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CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa

3 months ago
Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models...
Nicholas D Nolan

Optical coherence tomography as a potential surrogate marker of dopaminergic modulation across the life span

3 months ago
The retina has been considered a "window to the brain" and shares similar innervation by the dopaminergic system with the cortex in terms of an unequal distribution of D1 and D2 receptors. Here, we provide a comprehensive overview that Optical Coherence Tomography (OCT), a non-invasive imaging technique, which provides an "in vivo" representation of the retina, shows promise to be used as a surrogate marker of dopaminergic neuromodulation in cognition. Overall, most evidence supports reduced...
Julia Elmers

Structural mechanisms for VMAT2 inhibition by tetrabenazine

3 months ago
The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic...
Michael P Dalton

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

3 months ago
Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear....
Wayne Mitchell

Variable aging and storage of dissolved black carbon in the ocean

3 months ago
During wildfires and fossil fuel combustion, biomass is converted to black carbon (BC) via incomplete combustion. BC enters the ocean by rivers and atmospheric deposition contributing to the marine dissolved organic carbon (DOC) pool. The fate of BC is considered to reside in the marine DOC pool, where the oldest BC ^(14)C ages have been measured (>20,000 ^(14)C y), implying long-term storage. DOC is the largest exchangeable pool of organic carbon in the oceans, yet most DOC (>80%) remains...
Alysha I Coppola

Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases

3 months ago
As people age, the risk and progression of colorectal cancer (CRC), along with cholesterol levels, tend to increase. Nevertheless, epidemiological studies on serum lipids and CRC have produced conflicting results. We previously demonstrated that the reduction of squalene epoxidase (SQLE) due to accumulated cholesterol within cells accelerates CRC progression through the activation of the β-catenin pathway. This study aimed to investigate the mechanism by which age-related cholesterol...
Soo Young Jun

Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain

3 months ago
The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell...
Masashi Fujita

Disease staging of Alzheimer's disease using a CSF-based biomarker model

3 months ago
Biological staging of individuals with Alzheimer's disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center...
Gemma Salvadó

Evolution-inspired engineering of nonribosomal peptide synthetases

3 months ago
Science, Volume 383, Issue 6689, March 2024.
Kenan A. J. Bozhüyük, Leonard Präve, Carsten Kegler, Leonie Schenk, Sebastian Kaiser, Christian Schelhas, Yan-Ni Shi, Wolfgang Kuttenlochner, Max Schreiber, Joshua Kandler, Mohammad Alanjary, T. M. Mohiuddin, Michael Groll, Georg K. A. Hochberg, Helge B…