1) Rapamycin treatment significantly increased survival and delayed disease progression in a mouse model of Leigh syndrome (mitochondrial disease) that was deficient in the Ndufs4 gene.
2) Rapamycin treated mice did not develop neurological lesions in the brain that were present in untreated mice, and had reduced neurological symptoms and inflammation.
3) While rapamycin did not improve mitochondrial function directly, it induced metabolic changes in the mice including increased amino acid catabolism and decreased glycolysis, which helped alleviate symptoms of the mitochondrial disease.
This document is a thesis examining the effects of recombinant adeno-associated viral arginase 1 in transgenic mice with tau pathology. The introduction discusses Alzheimer's disease and tauopathies, L-arginine metabolism and associated pathways, and the mouse model used. The goal was to identify the effects of overexpressing arginase 1 in hippocampal neurons using viral vectors in this mouse model. Histological experiments included staining for various proteins and markers to analyze the effects.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Cre recombinase expression in cardiomyocytes using the αMHC-MerCreMer mouse model induces dose-dependent cardiac toxicity and lethality when higher doses of tamoxifen are used to increase recombination efficiency. Moderate and high tamoxifen doses caused heart failure and death in the mice through a DNA damage response leading to cardiomyocyte apoptosis and fibrosis. Lower tamoxifen doses achieved near maximal 80% recombination rates without toxicity. The optimal dose for recombination while minimizing effects was determined to be 30 μg tamoxifen/g body weight injected over three days. The study provides insights into the cellular mechanisms of cardiac Cre toxicity and an improved protocol for the αMHC-MerCreMer system.
This document summarizes a study that investigated the effects of icariin, a compound found in Herba epimedii, on male reproductive functions in rats. The study found that 100 mg/kg of icariin significantly increased epididymal sperm counts and testosterone levels. Gene expression analysis suggested icariin may increase testosterone production by regulating mRNA expression of genes involved in steroidogenesis like PBR and StAR. Doses of 50-100 mg/kg also improved antioxidant capacity in the testes, while 200 mg/kg increased oxidative stress. The results indicate icariin can benefit reproductive functions within a certain dose range but higher doses may cause damage through increased oxidative stress.
This document summarizes research on the physiological properties and potential health benefits and risks of exogenous melatonin supplementation. It discusses melatonin's role as an antioxidant and its potential anticancer, circadian rhythm regulating, and neuroprotective effects. However, it also notes that early morning melatonin administration may impair psychomotor performance and vigilance. More research is still needed to fully understand melatonin's long-term impacts and benefits, especially regarding cancer treatments and effects on memory.
1. The first study found that Sirt1 protein plays an important role in longevity and aging by deacetylating the Nkx2-1 protein, enhancing its activity and expression of its target gene Ox2r. This stimulates skeletal muscle function, allowing optimal mitochondrial function and delaying aging.
2. The second study showed that Sirt1 upregulates PGC-1α, a transcriptional coactivator involved in energy metabolism and mitochondrial biogenesis. Sirt1 positively regulates PGC-1α through interaction with MyoD. This pathway aids understanding of Sirt1's role in gene expression and potential regulation of aging.
3. The third study found that high-intensity interval training in humans
Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Syn...Balogun Wasiu Gbolahan
This study investigated the effects of elevated brain magnesium on cognitive deficits and synaptic loss in an Alzheimer's disease mouse model. The study found that elevating brain magnesium levels through supplementation prevented and reversed cognitive impairment and synaptic loss in transgenic Alzheimer's mouse models. Specifically, magnesium treatment prevented learning and memory deficits, preserved synapse density, and reversed impairments in NMDA receptor signaling pathways involved in learning and memory. The treatment also reduced amyloid plaque levels and decreased expression of the amyloid precursor protein cleaving enzyme BACE1. The results suggest elevated brain magnesium as a potential therapeutic approach for Alzheimer's disease.
This review article discusses recent research on the role of SIRT1 in longevity. SIRT1 is a protein that regulates gene expression and cellular stress response through deacetylation of target proteins like PGC-1α and FOX proteins. While some studies have linked SIRT1 overexpression in the hypothalamus to longevity, the evidence is controversial. The article summarizes recent studies investigating the tissue-specific effects of SIRT1 overexpression and how factors like aging, exercise and calorie restriction may upregulate SIRT1 activity in different tissues to influence longevity.
This document is a thesis examining the effects of recombinant adeno-associated viral arginase 1 in transgenic mice with tau pathology. The introduction discusses Alzheimer's disease and tauopathies, L-arginine metabolism and associated pathways, and the mouse model used. The goal was to identify the effects of overexpressing arginase 1 in hippocampal neurons using viral vectors in this mouse model. Histological experiments included staining for various proteins and markers to analyze the effects.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Cre recombinase expression in cardiomyocytes using the αMHC-MerCreMer mouse model induces dose-dependent cardiac toxicity and lethality when higher doses of tamoxifen are used to increase recombination efficiency. Moderate and high tamoxifen doses caused heart failure and death in the mice through a DNA damage response leading to cardiomyocyte apoptosis and fibrosis. Lower tamoxifen doses achieved near maximal 80% recombination rates without toxicity. The optimal dose for recombination while minimizing effects was determined to be 30 μg tamoxifen/g body weight injected over three days. The study provides insights into the cellular mechanisms of cardiac Cre toxicity and an improved protocol for the αMHC-MerCreMer system.
