Uncovering DNA methylation landscapes to decipher evolutionary footprints of phenotypic diversity in chickpea.

Genetic diversity and environmental factors are long believed to be the dominant contributors to phenotypic diversity in crop plants. However, it has been recently established that, besides genetic variation, epigenetic variation, especially variation in DNA methylation, plays a significant role in determining phenotypic diversity in crop plants. Therefore, assessing DNA methylation diversity in crop plants becomes vital, especially in the case of crops like chickpea, which has a narrow genetic base. Thus, in the present study, we employed whole-genome bisulfite sequencing to assess DNA methylation diversity in wild and cultivated (desi and kabuli) chickpea. This revealed extensive DNA methylation diversity in both wild and cultivated chickpea. Interestingly, the methylation diversity was found to be significantly higher than genetic diversity, suggesting its potential role in providing vital phenotypic diversity for the evolution and domestication of the Cicer gene pool. The phylogeny based on DNA methylation variation also indicates a potential complementary role of DNA methylation variation in addition to DNA sequence variation in shaping chickpea evolution. Besides, the study also identified diverse epi-alleles of many previously known genes of agronomic importance. The Cicer MethVarMap database developed in this study enables researchers to readily visualize methylation variation within the genes and genomic regions of their interest (http://223.31.159.7/cicer/public/). Therefore, epigenetic variation like DNA methylation variation can potentially explain the paradox of high phenotypic diversity despite the narrow genetic base in chickpea and can potentially be employed for crop improvement.

Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. Using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Functional allele of a MATE gene selected during domestication modulates seed color in chickpea.

Seed color is one of the key target traits of domestication and artificial selection in chickpeas due to its implications on consumer preference and market value. The complex seed color trait has been well dissected in several crop species; however, the genetic mechanism underlying seed color variation in chickpea remains poorly understood. Here, we employed an integrated genomics strategy involving QTL mapping, high-density mapping, map-based cloning, association analysis, and molecular haplotyping in an inter-specific RIL mapping population, association panel, wild accessions, and introgression lines (ILs) of Cicer gene pool. This delineated a MATE gene, CaMATE23, encoding a Transparent Testa (TT) and its natural allele (8-bp insertion) and haplotype underlying a major QTL governing seed color on chickpea chromosome 4. Signatures of selective sweep and a strong purifying selection reflected that CaMATE23, especially its 8-bp insertion natural allelic variant, underwent selection during chickpea domestication. Functional investigations revealed that the 8-bp insertion containing the third cis-regulatory RY-motif element in the CaMATE23 promoter is critical for enhanced binding of CaFUSCA3 transcription factor, a key regulator of seed development and flavonoid biosynthesis, thereby affecting CaMATE23 expression and proanthocyanidin (PA) accumulation in the seed coat to impart varied seed color in chickpea. Consequently, overexpression of CaMATE23 in Arabidopsis tt12 mutant partially restored the seed color phenotype to brown pigmentation, ascertaining its functional role in PA accumulation in the seed coat. These findings shed new light on the seed color regulation and evolutionary history, and highlight the transcriptional regulation of CaMATE23 by CaFUSCA3 in modulating seed color in chickpea. The functionally relevant InDel variation, natural allele, and haplotype from CaMATE23 are vital for translational genomic research, including marker-assisted breeding, for developing chickpea cultivars with desirable seed color that appeal to consumers and meet global market demand.

A Multi-Model Based Stability Analysis Employing Multi-Environmental Trials (METs) Data for Discerning Heat Tolerance in Chickpea (Cicer arietinum L.) Landraces.

