Alpha-crystallin mutations alter lens metabolites in mouse models of human cataracts

Cataracts are a major cause of blindness worldwide and commonly occur in individuals over 70 years old. Cataracts can also appear earlier in life due to genetic mutations. The lens proteins, αA- and αB-crystallins, are chaperone proteins that have important roles maintaining protein solubility to prevent cataract formation. Mutations in the CRYAA and CRYAB crystallin genes are associated with autosomal dominant early onset human cataracts. Although studies about the proteomic and genomic changes that occur in cataracts have been reported, metabolomics studies are very limited. Here, we directly investigated cataract metabolism using gas-chromatography-mass spectrometry (GC-MS) to analyze the metabolites in adult Cryaa-R49C and Cryab-R120G knock-in mouse lenses. The most abundant metabolites were myo-inositol, L-(+)-lactic acid, cholesterol, phosphate, glycerol phosphate, palmitic and 9-octadecenoic acids, α-D-mannopyranose, and β-D-glucopyranose. Cryaa-R49C knock-in mouse lenses had a significant decrease in the number of sugars and minor sterols, which occurred in concert with an increase in lactic acid. Cholesterol composition was unchanged. In contrast, Cryab-R120G knock-in lenses exhibited increased total amino acid content including valine, alanine, serine, leucine, isoleucine, glycine, and aspartic acid. Minor sterols, including cholest-7-en-3-ol and glycerol phosphate were decreased. These studies indicate that lenses from Cryaa-R49C and Cryab-R120G knock-in mice, which are models for human cataracts, have unique amino acid and metabolite profiles

Targeting EZH2 Reprograms Intratumoral Regulatory T Cells to Enhance Cancer Immunity.

Regulatory T cells (Tregs) are critical for maintaining immune homeostasis, but their presence in tumor tissues impairs anti-tumor immunity and portends poor prognoses in cancer patients. Here, we reveal a mechanism to selectively target and reprogram the function of tumor-infiltrating Tregs (TI-Tregs) by exploiting their dependency on the histone H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) in tumors. Disruption of EZH2 activity in Tregs, either pharmacologically or genetically, drove the acquisition of pro-inflammatory functions in TI-Tregs, remodeling the tumor microenvironment and enhancing the recruitment and function of CD8+ and CD4+ effector T cells that eliminate tumors. Moreover, abolishing EZH2 function in Tregs was mechanistically distinct from, more potent than, and less toxic than a generalized Treg depletion approach. This study reveals a strategy to target Tregs in cancer that mitigates autoimmunity by reprogramming their function in tumors to enhance anti-cancer immunity

Plant-associated symbiotic Burkholderia species lack hallmark strategies required in mammalian pathogenesis

Burkholderia is a diverse and dynamic genus, containing pathogenic species as well as species that form complex interactions with plants. Pathogenic strains, such as B. pseudomallei and B. mallei, can cause serious disease in mammals, while other Burkholderia strains are opportunistic pathogens, infecting humans or animals with a compromised immune system. Although some of the opportunistic Burkholderia pathogens are known to promote plant growth and even fix nitrogen, the risk of infection to infants, the elderly, and people who are immunocompromised has not only resulted in a restriction on their use, but has also limited the application of non-pathogenic, symbiotic species, several of which nodulate legume roots or have positive effects on plant growth. However, recent phylogenetic analyses have demonstrated that Burkholderia species separate into distinct lineages, suggesting the possibility for safe use of certain symbiotic species in agricultural contexts. A number of environmental strains that promote plant growth or degrade xenobiotics are also included in the symbiotic lineage. Many of these species have the potential to enhance agriculture in areas where fertilizers are not readily available and may serve in the future as inocula for crops growing in soils impacted by climate change. Here we address the pathogenic potential of several of the symbiotic Burkholderia strains using bioinformatics and functional tests. A series of infection experiments using Caenorhabditis elegans and HeLa cells, as well as genomic characterization of pathogenic loci, show that the risk of opportunistic infection by symbiotic strains such as B. tuberum is extremely low

