163 research outputs found
Horace Kephart to Dillin, May 29, 1924
No full textIn a letter to Mr. Dillin on May 29, 1924, Horace Kephart discusses rifles. Horace Kephart (1862-1931) was a noted naturalist, woodsman, journalist, and author and promoter of the Great Smoky Mountains National Park
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Tissue-Specific Aspects of Mitochondria and Longevity in C. elegans
No full textThe connection between aging and metabolism seems obvious, but the particulars of this relationship remain obscure. Theories linking the two abound, centered on the fact that mitochondria are the location of much of the cell's free radical production and on the general correlation between lifespan and metabolic rate. The connection between longevity and mitochondrial function was strengthened by RNAi-based screens in the worm C. elegans, where RNAi knock-down of mitochondrial Electron Transport Chain (ETC) subunits of Complex I (nuo-2), Complex III (cyc-1), Complex IV (cco-1) and Complex V (atp-3) extended lifespan (Dillin et al., 2002b; Lee et al., 2002). The effects of ETC knockdown on life span appear to depend on a mechanism more complex than direct effects on mitochondrial metabolic rates. Instead, they point towards the existence of signaling programs emanating from the mitochondria and capable of regulating the life span of the entire organism. The identity of components and timing requirements of the mitochondrial ETC that influence longevity have led us to search for a mechanism imposed during early development that sets the rate of aging for the remainder of the animal's life cycle as well as the critical tissues required for the mitochondrial ETC to set the rate of aging. I have found that disruption of cco-1, in the neurons or intestine of the worm is sufficient to confer a longevity phenotype. This tissue-specific knockdown was able to uncouple some of the detrimental phenotypes of organism-wide knockdown, such as reduced brood size and slow movement. Furthermore, the long lifespan that results from ETC perturbance is dependent on the mitochondrial Unfolded Protein Response (UPRmt) gene, ubl-5. Knowing that there are tissues in which ETC function is critical as well as the necessity for a functional UPRmt might allow us to better understand the basis of mitochondria-mediated longevity
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SKN-1 is a metabolic surveillance factor that surveils amino acid catabolism pathways to control stress resistance
No full textThe deleterious potential to generate oxidative stress and damage is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and physiological consequences of this remain unknown. To explore this connection, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance
Horace Kephart to Dillin, February 27, 1924
No full textIn a letter to Mr. Dillin on February 27, 1924, Horace Kephart discusses Dillin's writing on rifles. Horace Kephart (1862-1931) was a noted naturalist, woodsman, journalist, and author and promoter of the Great Smoky Mountains National Park.f
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HORACE KEPHART
BRYSON CITY, N. C.
Feb.27, 1924.
Dear Mr.' Dillin:-
I have known some rascally publishers, but I never heard of
another who would mistreat a writer as that fellow did you.
As I had seen the advance notices of your book in The
American Rifleman, and naturally supposed it was in press, I
am surprised to learn that nothing seems to have been done
about bringing it out. The thing is a mystery to me; though
it would seem that the publishers issued the ad. in order to
learn how many advance subscriptions could be obtained before
risking money on publication. I hope they will soon issue the
book. .Not having seen the manuscript, of course I do not know
whether it is in proper shape for the printer. It takes
special technical knowledge to prepare matter for the press;
the compositor himself merely "follows copy," and if the
manuscript is not perfect in construction, punctuation, etc.,
its errors will appear in type as in the original, and in
that case it would cost more to correct the proofs than it
would have cost to hire an expert to revise the manuscript
and type it for the printer.
I quit the Outing Publishing Company last spring, and they
have gone bankrupt, leaving me in the hole. Since then I have
done no outdoor stuff but have been busy on a novel.
Sincerely,
<sf
Horace Kephart to Captain Dillin, April 7, 1924
No full textIn a letter to Mr. Dillin on April 7, 1924, Horace Kephart discusses his writing on rifles. Horace Kephart (1862-1931) was a noted naturalist, woodsman, journalist, and author and promoter of the Great Smoky Mountains National Park.HORACE KEPHART
BRYSON CITY, N. C.
April ?, 1924.
My dear Captain Dillin:-
I was laid up for a time and so an answer to your last letter
has been delayed. I wish I could see "The Covered Wagon." Hough
was an old friend of mine. He got the material for his first
novel, "The Mississippi Bubble," in my collection and while a
guest at my home in St.Louis.
I have sent THE AMERICAN RIFLEMAN an article on the Hawken
rifles of St.Louis. It will appear before long. Woodmansee
wrote me that he had secured a good specimen. I gave mine to
the Mo. Historical Society.
I see the ad. of your book once more in the A.R. Hope they
will soon bring it out.
Am returning that fellow's letter herewith.