Identifying a congenially targeted production environment and understanding the effects of genotype by environmental interactions on the adaption of chickpea genotypes is essential for achieving an optimal yield stability. Different models like additive main effect and multiplicative interactions (AMMI 1, AMM2), weighted average absolute scores of BLUPs (WAASB), and genotype plus genotype-environment (GGE) interactions were used to understand their suitability in the precise estimation of variance and their interaction. Our experiment used genotypes that represent the West Asia-North Africa (WANA) region. This trial involved two different sowing dates, two distinct seasons, and three different locations, resulting in a total of 12 environments. Genotype IG 5871(G1) showed a lower heat susceptibility index (HSI) across environments under study. The first four interactions principal component axis (IPCA) explain 93.2% of variations with significant genotype-environment interactions. Considering the AMMI stability value (ASV), the genotypes IG5862(G7), IG5861(G6), ILC239(G40), IG6002(G26), and ILC1932(G39), showing ASV scores of 1.66, 1.80, 2.20, 2.60, and 2.84, respectively, were ranked as the most stable and are comparable to the weighted average absolute scores of BLUPs (WAASB) ranking of genotypes. The which-won-where pattern of genotype plus genotype-environment (GGE) interactions suggested that the target environment consists of one mega environment. IG5866(G10), IG5865(G9), IG5884(G14), and IG5862(G7) displayed higher stability, as they were nearer to the origin. The genotypes that exhibited a superior performance in the tested environments can serve as ideal parental lines for heat-stress tolerance breeding programs. The weighted average absolute scores of BLUPs (WAASB) serve as an ideal tool to discern the variations and identify the stable genotype among all methods.

Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents a substantial threat to health, especially in Middle East nations. Given that no FDA-approved specific therapy for MERS infection exists, designing and discovering a potent antiviral therapy for MERS-CoV is crucial. One pivotal strategy for inhibiting MERS replication is to focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting of cherry-picked molecules from the literature. The key features of the URDL library include synthetic tractability (1-2 pot synthesis) of the molecules scaffold and unexplored chemical space. The hits were ranked based on the docking score, MM-GBSA free energy of binding, and the interaction pattern with the active site residues. A molecular dynamics (MD) simulation study was performed for the first two top-ranked compounds to analyze the stability and free binding energy based on the molecular mechanics Poisson-Boltzmann surface area. The potential mean force calculated from the steered molecular dynamics (SMD) simulations of the hits indicates improved H-bond potential, enhanced conformational stability, and binding affinity toward the target, compared to the cocrystallized ligand. The discovered hits represent novel synthetically tractable scaffolds as potential MERS-CoV Mpro inhibitors.Communicated by Ramaswamy H. Sarma.

Patients' perception about polycystic ovarian syndrome (PCOS) in Sub-Himalayan region of India-A facility-based cross-sectional study.

Background: In modern times, metabolic disorders are most common and one of them is polycystic ovarian syndrome (PCOS) in women, which causes high morbidity and complications. PCOS has largely been a neglected and less researched area; however, it is gaining importance in recent times as PCOS is increasing as well as it can be prevented to a considerable extent. Methods: A cross-sectional study was conducted to assess knowledge among females in government hospitals in Northern India. Data were collected using a pretested structured questionnaire on 300 women (completed 270), selected by proportionate sampling technique, and admitted in government hospitals. Data were analyzed by SPSS version 23. Results: The results showed that the mean age of respondents was 33.02 ± 9.039 years, the mean age at menarche was 12.33 ± 2.13 years, and the mean of gravida status was 1.82 ± 0.78 years. Only half of the respondents had good knowledge about PCOS. Conclusion: This study suggests that efforts are needed to reinforce women's knowledge through setting-based awareness campaigns and health education in this context to enable them to identify and seek timely treatment and improve their quality of life.

"Never Judge a Book by its Cover"-The socio-cultural aspects of non-epileptic seizures in India-A case study.

"Health for All" will never be attained if sociocultural bias and pervasive hypocrisy are not eliminated. The patient mentioned in this case study had difficulty gaining access to health care for more than two decades. The seizure history was modified due to social pressure. The primary healthcare workers' ability to provide timely access to healthcare regardless of caste, religion, or gender, even in the most remote regions of the country, is of paramount importance. The patient was diagnosed with hypoparathyroidism and treated with calcium and vitamin D in high oral doses. The case also illustrates the significance of medical examination in preventing future difficulties in patients with presenile cataract.

