APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem ...cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
Evidence suggests interplay among the three major risk factors for Alzheimer’s disease (AD): age, APOE genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes ...and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas APOE4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, APOE genotype, and sex on unfolded protein response pathway. In the periphery, APOE2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
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•Aging leads to the most profound changes in brain gene expression networks•Immune module led by Alzheimer’s risk genes Trem2/Tyrobp is upregulated with aging•Alzheimer’s risk allele APOE4 increases the expression of Serpina3 family genes•Alzheimer’s protective allele APOE2 drives unique serum metabolome profiles
Zhao et al. present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. The study provides critical insight on the molecular pathways underlying three major Alzheimer’s risk factors age, APOE, and sex.
It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. ...To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and reprogrammed induced astrocytes from C9orf72 and sporadic amyotrophic lateral sclerosis cases we measured the production rate of reduced nicotinamide adenine dinucleotides (NADH) from 91 potential energy substrates simultaneously. Our screening approach identified that C9orf72 and sporadic amyotrophic lateral sclerosis induced astrocytes have distinct metabolic profiles compared to controls and displayed a loss of metabolic flexibility that was not observed in fibroblast models. This loss of metabolic flexibility, involving defects in adenosine, fructose and glycogen metabolism, as well as disruptions in the membrane transport of mitochondrial specific energy substrates, contributed to increased starvation induced toxicity in C9orf72 induced astrocytes. A reduction in glycogen metabolism was attributed to loss of glycogen phosphorylase and phosphoglucomutase at the protein level in both C9orf72 induced astrocytes and induced neurons. In addition, we found alterations in the levels of fructose metabolism enzymes and a reduction in the methylglyoxal removal enzyme GLO1 in both C9orf72 and sporadic models of disease. Our data show that metabolic flexibility is important in the CNS in times of bioenergetic stress.
TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, ...enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.
We have determined the three-dimensional (3D) architecture of the
Caulobacter crescentus genome by combining genome-wide chromatin interaction detection, live-cell imaging, and computational ...modeling. Using chromosome conformation capture carbon copy (5C), we derive ∼13 kb resolution 3D models of the
Caulobacter genome. The resulting models illustrate that the genome is ellipsoidal with periodically arranged arms. The
parS sites, a pair of short contiguous sequence elements known to be involved in chromosome segregation, are positioned at one pole, where they anchor the chromosome to the cell and contribute to the formation of a compact chromatin conformation. Repositioning these elements resulted in rotations of the chromosome that changed the subcellular positions of most genes. Such rotations did not lead to large-scale changes in gene expression, indicating that genome folding does not strongly affect gene regulation. Collectively, our data suggest that genome folding is globally dictated by the
parS sites and chromosome segregation.
► Chromatin interaction mapping and modeling elucidate
Caulobacter genome structure ► The genome is ellipsoidal with periodically arranged arms ► The
parS region shapes whole genome structure and affects chromatin compaction ► The
parS region is the only genomic region stably attached to the cell envelope
Background. Chronic coinfection with herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus (HIV) has been associated with an increased HIV viral load and more rapid disease ...progression, perhaps related to HSV-2-associated alterations in host immunity. Methods. Studies were nested within (1) a cross-sectional study of men coinfected with HIV and HSV-2 and (2) women not infected with HIV, both before and after HSV-2 acquisition. HSV-2 infection status was determined by ELISA. HIV-specific CD8+ T cell epitopes were mapped, and proliferation of HIV-specific cells was also assessed. Systemic inflammatory and regulatory T cell populations were assayed by flow cytometry. Results. The breadth of both the HIV-specific CD8+ T cell interferon-γ and proliferative responses was reduced in participants coinfected with HIV and HSV-2, independent of the HIV plasma viral load and CD4+ T cell count, and the magnitude of the responses was also reduced. HSV-2 infection in this group was associated with increased T cell CD38 expression but not with differences in the proportion of CD4+ FoxP3+ regulatory T cells. However, in women not infected with HIV, acquisition of HSV-2 was associated with an increase in the proportion of regulatory T cells. Conclusions. HSV-2 coinfection was associated with reduced HIV-specific T cell responses and systemic inflammation. The immune effects of HSV-2 may underlie the negative impact that this coinfection has on the clinical course of HIV infection.
