The Leap of Inulin Fructans from Food Industry to Medical Application.

As a dietary supplement, the efficacy of prebiotics has become a hot issue in recent years. Inulin is one of internationally recognized prebiotics and belongs to a group of non-digestible and fermentable carbohydrates. Currently, the food industry is increasingly using prebiotic inulin as a health-promoting substrate, not just as food supplement. In addition, inulin has also shown great promise in the treatment of various diseases. This article reviews the application of inulin in the food industry and summarizes physiological function of inulin. Through the review and prospect of the research on obesity, diabetes and mental illness, it provides the theoretical basis for the joint development of inulin in food industry and medical application.

Genetic polymorphisms and phylogenetic characteristics of Tibeto-Burman-speaking Lahu population from southwest China based on 41 Y-STR loci.

BACKGROUND: Male sex-linked Y-chromosome short tandem repeats (Y-STRs) have been widely used in forensic cases and population genetics research. At present, the forensic-related Y-STR data in the Chinese Lahu population are still poorly understood. AIM: To enrich the available Y-STR data of this Chinese minority population and investigate its phylogenetic relationships with other reported populations. SUBJECTS AND METHODS: The genetic polymorphisms of 41 Y-STR loci were analysed in 299 unrelated healthy Lahu male individuals from Southwest China. Phylogenetic analyses were performed by multidimensional scaling analysis and neighbor-joining phylogenetic tree construction. RESULTS: A total of 379 alleles were observed at the 41 Y-STR loci. The allele frequencies ranged from 0.0033 to 0.9666. The genetic diversity values ranged from 0.0653 to 0.9072. A total of 254 different haplotypes of the 41 Y-STR loci were observed in 299 individuals. The values of haplotype diversity, haplotype match probability, and discrimination capacity were 0.9987, 0.0047, and 0.8495, respectively. The phylogenetic analysis indicated that the Tibeto-Burman-speaking Lahu population showed a close genetic relationship with the Yunnan Yi population. CONCLUSIONS: The haplotype data of the present study can enrich the forensic databases of this Chinese minority population and will be useful for population genetics and forensic DNA application.

The effects of capital-biased tax incentives on firm energy intensity: Environmental dividend or consequence?

Capital and energy are essential input factors in the production and operation of firms, and they are closely interconnected. Nudging firms to improve energy performance during capital investment is crucial for attaining green competitiveness. Nonetheless, little is known about how capital-biased tax incentives affect firm energy performance in the process of encouraging firms to update or expand fixed assets. To fill this critical gap, this paper leverages the 2014 and 2015 accelerated depreciation policy for fixed assets as quasi-natural experiments to investigate the impact of capital-biased tax incentives on firm energy intensity. This study uses information from a unique dataset of Chinese firms, and the staggered difference-in-difference strategy is constructed to address identification challenges. The findings of this paper are as follows: (1) The accelerated depreciation policy for fixed assets significantly increases firm energy intensity by approximately 11.2%. A series of validations reinforce the robustness of this result. (2) Restructuring energy use and the factor substitution of energy for labour are the main channels through which the accelerated depreciation policy for fixed assets increases firm energy intensity. (3) The accelerated depreciation policy for fixed assets has a more remarkable effect on the energy intensity enhancement of small-scale firms, capital-intensive firms, and firms in energy-endowed regions. These conclusions support shaping policy options moderately by coordinating tax incentives and government regulation as key factors in promoting sustainable firm development. Overall, this research provides empirical evidence regarding the micro-environmental consequences of capital-biased tax incentives and offers valuable insights for enhancing corporate energy performance.

Mitochondrial Proteostasis Requires Genes Encoded in a Neurodevelopmental Syndrome Locus.