This document summarizes a study that investigated the effects of icariin, a compound found in Herba epimedii, on male reproductive functions in rats. The study found that 100 mg/kg of icariin significantly increased epididymal sperm counts and testosterone levels. Gene expression analysis suggested icariin may increase testosterone production by regulating mRNA expression of genes involved in steroidogenesis like PBR and StAR. Doses of 50-100 mg/kg also improved antioxidant capacity in the testes, while 200 mg/kg increased oxidative stress. The results indicate icariin can benefit reproductive functions within a certain dose range but higher doses may cause damage through increased oxidative stress.
This document summarizes research on the physiological properties and potential health benefits and risks of exogenous melatonin supplementation. It discusses melatonin's role as an antioxidant and its potential anticancer, circadian rhythm regulating, and neuroprotective effects. However, it also notes that early morning melatonin administration may impair psychomotor performance and vigilance. More research is still needed to fully understand melatonin's long-term impacts and benefits, especially regarding cancer treatments and effects on memory.
1. The first study found that Sirt1 protein plays an important role in longevity and aging by deacetylating the Nkx2-1 protein, enhancing its activity and expression of its target gene Ox2r. This stimulates skeletal muscle function, allowing optimal mitochondrial function and delaying aging.
2. The second study showed that Sirt1 upregulates PGC-1α, a transcriptional coactivator involved in energy metabolism and mitochondrial biogenesis. Sirt1 positively regulates PGC-1α through interaction with MyoD. This pathway aids understanding of Sirt1's role in gene expression and potential regulation of aging.
3. The third study found that high-intensity interval training in humans
Elevation of Brain Magnesium Prevents and Reverses Cognitive Deficits and Syn...Balogun Wasiu Gbolahan
This study investigated the effects of elevated brain magnesium on cognitive deficits and synaptic loss in an Alzheimer's disease mouse model. The study found that elevating brain magnesium levels through supplementation prevented and reversed cognitive impairment and synaptic loss in transgenic Alzheimer's mouse models. Specifically, magnesium treatment prevented learning and memory deficits, preserved synapse density, and reversed impairments in NMDA receptor signaling pathways involved in learning and memory. The treatment also reduced amyloid plaque levels and decreased expression of the amyloid precursor protein cleaving enzyme BACE1. The results suggest elevated brain magnesium as a potential therapeutic approach for Alzheimer's disease.
This review article discusses recent research on the role of SIRT1 in longevity. SIRT1 is a protein that regulates gene expression and cellular stress response through deacetylation of target proteins like PGC-1α and FOX proteins. While some studies have linked SIRT1 overexpression in the hypothalamus to longevity, the evidence is controversial. The article summarizes recent studies investigating the tissue-specific effects of SIRT1 overexpression and how factors like aging, exercise and calorie restriction may upregulate SIRT1 activity in different tissues to influence longevity.
L'idrossitirosolo è in grado di proteggere e aumentare l'attività dei mitocon...CreAgri Europe
L'idrossitirosolo, un polifenolo estratto dalle olive, attraverso una protezione dei mitocondri, le centrali energetiche della cellula, è in grado di aumentare la resistenza muscolare negli animali da esperimento
1) The document discusses recent research on the regulation of human skeletal muscle protein metabolism by exercise, amino acids, and aging.
2) It finds that resistance exercise increases muscle protein synthesis through activating mTORC1 signaling pathways, and that blood flow restriction exercise can provide similar benefits to high intensity resistance exercise.
3) Aging is associated with an impaired ability of muscle to respond to anabolic stimuli like resistance exercise, but blood flow restriction exercise may help overcome this impairment in older adults.
4) Essential amino acid ingestion, especially leucine, can stimulate muscle protein synthesis through mTORC1 signaling, and combining amino acids with resistance exercise enhances this response.
Sequence Characterization of Coding Regions of the Myostatin Gene (GDF8) from...Wani Ahad
The Bakerwal breed of goat in Kashmir valley is a good meat purpose breed of goat. That attains
an appreciable body weight under a low input production system. As these goats are mainly
reared by Gujjar and Bakarwal tribes of the J & K state, so they usually are fed with the weeds,
herbs, shrubs and grasses of pastures that will otherwise go waste. These goats constitute the
main livestock wealth. With the good productive and reproductive potential, it makes these animals
an important animal protein source for developing countries like India. The myostatin gene
(GDF8) is important in the physiology of stock animals because its product produces a direct effect
on muscle development and consequently also on meat production. The myostatin sequence is
known in several mammalian species and shows a high degree of amino acid sequence conservation,
although several alterations in the intron and exon regions have been identified. The objective
of our work is to characterize the myostatin coding regions using gene sequencing and polymerase
chain reaction methods of Capra hircus (Bakerwal breed) and to compare them with the
Ovis aries and other livestock species of animal, looking for variations in nucleotide and protein
sequences. As mutations in the myostatin gene can inactivate its expression and result in a
non-functional protein, which leads to increase in muscle growth in many species. In this way, we are able to identify 3 alterations on the presumed myostatin protein sequence as compared to non
double-muscled ovine sequences.
From Pregnancy to Menopause: Studies of Physical Activity, Behavior, and Ener...InsideScientific
Join Sharon Ladyman, PhD and Vicki Vieira-Potter, PhD as they present applications of rodent metabolic phenotyping with a focus on the effects of hormones and pregnancy on daily activity in mice.
