo uno de los mayores factores de riesgo para la enfermedad de las arterias coronarias, el accidente cerebrovascular (ACV) y la insuficiencia renal. Además, es altamente prevalente y afecta a más de un tercio de la población mundial. La medición de la presión arterial (PA) es un procedimiento OBLIGATORIO en cualquier atención médica o realizado por diferentes profesionales de la salud. Sin embargo, todavía se realiza comúnmente sin los cuidados técnicos necesarios. Dado que el diagnóstico se basa en la medición de la PA, es claro el cuidado que debe haber con las técnicas, los métodos y los equipos utilizados en su realización. Debemos enfatizar que una vez realizado el diagnóstico, todas las investigaciones y tratamientos a corto, mediano y largo plazo se basan en los resultados de la medición de la PA. Por lo tanto, las técnicas y/o equipos inadecuados pueden llevar a diagnósticos incorrectos, subestimando o sobreestimando valores y resultando en conductas inadecuadas y pérdidas significativas para la salud y la economía de las personas y las naciones. Una vez realizado el diagnóstico correcto, a medida que avanza el conocimiento sobre la importancia del tratamiento adecuado, con la adopción de valores de normalidad más detallados y objetivos de tratamiento más cuidadosos hacia metas de PA más estrictas, también se refuerza la importancia de la precisión en la medición de la PA. La medición de la PA (descrita a continuación) generalmente se realiza mediante el método tradicional, la llamada medición casual o de consultorio. Con el tiempo, se han agregado alternativas a través del uso de dispositivos semiautomáticos o automáticos por parte del propio paciente, en salas de espera o fuera del consultorio, en su propia residencia o en espacios públicos. Se dio un paso más con el uso de dispositivos semiautomáticos equipados con memoria que permiten mediciones secuenciales fuera del consultorio (AMPA; o MRPA) y otros automáticos que permiten mediciones programadas durante períodos más largos (MAPA). Algunos aspectos en la medición de la PA pueden interferir en la obtención de resultados confiables y, en consecuencia, causar daños en las decisiones a tomar. Estos incluyen la importancia de usar valores promedio, la variación de la PA durante el día y la variabilidad a corto plazo. Estos aspectos han alentado la realización de un mayor número de mediciones en diversas situaciones, y diferentes pautas han abogado por el uso de equipos que promuevan estas acciones. Los dispositivos que realizan MRPA o MAPA, que además de permitir una mayor precisión, cuando se usan juntos, detectan la hipertensión de bata blanca (HBB), la hipertensión enmascarada (HM), las alteraciones de la PA durante el sueño y la hipertensión resistente (HR) (definida en el Capítulo 2 de esta guía), están ganando cada vez más importancia. Teniendo en cuenta estos detalles, debemos enfatizar que la información relacionada con el diagnóstico, la clasificación y el establecimiento de objetivos todavía se basa en la medición de la presión arterial en el consultorio, y por esta razón, se debe prestar toda la atención a la ejecución adecuada de este procedimiento.A hipertensão arterial (HA) é um dos principais fatores de risco modificáveis para morbidade e mortalidade em todo o mundo, sendo um dos maiores fatores de risco para doença arterial coronária, acidente vascular cerebral (AVC) e insuficiência renal. Além disso, é altamente prevalente e atinge mais de um terço da população mundial. A medida da PA é procedimento OBRIGATÓRIO em qualquer atendimento médico ou realizado por diferentes profissionais de saúde. Contudo, ainda é comumente realizada sem os cuidados técnicos necessários. Como o diagnóstico se baseia na medida da PA, fica claro o cuidado que deve haver com as técnicas, os métodos e os equipamentos utilizados na sua realização. Deve-se reforçar que, feito o diagnóstico, toda a investigação e os tratamentos de curto, médio e longo prazos são feitos com base nos resultados da medida da PA. Assim, técnicas e/ou equipamentos inadequados podem levar a diagnósticos incorretos, tanto subestimando quanto superestimando valores e levando a condutas inadequadas e grandes prejuízos à saúde e à economia das pessoas e das nações. Uma vez feito o diagnóstico correto, na medida em que avança o conhecimento da importância do tratamento adequado, com a adoção de valores de normalidade mais detalhados e com objetivos de tratamento mais cuidadosos no sentido do alcance de metas de PA mais rigorosas, fica também reforçada a importância da precisão na medida da PA. A medida da PA (descrita a seguir) é habitualmente feita pelo método tradicional, a assim chamada medida casual ou de consultório. Ao longo do tempo, foram agregadas alternativas a ela, mediante o uso de equipamentos semiautomáticos ou automáticos pelo próprio paciente, nas salas de espera ou fora do consultório, em sua própria residência ou em espaços públicos. Um passo adiante foi dado com o uso de equipamentos semiautomáticos providos de memória que permitem medidas sequenciais fora do consultório (AMPA; ou MRPA) e outros automáticos que permitem medidas programadas por períodos mais prolongados (MAPA). Alguns aspectos na medida da PA podem interferir na obtenção de resultados fidedignos e, consequentemente, causar prejuízo nas condutas a serem tomadas. Entre eles, estão: a importância de serem utilizados valores médios, a variação da PA durante o dia e a variabilidade a curto prazo. Esses aspectos têm estimulado a realização de maior número de medidas em diversas situações, e as diferentes diretrizes têm preconizado o uso de equipamentos que favoreçam essas ações. Ganham cada vez mais espaço os equipamentos que realizam MRPA ou MAPA, que, além de permitirem maior precisão, se empregados em conjunto, detectam a HA do avental branco (HAB), HA mascarada (HM), alterações da PA no sono e HA resistente (HAR) (definidos no Capítulo 2 desta diretriz). Resguardados esses detalhes, devemos ressaltar que as informações relacionadas a diagnóstico, classificação e estabelecimento de metas ainda são baseadas na medida da PA de consultório e, por esse motivo, toda a atenção deve ser dada à realização desse procedimento

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5,6,7 vast areas of the tropics remain understudied.8,9,10,11 In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepresented in biodiversity databases.13,14,15 To worsen this situation, human-induced modifications16,17 may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost