Jack Humphrey

EVERY ALS MND scientific conference needs to allow for those with ALS MND who want to attend to be there in person or virtually. It is simply wrong to exclude them.

Evidence suggesting that microglia make amyloid from neuronally expressed APP: a hypothesis - Molecular Neurodegeneration While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.

'Evidence suggesting that #microglia make #amyloid from neuronally expressed APP: a hypothesis'

John Hardy & Patrick Lewis

molecularneurodegeneration.biomedcentral.com/articles/10....

With so many great tau researchers like @leatgrinberg.bsky.social @lucbuee.bsky.social @sjorsscheres.bsky.social @selinawray.bsky.social @karchlab.bsky.social on #SciSky could not help but put together my 1st starterpack⤵️

We are all fighting for you @curemaptftd.bsky.social 💙

go.bsky.app/KHno2VG

Genetic and functional analysis of unproductive splicing using LeafCutter2 Alternative splicing commonly generates unproductive mRNA transcripts that harbor premature termination codons, leading to their degradation by nonsense-mediated decay (NMD). These events reduce overall protein expression levels of affected genes, potentially contributing to gene regulation and disease mechanisms. Here, we present LeafCutter2, which enables identification and quantification of unproductive splicing from short-read RNA-seq data. LeafCutter2 requires minimal gene annotations (start and stop codons) to annotate NMD-inducing splicing events, and identifies differential unproductive splicing between groups, providing insights into its contributions to differential gene expression. Moreover, LeafCutter2 enables mapping of unproductive splicing quantitative trait loci (u-sQTLs), which often colocalize with expression QTLs and GWAS loci. Applying LeafCutter2 to RNA-seq data across human and 6 non-human species, we uncovered a broad landscape of unproductive splicing, which varies widely across tissues. Strikingly, we observed a conserved developmental-stage-specific increase in unproductive splicing during testis maturation across all species. In Alzheimer's disease (AD), we analyzed RNA-seq data from the AD Functional Genomics consortium FunGen-xQTL project and identified unproductive splicing events in 18 AD risk genes, including TSPAN14, PICALM, and CASS4, likely mediating genetic effects on disease risk. We performed an integrative analysis using gene expression QTLs, protein expression QTLs, and AD GWAS data, showing that unproductive splicing provides unique regulatory insights beyond traditional approaches. Thus, LeafCutter2 represents a powerful tool for understanding the functional impact of alternative splicing on gene expression and disease mechanisms. ### Competing Interest Statement The authors have declared no competing interest.

We are excited to share our new preprint on LeafCutter2! Our new method clusters, quantifies, and classifies splice junctions and intron clusters according to their molecular functionality (e.g., protein-coding or NMD-splicing).

doi.org/10.1101/2025...

Charity set up by Doddie Weir invests £4m in bid to accelerate MND research A charity set up by late rugby legend Doddie Weir has committed £4 million to an “open science framework” for research into motor neurone…

www.heraldscotland.com/news/2504883...

Seeded aggregation of TDP-43 induces its loss of function and reveals early pathological signatures TDP-43 pathology characterizes neurodegenerative diseases. Scialò et al. use in vitro-generated and patient-derived TDP-43 aggregates as seeds to show that seed-induced TDP-43 cytoplasmic aggregation ...

Happy to share our new study that was just published in Neuron! www.cell.com/neuron/fullt...

Cytosine-to-uracil RNA editing is upregulated by pro-inflammatory stimulation of myeloid cells Myeloid cells undergo large changes to their gene expression profile in response to inflammatory stimulation. This includes an increase in post-transcriptional modifications carried out by adenosine-t...

www.biorxiv.org/content/10.1... New work from Humphrey and Raj labs, exploring the role of RNA editing in myeloid cells. Hopefully will be a useful resource for the field. Next stop: genetics!

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing - Nature Genetics This isoform-centric microglia genomic atlas includes 35,879 novel human microglia isoforms identified by long-read RNA sequencing. A multi-ancestry quantitative trait locus meta-analysis of known and...

Ecstatic to see our paper "Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing" now published in @naturegenet.bsky.social with @trajnp.bsky.social and @panosroussos.bsky.social @sinaibrain.bsky.social www.nature.com/articles/s41...

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing - Nature Genetics This isoform-centric microglia genomic atlas includes 35,879 novel human microglia isoforms identified by long-read RNA sequencing. A multi-ancestry quantitative trait locus meta-analysis of known and...

Nice to see this finally published!
Congratulations @jack-humphrey.bsky.social

www.nature.com/articles/s41...

(Collaborative work with Panos Roussos and his team! )

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing

This is important! Satellite rallies too!

Going sends a message.

Not going also sends a message.

It's not self-serving for scientists to protest the war on science. Millions of people depend on us.

A huge thank you to the early career scientists who are leading this!

🧪 #standupforscience

The Genomic Code: the genome instantiates a generative model of the organism How does the genome encode the form of the organism? What is the nature of this genomic code? Inspired by recent work in machine learning and neuroscience, we propose that the genome encodes a generat...

The Genomic Code: the genome instantiates a generative model of the organism www.cell.com/trends/genet... - really delighted to see this in print in @cp-trendsgenetics.bsky.social! 😊

I fear that my crew of junior scientists are going to be absolutely decimated. We did postdocs during the pandemic (I had a 1.5 year old with no childcare!). Somehow, we got through that only to be met with an unprecedented freezing of the NIH.

If you do GWAS or rare variant association studies, check out this short thread on the concept of SPECIFICITY, and why it is a major determinant of what we find:

The future of Alzheimer's treatment A neurologist who studies Alzheimer’s disease says hopes are on the rise for new treatments that target tau proteins.

🧪Thanks to @rbaltman.bsky.social for having me on The Future of Everything podcast to talk about treatments for Alzheimer's disease. Give a listen if you're interested in an (anti)anti-amyloid antibody argument and some promising new drug targets. #Alzheimers
engineering.stanford.edu/news/future-...

I would post accompanying photos but they're all selfies taken late at night in various pubs.

I've had a fantastic week in London meeting old friends and new back at Queen Square #UCL. Thanks to @adrianisaacs.bsky.social and @frattalab.bsky.social for letting me crash their Christmas parties and Johh Hardy for inviting me to give a talk.