A reduction in voluntary physical activity during pregnancy in mice is mediated by prolactin
Sharon Ladyman, PhD
Pregnancy is an energetically demanding challenge for the mother and as such, pregnant females undergo numerous metabolic adaptations to meet these demands, including increased food intake and a rapid lowering of energy expenditure and physical activity levels. A particularly striking example is a profound reduction in voluntary running wheel activity (RWA) that occurs as soon as mice become pregnant. We hypothesized that prolactin, one of the first hormones to increase in response to mating in rodents, drives the pregnancy-induced suppression of physical activity levels.
Neuronal and Metabolic Pathways Influenced by Sex Hormones
Vicki Vieira-Potter, PhD
Estrogen-sufficient females are more physically active than males and are protected against adipose tissue and systemic metabolic dysfunction. The mechanisms are not fully understood, but we demonstrate that ovarian removal causes significant mRNA changes in the nucleus accumbens (NAc) brain region (i.e., the reward center), which correlate significantly with physical inactivity. We hypothesize that sex differences in the NAc may help explain differences in physical activity and metabolism.
This document summarizes a presentation on a study investigating the role of MED13 and Wingless signaling in muscle on obesity in Drosophila. The study found that knocking down MED13 or its downstream target Wingless in muscle tissue led to increased fat accumulation and triglyceride levels. Overexpressing Wingless in muscle suppressed obesity. Genetic interaction experiments supported Wingless acting downstream of MED13 in muscle to regulate obesity by signaling to fat tissue. The findings reveal a conserved MED13-Wingless signaling pathway in muscle that controls whole-body energy homeostasis and protects against obesity.
Corticosteroid induced disorders – an overviewpharmaindexing
This document provides an overview of corticosteroid-induced disorders and adverse effects. It discusses the mechanism of action of corticosteroids and their effects on muscle, including causing muscle atrophy primarily through increased protein breakdown and inhibition of protein synthesis. It also mentions other corticosteroid-induced disorders like osteoporosis, glaucoma, diabetes, psychosis, and Cushing's syndrome. Prevention of corticosteroid-induced muscle atrophy through growth factors, amino acids, glutamine, taurine, and creatine is also summarized.
The study investigated the effects of estrogen treatment on metabolic enzyme activities in the brains of ovariectomized female rats. Rats were implanted with low or high dose estrogen pellets and enzyme activities were examined in different brain areas. The decline in enzyme activities caused by ovariectomy was reversed by estrogen treatment, which upregulated enzymes of glycolysis and oxidative phosphorylation. This suggests estrogen promotes cellular metabolism and these beneficial effects may provide treatment strategies for age-related neurological disorders in females.
This study identifies the zinc transporter ZIP4 as mediating tissue plasminogen activator (tPA)'s ability to promote zinc uptake into neurons in a neuroprotective manner. ZIP4 expression is increased after excitotoxin stimulation in mouse hippocampus. ZIP4 physically interacts with tPA, leading to increased intracellular zinc sequestration in lysosomes. This sequestration protects neurons from the toxic effects of excessive extracellular zinc levels released during seizures or excitotoxicity.
This study investigated the effects of ingesting an essential amino acid supplement with or without leucine following resistance exercise in young females. The following key points were summarized:
1) Phosphorylation of mTOR and p70S6k, markers of muscle protein synthesis, were higher one hour after exercise when subjects ingested a supplement containing leucine compared to one without leucine.
2) Plasma and muscle concentrations of tyrosine and total essential amino acids were lower during recovery when subjects ingested the supplement containing leucine.
3) The presence of leucine in the supplement enhanced the stimulatory effect on mTORC1 signaling and protein synthesis following resistance exercise.
dkNET Webinar: A New Approach to the Study of Energy Balance and Obesity usin...dkNET
Abstract
We report a web-based tool for analysis of experiments using indirect calorimetry to measure physiological energy balance. CalR simplifies the process to import raw data files, generate plots, and determine the most appropriate statistical tests for interpretation. Analysis using the generalized linear model (which includes ANOVA and ANCOVA) allows for flexibility in interpreting diverse experimental designs, including those of obesity and thermogenesis. Users also may produce standardized output files for an experiment that can be shared and subsequently re-evaluated using CalR. This framework will provide the transparency necessary to enhance consistency, rigor, and reproducibility. The CalR analysis software will greatly increase the speed and efficiency with which metabolic experiments can be organized, analyzed per accepted norms, and reproduced and has become a standard tool for the field. CalR is accessible at https://CalRapp.org/
The top 4 key questions that our tool can answer:
1. Can I reproducibly and transparently analyze indirect calorimetry experiments in under 10 minutes?
2. How hard is it to use Analysis of Covariance (ANCOVA) to determine whether my groups of animals are significantly different?
3. Is there an automated, reproducible way to exclude “noisy” outlier data from our indirect calorimetry experiments?
4. What are the key factors in determining metabolic rate of mice?
Presenter: Alexander Banks, PhD, principal investigator and assistant professor at Harvard Medical School and the Beth Israel Deaconess Medical Center.
dkNET Webinar Information: https://dknet.org/about/webinar
This document discusses potential biomarkers for cancer risk based on estrogen metabolism. It describes how estrogens like estrone and estradiol are metabolized into catechol estrogens that can form quinones and react with DNA. Specific estrogen metabolites, conjugates, and DNA adducts are proposed as possible early biomarkers for breast, prostate, and other cancers. Methods for analyzing estrogens and their metabolites in tissues and blood are also reviewed, with some studies finding higher levels of certain metabolites in cancer patients.
