ABSTRACT
Artificial intelligence (AI) refers to computer systems doing tasks that usually need human intelligence. AI is constantly changing and is revolutionizing the healthcare field, including nutrition. This review's purpose is four-fold: (i) to investigate AI's role in nutrition research; (ii) to identify areas in nutrition using AI; (iii) to understand AI's future potential impact; (iv) to investigate possible concerns about AI's use in nutrition research. Eight databases were searched: PubMed, Web of Science, EBSCO, Agricola, Scopus, IEEE Explore, Google Scholar and Cochrane. A total of 1737 articles were retrieved, of which 22 were included in the review. Article screening phases included duplicates elimination, title-abstract selection, full-text review, and quality assessment. The key findings indicated AI's role in nutrition is at a developmental stage, focusing mainly on dietary assessment and less on malnutrition prediction, lifestyle interventions, and diet-related diseases comprehension. Clinical research is needed to determine AI's intervention efficacy. The ethics of AI use, a main concern, remains unresolved and needs to be considered for collateral damage prevention to certain populations. The studies' heterogeneity in this review limited the focus on specific nutritional areas. Future research should prioritize specialized reviews in nutrition and dieting for a deeper understanding of AI's potential in human nutrition.
Subject(s)
Artificial Intelligence , Humans , Nutritional Sciences , Biomedical Research/methodsABSTRACT
Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I antigen presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.
ABSTRACT
The field of Huntington's disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to determine, through a consensus exercise involving basic and clinical scientists working in the field, the most appropriate language to use across disciplines. Nominally, this article will serve as the style guide for the Journal of Huntington's Disease (JHD), the only journal devoted exclusively to HD, and we lay out the preferred and standardized terminology and nomenclature for use in JHD publications. However, we hope that this article will also serve as a useful resource to the HD research community at large and that these recommended naming conventions will be adopted widely.
Subject(s)
Huntington Disease , Terminology as Topic , Huntington Disease/classification , Huntington Disease/diagnosis , Humans , Biomedical Research/standardsABSTRACT
Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.
Subject(s)
Huntingtin Protein , Lysosomes , Mitochondria , RNA-Binding Proteins , Ubiquitin , Huntingtin Protein/metabolism , Huntingtin Protein/genetics , Lysosomes/metabolism , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Humans , Ubiquitin/metabolism , Mitochondria/metabolism , Autophagy , Animals , Mitochondrial Proteins/metabolism , Mitochondrial Proteins/genetics , Mice , Protein Binding , Huntington Disease/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Peptides/metabolismABSTRACT
The high heritability of amyotrophic lateral sclerosis (ALS) contrasts with its low molecular diagnosis rate post-genetic testing, pointing to potential undiscovered genetic factors. To aid the exploration of these factors, we introduced EpiOut, an algorithm to identify chromatin accessibility outliers that are regions exhibiting divergent accessibility from the population baseline in a single or few samples. Annotation of accessible regions with histone chromatin immunoprecipitation sequencing and Hi-C indicates that outliers are concentrated in functional loci, especially among promoters interacting with active enhancers. Across different omics levels, outliers are robustly replicated, and chromatin accessibility outliers are reliable predictors of gene expression outliers and aberrant protein levels. When promoter accessibility does not align with gene expression, our results indicate that molecular aberrations are more likely to be linked to post-transcriptional regulation rather than transcriptional regulation. Our findings demonstrate that the outlier detection paradigm can uncover dysregulated regions in rare diseases. EpiOut is available at github.com/uci-cbcl/EpiOut.
Subject(s)
Amyotrophic Lateral Sclerosis , Chromatin , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Humans , Chromatin/metabolism , Chromatin/genetics , Promoter Regions, Genetic/genetics , Algorithms , Gene Expression Regulation , Chromatin Immunoprecipitation Sequencing , Histones/metabolism , Histones/geneticsABSTRACT
NIH's Environmental influences on Child Health Outcome (ECHO) program is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO Cohort is to examine effects of a broad array of early environmental exposures on child health and development. It includes longitudinal data and biospecimens from over 100,000 children and family members from diverse settings across the U.S. ECHO investigators have published collaborative analyses showing associations of environmental exposures--primarily in the developmentally sensitive pre-, peri-, and post-natal periods--with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO Cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public use database, ECHO makes its deidentified data available to the general scientific community. ECHO Cohort data provide opportunities to fill major knowledge gaps in in environmental epidemiology, and to inform policies, practices, and programs to enhance child health.
