If Schumer won't step aside, he needs to be pushed aside. This process was an abomination. If my Democratic senators (Whitehouse and Reed) won't replace Schumer, we need to replace them with senators who will.

I don't like to speak ill of the dead. Thanks for doing it for me.

Study hard today. Pop quiz after potluck!

Exactly what you said. A lot of people are the same but a lot of people are also missing

To shameless quote my own piece, “The legacy media is apparently more interested in the climate musings of an erstwhile PC mogul than a sober assessment by the world’s leading climate scientists.”

If a temporary resident of the White House can totally demolish the East Wing to build a gaudy ballroom, without any authority, approval, or regulation, he can tear down the rest of the White House to build a Walmart. That this destruction is allowed underscores how off the rails our country is now.

A great letter! www.thedailybeast.com/a-strongly-w...

Italy to get 4 billion euros in 2026 from banks, insurers reut.rs/4oB5AaU

Sunrise the day after millions protested the impending dictatorship. Many media confused thousands with millions. My local paper printed no local coverage despite 30,000 marching a block from their office. @providencejournal.bsky.social should not wonder why circulation continues to drop

I don’t know how many thousands were at the providence rally today because there were too many to ever fit into a photo. Must have been more than 10K but don’t know how many more

#ashg25 room assignments maybe could have been better. Second session where you can’t even get in the room

Johnson, Emmer and Marshall denounce the No Kings rallies as something arranged by the "terrorist wing" of the Democratic Party. This is outrageous. Express your response in the time-honored way. Go to the rally. I'll be there next Saturday. www.nokings.org

Both my wife and I got double-vaxed yesterday, flu and Covid. I feel safer already and sorry for those who have been duped by RFK Jr and his deadly anti-vax friends. There is no safer, better preventative than a vaccine. We should be encouraging vaccinations, not making it difficult to get them

If this country was truly “pro-life,” we would have Medicare for All, a Green New Deal, gun reform, universal child care, and a living wage. The right-wing agenda isn’t about “life.” It’s about control.

firstwordhealthtech.com/story/6228854 #Nabsys will be well represented at #ASHG25 in two weeks in Boston. I will be presenting my own poster on Friday but also available to discuss posters on repeat expansions and use of CRISPR to customize EGM for genomic assays that are otherwise impossible

The up escalator at the Eagle Rock Target was broken today, forcing my wife and me to walk up. I expect an investigation and inclusion in the escalator files, never to be released.

Was walking around Harvard and saw this. Things have not gotten better in 62 years

www.mobilize.us/nokings/map/... October 18 just about everywhere

Turning off the fire alarms won’t prevent the fire.

#AGBTPH25 JY: Can do all by all testing of compounds x cancer models. 50 cancer models, 1200 drug treatments, 60K experiments, 100M cells

#AGBTPH25 Johnny Yu from Tahoe Therapeutics to talk about virtual cell models. Single cell work has advanced dramatically in 10 yrs

#AGBTPH25 JK: Could apply functional data to reclassify 682 VUS. Look at All of Us data, rare LOF missense have higher risk of cancer. AlphaMissense prediction calls too many variants pathogenic

#AGBTPH25 JK: Lynch syndrome is first inherited cancer risk syndrome, LOF in DNA mismatch repair genes. Most are missense with most being VUS. Apply 6-TG to cells to select MMR- proteins. Mapped 73,568 missense variants. Most have no effect but there are hot spots for impact

#AGBTPH25 Jacob Kitzman from UMich will talk about variants in hereditary cancer syndromes

#AGBTPH25 TY: N=1 collaborative working on sharing knowledge and guidelines for use, need innovative regulatory models

#AGBTPH25 TY: Another dozen genes being treated, more than 30 patients so far. ASOs great version 1 but gene editing could have broader applications

#AGBTPH25 TY: de novo KCNT1 R474H mutation leads to increased channel firing. Used ASO to shut down mutant protein. Daily seizures dropped from 10-15 to 0-2 and stayed down for 50 days but patients developed hydrocephalus. Now being tracked for other ASOs, try to keep dose lower.