Using intervention mapping and behavior change techniques to develop a digital intervention for self-management in stroke: Development study

BACKGROUND: Digital therapeutics, such as interventions provided via smartphones or the internet, have been proposed as promising solutions to support self-management in persons with chronic conditions. However, the evidence supporting self-management interventions through technology in stroke is scarce, and the intervention development processes are often not well described, creating challenges in explaining why and how the intervention would work. OBJECTIVE: This study describes a specific use case of using intervention mapping (IM) and the taxonomy of behavior change techniques (BCTs) in designing a digital intervention to manage chronic symptoms and support daily life participation in people after stroke. IM is an implementation science framework used to bridge the gap between theories and practice to ensure that the intervention can be implemented in real-world settings. The taxonomy of BCTs consists of a set of active ingredients designed to change self-management behaviors. METHODS: We used the first 4 steps of the IM process to develop a technology-supported self-management intervention, interactive Self-Management Augmented by Rehabilitation Technologies (iSMART), adapted from a face-to-face stroke-focused psychoeducation program. Planning group members were involved in adapting the intervention. They also completed 3 implementation measures to assess the acceptability, appropriateness, and feasibility of iSMART. RESULTS: In step 1, we completed a needs assessment consisting of assembling a planning group to codevelop the intervention, conducting telephone surveys of people after stroke (n=125) to identify service needs, and performing a systematic review of randomized controlled trials to examine evidence of the effectiveness of digital self-management interventions to improve patient outcomes. We identified activity scheduling, symptom management, stroke prevention, access to care resources, and cognitive enhancement training as key service needs after a stroke. The review suggested that digital self-management interventions, especially those using cognitive behavioral theory, effectively reduce depression, anxiety, and fatigue and enhance self-efficacy in neurological disorders. Step 2 identified key determinants, objectives, and strategies for self-management in iSMART, including knowledge, behavioral regulation, skills, self-efficacy, motivation, negative and positive affect, and social and environmental support. In step 3, we generated the intervention components underpinned by appropriate BCTs. In step 4, we developed iSMART with the planning group members. Especially, iSMART simplified the original psychoeducation program and added 2 new components: SMS text messaging and behavioral coaching, intending to increase the uptake by people after stroke. iSMART was found to be acceptable (mean score 4.63, SD 0.38 out of 5), appropriate (mean score 4.63, SD 0.38 out of 5), and feasible (mean score 4.58, SD 0.34 out of 5). CONCLUSIONS: We describe a detailed example of using IM and the taxonomy of BCTs for designing and developing a digital intervention to support people after stroke in managing chronic symptoms and maintaining active participation in daily life

An Improved Photometric Calibration of the Sloan Digital Sky Survey Imaging Data

We present an algorithm to photometrically calibrate wide field optical imaging surveys, that simultaneously solves for the calibration parameters and relative stellar fluxes using overlapping observations. The algorithm decouples the problem of "relative" calibrations, from that of "absolute" calibrations; the absolute calibration is reduced to determining a few numbers for the entire survey. We pay special attention to the spatial structure of the calibration errors, allowing one to isolate particular error modes in downstream analyses. Applying this to the Sloan Digital Sky Survey imaging data, we achieve ~1% relative calibration errors across 8500 sq.deg. in griz; the errors are ~2% for the u band. These errors are dominated by unmodelled atmospheric variations at Apache Point Observatory. These calibrations, dubbed "ubercalibration", are now public with SDSS Data Release 6, and will be a part of subsequent SDSS data releases.Comment: 16 pages, 17 figures, matches version accepted in ApJ. These calibrations are available at http://www.sdss.org/dr

Breast Mass Characterization Using 3‐Dimensional Automated Ultrasound as an Adjunct to Digital Breast Tomosynthesis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135628/1/jum201332193.pd