TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.

The nuclear RNA-binding protein TDP43 is integrally involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previous studies uncovered N-terminal TDP43 isoforms that are predominantly cytosolic in localization, prone to aggregation, and enriched in susceptible spinal motor neurons. In healthy cells, however, these shortened (s)TDP43 isoforms are difficult to detect in comparison to full-length (fl)TDP43, raising questions regarding their origin and selective regulation.

Enhanced detection and genotyping of disease-associated tandem repeats using HMMSTR and targeted long-read sequencing.

Tandem repeat sequences comprise approximately 8% of the human genome and are linked to more than 50 neurodegenerative disorders. Accurate characterization of disease-associated repeat loci remains resource intensive and often lacks high resolution genotype calls. We introduce a multiplexed, targeted nanopore sequencing panel and HMMSTR, a sequence-based tandem repeat copy number caller which outperforms current signal- and sequence-based callers relative to two assemblies and we show it performs with high accuracy in heterozygous regions and at low read coverage.

A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease.

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires a cellular understanding of treatment response. We describe a therapeutic atlas for Crohn's disease (CD) and ulcerative colitis (UC) following adalimumab, an anti-tumour necrosis factor (anti-TNF) treatment. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies (41 subjects), revealing disease-specific differences.

Shared fate was associated with sustained cooperation during the COVID-19 pandemic.

Did the COVID-19 pandemic bring people together or push them apart? While infectious diseases tend to push people apart, crises can also bring people together through positive interdependence. We studied this question by asking an international sample (N = 1,006) about their inclinations to cooperate, perceptions of interdependence (i.e.

Singapore's urbanised coral reefs: Changes in heavy metal pollution between 1994 and 2021.

The heavy metal load in coral reefs of Singapore has not been comprehensively assessed since 1994. Here, we repeated the surveys conducted 27 years ago to quantify the levels of Cd, Cu, Cr, Fe, Pb, Ti, Zn in sediment and the sea urchin Diadema setosum from seven reefs. Cu and Cd showed significant reductions, Pb and Cr remained stable, while Fe, Ti and Zn had increased significantly.