Tuberous sclerosis complex exhibits a new renal cystogenic mechanism

Tuberous sclerosis complex (TSC) is a tumor predisposition syndrome with significant renal cystic and solid tumor disease. While the most common renal tumor in TSC, the angiomyolipoma, exhibits a loss of heterozygosity associated with disease, we have discovered that the renal cystic epithelium is composed of type A intercalated cells that have an intact Tsc gene that have been induced to exhibit Tsc‐mutant disease phenotype. This mechanism appears to be different than that for ADPKD. The murine models described here closely resemble the human disease and both appear to be mTORC1 inhibitor responsive. The induction signaling driving cystogenesis may be mediated by extracellular vesicle trafficking.TSC renal cystic disease develops in about half of the patients. The disease appears to caused by an induction mechanism such that a small population of mutant cells can cause significant renal cystic disease comprised of mostly genetically normal cells.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147796/1/phy213983.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147796/2/phy213983_am.pd

Patterns of altered neural synchrony in the default mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): Relationship to clinical symptomatology

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142922/1/aur1908.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142922/2/aur1908_am.pd

Limits of Darwinian conditioning

Darwinian research focused on the insect population and the effect of coloration and toxicity upon the natural selection and survival of members of the prey species. Modern conditioned food aversion research focuses on the predator that eats the poisonous plant or animal and the mechanisms by which the predator learns to avoid poison and select safe food. The animal might go to sleep and digest the food, providing feedback (FB) which, if positive, maintains or enhances the palatability of the food. One limit of Darwinian conditioning is set by the reflexive neurophysiological US-FB coupling of the gustatory and visceral afferents within the gut system. The rubbing behavior delayed food reinforcement and became progressively worse, so that the planned commercial exhibit was finally abandoned. A reversal of roles would be too costly in terms of time and effort, though perhaps not impossible. The problem of reinforcing species-specific behavioral patterns with food was classically described by E. L. Thorndike

Patterns of altered neural synchrony in the default mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): Relationship to clinical symptomatology

Disrupted neural synchrony may be a primary electrophysiological abnormality in autism spectrum disorders (ASD), altering communication between discrete brain regions and contributing to abnormalities in patterns of connectivity within identified neural networks. Studies exploring brain dynamics to comprehensively characterize and link connectivity to large-scale cortical networks and clinical symptoms are lagging considerably. Patterns of neural coherence within the Default Mode Network (DMN) and Salience Network (SN) during resting state were investigated in 12 children with ASD (MAge  = 9.2) and 13 age and gender-matched neurotypicals (NT) (MAge  = 9.3) with magnetoencephalography. Coherence between 231 brain region pairs within four frequency bands (theta (4-7 Hz), alpha, (8-12 Hz), beta (13-30 Hz), and gamma (30-80 Hz)) was calculated. Relationships between neural coherence and social functioning were examined. ASD was characterized by lower synchronization across all frequencies, reaching clinical significance in the gamma band. Lower gamma synchrony between fronto-temporo-parietal regions was observed, partially consistent with diminished default mode network (DMN) connectivity. Lower gamma coherence in ASD was evident in cross-hemispheric connections between: angular with inferior/middle frontal; middle temporal with middle/inferior frontal; and within right-hemispheric connections between angular, middle temporal, and inferior/middle frontal cortices. Lower gamma coherence between left angular and left superior frontal, right inferior/middle frontal, and right precuneus and between right angular and inferior/middle frontal cortices was related to lower social/social-communication functioning. Results suggest a pattern of lower gamma band coherence in a subset of regions within the DMN in ASD (angular and middle temporal cortical areas) related to lower social/social-communicative functioning. Autism Res 2018, 11: 434-449. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Communication between different areas of the brain was observed in children with ASD and neurotypical children while awake, but not working on a task. Magnetoencephalography was used to measure tiny magnetic fields naturally generated via brain activity. The brains of children with ASD showed less communication between areas that are important for social information processing compared to the brains of neurotypical children. The amount of communication between these areas was associated with social and social communication difficulties

Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging

<div><p>Podocyte depletion plays a major role in focal segmental glomerular sclerosis (FSGS). Because cells of the renin lineage (CoRL) serve as adult podocyte and parietal epithelial cell (PEC) progenitor candidates, we generated <i>Ren1cCre/R26R-ConfettiTG/WT</i> and <i>Ren1dCre/R26R-ConfettiTG/WT</i> mice to determine CoRL clonality during podocyte replacement. Four CoRL reporters (GFP, YFP, RFP, CFP) were restricted to cells in the juxtaglomerular compartment (JGC) at baseline. Following abrupt podocyte depletion in experimental FSGS, all four CoRL reporters were detected in a subset of glomeruli at day 28, where they co-expressed de novo four podocyte proteins (podocin, nephrin, WT-1 and p57) and two glomerular parietal epithelial cell (PEC) proteins (claudin-1, PAX8). To monitor the precise migration of a subset of CoRL over a 2w period following podocyte depletion, intravital multiphoton microscopy was used. Our findings demonstrate direct visual support for the migration of single CoRL from the JGC to the parietal Bowman’s capsule, early proximal tubule, mesangium and glomerular tuft. In summary, these results suggest that following podocyte depletion, multi-clonal CoRL migrate to the glomerulus and replace podocyte and PECs in experimental FSGS.</p></div

Labeled cells of renin lineage (CoRL) co-express nephrin in glomeruli of <i>Ren1cCre /R26R-ConfettiTG/WT</i> mice with experimental FSGS.

<p>The confocal images in the left column (A-C) represent nephrin staining (magenta) detected by antibody, and 4 CoRL reporters (green, red, blue, yellow) detected without antibody. The confocal images in the right column represents the same image on the left, but for ease of viewing, all 4 confetti reporter channels have been converted to green, and nephrin has been converted to red, so that co-localization can be visualized as yellow. (A, B) At baseline: All four CoRL reporter colors are restricted to the JGC (dashed white box), and nephrin staining is restricted to the glomerular tuft. (B) all four Confetti CoRL reporters (green) are seen in the JGC, with no overlap with nephrin (red). (C, D) At D14 FSGS: (C) There is a segmental decrease in nephrin staining in the right upper quadrant of the glomerular tuft. Multi-clonal CoRL are detected in glomerular tuft, but do not co-localize with nephrin. (D) The CoRL reporters in the tuft do not co-localize with nephrin staining. (E, F) At D28 FSGS: (E) Multi-clonal CoRL are detected in the glomerular tuft. (F) CoRL reporters co-localize with nephrin, creating a yellow color (arrows indicate examples).</p

Partial podocyte replacement in <i>Ren1cCre /R26R-ConfettiTG/WT</i> mice with experimental FSGS.

<p>(A-C) Double staining was performed for the podocyte marker p57 (brown, nuclear) and counterstain with Periodic acid Schiff's (pink stains matrix, blue stains nuclei) in reporter mice at baseline (A), day 14 (D14) FSGS (B) and D28 FSGS (C). (D) Podocyte number was lower at D14 compared to baseline, and partial recovered by D28. (E) Glomerulosclerosis was highest at D14 FSGS, with a significant reduction by D28. (F) The urinary albumin to creatinine ratio (ACR) was significantly higher at D14 FSGS, with a significant decrease by D28 of FSGS.</p

Multi-colored reporters of CoRL are detected in glomerular tufts of <i>Ren1cCre /R26R-ConfettiTG/WT</i> mice with FSGS.

<p>Confocal images showing four CoRL reporter colors detected without the use of antibodies–nGFP (green), cRFP (red), mCFP (blue) and cYFP (yellow). (A) All four reporters are restricted to the JGC at baseline, and are not detected in the glomerular tuft (dashed white circles). At D14 FSGS (B) and at D28 FSGS (C), all four CoRL reporter colors were detected in a subpopulation of cells in the glomerular tufts. (D) Graph showing that the percentage of glomeruli with reporter positive CoRL within the tuft was higher at D28 of FSGS and that these glomeruli contained 2–4 clones. (E) Represenative image showing all four reporters (converted to green color) and BRDU(red) do not co-localize at baseline. BRDU is present in some tubular epithelial cells as expected, but is not readily detected in JGC or the glomerular tuft. (F) BRDU staining increased at D14 of FSGS, but BRDU positive cells are not present in the JGC and glomerular tuft. (G) At D28 of FSGS there is an increase in the number of reporter labeled cells present on the glomerular tuft, however there is no overlap of reporters with BRDU.</p

The formation of persistent CoRL-derived glomerular cell clusters after IgG-induced podocyte injury in <i>Ren1d-Confetti</i> mice.

<p>(A-B) Confetti+ cells (magenta, cytosolic RFP expressing) appear on the outside of glomerular capillaries 5 days after IgG injection (arrows) that resemble podocytes. Note the presence of several primary cell processes around capillaries. (B) Serial MPM imaging of the same glomerulus one day later showing the continued presence of same cells at the same locations. Plasma was labeled red using Alexa594-albumin. Bar is 20 μm.</p