DNA Methylation Analysis Validates Organoids as a Viable Model for Studying Human Intestinal Aging.

Background & aimsThe epithelia of the intestine and colon turn over rapidly and are maintained by adult stem cells at the base of crypts. Although the small intestine and colon have distinct, well-characterized physiological functions, it remains unclear if there are fundamental regional differences in stem cell behavior or region-dependent degenerative changes during aging. Mesenchyme-free organoids provide useful tools for investigating intestinal stem cell biology in vitro and have started to be used for investigating age-related changes in stem cell function. However, it is unknown whether organoids maintain hallmarks of age in the absence of an aging niche. We tested whether stem cell-enriched organoids preserved the DNA methylation-based aging profiles associated with the tissues and crypts from which they were derived.MethodsTo address this, we used standard human methylation arrays and the human epigenetic clock as a biomarker of age to analyze in vitro-derived, 3-dimensional, stem cell-enriched intestinal organoids.ResultsWe found that human stem cell-enriched organoids maintained segmental differences in methylation patterns and that age, as measured by the epigenetic clock, also was maintained in vitro. Surprisingly, we found that stem cell-enriched organoids derived from the small intestine showed striking epigenetic age reduction relative to organoids derived from colon.ConclusionsOur data validate the use of organoids as a model for studying human intestinal aging and introduce methods that can be used when modeling aging or age-onset diseases in vitro

Failure generates impulsivity only when outcomes cannot be controlled

Verbruggen, Chambers, Lawrence & McLaren (2017) recently challenged the view that individuals act with greater caution following the experience of a negative outcome by showing that a gambled loss resulted in faster reaction time on the next trial. Over three experiments, we replicate and establish the boundary conditions of this effect in the context of a simple game (Rock, Paper, Scissors). Choice responding against unexploitable opponents replicated the link between failure and faster responding. However, individuals with high win-rates against exploitable opponents initiated slower rather than faster responding following loss. The data suggest that the link between failure and impulsivity is limited to contexts where participants cannot exert control over outcomes

EpiSleeve: Multimodal Night-time Seizure Detection

This project involves the creation of a nighttime wearable device that can measure heart rate, blood oxygen saturation, temperature, motion, and skin resistivity using sensors placed on the upper and lower arm. Incorporating a wide variety of sensors allows for detection of focal and generalized epilepsy. These sensors will be used to collect data to wirelessly (via Bluetooth) transmit to a separate base station for processing to determine if a seizure has occurred. If a seizure is detected for a specified period of time, the base station can call (via cellular communications) for medical aid to prevent harm to users. Once this device is validated, the technology will help users track seizures better and grant peace of mind if a seizure were to occur.https://commons.case.edu/intersections-fa20/1037/thumbnail.jp

Simulations of the irradiation and temperature dependence of the efficiency of tandem photoelectrochemical water-splitting systems

The instantaneous efficiency of an operating photoelectrochemical solar-fuel-generator system is a complicated function of the tradeoffs between the light intensity and temperature-dependence of the photovoltage and photocurrent, as well as the losses associated with factors that include ohmic resistances, concentration overpotentials, kinetic overpotentials, and mass transport. These tradeoffs were evaluated quantitatively using an advanced photoelectrochemical device model comprised of an analytical device physics model for the semiconducting light absorbers in combination with a multi-physics device model that solved for the governing conservation equations in the various other parts of the system. The model was used to evaluate the variation in system efficiency due to hourly and seasonal variations in solar irradiation as well as due to variation in the isothermal system temperature. The system performance characteristics were also evaluated as a function of the band gaps of the dual-absorber tandem component and its properties, as well as the device dimensions and the electrolyte conductivity. The modeling indicated that the system efficiency varied significantly during the day and over a year, exhibiting local minima at midday and a global minimum at midyear when the solar irradiation is most intense. These variations can be reduced by a favorable choice of the system dimensions, by a reduction in the electrolyte ohmic resistances, and/or by utilization of very active electrocatalysts for the fuel-producing reactions. An increase in the system temperature decreased the annual average efficiency and led to less rapid ramp-up and ramp-down phases of the system, but reduced midday and midyear instantaneous efficiency variations. Careful choice of the system dimensions resulted in minimal change in the system efficiency in response to degradation in the quality of the light absorbing materials. The daily and annually averaged mass of hydrogen production for the optimized integrated system compared favorably to the daily and annually averaged mass of hydrogen that was produced by an optimized stand-alone tandem photovoltaic array connected electrically to a stand-alone electrolyzer system. The model can be used to predict the performance of the system, to optimize the design of solar-driven water splitting devices, and to guide the development of components of the devices as well as of the system as a whole

Metabolomics process modeling: A systems biology approach to understand variability in commercial biologics cell culture processes

