Dificuldades alimentares em pré-escolares de uma escola de educação infantil / Feeding difficulties in preschool children at an early childhood education school

Dificuldade alimentar é todo problema que afeta negativamente o processo dos pais ou cuidadores de suprirem alimento ou nutrientes à criança. O objetivo deste trabalho foi investigar as dificuldades alimentares em pré-escolares de uma escola municipal de educação infantil de Uruguaiana/RS. O estudo foi aprovado pelo Comitê de Ética em Pesquisa e realizado entre outubro e novembro de 2022. Foram convidadas a participar da pesquisa todos os pais ou responsáveis das crianças (n=70) que frequentavam a escola, na faixa etária de 4-5 anos. Todos receberam o Termo de Consentimento Livre e Esclarecido, bem como o questionário de pesquisa. O instrumento utilizado foi a Escala Brasileira de Alimentação Infantil (EBAI), que possui 14 perguntas referentes à alimentação das crianças. Foi realizada estatística descritiva, em termos de frequência e realizada análise de variância (ANOVA) para comparações entre os sexos (p<0,05). Foram obtidas 31 respostas dos pais relativas à alimentação das crianças. Os dados revelaram que 9,68% (n=3) possuíam algum grau de dificuldade alimentar, sendo 3,33% (n=1) com grau severo e 6,45% (n=2) com grau moderado. As demais crianças (n=28) também apresentaram comportamentos relacionados às dificuldades alimentares, porém, sem pontuação suficiente para serem classificadas com dificuldade alimentar. Os comportamentos mais frequentemente descritos foram: o responsável usar distrações ou ir atrás da criança para que ela coma, tempo de a alimentação em torno de 31-60min ou mais, criança que nauseia, cospe ou vomita com algum tipo de alimento e a influência negativa da alimentação nas relações familiares. Desta forma, observou-se um baixo percentual de dificuldades alimentares na população estudada, de acordo com a literatura estudada.

Feeding difficulties are any problem that negatively affects the process of parents or caregivers providing food or nutrients to the child. The objective of this work was to investigate eating difficulties in preschool children at a municipal early childhood education school in Uruguaiana/RS. The study was approved by the Research Ethics Committee and carried out between October and November 2022. All parents or guardians of children (n=70) who attended school, aged 4-5 years, were invited to participate in the research. Everyone received the Free and Informed Consent Form, as well as the research questionnaire. The instrument used was the Brazilian Infant Feeding Scale (EBAI), which has 14 questions regarding children's nutrition. Descriptive statistics were performed in terms of frequency and analysis of variance (ANOVA) was performed for comparisons between sexes (p<0.05). 31 responses were obtained from parents regarding children's nutrition. The data revealed that 9.68% (n=3) had some degree of feeding difficulty, 3.33% (n=1) with a severe degree and 6.45% (n=2) with a moderate degree. The remaining children (n=28) also presented behaviors related to feeding difficulties, however, without enough scores to be classified as having feeding difficulties. The most frequently described behaviors were: the caregiver using distractions or going after the child to make them eat, feeding time around 31-60 minutes or more, child who nauseates, spits or vomits with some type of food and the negative influence of food in family relationships. Thus, a low percentage of feeding difficulties was observed in the studied population, in accordance with the literature studied.

Trophic ecology of Acestrorhynchus falcirostris Cuvier, 1819 in island lakes on the lower stretch of the Solimões River, Amazon Basin / Ecologia trófica de Acestrorhynchus falcirostris Cuvier, 1819 em lagos de ilha no trecho inferior do Rio Solimões, Bacia Amazônica

Abstract The aim objective of this study was to determine the trophic ecology of juvenile and adult Acestrorhynchus falcirostris during the rising and flood (high-water) period in six island lakes adjacent to the Solimões River. As such, we investigated: i) the trophic position, through the fractional trophic niche; ii) the niche breadth; iii) niche overlap and iv) the food strategy of the species. The specimens were collected during the years 2014 to 2017, using gillnets with mesh sizes ranging from 30 to 120mm between opposite knots. Through the analysis of stomach contents, the preference in the consumption of items of animal origin was observed. Juveniles consumed insects in greater proportions (IAi% = 50%), while adults consumed fish (IAi%=99,98%). Despite the large supply of food items available in the high-water period, juveniles were the only ones to consume items of allochthonous origin, such as insects. Juveniles presented a different dietary strategy and dietary composition to adults. Juveniles were omnivores with a generalist strategy, while adults were piscivores with a specialist strategy. Thus, the food composition, niche breadth, trophic position and feeding strategy of Acestrorhynchus falcirostris change due to the stage of development.

