Small molecule disruption of RARα/NCoR1 interaction inhibits chaperone-mediated autophagy in cancer.

Chaperone-mediated autophagy (CMA), a type of selective degradation of cytosolic proteins in lysosomes, is commonly upregulated in cancer cells, contributing to their survival and growth. The lack of a specific target for CMA inhibition has limited CMA blockage to genetic manipulations or global lysosomal function inhibition. Here, using genetic modulation, transcriptional analysis, and functional studies, we demonstrate a regulatory role for the interaction of the retinoic acid receptor alpha (RARα) and its corepressor, the nuclear receptor corepressor 1 (NCoR1), on CMA in non-small cell lung cancer (NSCLC).

Tundra Plant Canopies Gradually Close Over Three Decades While Cryptogams Persist.

Global climate change phenomena are amplified in Arctic regions, driving rapid changes in the biota. Here, we examine changes in plant community structure over more than 30 years at two sites in arctic Alaska, USA, Imnavait Creek and Toolik Lake, to understand long-term trends in tundra response to changing climate. Vegetation cover was sampled every 4-7 years on permanent 1 m plots spanning a 1 km grid using a point-frame.

From geroscience to precision geromedicine: Understanding and managing aging.

Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.

Bcl-xL overexpression in T cells preserves muscle mitochondrial structure and function and prevents frailty in old mice.

Our previous transcriptomic analysis revealed an up-regulation of the antiapoptotic protein B cell lymphoma-extra large (Bcl-xL) in centenarians relative to octogenarians or younger cohorts. In this study, we used Bcl-xL-overexpressing mice to assess its impact on successful aging. Our findings indicate that Bcl-xL overexpression modifies T cell subsets and improves their metabolism, apoptosis resistance, macroautophagy, and cytokine production during aging.

Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging.

Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis.

Nucleic Acid Packaging in Viruses.

Viruses shield their genetic information by enclosing the viral nucleic acid inside a protein shell (capsid), in a process known as genome packaging. Viruses follow essentially two main strategies to package their genome: Either they co-assemble their genetic material together with the capsid protein or an empty shell (procapsid) is first assembled and then the genome is pumped inside the capsid by a molecular motor that uses the energy released by ATP hydrolysis. During packaging the viral nucleic acid is highly condensed through a meticulous arrangement in concentric layers inside the capsid.

3D Cryo-Correlative Methods to Study Virus Structure and Dynamics Within Cells.

Understanding the dynamic processes involving virus structural components within host cells is crucial for comprehending viral infection, as viruses rely entirely on host cells for replication. Viral infection involves various intracellular stages, including cell entry, genome uncoating, replication, transcription and translation, assembly of new virus particles in a complex morphogenetic process, and the release of new virions from the host cell. These events are dynamic and scarce and can be obscured by other cellular processes, necessitating novel approaches for their in situ characterization.

The Fifth Annual Symposium of the Midwest Aging Consortium.

As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms.

Reconstitution of Rab11-FIP4 Expression Rescues Cellular Homeostasis in Cystinosis.

Rab11 family interacting protein 4 (Rab11-FIP4) regulates endocytic trafficking. A possible role for Rab11-FIP4 in the regulation of lysosomal function has been proposed, but its precise function in the regulation of cellular homeostasis is unknown. By mRNA array and protein analysis, we found that Rab11-FIP4 is downregulated in the lysosomal storage disease cystinosis, which is caused by genetic defects in the lysosomal cystine transporter, cystinosin.

Calorie restriction and calorie-restriction mimetics activate chaperone-mediated autophagy.

Chaperone-mediated autophagy (CMA) is part of the mammalian cellular proteostasis network that ensures protein quality control, maintenance of proteome homeostasis, and proteome changes required for the adaptation to stress. Loss of proteostasis is one of the hallmarks of aging. CMA decreases with age in multiple rodent tissues and human cell types.

Transcription factor Nrf1 regulates proteotoxic stress-induced autophagy.

Cells exposed to proteotoxic stress invoke adaptive responses aimed at restoring proteostasis. Our previous studies have established a firm role for the transcription factor Nuclear factor-erythroid derived-2-related factor-1 (Nrf1) in responding to proteotoxic stress elicited by inhibition of cellular proteasome. Following proteasome inhibition, Nrf1 mediates new proteasome synthesis, thus enabling the cells to mitigate the proteotoxic stress.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA).

Scipion3: A workflow engine for cryo-electron microscopy image processing and structural biology.

Image-processing pipelines require the design of complex workflows combining many different steps that bring the raw acquired data to a final result with biological meaning. In the image-processing domain of cryo-electron microscopy single-particle analysis (cryo-EM SPA), hundreds of steps must be performed to obtain the three-dimensional structure of a biological macromolecule by integrating data spread over thousands of micrographs containing millions of copies of allegedly the same macromolecule. The execution of such complicated workflows demands a specific tool to keep track of all these steps performed.

Observation of Bacteriophage Ultrastructure by Cryo-Electron Microscopy.

Transmission electron microscopy (TEM) is an ideal method to observe and determine the structure of bacteriophages. From early studies by negative staining to the present atomic structure models derived from cryo-TEM, bacteriophage detection, classification, and structure determination have been mostly done by electron microscopy. Although embedding in metal salts has been a routine method for virus observation for many years, the preservation of bacteriophages in a thin layer of fast frozen buffer has proven to be the most convenient preparation method for obtaining images using cryo-electron microscopy (cryo-EM).

A machine learning and directed network optimization approach to uncover regulatory patterns.

TP53, the , is the most frequently mutated gene in human cancers and the functional characterization of its regulation is fundamental. To address this we employ two strategies: machine learning to predict the mutation status of , and directed regulatory networks to reconstruct the effect of mutations on the transcipt levels of targets. Using data from established databases (Cancer Cell Line Encyclopedia, The Cancer Genome Atlas), machine learning could predict the mutation status, but not resolve different mutations.

NGLY1 mutations cause protein aggregation in human neurons.

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1's activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the Study of Muscle, Mobility and Aging (SOMMA).

Autophagy is an essential component of proteostasis and a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility and Aging (SOMMA).