A single nephron model of acute tubular injury: Role of tubuloglomerular feedback

A single nephron model of acute tubular injury: Role of tubuloglomerular feedback. A single nephron model of nephrotoxic tubular injury was established to examine the mechanism whereby acute tubular damage contributes to reductions in nephron filtration rate (SNGFR). Acute microperfusion of 0.5ng of uranyl nitrate (UN) into the early proximal tubule produced a significant reduction (16 to 30%) in SNGFR measured in both distal and proximal tubules of the same nephron and a decrease in absolute proximal reabsorption. Microperfused inulin was retained in the tubule suggesting this finding reflected a true reduction in SNGFR. Concurrent infusion of high dose furosemide (2 × 10-4M) and bumetanide (2 × 10-5M), but not low dose furosemide (2 × 10-5M), prevented the UN induced reduction in SNGFR. High dose furosemide begun after UN perfusion also prevented reduction in SNGFR. Continuous direct measurement of glomerular capillary hydrostatic pressure revealed no change. Distal intratubular Na+ and CI- concentration increased significantly after UN perfusion. Activation of tubuloglomerular feedback mechanisms best explains the reduction in glomerular ultrafiltration that is characteristic of nephrotoxic forms of tubular injury

Devotional Biology: A Young-age Creationist, College-level, Conceptual Biology Textbook

Devotional Biology is being developed as a one-semester college-level conceptual biology textbook for non-science majors. Except for presenting a survey of organisms and an introduction to organismal anatomy and physiology (typically reserved for a second-semester course), Devotional Biology covers all the major topics of biology presented in secular texts as well as a few others not usually covered at all. Student surveys indicate students believe they learn biology through the Devotional Biology text. At the same time, Devotional Biology presents biology from the perspective of a distinctly biblical worldview—and on surveys, Devotional Biology students believe they improved their appreciation of biology as well. Devotional Biology also focuses on God, and how His attributes are evident in the biological world—and on surveys, Devotional Biology students believe they improved their recognition of God in the creation, their understanding of God, their relationship to God, and their use of the creation in witness to others. Devotional Biology also assumes a young-age creationist interpretation of biology, critiquing the naturalistic perspective of the field in the process—and on surveys, Devotional Biology students believe they grew in their faith and learned to defend their faith. Devotional Biology also includes responsibilities of believers as priests and kings in God’s creation—and on surveys, Devotional Biology students believe they grew in their understanding of their ethical responsibilities, in their worship of God, and in better ruling over the creation

The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells

Gefitinib is a specific inhibitor of the epidermal growth factor receptor (EGFR) that causes growth delay in cancer cell lines and human tumor xenografts expressing high levels of EGFR. An understanding of the downstream cellular targets of gefitinib will allow the discovery of biomarkers for predicting outcomes and monitoring anti-EGFR therapies and provide information for key targets for therapeutic intervention. In this study, we investigated the role of FOXO3a in gefitinib action and resistance. Using two gefitinib-sensitive (i.e., BT474 and SKBR3) as well as three other resistant breast carcinoma cell lines (i.e., MCF-7, MDA-MB-231, and MDA-MB-453), we showed that gefitinib targets the transcription factor FOXO3a to mediate cell cycle arrest and cell death in sensitive breast cancer cells. In the sensitive cells, gefitinib treatment causes cell cycle arrest predominantly at the G(0)-G(1) phase and apoptosis, which is associated with FOXO3a dephosphorylation at Akt sites and nuclear translocation, whereas in the resistant cells, FOXO3a stays phosphorylated and remains in the cytoplasm. The nuclear accumulation of FOXO3a in response to gefitinib was confirmed in tumor tissue sections from breast cancer patients presurgically treated with gefitinib as monotherapy. We also showed that knockdown of FOXO3a expression using small interfering RNA (siRNA) can rescue sensitive BT474 cells from gefitinib-induced cell-proliferative arrest, whereas reintroduction of active FOXO3a in resistant MDA-MB-231 cells can at least partially restore cell-proliferative arrest and sensitivity to gefitinib. These results suggest that the FOXO3a dephosphorylation and nuclear localization have a direct role in mediating the gefitinib-induced proliferative arrest and in determining sensitivity to gefitinib.Supported by the German Cancer Aide Foundation (J. Krol)and the Association of International Cancer Research (R. Francis).Andrew Sunters and Andreas Polychronic were fellows funded by CancerResearch UK. Andre Albergaria is a recipient of a grant from Fundação para a Ciência e a Tecnologia, Portugal. This work was sponsored by theBreast Cancer Research Trust and Cancer Research U

