Remapping the Chemical Space and the Pharmacological Space of Drugs: What Can We Expect from the Road Ahead?

This work examines the current landscape of drug discovery and development, with a particular focus on the chemical and pharmacological spaces. It emphasizes the importance of understanding these spaces to anticipate future trends in drug discovery. The use of cheminformatics and data analysis enabled in silico exploration of these spaces, allowing a perspective of drugs, approved drugs after 2020, and clinical candidates, which were extracted from the newly released ChEMBL34 (March 2024). This perspective on chemical and pharmacological spaces enables the identification of trends and areas to be occupied, thereby creating opportunities for more effective and targeted drug discovery and development strategies in the future.

Metabolic Signaling in Cancer.

Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.

Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-ß (Aß) oligomers.

BACKGROUND AND PURPOSE: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aß oligomer (AßO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD). EXPERIMENTAL APPROACH: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AßO. KEY RESULTS: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AßO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AßO-infused mice. CONCLUSION AND IMPLICATIONS: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

First Case Report of Bilateral Parotid Lymphoepithelial Carcinoma.

Background/Aim: The parotid is the largest salivary gland and is located anteriorly to the sternocleidomastoid muscle and laterally to the ramus of the mandible. Neoplasms in this gland are relatively rare, with 80% being benign and 20% malignant, primarily represented by mucoepidermoid carcinoma. In the head and neck region, lymphoepithelial carcinoma (LEC) accounts for 0.4% of malignant salivary gland tumors. Case Report: A 35-year-old man with no previous comorbidities was admitted to a Head and Neck Surgery Specialty Service for a painless right cervical mass of uncertain growth. Extensive diagnostic investigation revealed involvement of the contralateral parotid, associated with systemic lymph node enlargement. Thus, adjuvant radiotherapy was decided by the treating team. Conclusion: This case confirms the heterogeneous features and distinctive behavior that the disease can present, as seen with bilateral parotid LEC.

Molecular hybridization: a powerful tool for multitarget drug discovery.

INTRODUCTION: The current drug discovery paradigm of 'one drug, multiple targets' has gained attention from both the academic medicinal chemistry community and the pharmaceutical industry. This is in response to the urgent need for effective agents to treat multifactorial chronic diseases. The molecular hybridization strategy is a useful tool that has been widely explored, particularly in the last two decades, for the design of multi-target drugs. AREAS COVERED: This review examines the current state of molecular hybridization in guiding the discovery of multitarget small molecules. The article discusses the design strategies and target selection for a multitarget polypharmacology approach to treat various diseases, including cancer, Alzheimer's disease, cardiac arrhythmia, endometriosis, and inflammatory diseases. EXPERT OPINION: Although the examples discussed highlight the importance of molecular hybridization for the discovery of multitarget bioactive compounds, it is notorious that the literature has focused on specific classes of targets. This may be due to a deep understanding of the pharmacophore features required for target binding, making targets such as histone deacetylases and cholinesterases frequent starting points. However, it is important to encourage the scientific community to explore diverse combinations of targets using the molecular hybridization strategy.

Milk and Fresh Cheese Quality of Crossbred Cows Supplemented with Phytogenic Additives and Managed under Thermal Stress.

This investigation aimed to assess the physiological parameters and quality of milk and fresh cheeses produced by cows that were housed in paddocks, either with or without shade, and supplemented with a phytogenic additive. Sixteen crossbred cows were allocated in a 4 × 4 Latin square design, dividing them into paddocks with or without shade, and providing or not providing a phytogenic additive in their feed. This resulted in a total of four treatment groups and sixteen experimental plots, each containing four animals, over four periods of 21 days. Various parameters were examined, including haematology, rectal and skin temperature, respiratory rate, milk yield and composition, serum parameters, and cheese yield and quality. It is worth noting that the temperature and humidity, as measured by a black globe thermometer, did not display significant variations between the different environments and exhibited minimal fluctuations throughout the day. Additionally, the supplementation of the phytogenic additive led to a reduction in haematocrit levels (p = 0.011). Furthermore, the analysis showed that whey obtained from cheese production had a higher fat content when cows were without access to shade (p = 0.005). Notably, there was an interaction between factors in relation to the total dry extract content, which was lower when cows had access to shade and received the additive (p = 0.010). In summary, the provision of a phytogenic additive and the presence or absence of shade did not bring about significant changes in milk production and quality or in the yield and quality of fresh cheese.