Resumo O objetivo deste estudo foi determinar a ecologia trófica de juvenis e adultos de Acestrorhynchus falcirostris durante o período de enchente e cheia em seis lagos de ilha adjacentes ao rio Solimões. Assim, investigamos: i) a posição trófica, através do nicho trófico fracional; ii) a largura de nicho; iii) sobreposição de nicho; iv) a estratégia alimentar. Os espécimes foram coletados durante os anos de 2014 a 2017, utilizando redes de emalhar com malha variando de 30 a 120mm entre nós opostos. Por meio da análise do conteúdo estomacal, observamos a preferência no consumo de itens de origem animal. Os juvenis consumiram insetos em maiores proporções (IAi% = 50%), enquanto os adultos consumiram preferencialmente peixes (IAi% = 99,98%). Apesar da grande oferta de alimentos disponíveis no período da cheia, os juvenis eram os únicos a consumir itens de origem alóctone, como por exemplo, os insetos. Os juvenis apresentaram uma estratégia alimentar e composição alimentar diferente para os adultos. Os juvenis foram considerados onívoros com uma estratégia generalista, enquanto os adultos foram considerados piscívoros com uma estratégia alimentar mais especialista. Assim, a composição alimentar, amplitude do nicho, posição trófica e a estratégia alimentar de Acestrorhynchus falcirostris muda em função do estágio de desenvolvimento.

Trophic ecology of Acestrorhynchus falcirostris Cuvier, 1819 in island lakes on the lower stretch of the Solimões River, Amazon Basin

Abstract The aim objective of this study was to determine the trophic ecology of juvenile and adult Acestrorhynchus falcirostris during the rising and flood (high-water) period in six island lakes adjacent to the Solimões River. As such, we investigated: i) the trophic position, through the fractional trophic niche; ii) the niche breadth; iii) niche overlap and iv) the food strategy of the species. The specimens were collected during the years 2014 to 2017, using gillnets with mesh sizes ranging from 30 to 120mm between opposite knots. Through the analysis of stomach contents, the preference in the consumption of items of animal origin was observed. Juveniles consumed insects in greater proportions (IAi% = 50%), while adults consumed fish (IAi%=99,98%). Despite the large supply of food items available in the high-water period, juveniles were the only ones to consume items of allochthonous origin, such as insects. Juveniles presented a different dietary strategy and dietary composition to adults. Juveniles were omnivores with a generalist strategy, while adults were piscivores with a specialist strategy. Thus, the food composition, niche breadth, trophic position and feeding strategy of Acestrorhynchus falcirostris change due to the stage of development.

Resumo O objetivo deste estudo foi determinar a ecologia trófica de juvenis e adultos de Acestrorhynchus falcirostris durante o período de enchente e cheia em seis lagos de ilha adjacentes ao rio Solimões. Assim, investigamos: i) a posição trófica, através do nicho trófico fracional; ii) a largura de nicho; iii) sobreposição de nicho; iv) a estratégia alimentar. Os espécimes foram coletados durante os anos de 2014 a 2017, utilizando redes de emalhar com malha variando de 30 a 120mm entre nós opostos. Por meio da análise do conteúdo estomacal, observamos a preferência no consumo de itens de origem animal. Os juvenis consumiram insetos em maiores proporções (IAi% = 50%), enquanto os adultos consumiram preferencialmente peixes (IAi% = 99,98%). Apesar da grande oferta de alimentos disponíveis no período da cheia, os juvenis eram os únicos a consumir itens de origem alóctone, como por exemplo, os insetos. Os juvenis apresentaram uma estratégia alimentar e composição alimentar diferente para os adultos. Os juvenis foram considerados onívoros com uma estratégia generalista, enquanto os adultos foram considerados piscívoros com uma estratégia alimentar mais especialista. Assim, a composição alimentar, amplitude do nicho, posição trófica e a estratégia alimentar de Acestrorhynchus falcirostris muda em função do estágio de desenvolvimento.