Multi-centre, multi-vendor reproducibility of 7T QSM and R2* in the human brain: Results from the UK7T study

Introduction We present the reliability of ultra-high field T2* MRI at 7T, as part of the UK7T Network's “Travelling Heads” study. T2*-weighted MRI images can be processed to produce quantitative susceptibility maps (QSM) and R2* maps. These reflect iron and myelin concentrations, which are altered in many pathophysiological processes. The relaxation parameters of human brain tissue are such that R2* mapping and QSM show particularly strong gains in contrast-to-noise ratio at ultra-high field (7T) vs clinical field strengths (1.5–3T). We aimed to determine the inter-subject and inter-site reproducibility of QSM and R2* mapping at 7T, in readiness for future multi-site clinical studies. Methods Ten healthy volunteers were scanned with harmonised single- and multi-echo T2*-weighted gradient echo pulse sequences. Participants were scanned five times at each “home” site and once at each of four other sites. The five sites had 1× Philips, 2× Siemens Magnetom, and 2× Siemens Terra scanners. QSM and R2* maps were computed with the Multi-Scale Dipole Inversion (MSDI) algorithm (https://github.com/fil-physics/Publication-Code). Results were assessed in relevant subcortical and cortical regions of interest (ROIs) defined manually or by the MNI152 standard space. Results and Discussion Mean susceptibility (χ) and R2* values agreed broadly with literature values in all ROIs. The inter-site within-subject standard deviation was 0.001–0.005 ppm (χ) and 0.0005–0.001 ms−1 (R2*). For χ this is 2.1–4.8 fold better than 3T reports, and 1.1–3.4 fold better for R2*. The median ICC from within- and cross-site R2* data was 0.98 and 0.91, respectively. Multi-echo QSM had greater variability vs single-echo QSM especially in areas with large B0 inhomogeneity such as the inferior frontal cortex. Across sites, R2* values were more consistent than QSM in subcortical structures due to differences in B0-shimming. On a between-subject level, our measured χ and R2* cross-site variance is comparable to within-site variance in the literature, suggesting that it is reasonable to pool data across sites using our harmonised protocol. Conclusion The harmonized UK7T protocol and pipeline delivers on average a 3-fold improvement in the coefficient of reproducibility for QSM and R2* at 7T compared to previous reports of multi-site reproducibility at 3T. These protocols are ready for use in multi-site clinical studies at 7T

2006 SQ372: A Likely Long-Period Comet from the Inner Oort Cloud

We report the discovery of a minor planet (2006 SQ372) on an orbit with a perihelion of 24 AU and a semimajor axis of 796 AU. Dynamical simulations show that this is a transient orbit and is unstable on a timescale of 200 Myrs. Falling near the upper semimajor axis range of the scattered disk and the lower semimajor axis range of the Oort Cloud, previous membership in either class is possible. By modeling the production of similar orbits from the Oort Cloud as well as from the scattered disk, we find that the Oort Cloud produces 16 times as many objects on SQ372-like orbits as the scattered disk. Given this result, we believe this to be the most distant long-period comet ever discovered. Furthermore, our simulation results also indicate that 2000 OO67 has had a similar dynamical history. Unaffected by the "Jupiter-Saturn Barrier," these two objects are most likely long-period comets from the inner Oort Cloud