ABSTRACT
Amyotrophic Lateral Sclerosis (ALS), like many other neurodegenerative diseases, is highly heritable, but with only a small fraction of cases explained by monogenic disease alleles. To better understand sporadic ALS, we report epigenomic profiles, as measured by ATAC-seq, of motor neuron cultures derived from a diverse group of 380 ALS patients and 80 healthy controls. We find that chromatin accessibility is heavily influenced by sex, the iPSC cell type of origin, ancestry, and the inherent variance arising from sequencing. Once these covariates are corrected for, we are able to identify ALS-specific signals in the data. Additionally, we find that the ATAC-seq data is able to predict ALS disease progression rates with similar accuracy to methods based on biomarkers and clinical status. These results suggest that iPSC-derived motor neurons recapitulate important disease-relevant epigenomic changes.
Subject(s)
Amyotrophic Lateral Sclerosis , Induced Pluripotent Stem Cells , Motor Neurons , Humans , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/pathology , Amyotrophic Lateral Sclerosis/metabolism , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/metabolism , Motor Neurons/pathology , Male , Female , Middle Aged , Case-Control Studies , Chromatin/metabolism , Chromatin/genetics , Aged , Epigenomics/methods , Chromatin Immunoprecipitation Sequencing/methods , Disease Progression , Epigenesis, GeneticABSTRACT
Synaptic changes are early manifestations of neuronal dysfunction in Huntington's disease (HD). However, the mechanisms by which mutant HTT protein impacts synaptogenesis and function are not well understood. Herein we explored HD pathogenesis in the BACHD mouse model by examining synaptogenesis and function in long term primary cortical cultures. At DIV14 (days in vitro), BACHD cortical neurons showed no difference from WT neurons in synaptogenesis as revealed by colocalization of a pre-synaptic (Synapsin I) and a post-synaptic (PSD95) marker. From DIV21 to DIV35, BACHD neurons showed progressively reduced colocalization of Synapsin I and PSD95 relative to WT neurons. The deficits were effectively rescued by treatment of BACHD neurons with BDNF. The recombinant apical domain of CCT1 (ApiCCT1) yielded a partial rescuing effect. BACHD neurons also showed culture age-related significant functional deficits as revealed by multielectrode arrays (MEAs). These deficits were prevented by BDNF, whereas ApiCCT1 showed a less potent effect. These findings are evidence that deficits in BACHD synapse and function can be replicated in vitro and that BDNF or a TRiC-inspired reagent can potentially be protective against these changes in BACHD neurons. Our findings support the use of cellular models to further explicate HD pathogenesis and potential treatments.
Subject(s)
Brain-Derived Neurotrophic Factor , Cerebral Cortex , Disease Models, Animal , Huntington Disease , Neurons , Synapses , Animals , Huntington Disease/metabolism , Huntington Disease/pathology , Brain-Derived Neurotrophic Factor/metabolism , Synapses/metabolism , Synapses/drug effects , Synapses/pathology , Cerebral Cortex/metabolism , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Mice , Neurons/metabolism , Neurons/drug effects , Neurons/pathology , Mice, Transgenic , Cells, Cultured , Synapsins/metabolism , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Mice, Inbred C57BLABSTRACT
Microgreens have shown promise in improving the overall nutritional value of diets due to their high nutrient density. Agronomic biofortification, is an efficient strategy for enhancing the nutritional value of crops, including microgreens. This study aimed to biofortify vitamin C and other essential nutrients in arugula microgreens using four treatments containing 0.25 % ascorbic acid, pH adjusted with different bases: KOH, Ca(OH)2, ZnCO3, or NaOH and a deionized water control. The results indicate that ascorbic acid-treated microgreens had more vitamin C, greater fresh weight and % dry matter than the control. The ascorbic acid + Zn treatment had an 135 % average increase in vitamin C compared to the control. Microgreens treated with ascorbic acid also showed increased levels of minerals that are present in the nutrient solution, such as potassium, sodium, calcium, and zinc. This research contributes to the growing interest in microgreens biofortification and their role in addressing multi-nutrient deficiencies.