Jejunal Gastrointestinal Stromal Tumor: A Strange Cause of Massive Gastrointestinal Bleeding.

Jejunal gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors of the gastrointestinal (GI) tract and a rare cause of massive GI bleeding. Due to this rarity and non-specific presentation, diagnosis and treatment may be difficult and often delayed. Urgent surgical intervention is crucial for controlling the source of bleeding and total tumor excision. Herein, we present the case of a 40-year-old male who presented to the emergency room (ER) with features of upper GI bleeding. He referred astheny and black stools, and was pale, sweaty, and tachycardic despite normal blood pressure. Rectal examination revealed melena, and laboratory findings revealed decreased hemoglobin (Hb) and elevated blood urea. Upper endoscopy was normal, and the Hb level dropped again to 6.9 g/dL; therefore, blood transfusion was required during ER observation. For further investigation, the patient underwent an angio-computed tomography scan, which revealed a lesion located in a jejunal loop as the probable bleeding source. Emergency exploratory laparotomy revealed a jejunal loop tumor. Segmental enterectomy containing the tumor was performed and the post-operative period was uneventful. The anatomopathological examination was compatible with low-risk GIST, and the multidisciplinary board agreed that surveillance was the best ongoing treatment. Due to the rarity of jejunal GIST as the cause of massive GI bleeding, diagnosis may be challenging, delaying prompt treatment with bleeding source control. In such cases, surgery may be both lifesaving and curative. Therefore, these tumors should not be forgotten when managing patients with occult GI bleeding with an atypical presentation to prevent delays in treatment and severe outcomes.

The Magic Methyl and Its Tricks in Drug Discovery and Development.

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The "methylation effect", or the "magic methyl" effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates.

Exploring the Mechanisms behind the Anti-Tumoral Effects of Model C-Scorpionate Complexes.

The growing worldwide cancer incidence, coupled to the increasing occurrence of multidrug cancer resistance, requires a continuous effort towards the identification of new leads for cancer management. In this work, two C-scorpionate complexes, [FeCl2(κ3-Tpm)] (1) and [Co(κ3-TpmOH)2](NO3)2 (2), (Tpm = hydrotris(pyrazol-1-yl)methane and TpmOH = 2,2,2-tris(pyrazol-1-yl)ethanol), were studied as potential scaffolds for future anticancer drug development. Their cytotoxicity and cell migration inhibitory activity were analyzed, and an untargeted metabolomics approach was employed to elucidate the biological processes significantly affected by these two complexes, using two tumoral cell lines (B16 and HCT116) and a non-tumoral cell line (HaCaT). While [FeCl2(κ3-Tpm)] did not display a significant cytotoxicity, [Co(κ3-TpmOH)2](NO3)2 was particularly cytotoxic against the HCT116 cell line. While [Co(κ3-TpmOH)2](NO3)2 significantly inhibited cell migration in all tested cell lines, [FeCl2(κ3-Tpm)] displayed a mixed activity. From a metabolomics perspective, exposure to [FeCl2(κ3-Tpm)] was associated with changes in various metabolic pathways involving tyrosine, where iron-dependent enzymes are particularly relevant. On the other hand, [Co(κ3-TpmOH)2](NO3)2 was associated with dysregulation of cell adhesion and membrane structural pathways, suggesting that its antiproliferative and anti-migration properties could be due to changes in the overall cellular adhesion mechanisms.

