RT @alsassociation: URGENT: A leaked HHS memo proposes cutting all funding to the National #ALS Registry. This would erase decades of criti….

A detailed post can be found at 1patrickmurphy at bsky social, with the next questions we hope to address with input and support from @vascularbiology @AHAScience @alzassociation @AlzResearchUK @AFTDHope and @NINDSfunding @cshlmeetings.

Congratulations to Ashok, an exceptionally talented scientist who would be a tremendous junior faculty hire. Thank you to our collaborators @jacksonlab, lab members including @omaruximab and as others not on this platform, including Riqiang Yan.

Despite strong headwinds our work continues. @CheemalaAshok shows that even a single point mutation in TDP-43 leads to large defects in cell-cell junction and barrier, and that brain endothelial deletion disrupts the BBB and leads to FTD-like behavior

RT @RepGregLandsman: In the last 48 hours, congressional Republicans have done so much damage to Americans. Here are the 5 truly harmful t….

Many thanks to collaborator Dr. Riqiang Yan, members of the Murphy lab, our flow and sequencing cores, @vascularbiology, our funding at @NIH_NINDS and earlier awards from @AHAScience and @nih_nhlbi for contributing to this work. Most importantly, thank you to the donors.

In parallel work (Science Advances next month and bioRxiv here : ) from @CheemalaAshok we show that targeted deletion of TDP-43 in brain ECs compromises the BBB, and leads to dysfunction of pathways disrupted in human capillaries with reduced TDP-43.

Why does this matter? TDP-43 mutations drive ALS-FTD, and its nuclear depletion in neurons is a hallmark of neurodegeneration. Our findings reveal TDP-43 is also lost in the capillary endothelium, where it correlates with hallmarks of blood-brain barrier dysfunction.

We find a distinct transcriptional program that characterizes ~40% of the capillary endothelium in neurodegenerative diseases, including ALS-FTD @alsassociation , and Alzheimer’s @alzassociation @AlzResearchUK @alzheimerssoc , and is marked by nuclear loss TDP-43.

In a herculean effort led by talented MD/PhD student @omaruximab, we use a novel approach for endothelial cell enrichment to create a massive dataset of endothelial changes in healthy aging and ALS-FTD and Alzheimer's Disease (92 donors). Data portal :

I'm happy to announce that our paper describing the first in human tissue application of inCITE-seq, to assess nuclear levels of RNA-binding proteins, and key regulators of the blood brain barrier (b-Catenin and NF-kB) is now available online

RT @ZhichaoFan: We are happy to share that our work on cystic fibrosis and integrin clustering has been published @PNASNews CFTR dictates….

RT @takarginov: The latter part of my thesis work on RNA binding proteins and T cells is out in @ScienceMagazine ! Here we find that one of….

RT @Rong_A_Wang: Postdoc Positions at UCSF on Vascular Regeneration, 2P live imaging, VasPhysiology, Mouse models, Surgery, Single Cell+Spa….

Thanks to our funding @AHAScience @nih_nhlbi and for critical feedback from @vascularbiology @GordonConf @UCONN_ICG. Steve, Amy, Jess, and other members of the @MurphyLabUCONN and Annabelle Rodriquez-Oquendo for clinical perspective, in addition to those mentioned already.

Together, this reveals a translational switch in the endothelium that is required for full expression of an immunosuppressive phenotype induced by immune-cell recruitment. This switch, and therefore local T cell responses, are regulated by Elavl1/HuR.

Leveraging the ability to add specific cells, we found that the transcriptional switch, marked by C1q induction, occurred only in response to a combination of CD8 T cells and myeloid (BMDCs). But, as we had seen in vivo, led to C1q translation only in the Elavl1 deficient endos.

To dissect effects on recruitment from local expansion and survival, we tested each. We found no difference in activated CD8 T cell recruitment in vivo. However, a novel in vitro co-culture system found that Elavl1 deficient endothelial cells suppress CD8 T cell antigen response.

CITE-seq analysis of the recruited CD8 T cells in plaque and blood - performed by @cpathoulas , confirmed that in addition to the substantial local reduction - the CD8 T cells still recruited expressed less markers of activation. These differences were not apparent in blood.

This deficit even more profound in the partial carotid ligation model, where we could dissect the number of new recruited CD8 T cells from basal levels (as found in the contralateral normal flow artery), suggesting a large defect in recruitment, local expansion or retention.