540 results match your criteria: "Huffington Center on Aging.[Affiliation]"

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton's Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs.

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Transcription is regulated through a dynamic interplay of DNA-associated proteins, and the composition of gene-regulatory complexes is subject to continuous adjustments. Protein alterations include post-translational modifications and elimination of individual polypeptides. Spatially and temporally controlled protein removal is, therefore, essential for gene regulation and accounts for the short half-life of many transcription factors.

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Bioactive peptides are an emerging area of biomedical research in the study of numerous human diseases, including acute alcoholic liver injury (AALI). To study the role and mechanism of the milk‑derived hexapeptide Pro‑Gly‑Pro‑Ile‑Pro‑Asn (PGPIPN) in preventing and reducing AALI, the present study established a mouse model of AALI. PGPIPN was used as a therapeutic drug, and glutathione (GSH) was used as a positive control.

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We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders.

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Molecular Mechanisms of Lysosome and Nucleus Communication.

Trends Biochem Sci

November 2020

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Lysosomes transcend the role of degradation stations, acting as key nodes for interorganelle crosstalk and signal transduction. Lysosomes communicate with the nucleus through physical proximity and functional interaction. In response to external and internal stimuli, lysosomes actively adjust their distribution between peripheral and perinuclear regions and modulate lysosome-nucleus signaling pathways; in turn, the nucleus fine-tunes lysosomal biogenesis and functions through transcriptional controls.

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From its inception in 1980, advancement of research was one of the primary missions of the Alzheimer's Association (also known as Alzheimer's Disease and Related Disorders Association) in addition to leading in family caregiver support, better care, public education, and awareness. Over the past 30 years, the Association has grown and expanded its engagement with the scientific community. In the past 10 years, its research budget has more than doubled, greatly increasing the number of research grants funded and the number of strategic projects supported.

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The replicative aging of the budding yeast, Saccharomyces cerevisiae, has been a useful model for dissecting the molecular mechanisms of the aging process. Traditionally, the replicative lifespan (RLS) is measured by manually dissecting mother cells from daughter cells, which is a very tedious process. Since 2012, several microfluidic systems have been developed to automate the dissection process, significantly accelerating RLS determination.

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Structural changes in pre and postsynaptic neurons that accompany synapse formation often temporally and spatially overlap. Thus, it has been difficult to resolve which processes drive patterned connectivity. To overcome this, we use the laminated outer murine retina.

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Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and misfolded tau protein are a pathological hallmark of Alzheimer's disease and other tauopathy conditions. Tau is predominantly an intraneuronal protein but is also secreted in physiological and pathological conditions. The extracellular tau has been implicated in the seeding and propagation of tau pathology and is the prime target of the current tau immunotherapy.

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Olfactory and metabolic dysfunctions are intertwined phenomena associated with obesity and neurodegenerative diseases; yet how mechanistically olfaction regulates metabolic homeostasis remains unclear. Specificity of olfactory perception integrates diverse environmental odors and olfactory neurons expressing different receptors. Here, we report that specific but not all olfactory neurons actively regulate fat metabolism without affecting eating behaviors in Caenorhabditis elegans, and identified specific odors that reduce fat mobilization via inhibiting these neurons.

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Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.

Aging Cell

April 2020

State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.

Histone acetyltransferases (HATs) are important enzymes that transfer acetyl groups onto histones and thereby regulate both gene expression and chromosomal structures. Previous work has shown that the activation of sirtuins, which are histone deacetylases, can extend lifespan. This suggests that inhibiting HATs may have a similar beneficial effect.

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Article Synopsis
  • Guanine-rich DNA sequences can form four-stranded structures called G-quadruplexes (G4-DNA), which play a role in regulating key cellular processes like replication and transcription, especially in cancer cells.
  • Research shows that stabilizing G4-DNA in neurons using specific ligands can lead to decreased expression of a crucial gene involved in autophagy, which declines with age.
  • In experiments, aging mice exhibited increased G4-DNA structures in their brains compared to younger mice, and enhancing the levels of a G4-DNA helicase improved the negative effects caused by G4-DNA stabilization on memory.
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Type I interferon (IFN) is a key cytokine that curbs viral infection and cell malignancy. Previously, we demonstrated a potent IFN immunogenicity of nucleic acid-containing (NA-containing) amyloid fibrils in the periphery. Here, we investigated whether IFN is associated with β-amyloidosis inside the brain and contributes to neuropathology.

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Loss of chromatin structural integrity is a source of stress during aging.

Hum Genet

March 2020

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, USA.

