Decreased lipidated ApoE-receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes.

While apolipoprotein E (APOE) is the strongest genetic modifier for late-onset Alzheimer's disease (LOAD), the molecular mechanisms underlying isoform-dependent risk and the relevance of ApoE-associated lipids remain elusive. Here, we report that impaired low-density lipoprotein (LDL) receptor (LDLR) binding of lipidated ApoE2 (lipApoE2) avoids LDLR recycling defects observed with lipApoE3/E4 and decreases the uptake of cholesteryl esters (CEs), which are lipids linked to neurodegeneration. In human neurons, the addition of ApoE carrying polyunsaturated fatty acids (PUFAs)-CE revealed an allelic series (ApoE4 > ApoE3 > ApoE2) associated with lipofuscinosis, an age-related lysosomal pathology resulting from lipid peroxidation.

Arabic consonant length perception depends on the relative speech rate of the distal context.

Listeners adapt to the speech rate of talkers. Many studies of speech rate adaptation have focused on the influence of rate information on the perception of word segmentation or segmental perception in English. The effects of immediately adjacent (i.

Amphiphilic shuttle peptide delivers base editor ribonucleoprotein to correct the CFTR R553X mutation in well-differentiated airway epithelial cells.

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery.

The Cerebellum Is Sensitive to the Lexical Properties of Words During Spoken Language Comprehension.

Over the past few decades, research into the function of the cerebellum has expanded far beyond the motor domain. A growing number of studies are probing the role of specific cerebellar subregions, such as Crus I and Crus II, in higher-order cognitive functions including receptive language processing. In the current fMRI study, we show evidence for the cerebellum's sensitivity to variation in two well-studied psycholinguistic properties of words-lexical frequency and phonological neighborhood density-during passive, continuous listening of a podcast.

Individual differences in the use of top-down versus bottom-up cues to resolve phonetic ambiguity.

How listeners weight a wide variety of information to interpret ambiguities in the speech signal is a question of interest in speech perception, particularly when understanding how listeners process speech in the context of phrases or sentences. Dominant views of cue use for language comprehension posit that listeners integrate multiple sources of information to interpret ambiguities in the speech signal. Here, we study how semantic context, sentence rate, and vowel length all influence identification of word-final stops.