The development of a weighting and aggregating coefficient system used in urban sustainability assessment tools is a process that needs well-defined procedures using a series of steps, methodology, ...and a systematic approach in its development. The development of assessment tools has been successful in developed countries but developing countries would need to have a structured process that will assist in the development of an assessment tool that is tailored to its environs. This paper aims to understand the various weighting and aggregating coefficient systems employed in the development of sustainability assessment tools. Alongside using these findings to understand how these weighting and aggregating coefficients can be adopted in the development of sustainability assessment tools for developing countries based on their differences, advantages, and disadvantages. Qualitative Content Analysis based on a systematic review of existing literature was used in this study to understand various weighting and aggregating coefficients. It is imperative to note that this research will focus on how assessment tools are developed with a clear focus on sustainability assessment weighting and aggregating. The study also further analyses how a case study SUCCEED (Sustainable Composite Cities Environmental Evaluation and Design Tool) has benefited from the adoption of equal weighting and additive aggregation methods based on validation carried out. The findings of this research show that the selection of weighting and aggregating systems is defined by the relevance, importance, and purpose of the assessment tool. It also develops a guide/recommendations on the process utilised in the development of assessment tools for developing countries.
Objective
The myeloid‐related proteins 8 and 14 (MRP‐8/MRP‐14) and neutrophil‐derived S100A12 are biomarkers of inflammation. They can be used to determine the relapse risk in patients with juvenile ...idiopathic arthritis (JIA) after stopping antiinflammatory treatment. In this study, we tested the performance of different enzyme‐linked immunosorbent assays (ELISAs) in order to validate systems available for routine use.
Methods
MRP‐8/MRP‐14 and S100A12 serum concentrations of 188 JIA patients in remission were analyzed. Commercially available test systems were compared to experimental ELISAs established in house. The ability of the assays to identify JIA patients at risk for relapse was analyzed.
Results
For MRP‐8/MRP‐14, the PhiCal Calprotectin and Bühlmann MRP8/14 Calprotectin ELISAs revealed hazard ratios of 2.3 and 2.1, respectively. For S100A12, the CircuLex S100A12/EN‐RAGE ELISA revealed a hazard ratio of 3.1. The commercial assays allowed a JIA relapse prediction that was at least comparable to the experimental ELISAs.
Conclusion
For the prediction of JIA relapse after stopping medication, the biomarkers MRP‐8/MRP‐14 and S100A12 can be determined by using assays that are available for routine use. The tested commercial MRP‐8/MRP‐14 and S100A12 ELISAs showed a performance comparable to well‐established experimental ELISA protocols when assay‐specific cutoffs for the indication of relapse prediction are thoroughly applied.
The collective investment schemes in Kenya have witnessed increased volatility in their earnings, resulting in irregular growth in the industry. This necessitates the need to understand the factors ...contributing to poor financial returns from collective investment schemes. Hence this study sought to investigate the effect of equity investments and bond investments on Kenyan CIS’s performance. The specific objectives were: To assess the effect of equity investments, bond investments on financial performance of collective investment schemes in Kenya. The study was anchored on: modern portfolio theory and the efficient market hypothesis. The positivism philosophy was applied, with the firms adopting an explanatory research design. The target population was 17 Collective Investment Schemes registered by the Capital Markets Authority and were operational in the period 2010 to 2018. Secondary data was sought from the Capital Markets Authority Annual reports and from the respective websites of the CIS’. Data was analyzed using descriptive statistics, correlational analysis and panel regression analysis. Hypotheses were tested at a significance level of 0.05. Findings indicate that equity investment, bond investments have an insignificant effect on CIS’ return on assets. Further, equity investments had a positive and significant effect on liquidity whereas bond investments had an insignificant effect on liquidity. The study recommends that CISs actively revise their equity investments and bond investments to stimulate financial returns.
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