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Science, Volume 386, Issue 6725, November 2024.

Science, Volume 386, Issue 6725, November 2024.

Science, Volume 386, Issue 6725, November 2024.

Science, Volume 386, Issue 6725, November 2024.

Science, Volume 386, Issue 6725, November 2024.

Plethora of research has shed light on the critical role of synaptic dysfunction in various neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Synapses, the fundamental units for neural communication in the brain, are highly vulnerable to pathological conditions and are central to the progression of neurological diseases. The presynaptic terminal, a key component of synapses...

Neuroinflammation is closely related to the pathogenesis of Alzheimer's disease (AD). One of its prominent cellular components, microglia, is a potent coordinator of neuroinflammation in interplay with the characteristic AD pathological alterations including Aβ, tau, and neuronal defects, which constitute the AD-unique extracellular microenvironment. Mounting evidence implicates Triggering Receptors Expressed on Myeloid Cells 2 (TREM2) in the center of microglial activation, a vital event in the...

Exon skipping technologies enable exclusion of targeted exons from mature mRNA transcripts, which have broad applications in medicine and biotechnology. Existing techniques including antisense oligonucleotides, targetable nucleases, and base editors, while effective for specific applications, remain hindered by transient effects, genotoxicity, and inconsistent exon skipping. To overcome these limitations, here we develop SPLICER, a toolbox of next-generation base editors containing near-PAMless...

The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISR^(mt)) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISR^(mt) triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISR^(mt) can provoke an adaptive stress response that antagonizes...

Coronary heart disease (CHD) and cognitive impairment frequently co-occur in aging populations, yet the molecular mechanisms linking these conditions remain unclear. This study aims to elucidate the roles of key aging-related genes (ARGs), specifically FKBP5 and DDIT3, in the pathophysiology of CHD and cognitive impairment, and to evaluate the therapeutic potential of stellate ganglion block (SGB). Using single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) data, we...

Precipitation hardening has been recently validated as a new mechanism for domain wall pinning and mechanical loss reduction in piezoelectrics. While anisometric precipitates have high pinning strengths, there is limited knowledge about the electrical anisotropy of the precipitation-hardened piezoceramics. In the present work, we successfully orient the precipitates in Li(0.18)Na(0.82)NbO(3) piezoceramics by applying a uniaxial stress during the aging and studied its electrical anisotropy....

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder affecting up to one in five women. The aetiology remains unclear, but available evidence suggests it is a polygenic disorder with epigenetic, developmental, and environmental components. The diagnostic criteria for PCOS are based on reproductive features, and the syndrome is categorized into several phenotypes that can vary by race and ethnicity. Insulin resistance and metabolic dysfunction have a crucial role in the...