Seletividade socioterritorial e étnico-racial: papel das políticas sociais no enfrentamento de desigualdades históricas / Socio-territorial selectivity: the role of social policies in facing historical inequalities

O presente artigo tem como objetivo geral demonstrar a importância da dimensão étnico-racial na área da habitação, enfatizando os fenômenos socioespaciais atuais, com foco na seletividade socioterritorial. Para tal, utiliza-se de ampla revisão de literatura fundamentada no materialismo histórico e dialético em Marx, bem como nas análises sobre território e espaço de Milton Santos. Assim, evidenciando as motivações deste recorte fazer-se fundamental na área a partir de um resgate histórico sobre a formação socioespacial do espaço urbano no Brasil, tornando notória a consequente seletividade socioterritorial existente nos dias atuais. A partir da contextualização histórica, as ocupações irregulares são tidas como um reflexo desta questão e as Zonas Especiais de Interesse Social (ZEIS) tornam-se um importante suporte na garantia de moradia adequada à população de baixa renda; porém, ainda um tanto ineficazes sem um olhar atento para quem são os usuários das políticas e serviços ali presentes. Ademais, se fomenta o debate sobre a dimensão étnico racial precisar estar presente desde a formação acadêmica, visto que atualmente o conteúdo referente à temática é escasso ou quase nulo

This article aims to demonstrate the importance of the ethnic-racial dimension in housing, emphasizing current socio-spatial phenomena, with a focus on socio-territorial selectivity. In order to do so, it makes use of an extensive literature review based on Marx's historical and dialectical materialism, as well as Milton Santos' analysis of territory and space. Thus, evidencing the motivations of this cut, making itself fundamental in the area from a historical review of the socio-spatial formation of urban space in Brazil, making evident the consequent socio-territorial selectivity existing today. From the historical context, irregular occupations are seen as a reflection of this issue and the Special Zones of Social Interest (ZEIS) become an important support in guaranteeing adequate housing for the low-income population; however, they are still somewhat ineffective without a careful look at who the users of the policies and services present there are. Furthermore, the debate on the racial ethnic dimension is fostered, it needs to be present since academic training, as currently the content related to the subject is scarce or almost nil

A novel O-methyltransferase with substrate promiscuity from Ardisia japonica / 药学学报

italic>O-methyltransferases (OMTs) are one of the key tailoring enzymes in the biosynthesis of many natural products, O-methylation can not only reduce the reactivity of natural products, but also alter their solubility, stability and biological activities. Based on the transcriptome data of Ardisia japonica, a full-length cDNA sequence of candidate OMT (termed as AjOMT1) was cloned by reverse transcription-polymerase chain reaction (RT-PCR) and expressed in Escherichia coli (E. coli) for the first time. In vitro enzyme catalytic activity assay showed that the recombinant AjOMT1 could effectively catalyze quercetin to form O-methylated products. Most importantly, AjOMT1 showed unprecedented substrate promiscuity towards structurally various compounds including flavonoids, stilbenes, coumarins, alkaloids and phenylpropanoids, especially preferring to the compounds with adjacent phenolic hydroxyl groups, and showed regio-selectivity. These results suggested that AjOMT1 could be used as the tool enzyme to conduct O-methylation of different types of compounds to produce diverse active methylated products, and provide a new method for drug discovery, even universal part for synthetic biology of natural products.