Subject(s)
Ascorbic Acid , Biofortification , Biofortification/methods , Vitamins , Minerals , Crops, AgriculturalABSTRACT
The ultimate goal of world crop production is to produce more with less to meet the growing population demands. However, concentrating solely on increased quantity of production often impacts the quality of produce. Consumption of crops or foods that do not meet nutritional or dietary needs can lead to malnutrition. Malnutrition and undernutrition are prevalent in a significant portion of the population. Agronomic biofortification of minerals and vitamins in horticultural crops has emerged as a promising approach to address nutrient deficiencies and enhance the nutritional quality of food. Despite numerous research papers on plant nutrient biofortification, there remains a lack of systematic reviews that comprehensively summarize the latest knowledge on this topic. Herein we discuss different agronomic ways to biofortify several horticultural crops over the past decade. This systematic review aims to fill this gap by presenting various methodologies and comparing the outcomes of these methods in respect to nutrient content in plant parts. The review focuses on original research papers collected from various scientific databases including Scopus and Web of Knowledge, covering the most recent literature from the last ten years (2012-2022) for specific studies on the agronomic biofortification macronutrients, micronutrients, and vitamins in horticultural plants with exclusion of certain criteria such as 'genetic,' 'breeding,' and 'agronomic crops.' This review critically analyzes the current state of research and explores prospects for the future in this field. The biofortification of various minerals and vitamins, including calcium, selenium, iodine, B vitamins, vitamin A, and vitamin C, are examined, highlighting the achievements and limitations of existing studies. In conclusion, agronomic biofortification of minerals and vitamins in horticultural crops with further research offers a promising approach to address nutrient deficiencies and improve the nutritional quality of food.
Subject(s)
Malnutrition , Selenium , Crops, Agricultural , Nutritive Value , Plant Breeding , Systematic Reviews as Topic , Vitamin A , VitaminsABSTRACT
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene encoding huntingtin. Prior reports have established a correlation between CAG expanded HTT and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.
ABSTRACT
Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.
Subject(s)
Huntington Disease , Neural Stem Cells , Humans , Mice , Animals , Huntington Disease/genetics , Huntington Disease/therapy , Corpus Striatum , Neurons , Phenotype , Disease Models, Animal , Mice, Transgenic , Huntingtin Protein/geneticsABSTRACT
One of the more transformative findings in human genetics was the discovery that the expansion of unstable nucleotide repeats underlies a group of inherited neurological diseases. A subset of these unstable repeat neurodegenerative diseases is due to the expansion of a CAG trinucleotide repeat encoding a stretch of glutamines, i.e., the polyglutamine (polyQ) repeat neurodegenerative diseases. Among the CAG/polyQ repeat diseases are Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), in which the expansions are within widely expressed proteins. Although both HD and SCA1 are autosomal dominantly inherited, and both typically cause mid- to late-life-onset movement disorders with cognitive decline, they each are characterized by distinct clinical characteristics and predominant sites of neuropathology. Importantly, the respective affected proteins, Huntingtin (HTT, HD) and Ataxin 1 (ATXN1, SCA1), have unique functions and biological properties. Here, we review HD and SCA1 with a focus on how their disease-specific and shared features may provide informative insights.
