Top PDF Translational Control Mediates Lifespan Extension Due to Dietary Restriction in Drosophila

Translational Control Mediates Lifespan Extension Due to Dietary Restriction in Drosophila

Translational Control Mediates Lifespan Extension Due to Dietary Restriction in Drosophila

transcriptional induction of d4EBP under starvation (Teleman, Chen et al. 2005), we found that dFOXO is not necessary for the induction of the d4EBP protein in the DR conditions where YE is limited but sucrose is kept constant. We found that d4EBP is necessary for full lifespan extension upon DR and that upregulation of activated d4EBP is sufficient to extend the lifespan of the fly on a rich diet. This lifespan extension, from 4EBP overexpression, was correlated with the previously characterized growth inhibition properties of the various 4EBP insertions. Investigation of the metabolic changes upon DR found that there is a shift in metabolism towards metabolite storage that is partially dependent upon d4EBP. Given the role of 4EBP in inhibiting the translation initiation factor eIF4E, these data suggested that modulation of mRNA translation upon DR may alter the lifespan and metabolism of the fly. Investigation of genome-wide translation changes upon DR identified a correlation between mRNA translation changes and 5’UTR secondary structure. Control of mRNA translation by gross 5’UTR secondary structure may represent a novel means of regulating gene expression under nutrient limitation. Such a regulatory mechanism would have the advantage of being faster than
Show more

75 Read more

Translational Control Mediates Lifespan Extension Due to Dietary Restriction in Drosophila

Translational Control Mediates Lifespan Extension Due to Dietary Restriction in Drosophila

transcriptional induction of d4EBP under starvation (Teleman, Chen et al. 2005), we found that dFOXO is not necessary for the induction of the d4EBP protein in the DR conditions where YE is limited but sucrose is kept constant. We found that d4EBP is necessary for full lifespan extension upon DR and that upregulation of activated d4EBP is sufficient to extend the lifespan of the fly on a rich diet. This lifespan extension, from 4EBP overexpression, was correlated with the previously characterized growth inhibition properties of the various 4EBP insertions. Investigation of the metabolic changes upon DR found that there is a shift in metabolism towards metabolite storage that is partially dependent upon d4EBP. Given the role of 4EBP in inhibiting the translation initiation factor eIF4E, these data suggested that modulation of mRNA translation upon DR may alter the lifespan and metabolism of the fly. Investigation of genome-wide translation changes upon DR identified a correlation between mRNA translation changes and 5’UTR secondary structure. Control of mRNA translation by gross 5’UTR secondary structure may represent a novel means of regulating gene expression under nutrient limitation. Such a regulatory mechanism would have the advantage of being faster than
Show more

82 Read more

Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction.

Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction.

Pharmacological treatment with rapamycin, genetic impairments of the mTORC1 complex and reduced S6K activation are all expected to extend lifespan by operating through the same pathway. Indeed, separate manipulations of each of these components have been shown to extend lifespan in the four most popular model organisms in aging research: Saccharomyces cerevisiae (yeast), Caenorhabditis elegans (nematodes), Drosophila melanogaster (flies) and Mus musculus (mice) (Johnson et al., 2013). Although seemingly universal across species, there are several factors that might influence the degree of lifespan extension within and between species. In both mice and flies, manip- ulations of mTOR signalling have been reported as sex dependent, preferentially improving female lifespan over that of males (Bjedov et al., 2010; Miller et al., 2014). In flies, one study reported that rapamycin can decrease lifespan at high concentrations (Harrison et al., 2010), while in mice, lifespan extension has been positively associated with rapamycin concentration (Miller et al., 2014). Different manipulation types (e.g. rapamycin, genetic manipulations of mTORC1 or S6K) may also have physiological effects that influence survival outside of this simplified pathway, leading to possible differences in the degree of lifespan extension: examples include the possible inhibitory effects of rapamycin on mTORC2 (Lamming et al., 2012), and the additional regulatory effects of mTORC1 signalling on translation initiation factors in addition to S6K (Johnson et al., 2013).
Show more