Neural Correlates of Spatial Navigation in Primate Hippocampus / 神经科学通报·英文版

The hippocampus has been extensively implicated in spatial navigation in rodents and more recently in bats. Numerous studies have revealed that various kinds of spatial information are encoded across hippocampal regions. In contrast, investigations of spatial behavioral correlates in the primate hippocampus are scarce and have been mostly limited to head-restrained subjects during virtual navigation. However, recent advances made in freely-moving primates suggest marked differences in spatial representations from rodents, albeit some similarities. Here, we review empirical studies examining the neural correlates of spatial navigation in the primate (including human) hippocampus at the levels of local field potentials and single units. The lower frequency theta oscillations are often intermittent. Single neuron responses are highly mixed and task-dependent. We also discuss neuronal selectivity in the eye and head coordinates. Finally, we propose that future studies should focus on investigating both intrinsic and extrinsic population activity and examining spatial coding properties in large-scale hippocampal-neocortical networks across tasks.

PK/PD model of Chuanxiong gel plaster in treatment of rheumatoid arthritis / 中国中药杂志

In this experiment, the PK/PD fitting model of Chuanxiong(Chuanxiong Rhizoma) in the treatment of rheumatoid arthritis was established in the form of acupoint combined with external application gel paste. Firstly, the rheumatoid arthritis model was induced by ovalbumin, and the articular fluid of rabbits was extracted by microdialysis. The pharmacokinetic process of Chuanxiong in rabbit articular fluid was analyzed by UPLC-MS/MS, and the pharmacokinetic model was established. The pharmacodynamic effects of Chuanxiong on inflammatory factors IL-1β, TNF-α, and IL-6 were analyzed by enzyme-linked immunosorbent assay(ELISA). The pharmacodynamic model was established, and the PK/PD model was obtained by fitting the data of pharmacokinetics and pharmacodynamics. The results of pharmacokinetics showed that the concentration of ligustrolide A in the articular cavity by drug administration on classical acupoint Zusanli(ST 36) was higher than that by Yanglingquan(GB 34), which reflected the advantage of typical acupoint, while ligustrazine concentration was higher after administration through Yanglingquan than through Zusanli, which was different from the traditional acupoint theory. The results of pharmacodynamics showed that the drug had lag effect. The PK/PD model was constructed by fitting the data. When IL-1β was taken as the efficacy index, the PK/PD models of Chuanxiong in typical acupoint Zusanli group, atypical acupoint Yanglingquan group, and non-acupoint group were E=115.28C_e/(3 316.72+C_e), E=108.73C_e/(2 993.47+C_e), and E=101.34C_e/(3 028.51+C_e). When TNF-α was taken as the efficacy index, the PK/PD models of Chuanxiong in typical acupoint Zusanli group, atypical acupoint Yanglingquan group, and non-acupoint group were E=68.31C_e/(3 285.16+C_e), E=59.27C_e/(2 919.86+C_e), and E=53.61C_e/(2 862.87+C_e). When IL-6 was taken as the efficacy index, the PK/PD models of Chuanxiong in typical acupoint Zusanli group, atypical acupoint Yanglingquan group, and non-acupoint group were E=59.92C_e/(3 461.17+C_e), E=58.34C_e/(2 723.51+C_e), and E=49.17C_e/(2 862.76+C_e). The parameters showed that there were significant differences in E_(max), EC_(e50) and k_(eo). The analysis of data found that the PK/PD fitting effect of Zusanli, a typical acupoint, was the best, which proved that it was still the best site for drug administration. To sum up, it shows that there may be bidirectional selectivity between drugs and acupoints.

Direction Selectivity of TmY Neurites in Drosophila / 神经科学通报·英文版

The perception of motion is an important function of vision. Neural wiring diagrams for extracting directional information have been obtained by connectome reconstruction. Direction selectivity in Drosophila is thought to originate in T4/T5 neurons through integrating inputs with different temporal filtering properties. Through genetic screening based on synaptic distribution, we isolated a new type of TmY neuron, termed TmY-ds, that form reciprocal synaptic connections with T4/T5 neurons. Its neurites responded to grating motion along the four cardinal directions and showed a variety of direction selectivity. Intriguingly, its direction selectivity originated from temporal filtering neurons rather than T4/T5. Genetic silencing and activation experiments showed that TmY-ds neurons are functionally upstream of T4/T5. Our results suggest that direction selectivity is generated in a tripartite circuit formed among these three neurons-temporal filtering, TmY-ds, and T4/T5 neurons, in which TmY-ds plays a role in the enhancement of direction selectivity in T4/T5 neurons.