A superior gene allele involved in abscisic acid signaling enhances drought tolerance and yield in chickpea.

Identifying potential molecular tags for drought tolerance is essential for achieving higher crop productivity under drought stress. We employed an integrated genomics-assisted breeding and functional genomics strategy involving association mapping, fine mapping, map-based cloning, molecular haplotyping and transcript profiling in the introgression lines (ILs)- and near isogenic lines (NILs)-based association panel and mapping population of chickpea (Cicer arietinum). This combinatorial approach delineated a bHLH (basic helix-loop-helix) transcription factor, CabHLH10 (Cicer arietinum bHLH10) underlying a major QTL, along with its derived natural alleles/haplotypes governing yield traits under drought stress in chickpea. CabHLH10 binds to a cis-regulatory G-box promoter element to modulate the expression of RD22 (responsive to desiccation 22), a drought/abscisic acid (ABA)-responsive gene (via a trans-expression QTL), and two strong yield-enhancement photosynthetic efficiency (PE) genes. This, in turn, upregulates other downstream drought-responsive and ABA signaling genes, as well as yield-enhancing PE genes, thus increasing plant adaptation to drought with reduced yield penalty. We showed that a superior allele of CabHLH10 introgressed into the NILs improved root and shoot biomass and PE, thereby enhancing yield and productivity during drought without compromising agronomic performance. Furthermore, overexpression of CabHLH10 in chickpea and Arabidopsis (Arabidopsis thaliana) conferred enhanced drought tolerance by improving root and shoot agro-morphological traits. These findings facilitate translational genomics for crop improvement and the development of genetically tailored, climate-resilient, high-yielding chickpea cultivars.

Integrated breeding approaches to enhance the nutritional quality of food legumes.

Global food security, both in terms of quantity and quality remains as a challenge with the increasing population. In parallel, micronutrient deficiency in the human diet leads to malnutrition and several health-related problems collectively known as "hidden hunger" more prominent in developing countries around the globe. Biofortification is a potential tool to fortify grain legumes with micronutrients to mitigate the food and nutritional security of the ever-increasing population. Anti-nutritional factors like phytates, raffinose (RFO's), oxalates, tannin, etc. have adverse effects on human health upon consumption. Reduction of the anti-nutritional factors or preventing their accumulation offers opportunity for enhancing the intake of legumes in diet besides increasing the bioavailability of micronutrients. Integrated breeding methods are routinely being used to exploit the available genetic variability for micronutrients through modern "omic" technologies such as genomics, transcriptomics, ionomics, and metabolomics for developing biofortified grain legumes. Molecular mechanism of Fe/Zn uptake, phytate, and raffinose family oligosaccharides (RFOs) biosynthesis pathways have been elucidated. Transgenic, microRNAs and genome editing tools hold great promise for designing nutrient-dense and anti-nutrient-free grain legumes. In this review, we present the recent efforts toward manipulation of genes/QTLs regulating biofortification and Anti-nutrient accumulation in legumes using genetics-, genomics-, microRNA-, and genome editing-based approaches. We also discuss the success stories in legumes enrichment and recent advances in development of low Anti-nutrient lines. We hope that these emerging tools and techniques will expedite the efforts to develop micronutrient dense legume crop varieties devoid of Anti-nutritional factors that will serve to address the challenges like malnutrition and hidden hunger.

Identification of a new and diverse set of Mycobacterium tuberculosis uracil-DNA glycosylase (MtUng) inhibitors using structure-based virtual screening: Experimental validation and molecular dynamics studies.

