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The Role of Estrogen in Brain and Cognitive Aging
There are 3 common physiological estrogens, of which estradiol (E2) is seen to decline rapidly over the menopausal transition. This decline in E2 has been associated with a number of changes in the brain, including cognitive changes, effects on sleep, and effects on mood. These effects have been demonstrated in both rodent and non-human preclinical models. Furthermore, E2 interactions have been indicated in a number of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. In normal brain aging, there are a number of systems that undergo changes and a number of these show interactions with E2, particularly the cholinergic system, the dopaminergic system, and mitochondrial function. E2 treatment has been shown to ameliorate some of the behavioral and morphological changes seen in preclinical models of menopause; however, in clinical populations, the effects of E2 treatment on cognitive changes after menopause are mixed. The future use of sex hormone treatment will likely focus on personalized or precision medicine for the prevention or treatment of cognitive disturbances during aging, with a better understanding of who may benefit from such treatment.
Journal Article
The mighty Thor. Vol. 3, The Asgard/Shi'ar war
\"Thor must deal with the escalating war of the Realms! To face Malekith, Loki and an all-new Kurse, she'll need a team of her own. Prepare for the triumphant return of the League of Realms! Far across the galaxy, though, another conflict is brewing--as the most powerful super-army in the cosmos prepares a surprise attack on the city of the gods! The Shi-ar Empire will lay siege to Asgardia--and their target is the Goddess of Thunder! But why? And what does the fate of Midgard have to do with it? And where the Shi'ar go, the Phoenix Force tends to follow--which is bad news for Thor! Maybe the returning Odinson could lend a hand--or perhaps the rebel X-Man known as Quentin Quire?!\" -- cover
Book
Genetic determinants of gut microbiota composition and bile acid profiles in mice
The microbial communities that inhabit the distal gut of humans and other mammals exhibit large inter-individual variation. While host genetics is a known factor that influences gut microbiota composition, the mechanisms underlying this variation remain largely unknown. Bile acids (BAs) are hormones that are produced by the host and chemically modified by gut bacteria. BAs serve as environmental cues and nutrients to microbes, but they can also have antibacterial effects. We hypothesized that host genetic variation in BA metabolism and homeostasis influence gut microbiota composition. To address this, we used the Diversity Outbred (DO) stock, a population of genetically distinct mice derived from eight founder strains. We characterized the fecal microbiota composition and plasma and cecal BA profiles from 400 DO mice maintained on a high-fat high-sucrose diet for ~22 weeks. Using quantitative trait locus (QTL) analysis, we identified several genomic regions associated with variations in both bacterial and BA profiles. Notably, we found overlapping QTL for Turicibacter sp. and plasma cholic acid, which mapped to a locus containing the gene for the ileal bile acid transporter, Slc10a2. Mediation analysis and subsequent follow-up validation experiments suggest that differences in Slc10a2 gene expression associated with the different strains influences levels of both traits and revealed novel interactions between Turicibacter and BAs. This work illustrates how systems genetics can be utilized to generate testable hypotheses and provide insight into host-microbe interactions.
Journal Article
The Mighty Thor. Vol. 4, The War Thor
The Ultimate Universe's Thor died defending the Multiverse, but his hammer remains. Who wields it now? Ponder that question along with Jane Foster, the Mighty Thor, as she faces the Ultimate team-up! War is coming to the Ten Realms--and when the Queen of Cinders sets them ablaze, even the combined might of not one, not two, but three Thors may not be enough to put out the flames! Meanwhile, Malekith's army grows and the looming conflict reaches Asgard's doorstep! But even the fire of Muspelheim pales beside the fury of the War Thor--and with his thunder comes his vengeance! Plus: Generations collide as Jane and a young Odinson face an Apocalyptic encounter in ancient Egypt--one that may transform the future of both Thors! -- back cover.
Book
S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells
Purpose
Many transformed cells and embryonic stem cells are dependent on the biosynthesis of the universal methyl-donor
S
-adenosylmethionine (SAM) from methionine by the enzyme MAT2A to maintain their epigenome. We hypothesized that cancer stem cells (CSCs) rely on SAM biosynthesis and that the combination of methionine depletion and MAT2A inhibition would eradicate CSCs.
Methods
Human triple (ER/PR/HER2)-negative breast carcinoma (TNBC) cell lines were cultured as CSC-enriched mammospheres in control or methionine-free media. MAT2A was inhibited with siRNAs or cycloleucine. The effects of methionine restriction and/or MAT2A inhibition on the formation of mammospheres, the expression of CSC markers (CD44
hi
/C24
low
), MAT2A and CSC transcriptional regulators, apoptosis induction and histone modifications were determined. A murine model of metastatic TNBC was utilized to evaluate the effects of dietary methionine restriction, MAT2A inhibition and the combination.