Sincerely
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C. elegans glial HSF-1 protects from stress and aging via a novel neural mechanism
No full textThis work addresses two major unsolved questions in the field of C. elegans neuroscience and stress biology. First, are glia of the worm able to regulate the heat shock response (HSR) in a non-cell autonomous manner. Second, are these glia also required for regulation of such a response.In the first chapter, I introduce concepts relevant to the works herein presented. Aging induces cellular dysfunction partially by the decline of protein homeostasis stress responses. When this function is restored, animals live longer and healthier. Although stress responses are specialized to the functions of individual organelles, signaling can be transmitted from neural cells to peripheral tissues in a protective manner. The role for glia, the non-neuronal cells of the brain, in this process is not well described. Glia, including astrocytes, closely regulate homeostasis of brain tissues, including by immune and stress responses. As this homeostasis deteriorates with age, risk of neurodegenerative disease increases. Most neurodegenerative diseases are characterized by the accumulation of protein misfolding, including Alzheimer’s Disease (AD). AD patients, among those with other so-called “tauopathies,” exhibit misfolding of the microtubule-associated protein tau. Tau abnormalities are associated with neuronal dysfunction, but their role in organellar stress response induction has not been well characterized.In the second chapter, I examine the mechanism by which the cephalic sheath (CEPsh) glia of the nematode C. elegans coordinate the HSR across tissues to increase stress resistance, lifespan, and immune tolerance. When the main regulator of the heat shock response, heat shock factor 1 (hsf-1), is over-expressed in the four CEPsh cells, I identify an increase in lifespan alongside peripheral induction of heat shock chaperones and an increase in heat stress tolerance. The mechanism by which this non-cell autonomous communication occurs is independent of the neuronally-coordinated HSR system, operating without requirement for the AIY interneuron or serotonin synthesis. The response is also transmitted independent of previous glial-derived signals, which had originated from UNC-31-mediated dense core vesicles, and instead relies on transmission by UNC-13-mediated small clear vesicles. However, there is no clear requirement for a singular neurotransmitter that might be contained in such vesicles. In the periphery, hsf-1 itself is required, as the insulin signaling factor daf-16 in a partial manner. In addition, immune factors are highly upregulated in CEPsh glial hsf-1 animals, which are resistant to pathogenic bacteria. Taken together, I here identify a unique signaling mechanism by which CEPsh glia specifically modulate heat stress signaling.In the third chapter, I investigate the endogenous role for CEPsh glia in regulation of the HSR. I first characterized by imaging several types of developmental mutants causing CEPsh glial ablation. I next tested these strains for heat stress tolerance and found that mutants for the development of all four CEPsh cells, but not ventral CEPsh glia alone, displayed increased thermotolerance relative to wild type animals. This did not occur concomitant with increased chaperone induction. Further, I identified a requirement for CEPsh glia in neuronal HSR signaling, for both lifespan extension and for thermotolerance induction. These data suggest that CEPsh glia are naturally strong regulators of the heat shock response, and that such regulation may occur in a positive and negative fashion, in close interaction with neurons. More work is necessary to understand the dynamic nature of this regulation, and through what mechanism it occurs in the glial and neuronal systems.In sum, I here describe several unique roles and signaling mechanisms concerning the heat shock response for the CEPsh glia of C. elegans. These data, in combination with prior works, demonstrate that CEPsh glia flexibly and specifically respond to organelle-targeted stressors, coordinating an organismal response to that unique cue. In the case of heat stress, such cues may include heat or other protein misfolding insults, as previously shown, but also pathogen stress. Further, CEPsh cells serve a larger role supporting neuronal HSR signaling, which remains unprobed. Taken together, I show that CEPsh glia are both sufficient to regulate organismal heat stress and necessary to ensure endogenous HSR function range. These works will shed light on how neuronal and glial aging impact organismal health and longevity, particularly in the case of neurodegenerative diseases
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The effects of mitochondrial stress on organismal health in C. elegans
No full textMitochondria are an essential organelle, serving as a key site of energy production in metazoans. Animals have complex systems for monitoring the health and proteostasis of mitochondria, and activate multiple quality control mechanisms in response to dysfunction. Using the nematode Caenorhabditis elegans, we investigated mitochondrial health, dysfunction, and stress signaling in two different systems. Dysfunction of mitochondrial DNA replication machinery is a common cause of mitochondrial diseases. The minimal mammalian replisome is made up of DNA polymerase gamma, replicative helicase Twinkle, and single-stranded DNA binding protein. Recently, a sequence homolog of Twinkle was uncovered in the nematode C. elegans. Here, we characterized this homolog, twnk-1, and report that while twnk-1 does not appear function as the primary mitochondrial DNA replicative helicase in this species, as loss of twnk-1 does not result