Eukaryotic cells maintain proteostasis through mechanisms that require cytoplasmic and mitochondrial translation. Genetic defects affecting cytoplasmic translation perturb synapse development, neurotransmission, and are causative of neurodevelopmental disorders, such as Fragile X syndrome. In contrast, there is little indication that mitochondrial proteostasis, either in the form of mitochondrial protein translation and/or degradation, is required for synapse development and function. Here we focus on two genes deleted in a recurrent copy number variation causing neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. We demonstrate that SLC25A1 and MRPL40, two genes present in the microdeleted segment and whose products localize to mitochondria, interact and are necessary for mitochondrial ribosomal integrity and proteostasis. Our Drosophila studies show that mitochondrial ribosome function is necessary for synapse neurodevelopment, function, and behavior. We propose that mitochondrial proteostasis perturbations, either by genetic or environmental factors, are a pathogenic mechanism for neurodevelopmental disorders.SIGNIFICANCE STATEMENT The balance between cytoplasmic protein synthesis and degradation, or cytoplasmic proteostasis, is required for normal synapse function and neurodevelopment. Cytoplasmic and mitochondrial ribosomes are necessary for two compartmentalized, yet interdependent, forms of proteostasis. Proteostasis dependent on cytoplasmic ribosomes is a well-established target of genetic defects that cause neurodevelopmental disorders, such as autism. Here we show that the mitochondrial ribosome is a neurodevelopmentally regulated organelle whose function is required for synapse development and function. We propose that defective mitochondrial proteostasis is a mechanism with the potential to contribute to neurodevelopmental disease.

Does the Emission Trading Scheme achieve the dual dividend of reducing pollution and improving energy efficiency? Micro evidence from China.

Resolving the negative externality of environmental pollution has always been a concern in both the theoretical and practical space. To stimulate enterprises to participate in environmental governance actively, China has implemented a series of environmental regulation policies. The Emission Trading Pilot Scheme (ETPS) is an example of such policies implemented to ensure the gradual transition toward marketization. From a micro-enterprise perspective, the study examines how this policy achieves the dual effects of reducing emissions and promoting energy efficiency. We further explore potential channels through which this policy influences the dual effects. We empirically find ETPS to reduce the pollution emissions of enterprises significantly. However, the pollution reduction effect is mainly achieved by encouraging enterprises to strengthen cleaner production rather than through end governance. In addition to bringing environmental dividends, we observe ETPS to improve fossil energy efficiency by about 7.5% indirectly. We conclude by urging policy makers and participants to optimize energy structures and adjust intermediate input as they serve as significant pathways through which ETPS can affect fossil energy efficiency. The ETPS can encourage enterprises to actively step out of their "comfort zone" of environmental governance to be viewed as an effective environmental regulation policy.

Impaired mitochondrial dynamics underlie axonal defects in hereditary spastic paraplegias.

Mechanisms by which long corticospinal axons degenerate in hereditary spastic paraplegia (HSP) are largely unknown. Here, we have generated induced pluripotent stem cells (iPSCs) from patients with two autosomal recessive forms of HSP, SPG15 and SPG48, which are caused by mutations in the ZFYVE26 and AP5Z1 genes encoding proteins in the same complex, the spastizin and AP5Z1 proteins, respectively. In patient iPSC-derived telencephalic glutamatergic and midbrain dopaminergic neurons, neurite number, length and branching are significantly reduced, recapitulating disease-specific phenotypes. We analyzed mitochondrial morphology and noted a significant reduction in both mitochondrial length and their densities within axons of these HSP neurons. Mitochondrial membrane potential was also decreased, confirming functional mitochondrial defects. Notably, mdivi-1, an inhibitor of the mitochondrial fission GTPase DRP1, rescues mitochondrial morphology defects and suppresses the impairment in neurite outgrowth and late-onset apoptosis in HSP neurons. Furthermore, knockdown of these HSP genes causes similar axonal defects, also mitigated by treatment with mdivi-1. Finally, neurite outgrowth defects in SPG15 and SPG48 cortical neurons can be rescued by knocking down DRP1 directly. Thus, abnormal mitochondrial morphology caused by an imbalance of mitochondrial fission and fusion underlies specific axonal defects and serves as a potential therapeutic target for SPG15 and SPG48.

Targeting Hsc70-based autophagy to eliminate amyloid ß oligomers.