#AGBTPH25 TY: Proposal for N=1 medicine to help patients with no other options. Led to FDA guidance for individualized medicine. New trials in ATM kinase, KCNT1 and FLVCR1. ATM trial is longest running N=1. Have seen no clinical progression on primary outcomes.

#AGBTPH25 TY: Milasen is ASO that introduced N=1 medicine. SIgnificantly lowered seizure frequency and improved quality of life but did not save life. Post-mortem studies showed it was working.

#AGBTPH25 TY: Going straight from genetics to therapeutics will increase efficiency. Antisense oligonucleotides (ASOs) are easy to manufacture, easy to predict effects, multiple uses

#AGBTPH25 TY: Mind the gap. Genome sequencing has shortened diagnostic odyssey but not the path to therapy. Many rare diseases are too rare to be commercially investable. Not obvious they weren't being addressed because causes unknown. Now we know what we're not doing.

#AGBTPH25 Tim Yu from BCH/Harvard Med talking about interventional genetics.

#AGBTPH25 HM: ongoing trials of targeted therapies including SCN1A with ASO targeting poison exon and a cell selective gene therapy. For SCN2A, ASO knockdown. How to scale? 13 genes with ASO in preclinical development, 5 in clinic or trial

#AGBTPH25 HM: UBA5 Dad was Hypo/+, mom was LOF/+. Child was Hypo/LOF. Hypo/Hypo can be healthy so try to boost expression of Hypo allele. Tried SINEUPs using lncRNA and CRISPR dCAS9 with activator domain to boost protein expression

#AGBTPH25 HM: identify the target, model the disease, engage patients. Can try gene replacement, ASOs, gene editing, gene regulation

#AGBTPH25 HM: developmental and epileptic encephalopathies - most drugs don't work; early onset, intractable seizures; hundreds of genes identified, 50% diagnostic rate, de novo variants are important, overlap with ID, autism

#AGBTPH25 Heather Mefford from St Jude Childrens Hosp to discuss precision diagnosis to targeted therapies in epilepsies.

#AGBTPH25 SM: Used CRISPR to change isoform abundance (DESeq2). Depletion strongly enriches isoforms expressed in nerve, muscle, adipose, and skin. Depletes blood, spleen, small intestine, lung. Can find intron retentions not normally visible in blood

#AGBTPH25 SM: Looked at outliers of outliers of splicing. See people with hundreds of intron retentions. Even more dramatic if look at only products of minor splicesome. 5 had mutations in RNU4ATAG, one RNU12

#AGBTPH25 SM: If look at extreme outliers, can narrow down to a handful of individuals. Looked at teenage girl with apparent overgrowth syndrome, not Prader-Willi. Saw region on chr11 with reduced methylation near 2.7Mb. If look at all genomes, z score goes from -7.5 to -6.8

#AGBTPH25 SM: outlier molecular phenotypes can inform gene function. Looking at methylation outliers. Find deviant regions relative to the whole population. How unusual is a particular pattern?

#AGBTPH25 SM: Gregor - Genomics Research to Elucidate the Genetics fo Rare Diseases. U11 release >1000 RNAseq, lots more DNA seq

#AGBTPH25 SM: multi omics being used increasingly but usually applied to only a few cases and controls

#AGBTPH25 SM: Whole genome sequencing at scale increases likelihood of finding variants but increases interpretation burden. What is the strategy most likely to be effective for a patient?

#AGBTPH25 Stephen Montgomery from Stanford to talk about multi-omics strategies for diagnosis of rare diseases.

#AGBTPH25 JS: 3 factors and dosage give each disease a distinct signature

#AGBTPH25 JS: Diagnostic categories differ by cell type specific pathways - interaction terms most important

#AGBTPH25 JS: CNVs have dose-dependent effects on traits with SCZ but not ASD. Gene set burden analysis: captures enrichment of variants in genes. Depression and bipolar disorder have different gene set expression patterns across brain