7 Read more

Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression

Coronavirus Infection Modulates the Unfolded Protein Response and Mediates Sustained Translational Repression

We have investigated the UPR during MHV infection. Here, we show that both the IRE1 and ATF6 ␣ pathways are acti- vated during MHV infection; however, only minimal induction of UPR target genes occurs in MHV-infected cells. Further- more, in agreement with the results of previous studies, we show that translation initiation factor eIF2 ␣ is phosphorylated during MHV infection and that the translation of most cellular mRNAs is inhibited. ATF4, which is translated via a transla- tional shunting mechanism in the presence of phosphorylated eIF2 ␣ , is produced during MHV infection, but the expression of its downstream targets, such as CHOP and GADD34, is not realized. Thus, although MHV infection activates the proximal transducers of the UPR, this is not accompanied by the ex- pression of factors necessary to mediate the dephosphorylation of eIF2 ␣ and promote eIF2 ␣ -dependent translation. Interest- ingly, the translation of MHV mRNA occurs in the presence of phosphorylated eIF2 ␣ . Thus, MHV modulates the UPR and circumvents cellular mechanisms of translational control. The implications of these results for understanding how coronavi- ruses optimize viral replication and potentially evade innate defense signaling pathways are discussed.
Show more

10 Read more

Translational plasma stomatology: Applications of cold atmospheric plasmas in dentistry and their extension

Translational plasma stomatology: Applications of cold atmospheric plasmas in dentistry and their extension

The bacterial infection has long been recognised as the primary etiologic factor in the development of caries, pulp and periapical lesions and periodontitis [112]. The biofilms can be built up on the teeth surfaces, and can lead to the dental caries, which is a localised destruction of the tooth tissues by the bacterial fermentation of the dietary carbohydrates, if they are not removed regularly. In dentistry, the purpose of the root canal treatment is to eliminate the infections of the root canal system. On one hand, the endodontic infection is generally a polymicrobial infection of the dental root canal system; on the other hand, it is very difficult to achieve a complete elimination of the biofilms from the root canals using traditional methods, such as the mechanical debridement, chemical irrigation, and ultrasound, because of the complexity of the root canal system [113]. Many publications in recent years have demonstrated that the CAPs have outstanding sterilisation effects on the microorganisms. The possible reasons of the sterilisation ability of the CAPs on bacteria might be that the plasma can destroy the cell membrane, genetic materials and/or protein of the bacterial. The in vitro study by Pan et al. showed that the single- electrode non-thermal DBD plasma jet treatment could rupture the bacteria membrane and destroy the structure of the biofilm [114]. Yang et al. reported the bactericidal effect of a DC argon plasma brush on Streptococcus mutans and Lactobacillus acidophilus, which are the major pathogens in the dental caries [115]. Sun et al. [116] compared the bactericidal efficacy of the plasma treatment of the root canal infected with Enterococcus faecalis biofilms in vitro using two different types of CAPs (glow discharge and DBD). It was found that the DBD plasma had a better bactericidal effect on the bacteria than that using
Show more

12 Read more

Body dissatisfaction, dietary restraint and body image importance in females across the lifespan

Body dissatisfaction, dietary restraint and body image importance in females across the lifespan

In addition, in their 1994 study, Hetherington and Burnett revealed that both younger and older adult women were similar in levels of dietary restraint, suggesting that dietary restraint[r]

82 Read more

Impact of Sleep Extension and Restriction on Children’s Emotional Lability and Impulsivity

Impact of Sleep Extension and Restriction on Children’s Emotional Lability and Impulsivity

used to determine if any psychiatric condition was present. Only children with no reported sleep problems and no behavioral, medical, or academic issues were invited to participate in the study. Eligible participants were told to avoid products containing caf- feine (eg, chocolate or cola) and to avoid napping for the duration of the study. They completed a baseline protocol involving objective sleep eval- uation, employing actigraphy, in the natural home environment for 5 con- secutive nights. On the last day of the baseline period, the participants were randomly assigned (at a 1:1 ratio) to 1 of 2 experimental conditions. These conditions consisted of experimental sleep extension (addition of 1 hour of sleep relative to baseline habitual sleep duration on weekdays) and ex- perimental sleep restriction (elimina- tion of 1 hour of sleep relative to baseline habitual sleep duration on weekdays).
Show more

