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Highlights • Sub-components of working memory (WM) showed different lifespan trajectories. • WM capacity was related to apparent thinner cortex during childhood. • The WM-thickness effect could not be accounted for by general cognitive abilities. • The WM-thickness relationship was not mediated by genetics or socioeconomic status., Working memory (WM) supports several higher-level cognitive abilities, yet we know less about factors associated with development and decline in WM compared to other cognitive processes. Here, we investigated lifespan changes in WM capacity and their structural brain correlates, using a longitudinal sample including 2358 magnetic resonance imaging (MRI) scans and WM scores from 1656 participants (4.4–86.4 years, mean follow-up interval 4.3 years). 8764 participants (9.0–10.9 years) with MRI, WM scores and genetic information from the Adolescent Brain Cognitive Development study were used for follow-up analyses. Results showed that both the information manipulation component and the storage component of WM improved during childhood and adolescence, but the age-decline could be fully explained by reductions in passive storage capacity alone. Greater WM function in development was related to apparent thinner cortex in both samples, also when general cognitive function was accounted for. The same WM-apparent thickness relationship was found for young adults. The WM-thickness relationships could not be explained by SNP-based co-heritability or by socioeconomic status. A larger sample with genetic information may be necessary to disentangle the true gene-environment effects. In conclusion, WM capacity changes greatly through life and has anatomically extended rather than function-specific structural cortical correlates.

The heterogeneity of respirable particulates and compounds complicates our understanding of transcriptional responses to air pollution. Here, we address this by applying precision nuclear run-on sequencing and the assay for transposase-accessible chromatin sequencing to measure nascent transcription and chromatin accessibility in airway epithelial cells after wood smoke particle (WSP) exposure. We used transcription factor enrichment analysis to identify temporally distinct roles for ternary response factor–serum response factor complexes, the aryl hydrocarbon receptor (AHR), and NFκB in regulating transcriptional changes induced by WSP. Transcription of canonical targets of the AHR, such as CYP1A1 and AHRR, was robustly increased after just 30 min of WSP exposure, and we discovered novel AHR-regulated pathways and targets including the DNA methyltransferase, DNMT3L. Transcription of these genes and associated enhancers rapidly returned to near baseline by 120 min after exposure. The kinetics of AHR- and NFκB-regulated responses to WSP were distinguishable based on the timing of both transcriptional responses and chromatin remodeling, with induction of several cytokines implicated in maintaining NFκB-mediated responses through 120 min of exposure. In aggregate, our data establish a direct and primary role for AHR in mediating airway epithelial responses to WSP and identify crosstalk between AHR and NFκB signaling in controlling proinflammatory gene expression. This work also defines an integrated genomics-based strategy for deconvoluting multiplexed transcriptional responses to heterogeneous environmental exposures.

Amyloid beta (A beta) deposition in the neocortex is a major hallmark of Alzheimers disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain-like model of disease heterogeneity suggests the existence of different conformers of A beta. We explored this paradigm using conformation-dependent immunoassay (CDI) for A beta and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the A beta conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of A beta with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from A beta plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs-quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of A beta deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of A beta accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct A beta conformers (strains) in the rapid progression of AD. Funding Agencies|Alberta Innovates Bio Solutions [FP00209618]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1RF1AG061797, AG066512, AG060882]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2019-04405, 2016-00748]; Swedish Alzheimer Foundation; Swedish Brain Foundation; Torsten Soderberg Foundation

Autophagosome–lysosome pathway (ALP) insufficiency has been suggested to play a critical role in the pathogenesis of cardiac hypertrophy. However, the mechanisms underlying ALP insufficiency remain largely unknown, and strategies to specifically manipulate ALP insufficiency for treating cardiac hypertrophy are lacking. Transcription factor EB (TFEB), as a master regulator of ALP, regulates the generation and function of autophagosomes and lysosomes. We found that TFEB was significantly decreased, whereas autophagosome markers were increased in phenylephrine (PE)-induced and transverse aortic constriction–induced cardiomyocyte hypertrophy and failing hearts from patients with dilated cardiomyopathy. Knocking down TFEB induced ALP insufficiency, as indicated by increased autophagosome markers, decreased light chain 3II flux, and cardiomyocyte hypertrophy manifested through increased levels of atrial natriuretic peptide and β-myosin heavy chain and enlarged cell size. The effects of TFEB knockdown were abolished by promoting autophagy. TFEB overexpression improved autophagic flux and attenuated PE-stimulated cardiomyocyte hypertrophy and transverse aortic constriction–induced hypertrophic remodeling, fibrosis, and cardiac dysfunction. Curcumin analog compound C1, a specific TFEB activator, similarly attenuated PE-induced ALP insufficiency and cardiomyocyte hypertrophy. TFEB knockdown increased the accumulation of GATA4, a transcription factor for several genes causing cardiac hypertrophy by blocking autophagic degradation of GATA4, whereas knocking down GATA4 attenuated TFEB downregulation–induced cardiomyocyte hypertrophy. Both TFEB overexpression and C1 promoted GATA4 autophagic degradation and alleviated PE-induced cardiomyocyte hypertrophy. In conclusion, TFEB downregulation plays a vital role in the development of pressure overload–induced cardiac hypertrophy by causing ALP insufficiency and blocking autophagic degradation. Activation of TFEB represents a potential therapeutic strategy for treating cardiac hypertrophy.