Rodent Models of Pharmacotherapy and Chronotherapy for Obesity and Cardiometa...InsideScientific
Experts discuss research into combating obesity through new therapies targeting mitochondrial bioenergetics. One expert presents research on BAM15, a mitochondrial uncoupler. Studies in mice found BAM15 was well-tolerated and effective at preventing weight gain and improving glycemic control by increasing energy expenditure without altering food intake. BAM15 activated AMPK signaling, increased fatty acid oxidation in muscle, and restricted adipose tissue expansion, reducing obesity and related diseases without safety concerns. The research provides evidence that mitochondrial uncoupling may be a promising strategy for obesity treatment by increasing calorie burning through non-shivering thermogenesis.
Sex, Drugs, and Bad Choices: Modeling Human Decision Making in RatsInsideScientific
To learn more and watch the webinar, go to:
https://insidescientific.com/webinar/sex-drugs-and-bad-choices-modeling-human-decision-making-in-rats/
Nearly every aspect of life involves decisions between options that differ in both their expected rewards and the potential costs (such as delay to reward delivery or risk of harm) that accompany those rewards. The ability to choose adaptively when faced with such decisions is critical for well-being and overall quality of life; however, decision making is often compromised in neuropsychiatric conditions such as substance use disorders, which can prolong and exacerbate their severity and co-morbidities.
During this webinar, Dr. Barry Setlow discusses research in rodent models investigating behavioral and biological mechanisms of cost-benefit decision making. In particular, he focuses on factors (including sex) that contribute to differences in cost-benefit decision making across the population, how variability in decision making is related to substance use, and how substance use can produce long-lasting alterations in decision making. It is hoped that a better understanding of these relationships may lead to new therapeutic approaches for neuropsychiatric conditions characterized by maladaptive decision making.
Key Topics Include:
- Understand how different forms of cost-benefit decision making can be modeled in rats
- Understand the contributions of gonadal hormones to sex differences in cost-benefit decision making
- Understand the lasting effects of chronic cocaine on cost-benefit decision making
This document summarizes a study investigating the role of Set1-mediated histone H3 lysine 4 (H3K4) methylation in Saccharomyces cerevisiae survival under histidine starvation conditions. The study found that mono-methylation of H3K4 by Set1 is advantageous for optimal growth under these stressful conditions. New Set1 mutant strains, including ones capable of only mono-methylation or hyper methylation, were constructed to further examine the role of H3K4 methylation levels.
1) The document discusses Tay-Sachs disease (TSD), a neurodegenerative lysosomal storage disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A deficiency and GM2 ganglioside accumulation.
2) Accumulation of GM2 gangliosides is thought to trigger apoptosis, inflammation and synaptic dysfunction, though the specific mechanisms are unclear.
3) The author proposes a potential new therapeutic strategy for TSD involving silencing the GM2 activator protein to prevent GM2 transport to lysosomes and accumulation, combined with anti-inflammatory drugs. This approach aims to address current issues in understanding TSD pathogenesis and improving patient outcomes.
This study investigated the effects of cartilage oligomeric matrix protein (COMP) on gene and protein expression in human vascular smooth muscle cells. The researchers found that exposing the cells to COMP significantly upregulated the expression of four genes implicated in peripheral arterial disease: ANGPTL4, IL-8, IL-12A, and THBS2. The purpose of the study was to determine the effects of COMP on the expression of Group B thrombospondin genes and proteins as well as several other proteins. The researchers hypothesized that COMP would upregulate specific genes and proteins. They used qrt-PCR and quantitative immunoassays to analyze gene and protein expression changes in response to COMP exposure.
Mr. Payne's classroom has big goals for student achievement, clear behavior expectations, and organized classroom systems. The classroom promotes cooperation through discussion norms and conflict resolution. Relationship building occurs through student government campaigns and smaller class groups. Student work is showcased and the class website provides family involvement and resources. Community is built through discussions on social justice and contributions to local organizations.
It Starts with Analytics: How to Drive Better ROI for Your Recruitment Market...SmashFly Technologies
SmashFly's Chief Product Officer and Bright House Network's Senior Director of Talent Acquisition and Diversity talk recruitment marketing ROI and the specific metrics to define success.
L'idrossitirosolo è in grado di proteggere e aumentare l'attività dei mitocon...CreAgri Europe
L'idrossitirosolo, un polifenolo estratto dalle olive, attraverso una protezione dei mitocondri, le centrali energetiche della cellula, è in grado di aumentare la resistenza muscolare negli animali da esperimento
1) The document discusses recent research on the regulation of human skeletal muscle protein metabolism by exercise, amino acids, and aging.
2) It finds that resistance exercise increases muscle protein synthesis through activating mTORC1 signaling pathways, and that blood flow restriction exercise can provide similar benefits to high intensity resistance exercise.
3) Aging is associated with an impaired ability of muscle to respond to anabolic stimuli like resistance exercise, but blood flow restriction exercise may help overcome this impairment in older adults.
4) Essential amino acid ingestion, especially leucine, can stimulate muscle protein synthesis through mTORC1 signaling, and combining amino acids with resistance exercise enhances this response.