9 Read more

Dietary restriction, caloric value and the accumulation of hepatic fat

Dietary restriction, caloric value and the accumulation of hepatic fat

When considering food efficiency, meaning the ani- mal’s ability to transform ingested calories into body weight [30,31], animals belonging to the groups sub- jected to dietary restriction showed negative values, which were considered beneficial given that the aim of dietary restriction was to minimise weight gain. When comparing ad libitum groups, the animals that were fed the AIN-93M diet (AD) were more efficient in trans- forming ingested energy into body mass.

7 Read more

Translational Control in Plasmodium and Toxoplasma Parasites

Translational Control in Plasmodium and Toxoplasma Parasites

Comparisons of Plasmodium transcriptomes and proteomes show that gene silencing via translational repression of mRNA is a frequent event during the life cycle. This was first described during development of the parasite’s sexual stages. Male and female ga- metocytes circulate in the blood of the mammalian host. After being ingested by Anopheles mosquitoes, they differentiate into gametes and fertilization takes place in the lumen of the insect midgut. Soon the zygotes transform into the motile ookinetes that leave the hostile proteolytic environment of the lumen and take refuge in the wall of the mosquito stomach. Repression of mRNA translation encoding a surface protein of P. berghei (Pb21) was first documented during sexual development of gametocytes (24– 26). Although the Pb21 mRNA is expressed in female gametocytes circulating in the vertebrate host, the synthesis of Pb21 protein starts only in the insect vector. Posttranscriptional silencing of several additional messages was revealed by comparing transcrip- tomes and proteomes of Plasmodium, suggesting that transla- tional repression is an important regulatory mechanism (27). No- tably, the 3= untranslated regions of several repressed mRNAs contain a nucleotide motif known to bind to Pumilio (Puf) pro- teins, which repress translation and regulate RNA stability (27– 29). The nontranslated mRNAs accumulate in cytoplasmic gran- ules that contain an RNA-binding helicase named DOZI. The central role of DOZI in parasite development was revealed in a DOZI knockout. The mutants progressed normally through the blood cycle, but the complete absence in the female gametocytes led to an arrest of parasite development in mosquitoes (3). Anal- ysis of the cytoplasmic granules in female gametocytes showed that they contain nontranslated mRNAs, eIF4E, and PABP but lack the RNA degradation elements that are characteristic of P bodies in higher eukaryotes (30).
Show more

7 Read more

The STAR/Maxi KH domain protein GLD 1 mediates a developmental switch in
the translational control of C  elegans PAL 1

The STAR/Maxi KH domain protein GLD 1 mediates a developmental switch in the translational control of C elegans PAL 1

specifically precipitated from worm extracts by GRE RNA, and GLD-1 represses the distal germline expression of both PAL- 1 and a GH::2X GRE reporter, without destabilizing the respective mRNAs. GLD-1 could be the only regulator of the GRE, since the GH::2X GRE reporter is ectopically expressed in all distal germline nuclei following gld-1 RNAi, and removal of mex-3 activity in addition to gld-1 activity does not noticeably increase the level of ectopic expression (data not shown). In contrast, repression of full-length pal-1 mRNA may require regulators in addition to GLD-1, as ectopic PAL-1 is detected only in a subset of distal germline nuclei in gld-1 mutants. Moreover, even following reduction of ectopic mex-3 activity through gld-1; mex-3 double RNAi, PAL-1 is still not detected in all nuclei. This apparently incomplete derepression of PAL-1 expression could be due to the failure to eliminate all GLD-1 and MEX-3 protein via double RNAi, or due to the up-regulation of another PAL-1 repressor in the germline of gld-1 (RNAi) worms. Indeed, we found that SPN-4 and MEX- 5/6, which repress PAL-1 expression in embryos, are ectopically expressed in the distal germline following gld-1 RNAi, and they may contribute to PAL-1 repression. Alternatively, there may be additional protein(s) that normally contributes to PAL-1 repression in the distal gonad arm.
Show more