A highly selective C-rhamnosyltransferase from Viola tricolor and insights into its mechanisms

C-Glycosides are important natural products with various bioactivities. In plant biosynthetic pathways, the C-glycosylation step is usually catalyzed by C-glycosyltransferases (CGTs), and most of them prefer to accept uridine 5'-diphosphate glucose (UDP-Glc) as sugar donor. No CGTs favoring UDP-rhamnose (UDP-Rha) as sugar donor has been reported, thus far. Herein, we report the first selective C-rhamnosyltransferase VtCGTc from the medicinal plant Viola tricolor. VtCGTc could efficiently catalyze C-rhamnosylation of 2-hydroxynaringenin 3-C-glucoside, and exhibited high selectivity towards UDP-Rha. Mechanisms for the sugar donor selectivity of VtCGTc were investigated by molecular dynamics (MD) simulations and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) binding free energy calculations. Val144 played a vital role in recognizing UDP-Rha, and the V144T mutant could efficiently utilize UDP-Glc. This work provides a new and efficient approach to prepare flavonoid C-rhamnosides such as violanthin and iso-violanthin.

On improving the activity and selectivity of small molecule drugs / 药学学报

Although small molecule drugs (SMD) are still mainstream for the treatment of diseases, large molecule biologicss of many advantages, pose a challenge to the further discovery and use of SMD. The advantages of SMD are the convenience of oral administration and good patient compliance. However, the challenge with SMD is to integrate the PD, PK, selectivity and safety into a chemical structure. Because of their small size and surface area they often bind to various proteins, and off-target actions can cause adverse reactions. In this sense, selectivity is critical. Based upon target as the core to construct a chemical structure, it is necessary to consider the requirements of all the attributes, but achievement of the full-dimensional optimization is difficult. Modern drug discovery has been greatly enhanced by molecular biology and structural biology, and new strategies and technologies have emerged, which have created many successful medicines. For example, under the guidance of structural biology, covalent binding drugs connect moderate "electrophilic warheads" to the appropriate positions of molecules, and upon binding to their targets the electrophiles are irreversibly linked to the target by covalent bonds. Molecular biology can be directly applied to the development of antibody-coupled drugs (ADC). The antibody (A) acts as a carrier and a guide (for PK), and carries toxic molecules (D) into cancer cells, thus playing a killing role (for PD). The separate pharmacodynamic and pharmacokinetic entities are coupled (C) by linkers. PROTACs are also bifunctional molecules, which recruit a target protein and ubiquitin ligase E3 to form a ternary complex, which then acts as a catalyst to ubiquitinate the target protein and lead to degradation by the proteasome. In addition, in recent years, the combination of two fixed-dose drugs has improved selectivity, safety, and long-term benefit with many severe diseases, and can be regarded as an innovative strategy of physical combination. This review discusses some successful examples to briefly present the principles from the perspective of medicinal chemistry and therapeutic application.

Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

Development of small molecule extracellular signal-regulated kinases (ERKs) inhibitors for cancer therapy

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway is widely activated by a variety of extracellular stimuli, and its dysregulation is associated with the proliferation, invasion, and migration of cancer cells. ERK1/2 is located at the distal end of this pathway and rarely undergoes mutations, making it an attractive target for anticancer drug development. Currently, an increasing number of ERK1/2 inhibitors have been designed and synthesized for antitumor therapy, among which representative compounds have entered clinical trials. When ERK1/2 signal transduction is eliminated, ERK5 may provide a bypass route to rescue proliferation, and weaken the potency of ERK1/2 inhibitors. Therefore, drug research targeting ERK5 or based on the compensatory mechanism of ERK5 for ERK1/2 opens up a new way for oncotherapy. This review provides an overview of the physiological and biological functions of ERKs, focuses on the structure-activity relationships of small molecule inhibitors targeting ERKs, with a view to providing guidance for future drug design and optimization, and discusses the potential therapeutic strategies to overcome drug resistance.