Sequence Characterization of Coding Regions of the Myostatin Gene (GDF8) from...Wani Ahad
The Bakerwal breed of goat in Kashmir valley is a good meat purpose breed of goat. That attains
an appreciable body weight under a low input production system. As these goats are mainly
reared by Gujjar and Bakarwal tribes of the J & K state, so they usually are fed with the weeds,
herbs, shrubs and grasses of pastures that will otherwise go waste. These goats constitute the
main livestock wealth. With the good productive and reproductive potential, it makes these animals
an important animal protein source for developing countries like India. The myostatin gene
(GDF8) is important in the physiology of stock animals because its product produces a direct effect
on muscle development and consequently also on meat production. The myostatin sequence is
known in several mammalian species and shows a high degree of amino acid sequence conservation,
although several alterations in the intron and exon regions have been identified. The objective
of our work is to characterize the myostatin coding regions using gene sequencing and polymerase
chain reaction methods of Capra hircus (Bakerwal breed) and to compare them with the
Ovis aries and other livestock species of animal, looking for variations in nucleotide and protein
sequences. As mutations in the myostatin gene can inactivate its expression and result in a
non-functional protein, which leads to increase in muscle growth in many species. In this way, we are able to identify 3 alterations on the presumed myostatin protein sequence as compared to non
double-muscled ovine sequences.
From Pregnancy to Menopause: Studies of Physical Activity, Behavior, and Ener...InsideScientific
Join Sharon Ladyman, PhD and Vicki Vieira-Potter, PhD as they present applications of rodent metabolic phenotyping with a focus on the effects of hormones and pregnancy on daily activity in mice.
A reduction in voluntary physical activity during pregnancy in mice is mediated by prolactin
Sharon Ladyman, PhD
Pregnancy is an energetically demanding challenge for the mother and as such, pregnant females undergo numerous metabolic adaptations to meet these demands, including increased food intake and a rapid lowering of energy expenditure and physical activity levels. A particularly striking example is a profound reduction in voluntary running wheel activity (RWA) that occurs as soon as mice become pregnant. We hypothesized that prolactin, one of the first hormones to increase in response to mating in rodents, drives the pregnancy-induced suppression of physical activity levels.
Neuronal and Metabolic Pathways Influenced by Sex Hormones
Vicki Vieira-Potter, PhD
Estrogen-sufficient females are more physically active than males and are protected against adipose tissue and systemic metabolic dysfunction. The mechanisms are not fully understood, but we demonstrate that ovarian removal causes significant mRNA changes in the nucleus accumbens (NAc) brain region (i.e., the reward center), which correlate significantly with physical inactivity. We hypothesize that sex differences in the NAc may help explain differences in physical activity and metabolism.
This document summarizes a presentation on a study investigating the role of MED13 and Wingless signaling in muscle on obesity in Drosophila. The study found that knocking down MED13 or its downstream target Wingless in muscle tissue led to increased fat accumulation and triglyceride levels. Overexpressing Wingless in muscle suppressed obesity. Genetic interaction experiments supported Wingless acting downstream of MED13 in muscle to regulate obesity by signaling to fat tissue. The findings reveal a conserved MED13-Wingless signaling pathway in muscle that controls whole-body energy homeostasis and protects against obesity.
Corticosteroid induced disorders – an overviewpharmaindexing
This document provides an overview of corticosteroid-induced disorders and adverse effects. It discusses the mechanism of action of corticosteroids and their effects on muscle, including causing muscle atrophy primarily through increased protein breakdown and inhibition of protein synthesis. It also mentions other corticosteroid-induced disorders like osteoporosis, glaucoma, diabetes, psychosis, and Cushing's syndrome. Prevention of corticosteroid-induced muscle atrophy through growth factors, amino acids, glutamine, taurine, and creatine is also summarized.
The study investigated the effects of estrogen treatment on metabolic enzyme activities in the brains of ovariectomized female rats. Rats were implanted with low or high dose estrogen pellets and enzyme activities were examined in different brain areas. The decline in enzyme activities caused by ovariectomy was reversed by estrogen treatment, which upregulated enzymes of glycolysis and oxidative phosphorylation. This suggests estrogen promotes cellular metabolism and these beneficial effects may provide treatment strategies for age-related neurological disorders in females.
This study identifies the zinc transporter ZIP4 as mediating tissue plasminogen activator (tPA)'s ability to promote zinc uptake into neurons in a neuroprotective manner. ZIP4 expression is increased after excitotoxin stimulation in mouse hippocampus. ZIP4 physically interacts with tPA, leading to increased intracellular zinc sequestration in lysosomes. This sequestration protects neurons from the toxic effects of excessive extracellular zinc levels released during seizures or excitotoxicity.
This study investigated the effects of ingesting an essential amino acid supplement with or without leucine following resistance exercise in young females. The following key points were summarized:
1) Phosphorylation of mTOR and p70S6k, markers of muscle protein synthesis, were higher one hour after exercise when subjects ingested a supplement containing leucine compared to one without leucine.
2) Plasma and muscle concentrations of tyrosine and total essential amino acids were lower during recovery when subjects ingested the supplement containing leucine.
3) The presence of leucine in the supplement enhanced the stimulatory effect on mTORC1 signaling and protein synthesis following resistance exercise.
dkNET Webinar: A New Approach to the Study of Energy Balance and Obesity usin...dkNET
Abstract
We report a web-based tool for analysis of experiments using indirect calorimetry to measure physiological energy balance. CalR simplifies the process to import raw data files, generate plots, and determine the most appropriate statistical tests for interpretation. Analysis using the generalized linear model (which includes ANOVA and ANCOVA) allows for flexibility in interpreting diverse experimental designs, including those of obesity and thermogenesis. Users also may produce standardized output files for an experiment that can be shared and subsequently re-evaluated using CalR. This framework will provide the transparency necessary to enhance consistency, rigor, and reproducibility. The CalR analysis software will greatly increase the speed and efficiency with which metabolic experiments can be organized, analyzed per accepted norms, and reproduced and has become a standard tool for the field. CalR is accessible at https://CalRapp.org/
The top 4 key questions that our tool can answer:
1. Can I reproducibly and transparently analyze indirect calorimetry experiments in under 10 minutes?
2. How hard is it to use Analysis of Covariance (ANCOVA) to determine whether my groups of animals are significantly different?