Depression Screening in a population-based study: Brazilian National Health Survey 2019.

This study evaluated the prevalence of positive screening for depression in Brazil and its associated factors. We used data from National Health Survey 2019 (Pesquisa Nacional de Saúde - PNS), a population-based survey with 88,531 adults. The Patient Health Questionnaire (PHQ-9) was used with two scoring methods, the algorithm and the cutoff point≥10. The variables included sociodemographic characteristics. The prevalence ratios and 95% confidence intervals (95%CI) were estimated using Poisson regression. The positive screening for depression was 10.8% (95%CI: 10.4-11.0), at the cutoff point ≥10 and 5.7% (95%CI: 5.4-6.0) for algorithm. Significant differences were found in prevalence in some Brazilian states. Multivariable analyses showed that being female, black, under 70 years of age, having little education, being single, and living in an urban area were independently associated with a depressive symptoms. The highest association was found in the states of Sergipe, Goiás, Piauí, Espírito Santo, São Paulo, Alagoas and lowest in Pará, Mato Grosso and Maranhão. The prevalence of positive screening for depression in Brazil has increased in recent years. More investment in mental health resources is necessary and surveys such as the PNS should be continued.

Risk Of Venous Thrombosis In The Primary Care Setting During The Covid-19 Pandemic.

AIMS: This study aimed to evaluate the variability of risk factors among patients with lower limb venous thrombosis, either Deep Vein Thrombosis (DVT) or Superficial Vein Thrombosis (SVT) in community patients with recent or current SARS-CoV-2 infection compared to a historical cohort. METHODS: We performed a historical retrospective analysis of all patients who presented to a primary health care unit and were diagnosed with DVT or SVT from January 2020 to December 2021. Historic controls were selected from January 2018 to December 2019. Demographic and clinical data were collected, including BMI, use of oral combined contraception, smoking status and date of COVID-19 infection diagnosis. Univariate analysis was performed for data assessment, including Chi-Square and ANOVA tests. RESULTS: Of the 8547 patients who attended a non-programmed consultation in the timeframe, seventy-nine patients (0.9%) were diagnosed with DVT (19) or SVT (60) and were included in the study. Their mean age was 57.3 ± 15.93 years, with a female-to-male ratio of 3.2 to 1. There was no significant association between COVID-19 and the development of DVT or SVT (p=0.151). However, there was a trend observed indicating a shift in the predominant gender in patients diagnosed with these conditions (85% females in 2018 versus 53.8% in 2021; p=0.077). CONCLUSIONS: Outpatients seen by general practitioners during the pandemic of COVID-19 appear to present a trend towards an increased risk of combined DVT and SVT compared with patients of a historical cohort. Further studies are necessary to shed some light on this issue since robust evidence enables clinicians and policymakers to minimize venous thromboembolism risk in patients with SARS-CoV-2 infection.

Depression Screening in a population-based study: Brazilian National Health Survey 2019 / Rastreamento de sintomas depressivos em um estudo de base populacional: Pesquisa Nacional de Saúde 2019

Abstract This study evaluated the prevalence of positive screening for depression in Brazil and its associated factors. We used data from National Health Survey 2019 (Pesquisa Nacional de Saúde - PNS), a population-based survey with 88,531 adults. The Patient Health Questionnaire (PHQ-9) was used with two scoring methods, the algorithm and the cutoff point≥10. The variables included sociodemographic characteristics. The prevalence ratios and 95% confidence intervals (95%CI) were estimated using Poisson regression. The positive screening for depression was 10.8% (95%CI: 10.4-11.0), at the cutoff point ≥10 and 5.7% (95%CI: 5.4-6.0) for algorithm. Significant differences were found in prevalence in some Brazilian states. Multivariable analyses showed that being female, black, under 70 years of age, having little education, being single, and living in an urban area were independently associated with a depressive symptoms. The highest association was found in the states of Sergipe, Goiás, Piauí, Espírito Santo, São Paulo, Alagoas and lowest in Pará, Mato Grosso and Maranhão. The prevalence of positive screening for depression in Brazil has increased in recent years. More investment in mental health resources is necessary and surveys such as the PNS should be continued.

