Validating in vivo hyperpolarized 129 Xe diffusion MRI and diffusion morphometry in the mouse lung.

PURPOSE: Diffusion and lung morphometry imaging using hyperpolarized gases are promising tools to quantify pulmonary microstructure noninvasively in humans and in animal models. These techniques assume the motion encoded is exclusively diffusive gas displacement, but the impact of cardiac motion on measurements has never been explored. Furthermore, although diffusion morphometry has been validated against histology in humans and mice using 3 He, it has never been validated in mice for 129 Xe. Here, we examine the effect of cardiac motion on diffusion imaging and validate 129 Xe diffusion morphometry in mice. THEORY AND METHODS: Mice were imaged using gradient-echo-based diffusion imaging, and apparent diffusion-coefficient (ADC) maps were generated with and without cardiac gating. Diffusion-weighted images were fit to a previously developed theoretical model using Bayesian probability theory, producing morphometric parameters that were compared with conventional histology. RESULTS: Cardiac gating had no significant impact on ADC measurements (dual-gating: ADC = 0.020 cm2 /s, single-gating: ADC = 0.020 cm2 /s; P = .38). Diffusion-morphometry-generated maps of ADC (mean, 0.0165 ± 0.0001 cm2 /s) and acinar dimensions (alveolar sleeve depth [h] = 44 µm, acinar duct radii [R] = 99 µm, mean linear intercept [Lm ] = 74 µm) that agreed well with conventional histology (h = 45 µm, R = 108 µm, Lm = 63 µm). CONCLUSION: Cardiac motion has negligible impact on 129 Xe ADC measurements in mice, arguing its impact will be similarly minimal in humans, where relative cardiac motion is reduced. Hyperpolarized 129 Xe diffusion morphometry accurately and noninvasively maps the dimensions of lung microstructure, suggesting it can quantify the pulmonary microstructure in mouse models of lung disease.

The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of ß Cells.

Although glucose uniquely stimulates proinsulin biosynthesis in ß cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary ß cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective ß cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, ß cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in ß cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with ß cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the ß cell for increased proinsulin synthesis and to limit oxidative stress that leads to ß cell failure.

Exposure of U.S. National Parks to land use and climate change 1900-2100.

Many protected areas may not be adequately safeguarding biodiversity from human activities on surrounding lands and global change. The magnitude of such change agents and the sensitivity of ecosystems to these agents vary among protected areas. Thus, there is a need to assess vulnerability across networks of protected areas to determine those most at risk and to lay the basis for developing effective adaptation strategies. We conducted an assessment of exposure of U.S. National Parks to climate and land use change and consequences for vegetation communities. We first defined park protected-area centered ecosystems (PACEs) based on ecological principles. We then drew on existing land use, invasive species, climate, and biome data sets and models to quantify exposure of PACEs from 1900 through 2100. Most PACEs experienced substantial change over the 20th century (> 740% average increase in housing density since 1940, 13% of vascular plants are presently nonnative, temperature increase of 1 degree C/100 yr since 1895 in 80% of PACEs), and projections suggest that many of these trends will continue at similar or increasingly greater rates (255% increase in housing density by 2100, temperature increase of 2.5 degrees-4.5 degrees C/100 yr, 30% of PACE areas may lose their current biomes by 2030). In the coming century, housing densities are projected to increase in PACEs at about 82% of the rate of since 1940. The rate of climate warming in the coming century is projected to be 2.5-5.8 times higher than that measured in the past century. Underlying these averages, exposure of individual park PACEs to change agents differ in important ways. For example, parks such as Great Smoky Mountains exhibit high land use and low climate exposure, others such as Great Sand Dunes exhibit low land use and high climate exposure, and a few such as Point Reyes exhibit high exposure on both axes. The cumulative and synergistic effects of such changes in land use, invasives, and climate are expected to dramatically impact ecosystem function and biodiversity in national parks. These results are foundational to developing effective adaptation strategies and suggest policies to better safeguard parks under broad-scale environmental change.