3. Is there an automated, reproducible way to exclude “noisy” outlier data from our indirect calorimetry experiments?
4. What are the key factors in determining metabolic rate of mice?
Presenter: Alexander Banks, PhD, principal investigator and assistant professor at Harvard Medical School and the Beth Israel Deaconess Medical Center.
dkNET Webinar Information: https://dknet.org/about/webinar
This document discusses potential biomarkers for cancer risk based on estrogen metabolism. It describes how estrogens like estrone and estradiol are metabolized into catechol estrogens that can form quinones and react with DNA. Specific estrogen metabolites, conjugates, and DNA adducts are proposed as possible early biomarkers for breast, prostate, and other cancers. Methods for analyzing estrogens and their metabolites in tissues and blood are also reviewed, with some studies finding higher levels of certain metabolites in cancer patients.
Rodent Models of Pharmacotherapy and Chronotherapy for Obesity and Cardiometa...InsideScientific
Experts discuss research into combating obesity through new therapies targeting mitochondrial bioenergetics. One expert presents research on BAM15, a mitochondrial uncoupler. Studies in mice found BAM15 was well-tolerated and effective at preventing weight gain and improving glycemic control by increasing energy expenditure without altering food intake. BAM15 activated AMPK signaling, increased fatty acid oxidation in muscle, and restricted adipose tissue expansion, reducing obesity and related diseases without safety concerns. The research provides evidence that mitochondrial uncoupling may be a promising strategy for obesity treatment by increasing calorie burning through non-shivering thermogenesis.
Sex, Drugs, and Bad Choices: Modeling Human Decision Making in RatsInsideScientific
To learn more and watch the webinar, go to:
https://insidescientific.com/webinar/sex-drugs-and-bad-choices-modeling-human-decision-making-in-rats/
Nearly every aspect of life involves decisions between options that differ in both their expected rewards and the potential costs (such as delay to reward delivery or risk of harm) that accompany those rewards. The ability to choose adaptively when faced with such decisions is critical for well-being and overall quality of life; however, decision making is often compromised in neuropsychiatric conditions such as substance use disorders, which can prolong and exacerbate their severity and co-morbidities.
During this webinar, Dr. Barry Setlow discusses research in rodent models investigating behavioral and biological mechanisms of cost-benefit decision making. In particular, he focuses on factors (including sex) that contribute to differences in cost-benefit decision making across the population, how variability in decision making is related to substance use, and how substance use can produce long-lasting alterations in decision making. It is hoped that a better understanding of these relationships may lead to new therapeutic approaches for neuropsychiatric conditions characterized by maladaptive decision making.
Key Topics Include:
- Understand how different forms of cost-benefit decision making can be modeled in rats
- Understand the contributions of gonadal hormones to sex differences in cost-benefit decision making
- Understand the lasting effects of chronic cocaine on cost-benefit decision making
This document summarizes a study investigating the role of Set1-mediated histone H3 lysine 4 (H3K4) methylation in Saccharomyces cerevisiae survival under histidine starvation conditions. The study found that mono-methylation of H3K4 by Set1 is advantageous for optimal growth under these stressful conditions. New Set1 mutant strains, including ones capable of only mono-methylation or hyper methylation, were constructed to further examine the role of H3K4 methylation levels.
1) The document discusses Tay-Sachs disease (TSD), a neurodegenerative lysosomal storage disorder caused by mutations in the HEXA gene resulting in β-hexosaminidase A deficiency and GM2 ganglioside accumulation.
2) Accumulation of GM2 gangliosides is thought to trigger apoptosis, inflammation and synaptic dysfunction, though the specific mechanisms are unclear.
3) The author proposes a potential new therapeutic strategy for TSD involving silencing the GM2 activator protein to prevent GM2 transport to lysosomes and accumulation, combined with anti-inflammatory drugs. This approach aims to address current issues in understanding TSD pathogenesis and improving patient outcomes.
This study investigated the effects of cartilage oligomeric matrix protein (COMP) on gene and protein expression in human vascular smooth muscle cells. The researchers found that exposing the cells to COMP significantly upregulated the expression of four genes implicated in peripheral arterial disease: ANGPTL4, IL-8, IL-12A, and THBS2. The purpose of the study was to determine the effects of COMP on the expression of Group B thrombospondin genes and proteins as well as several other proteins. The researchers hypothesized that COMP would upregulate specific genes and proteins. They used qrt-PCR and quantitative immunoassays to analyze gene and protein expression changes in response to COMP exposure.
Mr. Payne's classroom has big goals for student achievement, clear behavior expectations, and organized classroom systems. The classroom promotes cooperation through discussion norms and conflict resolution. Relationship building occurs through student government campaigns and smaller class groups. Student work is showcased and the class website provides family involvement and resources. Community is built through discussions on social justice and contributions to local organizations.
It Starts with Analytics: How to Drive Better ROI for Your Recruitment Market...SmashFly Technologies
SmashFly's Chief Product Officer and Bright House Network's Senior Director of Talent Acquisition and Diversity talk recruitment marketing ROI and the specific metrics to define success.
That's a lofty talent acquisition and business goal, but Intel's Allyn Baily and Pam McKnight are on the right track, using a recruitment marketing strategy and Recruitment Marketing Platform to reach more targeted candidate personas.