Subject(s)
Huntington Disease , Nervous System Diseases , Spinocerebellar Ataxias , Humans , Huntington Disease/genetics , Spinocerebellar Ataxias/genetics , Ataxin-1/genetics , Proteins/genetics , Trinucleotide Repeats , Nervous System Diseases/genetics , Genetic Association Studies , Trinucleotide Repeat Expansion/geneticsSubject(s)
Huntington Disease , Humans , Huntington Disease/complications , Sleep , Circadian RhythmABSTRACT
The consumption of plants plays an important role in human health. In addition to providing macro and micronutrients, plants are the sole sources of several phytonutrients that play a major role in disease prevention. However, in modern diets, increased consumption of cheaper, processed foods with poor nutritional value over fruits and vegetables leads to insufficient consumption of essential nutrients such as vitamin C. Taking supplements can address some of the insufficient nutrients in a diet. However, supplements are not as diverse or bioavailable as the nutrients in plants. Improving the abundance of nutrients in plants will reduce the amounts that need to be consumed, thereby reducing the price barrier and use of supplements. In this study, broccoli (Brassica oleracea var. italica) microgreens grown in a controlled environment were biofortified for increased vitamin C content. The microgreens grown on growing pads were treated with supplemental nutrient solutions. Treatments were applied four to five days after germination and included four different concentrations of ascorbic acid specifically, 0% (control), 0.05%, 0.1%, 0.25% and 0.5%, added to the nutrient solution. Microgreens with turgid cotyledons and appearance of tip of first true leaves were harvested about 14 days after germination and were analyzed for biomass, chlorophylls, carotenoids, vitamin C and other minerals content. The ascorbic acid improved the microgreens' fresh biomass, percent dry matter, chlorophylls, carotenoids, vitamin C, and potassium content. Moreover, this study also mapped out the correlation between ascorbic acid, phytochemicals, and broccoli microgreens' mineral composition. The total vitamin C was positively correlated to K and negatively correlated to chlorophylls, N, P, Mg, Ca, S, and B (p < 0.01). These relationships can be applied in future vitamin C biofortification research across different microgreens. In conclusion, vitamin C was increased up to 222% by supplemental ascorbic acid without being detrimental to plant health and mineral composition.
ABSTRACT
Huntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.
Subject(s)
Huntington Disease , Induced Pluripotent Stem Cells , Animals , Mice , Artificial Intelligence , Disease Models, Animal , Huntingtin Protein/genetics , Huntingtin Protein/metabolism , Huntington Disease/metabolism , Induced Pluripotent Stem Cells/metabolism , Mitochondria/metabolism , Neurons/metabolism , Phenotype , Proteomics , HumansABSTRACT
Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack of well-curated lines from a large array of participants. Answer ALS has generated over 1,000 iPSC lines from control and amyotrophic lateral sclerosis (ALS) patients along with clinical and whole-genome sequencing data. The current report summarizes cell marker and gene expression in motor neuron cultures derived from 92 healthy control and 341 ALS participants using a 32-day differentiation protocol. This is the largest set of iPSCs to be differentiated into motor neurons, and characterization suggests that cell composition and sex are significant sources of variability that need to be carefully controlled for in future studies. These data are reported as a resource for the scientific community that will utilize Answer ALS data for disease modeling using a wider array of omics being made available for these samples.
Subject(s)
Amyotrophic Lateral Sclerosis , Induced Pluripotent Stem Cells , Humans , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/metabolism , Cell DifferentiationABSTRACT
Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly in the striatum and cortex. Astrocyte signaling that establishes and maintains neuronal functions are often altered under pathological conditions. We performed single-nuclei RNA-sequencing on human HD patient-induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from R6/2 HD mice to investigate high-resolution HD astrocyte cell state transitions. We observed altered maturation and glutamate signaling in HD human and mouse astrocytes. Human HD astrocytes also showed upregulated actin-mediated signaling, suggesting that some states may be cell-autonomous and human specific. In both species, astrogliogenesis transcription factors may drive HD astrocyte maturation deficits, which are supported by rescued climbing deficits in HD drosophila with NFIA knockdown. Thus, dysregulated HD astrocyte states may induce dysfunctional astrocytic properties, in part due to maturation deficits influenced by astrogliogenesis transcription factor dysregulation.
ABSTRACT
The National Institute of Health (NIH) Library of integrated network-based cellular signatures (LINCS) program is premised on the generation of a publicly available data resource of cell-based biochemical responses or "signatures" to genetic or environmental perturbations. NeuroLINCS uses human inducible pluripotent stem cells (hiPSCs), derived from patients and healthy controls, and differentiated into motor neuron cell cultures. This multi-laboratory effort strives to establish i) robust multi-omic workflows for hiPSC and differentiated neuronal cultures, ii) public annotated data sets and iii) relevant and targetable biological pathways of spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS). Here, we focus on the proteomics and the quality of the developed workflow of hiPSC lines from 6 individuals, though epigenomics and transcriptomics data are also publicly available. Known and commonly used markers representing 73 proteins were reproducibly quantified with consistent expression levels across all hiPSC lines. Data quality assessments, data levels and metadata of all 6 genetically diverse human iPSCs analysed by DIA-MS are parsable and available as a high-quality resource to the public.