Structure‒tissue exposure/selectivity relationship (STR) correlates with clinical efficacy/safety

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

Design, synthesis and antiplatelet activity evaluation of novel quinoxaline antagonists of protease activated receptor 4 (PAR4) / 药学学报

Twenty-five compounds of novel quinoxaline-based scaffold with antiplatelet activity were designed and synthesized on the basis of previous quinoxaline analogues, and the structures were confirmed by 1H NMR, 13C NMR, and MS. The antiplatelet activity was evaluated, structure-activity relationship (SAR) study was summarized and the selectivity of PAR4 was confirmed by calcium mobilization assays. It was indicated that compound 14a, 14g, 13i, 13p showed moderate activity against PAR4, especially, the activity of compound 14g (IC50 = 0.26 μmol·L-1) was 6.7 times than the lead compound A (IC50 = 1.73 μmol·L-1). Therefore, 2,3-dihydro-[1,4]dioxino[2,3-g]quinoxaline and [1,3]dioxolo[4,5-g]quinoxaline derivatives are promising compounds for the discovery of novel antiplatelet agents. It is worthy of further research to develop highly effective and selective PAR4 antagonists.

Why 90% of clinical drug development fails and how to improve it?

Ninety percent of clinical drug development fails despite implementation of many successful strategies, which raised the question whether certain aspects in target validation and drug optimization are overlooked? Current drug optimization overly emphasizes potency/specificity using structure‒activity-relationship (SAR) but overlooks tissue exposure/selectivity in disease/normal tissues using structure‒tissue exposure/selectivity-relationship (STR), which may mislead the drug candidate selection and impact the balance of clinical dose/efficacy/toxicity. We propose structure‒tissue exposure/selectivity-activity relationship (STAR) to improve drug optimization, which classifies drug candidates based on drug's potency/selectivity, tissue exposure/selectivity, and required dose for balancing clinical efficacy/toxicity. Class I drugs have high specificity/potency and high tissue exposure/selectivity, which needs low dose to achieve superior clinical efficacy/safety with high success rate. Class II drugs have high specificity/potency and low tissue exposure/selectivity, which requires high dose to achieve clinical efficacy with high toxicity and needs to be cautiously evaluated. Class III drugs have relatively low (adequate) specificity/potency but high tissue exposure/selectivity, which requires low dose to achieve clinical efficacy with manageable toxicity but are often overlooked. Class IV drugs have low specificity/potency and low tissue exposure/selectivity, which achieves inadequate efficacy/safety, and should be terminated early. STAR may improve drug optimization and clinical studies for the success of clinical drug development.

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Adrenocorticotrophic hormone stimulation in adrenal vein sampling / 中华内分泌代谢杂志

Objective:To explore the value of adrenocorticotrophic hormone (ACTH) stimulation in adrenal vein sampling (AVS) with its effect on the sampling success rate and lateralization determination.Methods:The clinical data of 54 patients with primary aldosteronism (PA) who underwent AVS in Nanjing Drum Tower Hospital from July 2018 to June 2020 were collected retrospectively. Blood samples from bilateral adrenal veins were collected simultaneously at baseline and after ACTH stimulation. The selectivity index (SI), lateralization index (LI), and relative aldosterone secretion index (RASI) were examined.Results:The concentration of serum cortisol level in left and right adrenal vein and peripheral vein increased significantly after ACTH stimulation ( P<0.001). SI of left adrenal vein increased from 18.00 (2.29, 20.29) to 34.76 (12.10, 46.86) , and the SI of right adrenal vein increased from 26.61(5.24, 31.85) to 28.40 (27.65, 56.05, P<0.001). The bilateral vein sampling success rate increased from 80%(43/54) to 93%(50/54). LI decreased from 2.85(1.78, 6.20) at baseline to 2.45(1.40, 6.10) after ACTH stimulation without significant difference( P>0.05). Eleven patients who identified unilateral secretion at baseline demonstrated bilateral after ACTH stimulation, and the RASI of these patients decreased from 0.50 (0.38, 1.25 ) to 0.37 (0.22, 0.84, P=0.019). Conclusion:ACTH stimulation significantly increased SI and the AVS success rate in patients with PA: ACTH stimulation decreased the relative aldosterone secretion in the dominant side of some patients with aldosterone producing adenoma, thus reduced the proportion of identified unilateral PA.