Mycobacterium tuberculosis uracil-DNA glycosylase (MtUng), a key DNA repair enzyme, represents an attractive target for the design of new antimycobacterial agents. However, only a limited number of weak MtUng inhibitors are reported, primarily based on the uracil ring, and hence, lack diversity. We report the first structure-based virtual screening (SBVS) using three separate libraries consisting of uracil and non-uracil small molecules, together with the FDA-approved drugs. Twenty diverse virtual hits with the highest predicted binding were procured and screened using a fluorescence-based assay to evaluate their potential to inhibit MtUng. Several of these molecules were found to inhibit MtUng activity at low mM and µM levels, comparable to or better than several other reported Ung inhibitors. Thus, these molecules represent a diverse set of scaffolds for developing next-generation MtUng inhibitors. The most active uracil-based compound 5 (IC50 = 0.14 mM) was found to be âˆ¼ 15-fold more potent than the positive control, uracil. The binding stability and conformation of compound 5 in complex with the enzyme were further confirmed using molecular dynamics simulation.

Characterization of 'QTL-hotspot' introgression lines reveals physiological mechanisms and candidate genes associated with drought adaptation in chickpea.

'QTL-hotspot' is a genomic region on linkage group 04 (CaLG04) in chickpea (Cicer arietinum) that harbours major-effect quantitative trait loci (QTLs) for multiple drought-adaptive traits, and it therefore represents a promising target for improving drought adaptation. To investigate the mechanisms underpinning the positive effects of 'QTL-hotspot' on seed yield under drought, we introgressed this region from the ICC 4958 genotype into five elite chickpea cultivars. The resulting introgression lines (ILs) and their parents were evaluated in multi-location field trials and semi-controlled conditions. The results showed that the 'QTL-hotspot' region improved seed yield under rainfed conditions by increasing seed weight, reducing the time to flowering, regulating traits related to canopy growth and early vigour, and enhancing transpiration efficiency. Whole-genome sequencing data analysis of the ILs and parents revealed four genes underlying the 'QTL-hotspot' region associated with drought adaptation. We validated diagnostic KASP markers closely linked to these genes using the ILs and their parents for future deployment in chickpea breeding programs. The CaTIFY4b-H2 haplotype of a potential candidate gene CaTIFY4b was identified as the superior haplotype for 100-seed weight. The candidate genes and superior haplotypes identified in this study have the potential to serve as direct targets for genetic manipulation and selection for chickpea improvement.

Study on the Quality of Life among Cancer Survivors Attending a Tertiary Care Cancer Center in Malaysia.

Background: Cancer is a major public health problem across the globe. According to the Malaysian National Cancer Registry Report (MNCR), between 2007 and 2011, there has been a greater increase in the number of reported cancer cases among females (99.3 per 100,000 people) than males (86.9 cases per 100,000 people). Nearly 15 million new cancer cases were projected by 2020. We conducted this study to assess the quality of life (QoL) among cancer patients. Design and Methods: This was a cross-sectional study conducted in the oncology department of Malaysian hospitals from October to November 2019. The study population comprised Malaysians in the age range of18 to 100 years diagnosed with cancer, irrespective of their treatment status, cancer type and prognosis. A pre-tested structured questionnaire was used in seventy cancer patients' using a convenient sampling method. Data were collected using a questionnaire survey after obtaining permission from the hospital administrators. Data were entered in MS Excel and analysis was done using the SPSS-version 23. Participants' socio-demographic characteristics were described using descriptive statistics. Results are presented using graphs, tables, mean, percentages, standard deviation, frequency, and significance. Analysis of variance (ANOVA) test was performed to find out the association between socio-demographic variables and overall QoL scores of the patients. Results: Of the seventycancer patients, 29 (41.43%) were males and 41 (58.57%) were females. The most affected socio-demographic factors were marital status and occupation (employment). It was found that there were 55 (78.57%) married patients and 49 (70%) employed patients. QoL of most of the patients was influenced by the education level and treatment. It was found that 35 (50%) of them had low QoL scores. It was observed that QoL among the study participants was significantly (p<0.05) associated with their level of education and the level of treatment. Conclusions: There is a need to develop measures for community education, involvement of family physicians for the treatment of cancer and to increase awareness to improve the QoL among cancer patients. The focus should be on the development of strategies empowering patients to seek treatment and gain control over their illness with the collaboration with primary care physicians.