Resumo Este estudo avaliou a prevalência de triagem positiva para depressão no Brasil e seus fatores associados. Utilizou-se dados da Pesquisa Nacional de Saúde 2019 (PNS), um inquérito de base populacional com 88.531 adultos. Para avaliar os sintomas depressivos utilizou-se o Patient Health Questionnaire (PHQ-9) com dois métodos de pontuação: o algoritmo e o ponto de corte ≥10. As variáveis incluíram características sociodemográficas. Utilizou-se a regressão de Poisson para obter razões de prevalência, com intervalo de confiança de 95% (IC95%). A triagem positiva para depressão foi de 10,8% (IC95%: 10,4-11,0), no ponto de corte ≥10 e 5,7% (IC95%: 5,4-6,0) para o algoritmo. Houve diferenças significativas na prevalência entre alguns estados brasileiros. Análises multivariadas mostraram que ser do sexo feminino, negro, ter menos de 70 anos, ter baixa escolaridade, ser solteiro e residir em área urbana estiveram independentemente associados a sintomas depressivos. A maior associação foi encontrada nos estados de Sergipe, Goiás, Piauí, Espírito Santo, São Paulo, Alagoas e a menor no Pará, Mato Grosso e Maranhão. A prevalência de triagem positiva para depressão no Brasil tem aumentado nos últimos anos. É necessário mais investimento em saúde mental e pesquisas como a PNS devem ser feitas continuamente.

Protocol to study in vitro drug metabolism and identify montelukast metabolites from purified enzymes and primary cell cultures by mass spectrometry.

We present an optimized protocol set to study the production of drug metabolites in different in vitro systems. We detail the necessary steps to identify the metabolites of xenobiotics produced in different metabolic-competent systems, from purified enzymes to primary cell cultures. It is coupled to a high-resolution mass spectrometry analytical approach and can be adapted to study any xenobiotic. This protocol was optimized using montelukast, an antagonist of the cysteinyl leukotriene receptor 1, widely used for asthma management. For complete details on the use and execution of this protocol, please refer to Marques et al. (2022).1.

Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing.

Mutations in the mitochondrial genome (mtDNA) have been associated with maternally inherited genetic diseases. However, interest in mtDNA polymorphisms has increased in recent years due to the recently developed ability to produce models by mtDNA mutagenesis and a new appreciation of the association between mitochondrial genetic aberrations and common age-related diseases such as cancer, diabetes, and dementia. Pyrosequencing is a sequencing-by-synthesis technique that is widely employed across the mitochondrial field for routine genotyping experiments. Its relative affordability when compared to massive parallel sequencing methods and ease of implementation make it an invaluable technique in the field of mitochondrial genetics, allowing for the rapid quantification of heteroplasmy with increased flexibility. Despite the practicality of this method, its implementation as a means of mtDNA genotyping requires the observation of certain guidelines, specifically to avoid certain biases of biological or technical origin. This protocol outlines the necessary steps and precautions in designing and implementing pyrosequencing assays for use in the context of heteroplasmy measurement.

Hybrid model for early identification post-Covid-19 sequelae.

Artificial Intelligence techniques based on Machine Learning algorithms, Neural Networks and Naïve Bayes can optimise the diagnostic process of the SARS-CoV-2 or Covid-19. The most significant help of these techniques is analysing data recorded by health professionals when treating patients with this disease. Health professionals' more specific focus is due to the reduction in the number of observable signs and symptoms, ranging from an acute respiratory condition to severe pneumonia, showing an efficient form of attribute engineering. It is important to note that the clinical diagnosis can vary from asymptomatic to extremely harsh conditions. About 80% of patients with Covid-19 may be asymptomatic or have few symptoms. Approximately 20% of the detected cases require hospital care because they have difficulty breathing, of which about 5% may require ventilatory support in the Intensive Care Unit. Also, the present study proposes a hybrid approach model, structured in the composition of Artificial Intelligence techniques, using Machine Learning algorithms, associated with multicriteria methods of decision support based on the Verbal Decision Analysis methodology, aiming at the discovery of knowledge, as well as exploring the predictive power of specific data in this study, to optimise the diagnostic models of Covid-19. Thus, the model will provide greater accuracy to the diagnosis sought through clinical observation.

