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Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.

Objective: Restless legs syndrome (RLS) is a neurological condition that causes uncomfortable sensations in the legs and an irresistible urge to move them, typically during periods of rest. The genetic basis and pathophysiology of RLS are incompletely understood. We sought to identify additional novel genetic risk factors associated with RLS susceptibility. Methods: We performed a whole‐genome sequencing and genome‐wide association meta‐analysis of RLS cases (n = 9,851) and controls (n = 38,957) in 3 population‐based biobanks (All of Us, Canadian Longitudinal Study on Aging, and CARTaGENE). Results: Genome‐wide association analysis identified 9 independent risk loci, of which 8 had been previously reported, and 1 was a novel risk locus (LMX1B, rs35196838, OR 1.14, 95% CI 1.09–1.19, p value = 2.2 × 10−9). Furthermore, a transcriptome‐wide association study also identified GLO1 and a previously unreported gene, ELFN1. A genetic correlation analysis revealed significant common variant overlaps between RLS and neuroticism (rg = 0.40, se = 0.08, p value = 5.4 × 10−7), depression (rg = 0.35, se = 0.06, p value = 2.17 × 10−8), and intelligence (rg = −0.20, se = 0.06, p value = 4.0 × 10−4). Interpretation: Our study expands the understanding of the genetic architecture of RLS, and highlights the contributions of common variants to this prevalent neurological disorder. ANN NEUROL 2024;96:994–1005 [ABSTRACT FROM AUTHOR]

This paper reports findings and observations on using the Social Construction of Technology (SCOT) framework in a questionnaire study of literary translators' self-imaging strategies and attitudes towards technology. The study took advantage of SCOT's methodological flexibility to prioritise literary translators as a social group, hence compensating for the lack of opportunities to voice their interpretations of technology and become an active part in the framework's development and implementation. Ultimately, the use (and adaptation) of SCOT proved useful for the identification, analysis, and discussion of recurrent themes in respondents' narratives about technology and their position in society. In particular, SCOT helped to uncover the gap between how literary translators choose to (re)present themselves in society and how they see technology, and what other social groups might be pivotal for a more comprehensive, socially-relevant analysis. Finally, the paper presents suggestions for the use of SCOT in future research projects concerning the technologisation of the literary translation profession. [ABSTRACT FROM AUTHOR]

Adiponectin is the major adipocytes‐secreted protein involved in obesity‐related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα‐positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα‐coactivator. Here, we showed that adiponectin‐mediated ERα transactivation enhances E‐cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E‐cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E‐cadherin expression in ERα‐positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E‐cadherin gene promoter by ERα/LKB1‐complex. The impact of E‐cadherin on ERα‐positive breast cancer cell proliferation comes from the evidence that in the presence of E‐cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E‐cadherin connects cell polarity and growth, we investigated if the adiponectin‐enhanced E‐cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin‐treated MCF‐7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF‐7 cells revealed an enhanced E‐cadherin‐mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF‐7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin‐treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E‐cadherin expression, alters cell polarity and stimulates ERα‐positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT , KCTD7 , and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis -expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies. [Display omitted] • Generation of a foundational genomic resource in multiple system atrophy • GWAS identifies novel risk loci at GAB1 , lnc-LRRC49-3 , TENM2 , and RABGEF1 • Functional genomics implicates USP38-DT , KCTD7 , and lnc-KCTD7-2 within these loci • Gene-burden analysis identifies nominal enrichment of rare missense mutations in KCTD7 Chia et al. comprehensively analyzed genome sequence data from patients with multiple system atrophy (MSA) and controls. The study identified four novel risk loci associated with MSA and prioritized significantly associated genes (USP38-DT , KCTD7 , and lnc-KCTD7-2) within these loci. This initiative's data constitute a valuable resource for the research community. [ABSTRACT FROM AUTHOR]