Blood protein assessment of leading incident diseases and mortality in the UK Biobank.

The circulating proteome offers insights into the biological pathways that underlie disease. Here, we test relationships between 1,468 Olink protein levels and the incidence of 23 age-related diseases and mortality in the UK Biobank (n = 47,600). We report 3,209 associations between 963 protein levels and 21 incident outcomes.

TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.

A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding of motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes in protein expression in single MNs from postmortem ALS and control tissues. In a follow-up analysis, we examine the impact of stratification of MNs based on cytoplasmic transactive response DNA-binding protein 43 (TDP-43)+ inclusion pathology on the profiles of 2,238 proteins.

A novel method for quantitation of AAV genome integrity using duplex digital PCR.

Recombinant adeno-associated virus (rAAV) vectors have become a reliable strategy for delivering gene therapies. As rAAV capsid content is known to be heterogeneous, methods for rAAV characterization are critical for assessing the efficacy and safety of drug products. Multiplex digital PCR (dPCR) has emerged as a popular molecular approach for characterizing capsid content due to its high level of throughput, accuracy, and replicability.

TDP-43-stratified single-cell proteomic profiling of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis.

Unbiased proteomics has been employed to interrogate central nervous system (CNS) tissues (brain, spinal cord) and fluid matrices (CSF, plasma) from amyotrophic lateral sclerosis (ALS) patients; yet, a limitation of conventional bulk tissue studies is that motor neuron (MN) proteome signals may be confounded by admixed non-MN proteins. Recent advances in trace sample proteomics have enabled quantitative protein abundance datasets from single human MNs (Cong et al., 2020b).

Independent study demonstrates amyloid probability score accurately indicates amyloid pathology.

Background: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD blood test that incorporates the plasma Aβ42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease.

Purpose: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals.

Methods: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available.

Recommendations of scRNA-seq Differential Gene Expression Analysis Based on Comprehensive Benchmarking.

To guide analysts to select the right tool and parameters in differential gene expression analyses of single-cell RNA sequencing (scRNA-seq) data, we developed a novel simulator that recapitulates the data characteristics of real scRNA-seq datasets while accounting for all the relevant sources of variation in a multi-subject, multi-condition scRNA-seq experiment: the cell-to-cell variation within a subject, the variation across subjects, the variability across cell types, the mean/variance relationship of gene expression across genes, library size effects, group effects, and covariate effects. By applying it to benchmark 12 differential gene expression analysis methods (including cell-level and pseudo-bulk methods) on simulated multi-condition, multi-subject data of the 10x Genomics platform, we demonstrated that methods originating from the negative binomial mixed model such as glmmTMB and NEBULA-HL outperformed other methods. Utilizing NEBULA-HL in a statistical analysis pipeline for single-cell analysis will enable scientists to better understand the cell-type-specific transcriptomic response to disease or treatment effects and to discover new drug targets.

Cell-autonomous and non-cell autonomous effects of neuronal BIN1 loss in vivo.

BIN1 is the most important risk locus for Late Onset Alzheimer's Disease (LOAD), after ApoE. BIN1 AD-associated SNPs correlate with Tau deposition as well as with brain atrophy. Furthermore, the level of neuronal-specific BIN1 isoform 1 protein is decreased in sporadic AD cases in parallel with neuronal loss, despite an overall increase in BIN1 total mRNA.