Amyloid ß (Aß) oligomers may be a real culprit in the pathogenesis of Alzheimer's disease (AD); therefore, the elimination of these toxic oligomers may be of great significance for AD therapy. Autophagy is the catabolic process by which lysosomes degrade cytosolic components, and heat shock cognate 70 kDa protein (Hsc70) binds to proteins with their KFERQ-like motifs [also known as chaperone-mediated autophagy (CMA) motifs] and carries them to lysosomes through CMA or late endosomes through endosomal microautophagy (eMI) for degradation. In this study, our strategy is to make the pathological Aß become one selective and suitable substrate for CMA and eMI (termed as Hsc70-based autophagy) by tagging its oligomers with multiple CMA motifs. First, we design and synthesize Aß oligomer binding peptides with three CMA motifs. Second, we determine that the peptide can help Aß oligomers enter endosomes and lysosomes, which can be further enhanced by ketone. More importantly, we find that the peptide can dramatically reduce Aß oligomers in induced pluripotent stem cell (iPSC) cortical neurons derived from AD patient fibroblasts and protect primary cultured cortical neurons against the Aß oligomer-induced neurotoxicity. In conclusion, we demonstrate that the peptide targeting Hsc70-based autophagy can effectively eliminate Aß oligomers and have superior neuroprotective activity.

Zika Virus Infection Induces DNA Damage Response in Human Neural Progenitors That Enhances Viral Replication.

Zika virus (ZIKV) infection attenuates the growth of human neural progenitor cells (hNPCs). As these hNPCs generate the cortical neurons during early brain development, the ZIKV-mediated growth retardation potentially contributes to the neurodevelopmental defects of the congenital Zika syndrome. Here, we investigate the mechanism by which ZIKV manipulates the cell cycle in hNPCs and the functional consequence of cell cycle perturbation on the replication of ZIKV and related flaviviruses. We demonstrate that ZIKV, but not dengue virus (DENV), induces DNA double-strand breaks (DSBs), triggering the DNA damage response through the ATM/Chk2 signaling pathway while suppressing the ATR/Chk1 signaling pathway. Furthermore, ZIKV infection impedes the progression of cells through S phase, thereby preventing the completion of host DNA replication. Recapitulation of the S-phase arrest state with inhibitors led to an increase in ZIKV replication, but not of West Nile virus or DENV. Our data identify ZIKV's ability to induce DSBs and suppress host DNA replication, which results in a cellular environment favorable for its replication.IMPORTANCE Clinically, Zika virus (ZIKV) infection can lead to developmental defects in the cortex of the fetal brain. How ZIKV triggers this event in developing neural cells is not well understood at a molecular level and likely requires many contributing factors. ZIKV efficiently infects human neural progenitor cells (hNPCs) and leads to growth arrest of these cells, which are critical for brain development. Here, we demonstrate that infection with ZIKV, but not dengue virus, disrupts the cell cycle of hNPCs by halting DNA replication during S phase and inducing DNA damage. We further show that ZIKV infection activates the ATM/Chk2 checkpoint but prevents the activation of another checkpoint, the ATR/Chk1 pathway. These results unravel an intriguing mechanism by which an RNA virus interrupts host DNA replication. Finally, by mimicking virus-induced S-phase arrest, we show that ZIKV manipulates the cell cycle to benefit viral replication.

Neuronal-enriched small extracellular vesicles trigger a PD-L1-mediated broad suppression of T cells in Parkinson's disease.

Many clinical studies indicate a significant decrease of peripheral T cells in Parkinson's disease (PD). There is currently no mechanistic explanation for this important observation. Here, we found that small extracellular vesicles (sEVs) derived from in vitro and in vivo PD models suppressed IL-4 and INF-γ production from both purified CD4+ and CD8+ T cells and inhibited their activation and proliferation. Furthermore, neuronal-enriched sEVs (NEEVs) isolated from plasma of A53T-syn mice and culture media of human dopaminergic neurons carrying A53T-syn mutation also suppressed Th1 and Th2 differentiation of naive CD4+ T cells. Mechanistically, the suppressed phenotype induced by NEEVs was associated with altered programmed death ligand 1 (PD-L1) level in T cells. Blocking PD-L1 with an anti-PD-L1 antibody or a small molecule inhibitor BMS-1166 reversed T cell suppression. Our study provides the basis for exploring peripheral T cells in PD pathogenesis and as biomarkers or therapeutic targets for the disease.

Connecting the Gut Microbiota and Neurodegenerative Diseases: the Role of Bile Acids.

