Large animal model species in pluripotent stem cell therapy research and development for retinal diseases: a systematic review

Aim: Retinal cell therapy modalities, in the category of advanced therapy medicinal products (ATMPs), are being developed to target several retinal diseases. Testing in large animal models (LAMs) is a crucial step in translating retinal ATMPs into clinical practice. However, challenges including budgetary and infrastructure constraints can hinder LAM research design and execution. Here, to facilitate the comparison of the various LAMs in pluripotent retinal cell therapy research, we aimed to systematically evaluate the species distribution, reported scientific utility, and methodology of a range of LAMs. Methods: A systematic search using the words retina, stem cell, transplantation, large animal, pig, rabbit, dog, and nonhuman primate was conducted in the PubMed, Embase, Science Direct and GoogleScholar databases in February 2023. Results: We included 22 studies involving pluripotent stem cells (induced pluripotent stem cells or human embryonic stem cells) in LAMs, including non-human primates (NHP), pigs, dogs, and rabbits. Nearly half of the studies utilized wild-type animal models. In other studies, retinal degeneration features were simulated via laser, chemical, or genetic insult. Transplants were delivered subretinally, either as cell suspensions or pre-formed monolayers (with or without biodegradable scaffolding). The transplanted cells dose per eye varied widely (40,000 – 4,000,000 per dose). Cells were delivered via vitrectomy surgery in 15 studies and by an “ab externo” approach in one study. Structural outcomes were assessed using confocal scanning laser ophthalmoscopy imaging. Functional outcomes included multifocal electroretinogram and, in one case, a measure of visual acuity. Generally, cell suspension transplants exhibited low intraretinal incorporation, while monolayer transplants incorporated more efficiently. Immune responses posed challenges for allogeneic transplants, suggesting that autologous iPSC-derived transplants may be required to decrease the likelihood of rejection. Conclusion: The use of appropriate LAMs helps to advance the development of retinal ATMPs. The anatomical similarity of LAM and human eyes allows the implementation of clinically-relevant surgical techniques. While the FDA Modernization Act 2.0 has provided a framework to consider alternative methods including tissue-on-a-chip and human cell culture models for pharmacologic studies, LAM testing remains useful for cell and tissue replacement studies to inform the development of clinical trial protocols

Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

Background:In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations.Methods:Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. Findings: In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences −0.07 (95% CI −0.13, −0.02), −0.09 (−0.15, −0.02), −0.08 (95% CI −0.14, −0.02), and −0.08 (−0.13, −0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values &lt; 0.05). Interpretation: We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. Funding: This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.</p

Stimulated and spontaneous optical generation of electron spin coherence in charged GaAs quantum dots

We report on the coherent optical excitation of electron spin polarization in the ground state of charged GaAs quantum dots via an intermediate charged exciton (trion) state. Coherent optical fields are used for the creation and detection of the Raman spin coherence between the spin ground states of the charged quantum dot. The measured spin decoherence time, which is likely limited by the nature of the spin ensemble, approaches 10 ns at zero field. We also show that the Raman spin coherence in the quantum beats is caused not only by the usual stimulated Raman interaction but also by simultaneous spontaneous radiative decay of either excited trion state to a coherent combination of the two spin states.Comment: 4 pages, 3 figures. Minor modification

Development of a Coaxial 3D Printing Platform for Biofabrication of Implantable Islet-Containing Constructs

Over the last two decades, pancreatic islet transplantations have become a promising treatment for Type I diabetes. However, although providing a consistent and sustained exogenous insulin supply, there are a number of limitations hindering the widespread application of this approach. These include the lack of sufficient vasculature and allogeneic immune attacks after transplantation, which both contribute to poor cell survival rates. Here, these issues are addressed using a biofabrication approach. An alginate/gelatin-based bioink formulation is optimized for islet and islet-related cell encapsulation and 3D printing. In addition, a custom-designed coaxial printer is developed for 3D printing of multicellular islet-containing constructs. In this work, the ability to fabricate 3D constructs with precise control over the distribution of multiple cell types is demonstrated. In addition, it is shown that the viability of pancreatic islets is well maintained after the 3D printing process. Taken together, these results represent the first step toward an improved vehicle for islet transplantation and a potential novel strategy to treat Type I diabetes

Normalizing biomedical terms by minimizing ambiguity and variability

<p>Abstract</p> <p>Background</p> <p>One of the difficulties in mapping biomedical named entities, e.g. genes, proteins, chemicals and diseases, to their concept identifiers stems from the potential variability of the terms. Soft string matching is a possible solution to the problem, but its inherent heavy computational cost discourages its use when the dictionaries are large or when real time processing is required. A less computationally demanding approach is to normalize the terms by using heuristic rules, which enables us to look up a dictionary in a constant time regardless of its size. The development of good heuristic rules, however, requires extensive knowledge of the terminology in question and thus is the bottleneck of the normalization approach.</p> <p>Results</p> <p>We present a novel framework for discovering a list of normalization rules from a dictionary in a fully automated manner. The rules are discovered in such a way that they minimize the ambiguity and variability of the terms in the dictionary. We evaluated our algorithm using two large dictionaries: a human gene/protein name dictionary built from BioThesaurus and a disease name dictionary built from UMLS.</p> <p>Conclusions</p> <p>The experimental results showed that automatically discovered rules can perform comparably to carefully crafted heuristic rules in term mapping tasks, and the computational overhead of rule application is small enough that a very fast implementation is possible. This work will help improve the performance of term-concept mapping tasks in biomedical information extraction especially when good normalization heuristics for the target terminology are not fully known.</p