10 Read more

An Extension of Some Results Due to Cox and Leland

An Extension of Some Results Due to Cox and Leland

In the working papers by [18,19], for a given utility function, the Feynman-Kac formula is used to find controls satisfying certain PDEs for utility maximization. We show that the Feynman-Kac formula can generally provide the solution to a control in terms of its terminal value. We also show that the terminal value satisfies some concave utility, without specifying its functional form.

10 Read more

Effects of Formalin Contaminated Food on Reproductive Cycle and Lifespan of Drosophila Melanogaster

Effects of Formalin Contaminated Food on Reproductive Cycle and Lifespan of Drosophila Melanogaster

Five bottles were used and labeling with respective concentrations of formalin (0% [control], 0.1%, 0.25%, 0.5% and 1% formalin). Drosophila were then transferred to an ice pad and put under anaesthesia. Healthy flies were then sorted by gender and separated into males and females. Six males of D. melanogaster were stocked with the same number of females in each bottle. The culture medium was used as substrate for feeding. Parents were removed from culture bottles after 4 days. New generation initiated its emergence after nine to twelve days from the start of the experiment (F 1 ).
Show more

6 Read more

Anti-Oxidative Effect of Murraya Koenigii That Prolongs the Lifespan of Drosophila Melanogaster

Anti-Oxidative Effect of Murraya Koenigii That Prolongs the Lifespan of Drosophila Melanogaster

other Asian countries. It is locally dilects known as curry leaf or meetha neem plant due to presence of pleasant aromatic smell, ornament creature and also used as a spicing flavoring agent for various food and home made preparations. The leaves have somewhat pungent, bitter and weakly acidulous taste and these characteristics retained after drying. M. koenigii in India used as herb in Ayurvedic medicine preparations. Leaves and roots can be used to cure piles and relieve heat of the body, dehydration, tenderness and itching. It has been reported previously that much valued as an anti-diabetic, antioxidant, antifungal, antimicrobial, cytotoxic properties, anti inflammatory, antitumor promoting, anti-hypercholesterolemic, kidney painrelief, hepatoprotective activities. Murraya koenigii is recognized to be the good source of carbazole alkaloids. The other phytochemicals isolated and characterized so far from the leaves are alkaloids such as mahanine, koenine, koenigine, koenidine, girinimbiol, girinimibine, koenimbine, O-methyl murrayamine A, O-methyl mahanine, isomahanine, bismahanine, bispyrayafoline and rich source of iron. It is also reported to contain 5,8- dimethylfuranocoumarin, 1-al, 3[6’, 6’ dimethyl 5-hexene] carbazole and β-sitosterol [2-4].
Show more

5 Read more

Extension of a quadratic transformation due to Whipple with an application

Extension of a quadratic transformation due to Whipple with an application

The aim of this research is twofold. First, by utilizing the extension of Saalschütz’s sum- mation theorem (.), we obtain a natural extension of Whipple’s transformation (.). Then, by employing the beta integral method, we obtain a new hypergeometric identity. The results derived in this paper are simple, easily established and may be potentially use- ful.