With the acceleration of global population aging, neurodegenerative diseases (NDs) will become the second leading cause of death in the world, which seriously threatens human life and health. Alzheimer's disease and Parkinson's disease are the most common and typical NDs. The exact mechanisms of the NDs occurrence and development remain unclear, which may be related to immune, oxidative stress, and abnormal aggregation of pathogenic proteins. Studies have suggested that gut microbiota (GM) influences brain function and plays an important role in regulating emotional and cognitive function. Recently, bile acids (BAs) have become the "star molecule" in the microbiota-gut-brain (MGB) axis research. BAs have been reported to exert anti-inflammatory, antioxidant, and neuroprotective activities in NDs. However, the role of BAs in the connection between GM and the central nervous system (CNS) is still unclear. In this review, we will review the possible mechanisms of BAs between GM and NDs and explore the function of BAs to provide ideas for the prevention and treatment of NDs in the future.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.

Novel brain-penetrant inhibitor of G9a methylase blocks Alzheimer's disease proteopathology for precision medication.

Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects. One-Sentence Summary: A brain-penetrant inhibitor of G9a methylase blocks G9a translational mechanism to reverse Alzheimer's disease related proteome for effective therapy.

APOE expression and secretion are modulated by mitochondrial dysfunction.

Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.

Does environmental decentralization aggravate pollution emissions? Microscopic evidence from Chinese industrial enterprises.

Rational division of environmental management power among governments is a necessary institutional support for speeding up the realization of green development goals. Based on the combined microdata of China Industrial Enterprise Database and China Enterprise Pollution Database from 2000 to 2012, the effect of environmental decentralization on enterprise pollution emission is empirically examined in this research. Results show that Chinese-style environmental decentralization, especially environmental supervision decentralization and environmental monitoring decentralization, significantly aggravates the pollution emissions of enterprises. Moreover, the impact of environmental decentralization on enterprise pollution emissions has regional and enterprise ownership heterogeneity. The mechanism test results denote that the production scale effect, energy structure effect and pollution control effect are the micro mechanisms of environmental decentralization aggravating the pollution emission of enterprises. This research confirms the existence of "race to the bottom" among local governments in China and provides evidence support and beneficial enlightenment for the vertical reform of the environmental management system.

Gut microbiota, pathogenic proteins and neurodegenerative diseases.

As the world's population ages, neurodegenerative diseases (NDs) have brought a great burden to the world. However, effective treatment measures have not been found to alleviate the occurrence and development of NDs. Abnormal accumulation of pathogenic proteins is an important cause of NDs. Therefore, effective inhibition of the accumulation of pathogenic proteins has become a priority. As the second brain of human, the gut plays an important role in regulate emotion and cognition functions. Recent studies have reported that the disturbance of gut microbiota (GM) is closely related to accumulation of pathogenic proteins in NDs. On the one hand, pathogenic proteins directly produced by GM are transmitted from the gut to the central center via vagus nerve. On the other hand, The harmful substances produced by GM enter the peripheral circulation through intestinal barrier and cause inflammation, or cross the blood-brain barrier into the central center to cause inflammation, and cytokines produced by the central center cause the production of pathogenic proteins. These pathogenic proteins can produced by the above two aspects can cause the activation of central microglia and further lead to NDs development. In addition, certain GM and metabolites have been shown to have neuroprotective effects. Therefore, modulating GM may be a potential clinical therapeutic approach for NDs. In this review, we summarized the possible mechanism of NDs caused by abnormal accumulation of pathogenic proteins mediated by GM to induce the activation of central microglia, cause central inflammation and explore the therapeutic potential of dietary therapy and fecal microbiota transplantation (FMT) in NDs.

Intrinsic antiviral immunity of barrier cells revealed by an iPSC-derived blood-brain barrier cellular model.

Physiological blood-tissue barriers play a critical role in separating the circulation from immune-privileged sites and denying access to blood-borne viruses. The mechanism of virus restriction by these barriers is poorly understood. We utilize induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (iBMECs) to study virus-blood-brain barrier (BBB) interactions. These iPSC-derived cells faithfully recapitulate a striking difference in in vivo neuroinvasion by two alphavirus isolates and are selectively permissive to neurotropic flaviviruses. A model of cocultured iBMECs and astrocytes exhibits high transendothelial electrical resistance and blocks non-neurotropic flaviviruses from getting across the barrier. We find that iBMECs constitutively express an interferon-induced gene, IFITM1, which preferentially restricts the replication of non-neurotropic flaviviruses. Barrier cells from blood-testis and blood-retinal barriers also constitutively express IFITMs that contribute to the viral resistance. Our application of a renewable human iPSC-based model for studying virus-BBB interactions reveals that intrinsic immunity at the barriers contributes to virus exclusion.

Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels.

The synthetic Liver X receptor (LXR) activator T0901317 has been reported to exert neuroprotective effect in Alzheimer's disease, but the relationship between LXR activation and beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) remains uncertain. This study investigated the effect of T0901317 on membrane cholesterol levels, BACE1 expression and activity. We found that T0901317 decreased membrane cholesterol levels, reduced BACE1 expression and activity as well as ß-secretase cleaved C-terminal fragment (ß-CTF) levels in vivo and in vitro. Meanwhile, the expression of ATP-binding membrane cassette transport protein A1 (ABCA1) enhanced. Additionally, inhibition of ABCA1 abrogated the effects of T0901317 on membrane cholesterol levels and ß-secretase activity. Moreover, addition of LXR antagonist reversed the effect of T0901317 on ABCA1 mRNA expression, membrane cholesterol levels and ß-secretase activity. Our results suggest that activation of LXR may decrease BACE1 expression and activity through a pathway associated with ABCA1-mediated reduction in membrane cholesterol levels.

5-hydroxymethylcytosine is dynamically regulated during forebrain organoid development and aberrantly altered in Alzheimer's disease.

5-hydroxymethylcytosine (5hmC) undergoes dynamic changes during mammalian brain development, and its dysregulation is associated with Alzheimer's disease (AD). The dynamics of 5hmC during early human brain development and how they contribute to AD pathologies remain largely unexplored. We generate 5hmC and transcriptome profiles encompassing several developmental time points of healthy forebrain organoids and organoids derived from several familial AD patients. Stage-specific differentially hydroxymethylated regions demonstrate an acquisition or depletion of 5hmC modifications across developmental stages. Additionally, genes concomitantly increasing or decreasing in 5hmC and gene expression are enriched in neurobiological or early developmental processes, respectively. Importantly, our AD organoids corroborate cellular and molecular phenotypes previously observed in human AD brains. 5hmC is significantly altered in developmentally programmed 5hmC intragenic regions in defined fetal histone marks and enhancers in AD organoids. These data suggest a highly coordinated molecular system that may be dysregulated in these early developing AD organoids.

A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies.

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), an RNA-binding protein that can regulate the translation of specific mRNAs. In this study, we developed an FXS human forebrain organoid model and observed that the loss of FMRP led to dysregulated neurogenesis, neuronal maturation and neuronal excitability. Bulk and single-cell gene expression analyses of FXS forebrain organoids revealed that the loss of FMRP altered gene expression in a cell-type-specific manner. The developmental deficits in FXS forebrain organoids could be rescued by inhibiting the phosphoinositide 3-kinase pathway but not the metabotropic glutamate pathway disrupted in the FXS mouse model. We identified a large number of human-specific mRNAs bound by FMRP. One of these human-specific FMRP targets, CHD2, contributed to the altered gene expression in FXS organoids. Collectively, our study revealed molecular, cellular and electrophysiological abnormalities associated with the loss of FMRP during human brain development.

Pharmacological rescue in patient iPSC and mouse models with a rare DISC1 mutation.

We previously identified a causal link between a rare patient mutation in DISC1 (disrupted-in-schizophrenia 1) and synaptic deficits in cortical neurons differentiated from isogenic patient-derived induced pluripotent stem cells (iPSCs). Here we find that transcripts related to phosphodiesterase 4 (PDE4) signaling are significantly elevated in human cortical neurons differentiated from iPSCs with the DISC1 mutation and that inhibition of PDE4 or activation of the cAMP signaling pathway functionally rescues synaptic deficits. We further generated a knock-in mouse line harboring the same patient mutation in the Disc1 gene. Heterozygous Disc1 mutant mice exhibit elevated levels of PDE4s and synaptic abnormalities in the brain, and social and cognitive behavioral deficits. Pharmacological inhibition of the PDE4 signaling pathway rescues these synaptic, social and cognitive behavioral abnormalities. Our study shows that patient-derived isogenic iPSC and humanized mouse disease models are integral and complementary for translational studies with a better understanding of underlying molecular mechanisms.