The @greenhouse employee experience team Q1 reviewDaniel Chait
The document summarizes the accomplishments of the Employee Experience team in Q1. Key points include launching a new site to centralize information about employee clubs, improving communication through the weekly employee newsletter, creating more beautiful and functional office spaces, upgrading conference rooms and informal work areas, streamlining administrative tasks like calendar management and business travel, and saving executives hundreds of hours through coordinating emails.
Catalogue 2017 du Centre de Formations en Développement durable et en Environ...CCI France
Le CFDE est un organisme de formation créé en 1969, proposant une offre variée sur des thématiques réglementaires et techniques dans les grands domaines de l’environnement industriel et du développement durable.
Stride gum is manufactured by Mondelēz International and distributed in Canada by Mondelēz Canada Inc. The document provides a detailed analysis of Stride gum's marketing mix, including its product details, distribution channels, pricing strategy, and promotional activities. It identifies convenience stores, supermarkets, gas stations and online retailers as the primary places where Stride gum is sold. Pricing varies by location but averages $1.74 per pack in Canada. Stride uses social media, websites, videos and apps to promote brand awareness and connects with its target market of 25-40 year olds.
L’INNOVATION PAR LES NOUVEAUX MODÈLES ÉCONOMIQUESUtopies
Une démarche de développement durable n’a de sens que si elle est pleinement intégrée à l’activité de l’entreprise – dans sa mission et son modèle économique, son offre de produits et services, ses objectifs stratégiques et critères d’investissement, etc.
Dans la continuité de nos précédents travaux sur la convergence entre innovation et développement durable, l’étude « L’innovation par les nouveaux modèles économiques » entend répondre à trois objectifs :
1/ faire œuvre de pédagogie dans la compréhension de ce contexte et de ces nouvelles formes d’économie (fonctionnelle, collaborative et circulaire) qui, même si elles sont analysées séparément, se complètent parfaitement pour illustrer le sujet de l’innovation par les modèles économiques.
2/ montrer en quoi une intégration « globale et en profondeur » de ces nouvelles formes d’économie dans les modèles économiques permet de garantir une innovation « durable » – prenant en compte les externalités négatives et positives de ces modèles, leurs impacts au-delà du client sur l’ensemble des parties prenantes concernées, et donnant aux entreprises qui les portent une vraie différenciation dans leur performance comme leur pérennité.
3/ proposer des pistes concrètes pour intégrer ces nouveaux modèles à toutes les entreprises ouvertes, engagées et agiles qui y voient à juste titre de nouvelles opportunités de créer de la valeur avec des valeurs !
Cette étude vous présente le fruit de ces réflexions. Elle influera également sur l’évolution du séminaire NOÉ - suivre l'actualité du séminaire d'innovation et de leadership sur programmenoe.com - et fera l’objet de journées de formation à l’innovation par les modèles économiques - voir agenda sur utopies.com/events.
So John Cotton, CH2M, schooled us on SEO, strategy and technology at SmashFly Transform. John deep dives into search, career site optimization, job descriptions and more to prove that strategy needs to be backed by technology for recruitment marketing success.
Glassdoor and SmashFly get inside the candidate's head in this webinar on the 5 stages of the experience. Get tips on how to craft your recruitment marketing strategy to speak to the candidate from awareness to hire.
Deep Learning Into Advance - 1. Image, ConvNetHyojun Kim
[본 자료는 AB180 사내 스터디의 일환으로 제작되었습니다.]
딥러닝에 대한 기초적인 이해 및 적용 예시를 알아보고, 인사이트를 공유하기 위해 만들었습니다. 첫번째로 딥러닝이 이미지 프로세싱에 적용된 방식 및, Convolutional Neural Network (ConvNet)의 기초에 대해 다루었습니다.
* 본 스터디 자료는 Stanford 강좌인 CS231n (http://cs231n.stanford.edu)의 내용을 참고했습니다.
International marketing mistakes related to cultureMohamed Khalifa
This document discusses several examples of cultural mistakes made by companies when expanding their marketing internationally. It provides three case studies where companies failed to account for cultural differences: 1) An Iranian razor company that used a brand name that had an offensive meaning in Arabic; 2) A Dutch milk company that changed its packaging without considering customer needs; 3) A beer company that printed holy Islamic verses on bottle caps without realizing the cultural taboo. The document emphasizes the importance of understanding local cultural norms and perspectives when marketing products globally.
The document discusses various Boolean search techniques recruiters can use to find candidates, including:
- Searching for terms related to a person's expertise, accomplishments, interests and previous employers to find candidates who actively promote themselves.
- Using list and conference speaker searches to find contact details of potential candidates.
- Searching terms like "people on the move" to uncover profiles of high-performing candidates.
- Employing country coding and filtering search results by date to target recently active profiles.
The document provides examples of searches using each technique to help recruiters uncover hidden candidates for their roles.
This study found that inhibiting mTOR with rapamycin in a mouse model of Alzheimer's disease (AD):
1) Prevented cognitive deficits in tasks of learning and memory. Rapamycin treated mice performed similarly to healthy mice.
2) Reduced levels of amyloid-beta 42 (Aβ42), a toxic protein associated with AD. Levels of Aβ40 were unchanged.
3) Increased autophagy, a process for degrading proteins, in the hippocampus of transgenic AD mice treated with rapamycin. This suggests increased autophagy contributed to reduced Aβ levels and improved cognition.