A library of base editors for the precise ablation of all protein-coding genes in the mouse mitochondrial genome.

The development of curative treatments for mitochondrial diseases, which are often caused by mutations in mitochondrial DNA (mtDNA) that impair energy metabolism and other aspects of cellular homoeostasis, is hindered by an incomplete understanding of the underlying biology and a scarcity of cellular and animal models. Here we report the design and application of a library of double-stranded-DNA deaminase-derived cytosine base editors optimized for the precise ablation of every mtDNA protein-coding gene in the mouse mitochondrial genome. We used the library, which we named MitoKO, to produce near-homoplasmic knockout cells in vitro and to generate a mouse knockout with high heteroplasmy levels and no off-target edits. MitoKO should facilitate systematic and comprehensive investigations of mtDNA-related pathways and their impact on organismal homoeostasis, and aid the generation of clinically meaningful in vivo models of mtDNA dysfunction.

Premature mortality due to noncommunicable diseases in Brazilian capitals: redistribution of garbage causes and evolution by social deprivation strata / Mortalidade prematura por doenças crônicas não transmissíveis em capitais brasileiras: redistribuição de causas garbage e evolução por estratos de privação social

ABSTRACT Objective: To analyze premature mortality due to noncommunicable chronic diseases (NCDs) in Brazilian capitals and the Federal District (DF) after redistribution of garbage causes and the temporal evolution according to social deprivation strata in the 2010 to 2012 and 2017 to 2019 triennia. Methods: Corrections were applied to the Mortality Information System (Sistema de Informação sobre Mortalidade - SIM) data such as the redistribution of garbage codes (GC). Premature mortality rates due to NCDs were calculated and standardized by age. The differences among NCDs mortality rates were analyzed according to the Brazilian Deprivation Index (Índice Brasileiro de Privação - IBP) categories and between the three-year periods. Results: In the capitals as a whole, rates increased between 8 and 12% after GC redistribution and the greatest increases occurred in areas of high deprivation: 11.9 and 11.4%, triennia 1 and 2, respectively. There was variability between the capitals. There was a reduction in rates in all strata of deprivation between the three-year periods, with the greatest decrease in the stratum of low deprivation (-18.2%) and the lowest in the stratum of high deprivation (-7.5%). Conclusion: The redistribution of GC represented an increase in mortality rates, being higher in the strata of greater social deprivation. As a rule, a positive gradient of mortality was observed with increasing social deprivation. The analysis of the temporal evolution showed a decrease in mortality from NCDs between the triennia, especially in areas of lower social deprivation.

RESUMO Objetivo: Analisar a mortalidade prematura por doenças crônicas não transmissíveis (DCNT) nas capitais brasileiras e Distrito Federal (DF) após redistribuição das causas garbage, e a evolução temporal segundo estratos de privação social nos triênios 2010 a 2012 e 2017 a 2019. Métodos: Foram aplicadas correções ao Sistema de Informação sobre Mortalidade (SIM), sendo empregada metodologia para redistribuição das causas garbage (CG). As taxas de mortalidade prematura por DCNT padronizadas por idade foram estimadas. Foram analisadas as diferenças entre as taxas de mortalidade por DCNT segundo categorias do Índice Brasileiro de Privação (IBP) e entre os triênios. Resultados: No conjunto das capitais, as taxas aumentaram entre 8 e 12% após a redistribuição de CG, e os maiores acréscimos ocorreram em áreas de alta privação: 11,9 e 11,4%, triênios 1 e 2, respectivamente. Houve variabilidade entre as capitais. Observou-se redução das taxas em todos os estratos de privação entre os triênios, sendo maior decréscimo no estrato de baixa privação (-18,2%), e menor no estrato de alta privação (-7,5%). Conclusão: A redistribuição de CG representou aumento das taxas de mortalidade, sendo maior nos estratos de maior privação social. Via de regra, observou-se gradiente positivo de mortalidade com o aumento da privação social. A análise da evolução temporal evidenciou decréscimo da mortalidade por DCNT entre os triênios, sobretudo em áreas de menor privação social.