Genome Editing Targets for Improving Nutrient Use Efficiency and Nutrient Stress Adaptation.

In recent years, the development of RNA-guided genome editing (CRISPR-Cas9 technology) has revolutionized plant genome editing. Under nutrient deficiency conditions, different transcription factors and regulatory gene networks work together to maintain nutrient homeostasis. Improvement in the use efficiency of nitrogen (N), phosphorus (P) and potassium (K) is essential to ensure sustainable yield with enhanced quality and tolerance to stresses. This review outlines potential targets suitable for genome editing for understanding and improving nutrient use (NtUE) efficiency and nutrient stress tolerance. The different genome editing strategies for employing crucial negative and positive regulators are also described. Negative regulators of nutrient signalling are the potential targets for genome editing, that may improve nutrient uptake and stress signalling under resource-poor conditions. The promoter engineering by CRISPR/dead (d) Cas9 (dCas9) cytosine and adenine base editing and prime editing is a successful strategy to generate precise changes. CRISPR/dCas9 system also offers the added advantage of exploiting transcriptional activators/repressors for overexpression of genes of interest in a targeted manner. CRISPR activation (CRISPRa) and CRISPR interference (CRISPRi) are variants of CRISPR in which a dCas9 dependent transcription activation or interference is achieved. dCas9-SunTag system can be employed to engineer targeted gene activation and DNA methylation in plants. The development of nutrient use efficient plants through CRISPR-Cas technology will enhance the pace of genetic improvement for nutrient stress tolerance of crops and improve the sustainability of agriculture.

Attention deficit hyperactivity disorder and associated learning difficulties among primary school children in district Dehradun, Uttarakhand, India.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a considerably common childhood-onset neurodevelopmental disorder, often associated with socio-behavioral and academic difficulties. There is an increased risk for development of a range of future problems such as psychiatric disorders, difficulties in employment, and relationships. The aim of this study was to know the prevalence and determinants of ADHD among primary school children in district Dehradun and to assess the learning difficulties and classroom behavior in these students. MATERIALS AND METHODS: In this cross-sectional study, overall, 228 students (aged 6-12 years) studying in a primary school were assessed for ADHD after seeking the written informed consent from their parents. The data were analyzed using Excel sheet and SPSS software (22.0 version). For all qualitative measures, frequency and percentages were calculated, and for quantitative measures, mean and standard deviation were calculated. For analysis of categorical values, Chi-square test was used. P < 0.05 was considered statistically significant. RESULTS: The prevalence of ADHD was found to be 11.8% based on the teacher tool only and 1.75% based on the parent and teacher tools combined. ADHD was found to be significantly more in males. Inattention was the most prevalent subtype of ADHD, and children screened positive for ADHD had significant learning difficulties at various levels. CONCLUSION: The possibility of ADHD in students with academic difficulties should not be ignored as children with ADHD usually face significant problems at school such as learning difficulties and have been shown to be at increased risk for a broad range of negative outcomes. Early identification and treatment of ADHD can significantly reduce the rates of some of these poor outcomes. Screening these children in the early years will help the parents, children, teachers, and community at large.

Identification of Novel GSK-3ß Hits Using Competitive Biophysical Assays.

Glycogen synthase kinase 3 beta (GSK-3ß) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer's disease and cancer. Even though GSK-3ß is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3ß complete inhibition which translates into the impairment of the plethora of pathways GSK-3ß is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3ß inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3ß in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3ß, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3ß inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3ß activity without leading to its complete inhibition.

Dietary salt consumption pattern as an antecedent risk factor for hypertension: Status, vision, and future recommendations.