in reduce mitochondrial DNA levels, or result in other expected mitochondrial dysfunctions such as reduced oxygen consumption rates, increased sensitivity to metabolic perturbations, or reduced muscle function. However, twnk-1 mutants exhibit phenotypes associated with mitochondrial stress, including reduced fecundity, an activation of the mitochondrial unfolded protein response (UPRmt), and mitochondrial fragmentation. Our results suggest that in C. elegans, twnk-1 does not function as the mitochondrial DNA replicative helicase, but has an alternative function in regulating mitochondrial function.In a second project, we focused on the UPRmt, a transcriptional program initiated when mitochondrial proteostasis is challenged. Previous work from our lab shows that when mitochondrial health is challenged in neurons alone, they signal to distal tissues, activating the UPRmt in the intestine. This causes hormesis as shown through extended lifespan. We found that when the UPRmt component and chromatin modifier PHF8/jmjd-1.2a is overexpressed in a second neural cell type, astrocyte-like cephalic sheath glia, they signal the UPRmt to distal tissues as well. We used two UPRmt reporters to investigate this effect, and to dissect the details of the two branches of UPRmt signaling. Glial UPRmt induced hormesis as shown through extended lifespan, as well as resistance to the mitochondrial stressor paraquat. This work contributes to the growing field of glia biology and supports the hypothesis that glia are actively involved in information processing and signaling
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Cell non-autonomous control of autophagy, metabolism, and the unfolded protein response of the endoplasmic reticulum by glial cells
No full textGlia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy. Cell non-autonomous signaling of organellar stress response pathways requires the detection of stress, release of a signal, detection of that signal in a separate tissue, and activation of the same stress response pathway in peripheral tissue. Here, I investigate the role of another signaling pathway, TGF-ꞵ, in the cell autonomous and cell non-autonomous signaling pathways of the UPRER, UPRmt, and HSR. Interestingly, I find that knockdown of components in the TGF-ꞵ pathway, specifically the DBL-1/SMA pathway, leads to a myriad of effects on the activation of transcriptional reporters of the UPRER, UPRmt, and HSR
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Olfaction regulates peripheral mitophagy and mitochondrial function
No full textThe central nervous system coordinates peripheral cellular-stress responses, including the unfolded protein response of the mitochondria (UPRMT); however, the contexts for which this regulatory capability evolved is unknown. The UPRMT is upregulated upon pathogenic infection and in metabolic flux, and the olfactory system has been shown to regulate pathogen resistance and peripheral metabolic activity. Therefore, we asked whether the olfactory nervous system in C. elegans controls the UPRMT cell nonautonomously. In Chapter 2, we found that silencing a single inhibitory olfactory neuron pair, AWC, led to robust induction of the UPRMT and reduction of oxidative phosphorylation dependent on serotonin signaling and parkin-mediated mitophagy. Further, AWC ablation confers resistance to the pathogenic bacteria Pseudomonas aeruginosa partially dependent on the UPRMT transcription factor atfs-1, and fully dependent on mitophagy machinery. In Chapter 3, we found that in addition to UPRMT induction, olfaction regulates a distinct pathway that results in a peripheral skn-1-dependent oxidative stress response. Finally, in Chapter 4, we explore a skn-1-dependent starvation resistance phenotype regulated by olfaction. These data illustrate a role for the olfactory nervous system in regulating whole-organism mitochondrial dynamics, cellular-stress responses, and energy homeostasis, perhaps in preparation for postprandial metabolic stress, starvation, or pathogenic infection
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Lipid Homeostasis Is Essential for Endoplasmic Reticulum Protein Quality Control
No full textThe endoplasmic reticulum (ER) is a critical organelle for protein synthesis, protein trafficking, and lipid synthesis. As such, cells have evolved a quality control system known as the ER Unfolded Protein Response (UPRER). Capable of monitoring protein folding and membrane lipid composition to preserve ER homeostasis, the UPRER is crucial for responding to cellular stress brought on by increased metabolic demand, environmental factors, and aging. In this study, we have identified let-767 as an essential gene for ER homeostasis. Through an RNAi screen of lipid droplet associated genes, we found that knockdown of let-767 resulted in reduced lipid droplets, aberrant ER morphology, and compromised UPRER induction, which impacted growth and lifespan. We found that these deficiencies in ER quality were independent of let-767’s previously characterized function in mono-methyl branched chain fatty acid synthesis (mmBCFAs), as supplementation of mmBCFAs did not ameliorate the detrimental phenotypes. However, supplementation of whole animal lysate was able to rescue the lipid droplet depletion, ER morphology, and animal growth, but not the UPRER function. The UPRER induction was instead rescued by reducing the let-767 pathway through knockdown of the upstream transcription factor sbp-1, suggesting accumulation of a potential toxic metabolite within the let-767 pathway. Our results indicate that let-767 may play a more significant role in lipid metabolism than has been previously described and highlight the importance of lipid homeostasis to protein quality control
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