Compact zinc finger base editors that edit mitochondrial or nuclear DNA in vitro and in vivo.

DddA-derived cytosine base editors (DdCBEs) use programmable DNA-binding TALE repeat arrays, rather than CRISPR proteins, a split double-stranded DNA cytidine deaminase (DddA), and a uracil glycosylase inhibitor to mediate C•G-to-T•A editing in nuclear and organelle DNA. Here we report the development of zinc finger DdCBEs (ZF-DdCBEs) and the improvement of their editing performance through engineering their architectures, defining improved ZF scaffolds, and installing DddA activity-enhancing mutations. We engineer variants with improved DNA specificity by integrating four strategies to reduce off-target editing. We use optimized ZF-DdCBEs to install or correct disease-associated mutations in mitochondria and in the nucleus. Leveraging their small size, we use a single AAV9 to deliver into heart, liver, and skeletal muscle in post-natal mice ZF-DdCBEs that efficiently install disease-associated mutations. While off-target editing of ZF-DdCBEs is likely too high for therapeutic applications, these findings demonstrate a compact, all-protein base editing research tool for precise editing of organelle or nuclear DNA without double-strand DNA breaks.

Methyl Effect on the Metabolism, Chemical Stability, and Permeability Profile of Bioactive N-Sulfonylhydrazones.

Sulfonylhydrazones are privileged structures with multifaceted pharmacological activity. Exploring the hypoglycemic properties of these organic compounds, we previously revealed a new series of N-sulfonylhydrazones (NSH) as antidiabetic drug candidates. Here, we evaluated the microsomal metabolism, chemical stability, and permeability profile of these NSH prototypes, focusing on the pharmacokinetic differences in N-methylated and non-N-methylated analogs. Our results demonstrated that the N-methylated analogs (LASSBio-1772 and LASSBio-1774) were metabolized by CYP, forming three and one metabolites, respectively. These prototypes exhibited chemical stability at pH 2.0 and 7.4 and brain penetration ability. On the other hand, non-N-methylated analogs (LASSBio-1771 and LASSBio-1773) were hydrolyzed in acid pH and could not cross the artificial blood-brain barrier. The cyano group in LASSBio-1771 was postulated as a possible site of interaction with the heme group, potentially inhibiting CYP enzymes. Moreover, prototypes with the methyl ester group were metabolized by carboxylesterase, and non-N-methylated analogs did not show oxidative metabolism. The prototypes (except LASSBio-1774) showed excellent gastrointestinal absorption. Altogether, our data support the idea that the methyl effect on NSH strongly alters their pharmacokinetic profile, enhances the recognition by CYP enzymes, promotes brain penetration, and plays a protective effect upon acid hydrolysis.

Optimized protocol for obtaining and characterizing primary neuron-enriched cultures from embryonic chicken brains.

We present here an optimized protocol to obtain primary neuron-enriched cultures from embryonic chicken brains with no need for an animal facility. The protocol details the steps to isolate a neuron-enriched cell fraction from chicken embryos, followed by characterization of the chicken neurons with mass spectrometry proteomics and cell staining. Because of the high homology between chicken and human amyloid precursor protein processing machinery, these chicken neurons can be used as an alternative to rodent models for studying Alzheimer disease.