ACS Nano最新文献

Integrating proteomic and transcriptomic data with genetic architectures of problematic alcohol use and alcohol consumption behaviours can advance our understanding and help identify therapeutic targets. We conducted systematic screens using genome-wise association study data from ~3,500 cortical proteins (N = 722) and ~6,100 genes in 8 canonical brain cell types (N = 192) with 4 alcohol-related outcomes (N ≤ 537,349), identifying 217 cortical proteins and 255 cell-type genes associated with these behaviours, with 36 proteins and 37 cell-type genes being new. Although there was limited overlap between proteome and transcriptome targets, downstream neuroimaging revealed shared neurophysiological pathways. Colocalization with independent genome-wise association study data further prioritized 16 proteins, including CAB39L and NRBP1, and 12 cell-type genes, implicating mechanisms such as mTOR signalling. In addition, genes such as SAMHD1, VIPAS39, NUP160 and INO80E were identified as having favourable neuropsychiatric profiles. These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviours, highlighting promising therapeutic targets for future research.

We use the rise of Black Lives Matter and the sentiment of racial sympathy to examine the interplay between the social movement and citizens’ sympathetic actions in supporting Black people. Using detailed food order flow information from one of the largest online food delivery platforms in the USA, we find that the total number of food orders from Black-owned restaurants increased by 39% relative to nearby non-Black-owned restaurants in the 140 days following the murder of George Floyd on the basis of a difference-in-difference model. The platform company’s strategic traffic allocation acted as an accelerator, enhancing the sympathetic responses of individuals, but it did not drive the entire surge in food orders. Protests resulting in severe injuries and those linked to demands for defunding the police diminished the positive sympathetic responses, highlighting a potential risk associated with protests. Our study provides large-scale, micro-level evidence that social movements and increased sympathy can foster collective actions to support marginalized communities.

In many contemporary democracies, political polarization increasingly involves deep-seated intolerance of opposing partisans. The decades-old contact hypothesis suggests that cross-partisan interactions might reduce intolerance if individuals interact with equal social status. Here we test this idea by implementing collaborative contact between 1,227 pairs of citizens (2,454 individuals) with opposing partisan sympathies in Mexico, using the online medium to credibly randomize participants’ relative social status within the interaction. Interacting under both equal and unequal status enhanced tolerant behaviour immediately after contact; however, 3 weeks later, only the salutary effects of equal contact endured. These results demonstrate that a simple, scalable intervention that puts people on equal footing can reduce partisan polarization and make online contact into a prosocial force.

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Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

Astrocytes are crucial to brain homeostasis, yet their changes along the spatiotemporal progression of Alzheimer’s disease (AD) neuropathology remain unexplored. Here we performed single-nucleus RNA sequencing of 628,943 astrocytes from five brain regions representing the stereotypical progression of AD pathology across 32 donors spanning the entire normal aging to severe AD continuum. We mapped out several unique astrocyte subclusters that exhibited varying responses to neuropathology across the AD-vulnerable neural network (spatial axis) or AD pathology stage (temporal axis). The proportion of homeostatic, intermediate and reactive astrocytes changed only along the spatial axis, whereas two other subclusters changed along the temporal axis. One of these, a trophic factor-rich subcluster, declined along pathology stages, whereas the other increased in the late stage but returned to baseline levels in the end stage, suggesting an exhausted response with chronic exposure to neuropathology. Our study underscores the complex dynamics of astrocytic responses in AD.

Learning to read is the most important outcome of primary education. However, despite substantial improvements in primary school enrolment, most students in low- and middle-income countries (LMICs) fail to learn to read by age 10. We report reading assessment data from over half a million pupils from 48 LMICs tested primarily in a language of instruction and show that these pupils are failing to acquire the most basic skills that contribute to reading comprehension. Pupils in LMICs across the first three instructional years are not acquiring the ability to decode printed words fluently and, in most cases, are failing to master the names and sounds associated with letters. Moreover, performance gaps against benchmarks widen with each instructional year. Literacy goals in LMICs will be reached only by ensuring focus on decoding skills in early-grade readers. Effective literacy instruction will require rigorous systematic phonics programmes and assessments suitable for LMIC contexts.