Feeding habits of Holothuria (Stauropora) fuscocinerea (Echinodermata: Holothuroidea) in a Mexican Pacific reef / Hábitos alimenticios de Holothuria (Stauropora) fuscocinerea (Echinodermata: Holothuroidea) en un arrecife del Pacífico Mexicano

Introduction: The importance of holothuroids in marine ecosystems is related to their feeding activities, which have been little studied in the eastern Pacific. Objective: To describe the feeding habits of the sea cucumber Holothuria (Stauropora) fuscocinerea and their bioturbation potential in La Entrega reef, México. Methods: The population size of H. (Stauropora) fuscocinerea was determined by means of four 20 x 4 m (320 m2) band transects, while the available sediment for the sea cucumbers and their feces were characterized in three stations (A-C) via granulometry and quantification of organic carbon and organic matter. Excretion rate was determined every 4 hr over a 24 hr period and the relationship between sea cucumber length and biomass and the excretion rate evaluated. Results: According to non-parametric permutation, ordination and percentage similarity analyses, sea cucumber feces mostly comprised a large proportion of small grains compared to the available sediment, indicating that H. (Stauropora) fuscocinerea is selective on grain size. Preliminary bioturbation potential of the species may reach up to 8.71 ± 0.17 kg day of sediment in the study area. Conclusion: The spatial distribution of H. (Stauropora) fuscocinerea in the study area is a product of its selective feeding activity, evidencing the preliminary importance of the species in the trophic dynamics of La Entrega reef.

Introducción: La relevancia de los holoturoideos en los ecosistemas marinos está relacionada con sus actividades alimenticias, las cuales han sido escasamente estudiadas en el Pacífico oriental. Objetivo: Describir los hábitos alimenticios del pepino de mar Holothuria (Stauropora) fuscocinerea y su potencial de bioturbación en el arrecife La Entrega, México. Métodos: Se determinó el tamaño poblacional de H. (Stauropora) fuscocinerea mediante cuatro transectos de banda de 20 x 4 m (320 m2), mientras que la caracterización de los sedimentos disponibles y las heces de los pepinos se realizó en tres estaciones (A-C) mediante granulometría y cuantificación de carbono orgánico y materia orgánica. Se determinó la tasa de excreción cada 4 hr durante un periodo de 24 hr y se evaluó la relación entre la talla y la biomasa con la tasa de excreción. Resultados: De acuerdo con un análisis no paramétrico mediante permutaciones, ordenación y similitud, las heces de los pepinos estuvieron compuestas en su mayoría por una gran cantidad de granos pequeños en comparación con el sedimento disponible, lo que sugiere que H. (Stauropora) fuscocinerea es una especie selectiva respecto al tamaño de grano. El potencial de bioturbación preliminar de la especie puede alcanzar 8.71 ± 0.17 kg día en el área de estudio. Conclusiones: La distribución espacial de H. (Stauropora) fuscocinerea en el área de estudio es producto de su selectividad alimenticia, evidenciando la importancia de la especie en la dinámica trófica del arrecife La Entrega.

Review of novel compounds that act on the AT2 receptor / 药学学报

Selective activation or inhibition of the angiotensin II type 2 (AT2) receptor can cause vasodilation, decrease cell proliferation, promote neurite outgrowth and block neuronal excitability. The AT2 receptor can be used as a potential drug target for the treatment of cardiovascular diseases, fibrosis, inflammation, neuronal diseases and tumors. Research and development of new drugs that selectively act on the AT2 receptor and the mechanism of intracellular signal transduction involving the AT2 receptor is a challenging but worthy endeavor. We review research progress on the AT2 receptor and compounds that act on the AT2 receptor, along with structure-activity relationship analysis, to provide reference and guidance for further research in this field.

Ligand-based substituent-anchoring design of selective receptor-interacting protein kinase 1 necroptosis inhibitors for ulcerative colitis therapy

Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation. Our group previously identified TAK-632 (