Dysfunction and dysregulation at multiple levels, from organismal to molecular, are associated with the biological process of aging. In a eukaryotic nucleus, multiple lines of evidence have shown that the fundamental structure of chromatin is affected by aging. Not only euchromatic and heterochromatic regions shift locations, global changes, such as reduced levels of histones, have been reported for certain aged cell types and tissues.

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Microglia in the developing retina.

Neural Dev

December 2019

Department of Neuroscience, Huffington Center on Aging, Baylor College of Medicine, Houston, TX, 77030, USA.

Microglia are increasingly shown to be key players in neuron development and synapse connectivity. However, the underlying mechanisms by which microglia regulate neuron function remain poorly understood in part because such analysis is challenging in the brain where neurons and synapses are intermingled and connectivity is only beginning to be mapped. Here, we discuss the features and function of microglia in the ordered mammalian retina where the laminar organization of neurons and synapses facilitates such molecular studies.

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NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress.

Cell Signal

February 2020

Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China. Electronic address:

Mitochondria plays a key role in regulating cell death process under stress conditions and it has been indicated that NAMPT overexpression promotes cell survival under genotoxic stress by maintaining mitochondrial NAD level. NAMPT is a rate-limiting enzyme for NAD production in mammalian cells and it was suggested that NAMPT and NMNAT3 are responsible for mitochondrial NAD production to maintain mitochondrial NAD pool. However, subsequent studies suggested mitochondrial may lack the NAMPT-NMANT3 pathway to maintain NAD level.

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Article Synopsis
  • The genotype-phenotype relationship in animals can be significantly influenced by microbial environments, which provide key metabolic cues.
  • Different bacterial strains, like B strain OP50 and K-12 strain MG1655, induce varied cellular, developmental, and behavioral phenotypes in host organisms.
  • Specific metabolites, particularly betaine levels from these bacteria, impact fat storage traits and mitochondrial morphology, highlighting the need to consider microbial contributions when studying genetic effects on physiology.
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Lysosomes: Signaling Hubs for Metabolic Sensing and Longevity.

Trends Cell Biol

November 2019

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Lysosomes are sites of active metabolism in a cell. They contain various hydrolases that degrade extracellular and intracellular materials during endocytosis and autophagy, respectively. In addition to their long-recognized roles in degradation and recycling, emerging studies have revealed that lysosomes are organizing centers for signal transduction.

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In several areas of the central nervous system, neurons are regionally organized into groups or layers that carry out specific activities. In this form of patterning, neurons of distinct types localize their cell bodies to just one or a few of the layers within a structure. However, little is known about whether diverse neuron types within a lamina share molecular features that coordinate their organization.

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Article Synopsis
  • - Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder tied to intellectual disabilities and optic nerve issues, caused by mutations in the NR2F1 gene, which helps regulate gene expression in the brain.
  • - Researchers created a heterozygous knockout mouse model to better mimic human BBSOAS and discovered it exhibited several neurological issues, such as problems with learning/memory, reduced hippocampal volume, and altered fear memory.
  • - The study revealed significant gene expression changes in the hippocampus of the mouse model, indicating that disruption of synaptic plasticity may play a role in the cognitive impairments associated with BBSOAS.
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Becoming a Principal Investigator: Designing and Navigating Your Academic Adventure.

Neuron

September 2019

Huffington Center on Aging and Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

Starting your own academic lab is a wonderful opportunity to impact science through research and trainee mentoring. In this article, we share some thoughts and resources for this undertaking in the hope that they may enhance the experience of others.

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Telomeres and sirtuins: at the end we meet again.

Mol Cell Oncol

July 2019

Department of Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.

Telomeres and sirtuins are independently implicated in causing disease and aging, but how they cooperate is not well understood. A recent study demonstrates that telomere shortening represses sirtuins and increasing sirtuin activity stabilizes telomeres and improves telomere-dependent disease, suggesting that these two pathways are tightly intertwined.

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Here we elucidate the effect of Alzheimer disease (AD)-predisposing genetic backgrounds, APOE4, PSEN1ΔE9, and APPswe, on functionality of human microglia-like cells (iMGLs). We present a physiologically relevant high-yield protocol for producing iMGLs from induced pluripotent stem cells. Differentiation is directed with small molecules through primitive erythromyeloid progenitors to re-create microglial ontogeny from yolk sac.

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Cellular response to moderate chromatin architectural defects promotes longevity.

Sci Adv

July 2019

Department of Molecular and Human Genetics, and Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.

Changes in chromatin organization occur during aging. Overexpression of histones partially alleviates these changes and promotes longevity. We report that deletion of the histone H3-H4 minor locus extended the replicative life span of .

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