8 Read more

Oxidative stress mediates tau induced neurodegeneration in Drosophila

Oxidative stress mediates tau induced neurodegeneration in Drosophila

How might increased levels of oxidative stress enhance tau neuro- toxicity? Given the importance of tau phosphorylation in promot- ing neurotoxicity (Steinhilb et al., unpublished observations; refs. 28, 29, 34, 35, 49), we first determined whether oxidative damage could influence tau phosphorylation. Our analysis suggests that oxidative stress does not act by promoting tau phosphorylation at major disease-associated sites because phosphorylation of tau is not altered in contexts of exacerbated oxidative stress (Figure 5A). Additionally, increased levels of oxidative stress can significantly enhance neurodegeneration associated with a kinase insensitive form of tau that is pseudophosphorylated at 14 SP/TP sites (Figure 5B). These observations support a model in which oxidative dam- age acts downstream of tau phosphorylation to promote neurotox- icity. Alternatively, oxidative damage generated in a tau-indepen- dent manner may synergize with phosphorylated tau to enhance neurotoxicity. It is well established that oxidative damage accumu- lates in the aging brain and as a result of excitotoxicity in degenera- tive disease states (2, 50). Moreover, we show that tau transgenic flies are significantly more vulnerable to the free radical generator paraquat than control flies (Figure 4), indicating that tau overex- pression hypersensitizes Drosophila to oxidative injury. Therefore, a time-dependent buildup of oxidative damage in the brain, caused by aging or by a pathological condition, may act in concert with phosphorylated tau to promote neurodegeneration. Determining whether oxidative stress influences other aspects of tau biochemis- try, including aggregation, will require further investigation.
Show more

11 Read more

Lifespan and oxidative stress show a non linear response to atmospheric oxygen in Drosophila

Lifespan and oxidative stress show a non linear response to atmospheric oxygen in Drosophila

Organisms exhibit many physiological and developmental responses to changes in atmospheric oxygen level. Physiological responses include variation in ventilation and behavior, and changes at the molecular level. Many insects respond to variation in atmospheric oxygen level by varying the degree of spiracular opening, convective ventilation, and/or the level of fluid in the tracheoles (Harrison et al., 2006). It was recently proposed that discontinuous gas exchange in insects, a cyclical respiratory pattern characterized by three spiracular phases (closed, flutter, open), may function primarily to maintain low internal P O2 levels to prevent oxidative damage (Hetz and Bradley, 2005). Although Drosophila do not breathe discontinuously, they can alter convective oxygen delivery (Lehmann et al., 2000). Further, hypoxic exposure during development causes the induction of Hypoxia Inducible Factor (HIF), a transcription factor that mediates a variety of responses to hypoxia including tracheal proliferation and cell growth (Centanin et al., 2008; Lavista-Llanos et al., 2002).
Show more

8 Read more

Mito-Nuclear Interactions Affecting Lifespan and Neurodegeneration in a Drosophila Model of Leigh Syndrome

Mito-Nuclear Interactions Affecting Lifespan and Neurodegeneration in a Drosophila Model of Leigh Syndrome

pulmonary, cardiac, metabolic). The cellular and molecular mechanisms responsible for this clinical variability are not fully understood. Here, we demonstrate that the shortened lifespan and neurodegeneration in ND23 mutants can be substantially rescued by expression of wild-type ND23 in neurons, but not in glia. Thus, ND23 dysfunction in the nervous system, and specifically in neurons rather than glia, is responsible for much of the neurodegeneration and early death. This is likely due to the increased energy demands of the nervous system, particularly neurons, compared with glia and other tissues, which may explain why glia can sur- vive without the citric acid cycle, using only glycolysis to satisfy their energy demands, whereas neurons cannot (Volkenhoff et al. 2015). Furthermore, our data suggests that although brain lesions in Leigh syndrome are often accompanied by demyelination, this is not a direct conse- quence of ND23 defects within glia, but instead a compli- cation from disrupted homeostasis from compromised neurons. However, the fact that ubiquitous expression of wild-type ND23 provides a somewhat greater degree of res- cue (of both lifespan and neurodegeneration) than neuro- nal-specific rescue suggests that ND23 dysfunction may also have important phenotypic consequences in cells other than neurons. Although a variety of cells that support nervous system function could be impaired, the most likely candi- dates are glia. Alternatively, the somewhat greater degree of rescue seen with ubiquitous expression of wild-type ND23
Show more