Results
Methionine restriction inhibited mammosphere formation and reduced the CD44
hi
/C24
low
CSC population; these effects were partly rescued by SAM. Methionine depletion induced MAT2A expression (mRNA and protein) and sensitized CSCs to inhibition of MAT2A (siRNAs or cycloleucine). Cycloleucine enhanced the effects of methionine depletion on H3K4me3 demethylation and suppression of Sox9 expression. Dietary methionine restriction induced MAT2A expression in mammary tumors, and the combination of methionine restriction and cycloleucine was more effective than either alone at suppressing primary and lung metastatic tumor burden in a murine TNBC model.
Conclusions
Our findings point to SAM biosynthesis as a unique metabolic vulnerability of CSCs that can be targeted by combining methionine depletion with MAT2A inhibition to eradicate drug-resistant CSCs.
Journal Article
Thor. Vol. 1, The Goddess of Thunder
\"Mjolnir lies on the moon, unable to be lifted! Something dark has befallen the God of Thunder, leaving him unworthy for the first time ever! But when Frost Giants invade Earth, the hammer will be lifted - and a mysterious woman will be transformed into an all-new version of the mighty Thor! Who is this new Goddess of Thunder? Not even Odin knows, but she may be Earth's only hope against the Frost Giants! Get ready for a Thor like you've never seen before, as this all-new heroine takes Midgard by storm! Plus: The Odinson clearly doesn't like that someone else is holding his hammer-- it's Thor vs. Thor! And Odin, desperate to see Mjolnir returned, will call on some very dangerous, very unexpected allies. It's a bold new chapter in the storied history of Thor!\" -- summary from forbiddenplanet.com.
Book
Relationship of cholinergic basal forebrain atrophy with the time course of Alzheimer's disease pathology and cognitive decline in adults with Down syndrome: a longitudinal cohort study
INTRODUCTION Adults with Down syndrome (DS) display increased Alzheimer's disease (AD) risk. The cholinergic system declines early in the AD continuum and relates to cognitive and functional decline. We aimed to identify the timeline of cholinergic decline in relation to hippocampal atrophy within the AT(N) framework in DS. METHODS Three‐hundred fifty‐eight adults with DS were assessed for longitudinal changes in cholinergic basal forebrain and hippocampal volume, amyloid positron emission tomography (PET), tau PET, and cognitive performance. RESULTS Amyloid PET increased at 36.5 years old, while tau accumulation, cholinergic basal forebrain (ChBF), and hippocampal volumetric changes occurred in the participants’ 40s. Cognitive decline on the modified cued recall test initiated at 41.7 years old. ChBF and hippocampal volumes negatively associated with AD pathology and positively associated with cognitive performance, with ChBF effects moderated by hippocampal volume. DISCUSSION The timeline presented will inform the design of clinical trials targeting the cholinergic system or utilizing volumetric measures as biomarkers of efficacy or cognition. Highlights The first longitudinal assessment of cholinergic basal forebrain and hippocampal volume in DSAD. The AT(N) framework utilized sporadic AD is consistent in DSAD. Cholinergic basal forebrain volume is an alternate measure of neurodegeneration in the AT(N) framework. Cholinergic effects on total recall on the mCRT are moderated by the hippocampus.
Journal Article
Juno
Faced with an unplanned pregnancy, an offbeat young woman makes an unusual decision regarding her unborn child.
DVD
Phosphorylation regulates human OCT4
The transcription factor OCT4 is fundamental to maintaining pluripotency and self-renewal. To better understand protein-level regulation of OCT4, we applied liquid chromatography–MS to identify 14 localized sites of phosphorylation, 11 of which were previously unknown. Functional analysis of two sites, T234 and S235, suggested that phosphorylation within the homeobox region of OCT4 negatively regulates its activity by interrupting sequence-specific DNA binding. Mutating T234 and S235 to mimic constitutive phosphorylation at these sites reduces transcriptional activation from an OCT4-responsive reporter and decreases reprogramming efficiency. We also cataloged 144 unique phosphopeptides on known OCT4 interacting partners, including SOX2 and SALL4, that copurified during immunoprecipitation. These proteins were enriched for phosphorylation at motifs associated with ERK signaling. Likewise, OCT4 harbored several putative ERK phosphorylation sites. Kinase assays confirmed that ERK2 phosphorylated these sites in vitro, providing a direct link between ERK signaling and the transcriptional machinery that governs pluripotency.
Journal Article