The biopharmaceutical industry strives to develop and operate efficient, robust, reproducible commercial biologics processes. A major challenge of industrial biologics processes is optimization of cell culture conditions to increase productivity while maintaining consistent product quality. The cell culture operations, which involve the use of live cell hosts, have historically introduced significant variability to the overall process. Technological improvements which include the implementation of advanced cell line engineering, chemically defined media, quality by design (QbD) development approaches, and in-line and at-line monitoring, have significantly reduced process variability. Nonetheless, performance variability remains a challenge for many commercial programs. This variability in turn can impact both product yields and product quality. Even small performance differences can become significant in low-yield processes with large campaign sizes, or processes manufactured at multiple sites. The ability to understand and eliminate sources of variability is greatly enhanced by augmenting the quality and quantity of data available from commercial campaigns. Metabolomics Process Monitoring (MPM) is a data-driven approach to understand sources of manufacturing variability on a cellular level. Here we present a case study of MPM implementation in a legacy commercial biologics program. First, we describe how the MPM workflow was successfully integrated into a commercial manufacturing process. Second, we discuss novel data normalization techniques developed to enable long term trending. Third, we describe the selection of an orthogonal projections to latent structures (OPLS) model to link systems biology and process data. Finally, we share key mechanistic insights obtained from the case study, and provide a vision for how MPM can enhance commercial biologics capabilities going forward

Modeling, simulation, and design criteria for photoelectrochemical water-splitting systems

A validated multi-physics numerical model that accounts for charge and species conservation, fluid flow, and electrochemical processes has been used to analyze the performance of solar-driven photoelectrochemical water-splitting systems. The modeling has provided an in-depth analysis of conceptual designs, proof-of-concepts, feasibility investigations, and quantification of performance. The modeling has led to the formulation of design guidelines at the system and component levels, and has identified quantifiable gaps that warrant further research effort at the component level. The two characteristic generic types of photoelectrochemical systems that were analyzed utilized: (i) side-by-side photoelectrodes and (ii) back-to-back photoelectrodes. In these designs, small electrode dimensions (mm to cm range) and large electrolyte heights were required to produce small overall resistive losses in the system. Additionally, thick, non-permeable separators were required to achieve acceptably low rates of product crossover

Adverse childhood experiences, support, and the perception of ability to work in adults with disability

Objective To examine the impact of adverse childhood experiences (ACEs) and support on self-reported work inability of adults reporting disability. Participants Adults (ages 18–64) who participated in the Behavioral Risk Factor Surveillance System in 2009 or 2010 and who reported having a disability (n = 13,009). Design and Main Outcome Measures The study used a retrospective cohort design with work inability as the main outcome. ACE categories included abuse (sexual, physical, emotional) and family dysfunction (domestic violence, incarceration, mental illness, substance abuse, divorce). Support included functional (perceived emotional/social support) and structural (living with another adult) support. Logistic regression was used to adjust for potential confounders (age, sex and race) and to evaluate whether there was an independent effect of ACEs on work inability after adding other important predictors (support, education, health) to the model. Results ACEs were highly prevalent with almost 75% of the sample reporting at least one ACE category and over 25% having a high ACE burden (4 or more categories). ACEs were strongly associated with functional support. Participants experiencing a high ACE burden had a higher adjusted odds ratio (OR) [95% confidence interval] of 1.9 [1.5–2.4] of work inability (reference: zero ACEs). Good functional support (adjusted OR 0.52 [0.42–0.63]) and structural support (adjusted OR 0.48 [0.41–0.56]) were protective against work inability. After adding education and health to the model, ACEs no longer appeared to have an independent effect. Structural support remained highly protective, but functional support only appeared to be protective in those with good physical health. Conclusions ACEs are highly prevalent in working-age US adults with a disability, particularly young adults. ACEs are associated with decreased support, lower educational attainment and worse adult health. Health care providers are encouraged to screen for ACEs. Addressing the effects of ACEs on health and support, in addition to education and retraining, may increase ability to work in those with a disability

Discovery of non-directional and directional pioneer transcription factors by modeling DNase profile magnitude and shape

Here we describe Protein Interaction Quantitation (PIQ), a computational method that models the magnitude and shape of genome-wide DNase profiles to facilitate the identification of transcription factor (TF) binding sites. Through the use of machine learning techniques, PIQ identified binding sites for >700 TFs from one DNase-seq experiment with accuracy comparable to ChIP-seq for motif-associated TFs (median AUC=0.93 across 303 TFs). We applied PIQ to analyze DNase-seq data from mouse embryonic stem cells differentiating into pre-pancreatic and intestinal endoderm. We identified (n=120) and experimentally validated eight ‘pioneer’ TF families that dynamically open chromatin, enabling other TFs to bind to adjacent DNA. Four pioneer TF families only open chromatin in one direction from their motifs. Furthermore, we identified a class of ‘settler’ TFs whose genomic binding is principally governed by proximity to open chromatin. Our results support a model of hierarchical TF binding in which directional and non-directional pioneer activity shapes the chromatin landscape for population by settler TFs