Multiple salt reduction strategies have been devised from time to time, addressing the issues of hypertension without considering the other essential factors, like the variability of salt sensitivity from the person to person. In this paper, we discuss how high salt consumption is one modifiable risk factor associated with hypertension among Indians, and there needs to be updated cut-off values. A thorough literature search on salt consumption articles on well-known search engines like Cochrane Library, PubMed, Google Scholar and Embase electronic database revealed a paucity of data in this field for India. Several studies revealed that the mean salt intake among the Indian populations ranges between 5.22 and 42.30 g/day. Moreover, among other risk factors analysed, salt intake (≥ 5 gm/day) was significantly associated with the development of hypertension. Although the need to address reduced salt intake for primordial prevention of hypertension and related cardiovascular diseases (CVDs) in India is well acknowledged by the key stakeholders, social and cultural beliefs, unorganized food retail sector and lack of existing food policing are some of the potential barriers that affect the progress and employment of such effective strategies. Some multinational food companies have already research is warranted to evaluate the contextual barriers and facilitators and to adopt effective strategies to improve awareness among consumers, to encourage the endorsement of salt reduction by the food industry, and to facilitate the adoption of countrywide consumer-friendly food labelling. We concluded that salt consumption is high in India, although this assessment has been done primarily by subjective methods in India. People all across are recommended the same cut-off value of dietary salt consumption regardless of the diversity in dietary patterns and environmental conditions across the country. There is an urgent need to address these issues through evidence-based population research.

Expanding the horizon for breast cancer screening in India through artificial intelligent technologies -A mini-review.

Introduction: Breast cancer is one of the most common cancer among Indian women, with an incidence of 25.8 per 100,000 women according to the Ministry of Health and Family Welfare. Late detection is responsible for poor quality of life (QOL), and it is the leading cause of death. In metropolitan regions, one in every 22 women will have breast cancer over their lifetime; but in rural areas, one in every 60 women will develop breast cancer as per estimates. Aim and objective: This paper aims to describe the various AI based breast screening technologies which are used in breast cancer screening in India. Methodology: The literature search was done using "Pub Med," "Google scholar," and "Scopus" databases for the key terms "technology," "cancer research," "artificial intelligence," "mammography", "breast cancer," "cancer," and/or "neoplasia in breast." All the relevant articles were included to support this mini review. Results: We found that emerging artificial intelligent technologies namely "Niramai", "iBreastExam," "MammoAssist" are emerging as an hope for early detection by screening in resource poor settings, in turn, which can improve the QOL among breast cancer patients.

ARN25068, a versatile starting point towards triple GSK-3ß/FYN/DYRK1A inhibitors to tackle tau-related neurological disorders.

The human kinome plays a crucial role in several pathways. Its dysregulation has been linked to diverse central nervous system (CNS)-related disorders with a drastic impact on the aging population. Among them, tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Lobar degeneration (FTLD-tau), are neurodegenerative disorders pathologically defined by the presence of hyperphosphorylated tau-positive intracellular inclusions known as neurofibrillary tangles (NFTs). Compelling evidence has reported the great potential of the simultaneous modulation of multiple protein kinases (PKs) involved in abnormal tau phosphorylation through a concerted pharmacological approach to achieve a superior therapeutic effect relative to classic "one target, one drug" approaches. Here, we report on the identification and characterization of ARN25068 (4), a low nanomolar and well-balanced dual GSK-3ß and FYN inhibitor, which also shows inhibitory activity against DYRK1A, an emerging target in AD and tauopathies. Computational and X-Ray studies highlight compound 4's typical H-bonding pattern of ATP-competitive inhibitors at the binding sites of all three PKs. In a tau phosphorylation assay on Tau0N4R-TM-tGFP U2OS cell line, 4 reduces the extent of tau phosphorylation, promoting tau-stabilized microtubule bundles. In conclusion, this compound emerges as a promising prototype for further SAR explorations to develop potent and well-balanced triple GSK-3ß/FYN/DYRK1A inhibitors to tackle tau hyperphosphorylation.