A prospective study of symptoms, function, and medication use during acute illness in nursing home residents: design, rationale and cohort description

<p>Abstract</p> <p>Background</p> <p>Nursing home residents are at high risk for developing acute illnesses. Compared with community dwelling adults, nursing home residents are often more frail, prone to multiple medical problems and symptoms, and are at higher risk for adverse outcomes from acute illnesses. In addition, because of polypharmacy and the high burden of chronic disease, nursing home residents are particularly vulnerable to disruptions in transitions of care such as medication interruptions in the setting of acute illness. In order to better estimate the effect of acute illness on nursing home residents, we have initiated a prospective cohort which will allow us to observe patterns of acute illnesses and the consequence of acute illnesses, including symptoms and function, among nursing home residents. We also aim to examine the patterns of medication interruption, and identify patient, provider and environmental factors that influence continuity of medication prescribing at different points of care transition.</p> <p>Methods</p> <p>This is a prospective cohort of nursing home residents residing in two nursing homes in a metropolitan area. Baseline characteristics including age, gender, race, and comorbid conditions are recorded. Participants are followed longitudinally for a planned period of 3 years. We record acute illness incidence and characteristics, and measure symptoms including depression, pain, withdrawal symptoms, and function using standardized scales.</p> <p>Results</p> <p>76 nursing home residents have been followed for a median of 666 days to date. At baseline, mean age of residents was 74.4 (± 11.9); 32% were female; 59% were white. The most common chronic conditions were dementia (41%), depression (38%), congestive heart failure (25%) and chronic obstructive lung disease (27%). Mean pain score was 4.7 (± 3.6) on a scale of 0 to 10; Geriatric Depression Scale (GDS-15) score was 5.2 (± 4.4). During follow up, 138 acute illness episodes were identified, for an incidence of 1.5 (SD 2.0) episodes per resident per year; 74% were managed in the nursing home and 26% managed in the acute care setting.</p> <p>Conclusion</p> <p>In this report, we describe the conceptual model and methods of designing a longitudinal cohort to measure acute illness patterns and symptoms among nursing home residents, and describe the characteristics of our cohort at baseline. In our planned analysis, we will further estimate the effect of the use and interruption of medications on withdrawal and relapse symptoms and illness outcomes.</p

Scaling carbon fluxes from eddy covariance sites to globe: Synthesis and evaluation of the FLUXCOM approach

FLUXNET assembles globally-distributed eddy covariance-based estimates of carbon fluxes between the biosphere and the atmosphere. Since eddy covariance flux towers have a relatively small footprint and are distributed unevenly across the world, upscaling the observations is necessary in order to obtain global-scale estimates of biosphere-atmosphere exchange from the flux tower network. Based on cross-consistency checks with atmospheric inversions, sun-induced fluorescence (SIF) and dynamic global vegetation models (DGVM), we provide here a systematic assessment of the latest upscaling efforts for gross primary production (GPP) and net ecosystem exchange (NEE) of the FLUXCOM initiative, where different machine learning methods, forcing datasets, and sets of predictor variables were employed. Spatial patterns of mean GPP are consistent among FLUXCOM and DGVM ensembles (R2 > 0.94 at 1° spatial resolution) while the majority of DGVMs are outside the FLUXCOM range for 70 % of the land surface. Global mean GPP magnitudes for 2008–2010 from FLUXCOM members vary within 106 and 130 PgC yr−1 with the largest uncertainty in the tropics. Seasonal variations of independent SIF estimates agree better with FLUXCOM GPP (mean global pixel-wise R2 ~ 0.75) than with GPP from DGVMs (mean global pixel wise R2 ~ 0.6). Seasonal variations of FLUXCOM NEE show good consistency with atmospheric inversion-based net land carbon fluxes, particularly for temperate and boreal regions (R2 > 0.92). Interannual variability of global NEE in FLUXCOM is underestimated compared to inversions and DGVMs. The FLUXCOM version which uses also meteorological inputs shows a strong co-variation of interannual patterns with inversions (R2 = 0.88 for 2001–2010). Mean regional NEE from FLUXCOM shows larger uptake than inversion and DGVM-based estimates, particularly in the tropics with discrepancies of up to several hundred gC m2 yr−1. These discrepancies can only partly be reconciled by carbon loss pathways that are implicit in inversions but not captured by the flux tower measurements such as carbon emissions from fires and water bodies. We hypothesize that a combination of systematic biases in the underlying eddy covariance data, in particular in tall tropical forests, and a lack of site-history effects on NEE in FLUXCOM are likely responsible for the too strong tropical carbon sink estimated by FLUXCOM. Furthermore, as FLUXCOM does not account for CO2 fertilization effects carbon flux trends are not realistic. Overall, current FLUXCOM estimates of mean annual and seasonal cycles of GPP as well as seasonal NEE variations provide useful constraints of global carbon cycling, while interannual variability patterns from FLUXCOM are valuable but require cautious interpretation. Exploring the diversity of Earth Observation data and of machine learning concepts along with improved quality and quantity of flux tower measurements will facilitate further improvements of the FLUXCOM approach overall