18 Read more

Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges

Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges

attractive for preventing dementia and geriatric cognitive disorders. Brain aging predisposes to neurodegeneration via several mechanisms that in part converge on dysreg- ulation of redox-state and inflammatory pathways. From the topics discussed above, light and shade rise on the effects of phytochemicals on human brain health. How- ever, even though experimental findings have not always translated to a definitive clinical effect, the antioxidant and anti-inflammatory properties of phytochemicals have been widely accepted. Despite the abundance of the litera- ture in this field, a clearer understanding of the mecha- nisms of action of phytochemicals as modulators of cell signalling pathways involved in neuro-inflammaging play a pivotal role for the evaluation of these molecules in short-term or long-term nutritional intervention trials. Furthermore, the preventive effects of phytochemicals on the onset of neurodegenerative conditions still needs to be critically explored. Many dietary supplements containing phytochemicals are already commercially available and marketed to prevent or ameliorate specific diseases, in- cluding age-related cognitive decline. The majority of these products are not substantiated by solid scientific evi- dence and have not yet been approved by the EFSA and/ or FDA. For instance, it is unclear the concentrations of phytochemicals that enter the bloodstream and cross the blood-brain barrier. Although delivery systems, such as nanoparticles, might represent a successful strategy for drug delivery into CNS, the bioavailability continues to be highlighted as a major concern in human intervention studies. The quality of the compounds is another major source of variability and conflicting results. A further chal- lenge is to understand whether dietary phytochemicals have appropriate effects on specific epigenetic mecha- nisms in specific genes or sets of genes. Brain aging is in- deed associated with substantial changes in epigenetic profiles and several preclinical studies have revealed that bioactive phytochemicals play an important role in the modulation of overall epigenetic modifications (histone modifications, DNA methylations and microRNA). An- other limitation to the clinical application of these compounds is the lack of knowledge on questions concerning the complex metabolic fate of dietary phy- tochemicals, the role of the gut microbiota in the bioconversion of phytochemicals, and whether the bac- terial transformations produce metabolites with in- creased biological activity. Future studies addressing these issues are needed. Observational studies and diet- ary intervention trials in large cohorts of healthy subjects are essential to evaluate whether these phyto- chemicals can help to prevent age-related neurodegener- ative disorders.
Show more

17 Read more

Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

LDL-C and of triglyceride-rich lipoproteins to HDL-C and LDL-C [39], thereby providing a mechanistic link to explain the triglyceride lowering and remodeling effects of LDL and HDL observed with low CHO diets [22,40]. Sev- eral studies have linked polymorphisms in the CETP gene to lipoprotein responses and risk for cardiovascular dis- ease, and it has been hypothesized that these relations may be altered by weight loss [41]. Our study is the first study to show an association of a polymorphism in CETP gene to weight loss. The finding suggests that the weight loss response to CHO restriction may be mechanistically linked to the intravascular processing of lipoproteins. Hormonal regulation of food intake was hypothesized to be one mechanism by which CHO restricted diets affect weight loss. We examined polymorphisms in galanin, neuropeptide Y, and ghrelin. Galanin was the only hor- mone significantly associated with weight loss. Galanin stimulates food consumption, particularly fat intake. A prior study that measured polymorphisms in galanin failed to find an association with fat intake or obesity [42]. Prior work has shown that galanin in the para-ventricular nucleus is stimulated by a fat feeding and increased circu- LOESS plots for six lipase genes listed in order of genetic association significance, as follows: LIPF gastric lipase, LIPC hepatic lipase, LIPG endothelial lipase, LIPE hormone-sensitive lipase, LPL lipoprotein lipase, LIPA lipase A lysosomal acid
Show more

10 Read more

Substitution Rates in Drosophila Nuclear Genes: Implications for Translational Selection

Substitution Rates in Drosophila Nuclear Genes: Implications for Translational Selection

represent the range observed in the sampled Drosophila very different relationship between synonymous rate genes. In total, 56 pairs of sequences were simulated, each 1 and codon usage bias as compared with all previous million codons in length. d S and d N were estimated for each pair of sequences using both ML and NG methods. The studies. A simulation study was thus conducted to investi-

11 Read more

Show all 10000 documents...