The prospects for using autologous induced pluripotent stem cells (iPSCs) in cell replacement therapy have been tempered by evidence that undifferentiated, syngeneic mouse iPSCs are immunogenic upon ...transplantation. However, the immunogenicity of more therapeutically relevant differentiated cells remains unexplored. Here, we differentiated mouse iPSCs into embryoid bodies (EBs) or representative cell types spanning the three embryonic germ layers and assessed their immunogenicity in vitro and after their transplantation into syngeneic recipients. We found no evidence of increased T cell proliferation in vitro, rejection of syngeneic iPSC-derived EBs/tissue-specific cells (TSCs) after transplantation, or an antigen-specific secondary immune response. Thus, differentiated cells derived from syngeneic iPSCs do not appear to be rejected after transplantation. We also found little evidence of an immune response to undifferentiated, syngeneic iPSCs. Our data support the idea that differentiated cells generated from autologous iPSCs could be applied for cell replacement therapy without eliciting immune rejection.
► Undifferentiated and differentiated syngeneic iPSCs are not immunogenic in vitro ► iPSC-derived cells are not rejected after syngeneic transplantation ► Low Hormad, Zg16, and Retn expression in syngeneic iPSCs posttransplant ► The progeny of syngeneic iPSCs are not susceptible to a secondary immune response
Testing the immunogenicity of syngeneic iPSCs and their differentiated derivatives reveals little evidence for a specific iPSC-dependent immune response, reestablishing hopes for autologous iPSC-based stem cell therapy.
Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ...ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the complement cascade in synaptic pruning in glaucoma and other diseases.
Using a genetic (DBA/2J mouse) and an inducible (rat microbead) model of glaucoma we first demonstrate that there is loss of retinal ganglion cell synapses and dendrites at time points that precede axon or soma loss. We next determine the role of complement component 1 (C1) in early synaptic loss and dendritic atrophy during glaucoma. Using a genetic knockout of C1qa (D2.C1qa (-/-) mouse) or pharmacological inhibition of C1 (in the rat bead model) we show that inhibition of C1 is sufficient to preserve dendritic and synaptic architecture.
This study further supports assessing the potential for complement-modulating therapeutics for the prevention of retinal ganglion cell degeneration in glaucoma.
Identifying sociodemographic disparities in chemotherapy and hematopoietic cell transplantation (HCT) utilization for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) may improve ...survival for underserved populations. In this study, we incorporate neighborhood socioeconomic status (nSES), marital status, and distance from transplant center with previously studied factors to provide a comprehensive analysis of sociodemographic factors influencing treatments for ALL and AML.
Using the California Cancer Registry, we performed a retrospective, population-based study of patients ≥15 years old with ALL (n = 3,221) or AML (n = 10,029) from 2003 through 2012. The effect of age, sex, race/ethnicity, marital status, nSES, and distance from nearest transplant center on receiving no treatment, chemotherapy alone, or chemotherapy then HCT was analyzed.
No treatment, chemotherapy alone, or chemotherapy then HCT were received by 11%, 75%, and 14% of ALL patients and 36%, 53%, and 11% of AML patients, respectively. For ALL patients ≥60 years old, HCT utilization increased from 5% in 2005 to 9% in 2012 (p = 0.03). For AML patients ≥60 years old, chemotherapy utilization increased from 39% to 58% (p<0.001) and HCT utilization from 5% to 9% from 2005 to 2012 (p<0.001). Covariate-adjusted analysis revealed decreasing relative risk (RR) of chemotherapy with increasing age for both ALL and AML (trend p <0.001). Relative to non-Hispanic whites, lower HCT utilization occurred in Hispanic ALL, RR = 0.80 (95% CI = 0.65-0.98); AML, RR = 0.86 (95% CI = 0.75-0.99) and non-Hispanic black patients ALL, RR = 0.40 (95% CI = 0.18-0.89); AML, RR = 0.60 (95% CI = 0.44-0.83). Compared to married patients, never married patients had a lower RR of receiving chemotherapy ALL, RR = 0.96 (95% CI = 0.92-0.99); AML, RR = 0.94 (95% CI = 0.90-0.98) or HCT ALL, RR = 0.58 (95% CI = 0.47-0.71); AML, RR = 0.80 (95% CI = 0.70-0.90). Lower nSES quintiles predicted lower chemotherapy and HCT utilization for both ALL and AML (trend p <0.001).
Older age, lower nSES, and being unmarried predicted lower utilization of chemotherapy and HCT among ALL and AML patients whereas having Hispanic or black race/ethnicity predicted lower rates of HCT. Addressing these disparities may increase utilization of curative therapies in underserved acute leukemia populations.
DNA barcoding has transformed the fields of ecology, evolution, and conservation by providing a rapid and effective tool for species identification. The growth of DNA barcodes as a resource for ...biologists has followed advances in computational and sequencing technology that have enabled high-throughput barcoding applications. The global DNA barcode database is expanding to represent the diversity of species on Earth thanks to efforts by international consortia and expanding biological collections. Today, DNA barcoding is instrumental in advancing our understanding of how species evolve, how they interact, and how we can slow down their extirpation and extinction. This review focuses on current applications of DNA barcode sequences to address fundamental lines of research, as well as new and expanding applications of which DNA barcoding will play a central role.
Despite continued efforts to improve health systems worldwide, emerging pathogen epidemics remain a major public health concern. Effective response to such outbreaks relies on timely intervention, ...ideally informed by all available sources of data. The collection, visualization and analysis of outbreak data are becoming increasingly complex, owing to the diversity in types of data, questions and available methods to address them. Recent advances have led to the rise of outbreak analytics, an emerging data science focused on the technological and methodological aspects of the outbreak data pipeline, from collection to analysis, modelling and reporting to inform outbreak response. In this article, we assess the current state of the field. After laying out the context of outbreak response, we critically review the most common analytics components, their inter-dependencies, data requirements and the type of information they can provide to inform operations in real time. We discuss some challenges and opportunities and conclude on the potential role of outbreak analytics for improving our understanding of, and response to outbreaks of emerging pathogens. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are ...major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10
), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10
), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
A database of minima and transition states corresponds to a network where the minima represent nodes and the transition states correspond to edges between the pairs of minima they connect
via
...steepest-descent paths. Here we construct networks for small clusters bound by the Morse potential for a selection of physically relevant parameters, in two and three dimensions. The properties of these unweighted and undirected networks are analysed to examine two features: whether they are small-world, where the shortest path between nodes involves only a small number or edges; and whether they are scale-free, having a degree distribution that follows a power law. Small-world character is present, but statistical tests show that a power law is not a good fit, so the networks are not scale-free. These results for clusters are compared with the corresponding properties for the molecular and atomic structural glass formers
ortho
-terphenyl and binary Lennard-Jones. These glassy systems do not show small-world properties, suggesting that such behaviour is linked to the structure-seeking landscapes of the Morse clusters.
Small-world and scale-free properties are analysed for kinetic transition networks of clusters and glassy systems.
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