4) Had no effect on Aβ levels or cognition in healthy mice without increased autophag
This study examined the effects of cerium oxide nanoparticles (CeO2 NPs) on disease progression in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). The mice expressed a mutation in the SOD1 gene associated with familial ALS. Following disease onset, mice were given injections of either saline (control) or CeO2 NPs. Mice treated with CeO2 NPs showed improved motor performance and increased survival time, particularly female mice. The results suggest CeO2 NPs may be a potential treatment for slowing progression of ALS and other neurodegenerative diseases associated with oxidative stress.
The antibody aducanumab reduces amyloid beta (Aβ) plaques in patients with Alzheimer's disease in a dose- and time-dependent manner according to interim results from a phase 1b clinical trial. Monthly intravenous infusions of aducanumab for one year reduced brain Aβ plaques as measured by PET imaging in patients with prodromal or mild Alzheimer's disease. This Aβ reduction was accompanied by a slowing of clinical decline on measures of cognition and function. The main safety finding was amyloid-related imaging abnormalities that generally resolved over time and did not require hospitalization. These results support further development of aducanumab as a potential disease-modifying therapy for Alzheimer's disease.
- The document examines the role of plasminogen activator inhibitor 1 (PAI-1) in the recruitment of mast cells (MCs) to glioma tumors.
- It finds that neutralizing PAI-1 attenuates the infiltration of MCs into glioma tumors. It also finds that MCs express the PAI-1 receptor LRP1, and blocking LRP1 also attenuates MC migration.
- Activation of the potential PAI-1/LRP1 axis in MCs by purified PAI-1 promotes increased phosphorylation of STAT3 and subsequent MC exocytosis. This indicates the PAI-1/LRP1 axis influences MC recruitment in glioma tumors.
Background and objectives: the 5’nucleotidase (5’NT) is one of
hydrolytic enzymes present in different organs which catalyze
hydrolysis of 5’ nucleotides to ribonucleosides and phosphate.
Malondialdehyde (MDA) is the end product of lipid peroxidation
by oxidative stress (free radicals).
The aim of present study was to measure the serum activity of
5’NT, and MDA concentration in breast tumors.
Material and method: A prospective study was carried out from
May to December 2013 by clinical biochemistry department in
College of Medicine-Hawler Medical University on (30) healthy
female individuals, (group 1) and (30) females with breast tumor
(group 2).
Results: The mean value of serum MDA was significantly higher
in females with breast tumors (group 2), than that of healthy
female individuals, (group 1) (p<0.01),><0.01).
Conclusion: Based on findings of the present study it can be
concluded that breast tumors can cause release of the enzyme
5’NT from tumor cells, and lipid peroxidation by reactive oxygen
species (ROS), which cause elevation of MDA.
Citalopram enhances action inhibition systems in Parkinson’s diseaseZheng Ye
1) The study investigated whether the selective serotonin reuptake inhibitor (SSRI) citalopram could reduce impulsivity and enhance response inhibition systems in patients with Parkinson's disease (PD).
2) The results showed that PD impaired both action restraint and cancellation compared to healthy controls. Citalopram improved behavioral performance on inhibition tasks in PD patients depending on disease severity.
3) Citalopram enhanced activation in the right inferior frontal gyrus, a brain region involved in response inhibition. The degree of enhancement correlated with reductions in impulsivity, supporting the role of serotonin in regulating inhibitory control.
This study investigated the effects of chronic diabetes mellitus type 1 on the ventral and dorsal zones of the hippocampus. Rats were induced with diabetes through streptozotocin injection. After 8 weeks, the brains were analyzed. The number of dead neurons in the CA1 and CA3 regions of the ventral hippocampus were significantly higher than in the dorsal hippocampus. This provides evidence that the ventral zone is more vulnerable to neuronal degeneration from diabetes mellitus type 1 compared to the dorsal zone. The ventral hippocampus is involved in emotional processes, so greater neuronal loss could impact those functions.
This study examined the effects of chronic diabetes mellitus type 1 on the dorsal and ventral zones of the hippocampus in rats. Diabetes was induced in rats using streptozotocin injections. After 8 weeks, the brains were analyzed. The number of dead neurons was significantly higher in the CA1 and CA3 regions of the ventral hippocampus compared to the dorsal hippocampus. This provides evidence that the ventral hippocampus is more vulnerable to neuronal degeneration from diabetes mellitus type 1 than the dorsal hippocampus. The ventral hippocampus plays a role in emotion and stress responses, so greater neuronal loss could impact those functions.
This study examined the effects of chronic diabetes mellitus type 1 on the dorsal and ventral zones of the hippocampus in rats. Diabetes was induced in rats using streptozotocin injections. After 8 weeks, the brains were analyzed. The number of dead neurons was significantly higher in the CA1 and CA3 regions of the ventral hippocampus compared to the dorsal hippocampus. This provides evidence that the ventral hippocampus is more vulnerable to neuronal degeneration from diabetes mellitus type 1 than the dorsal hippocampus. The ventral hippocampus plays a role in emotion and stress responses, so greater neuronal loss could impact those functions.
Morphological and functional state of immune organs in rats with experimental...QUESTJOURNAL
This study examined the morphological and functional changes in the immune organs (thymus and spleen) of rats with experimentally induced type 1 diabetes mellitus (DM-1). Rats with DM-1 showed initial pathological changes in these organs, including increased medulla in the thymus and increased white pulp in the spleen, indicating early inflammatory and degenerative processes. Treatment with the phytopreparation BNO 10.30 was found to help restore cell structure in the thymus and spleen by stimulating immune function. The results demonstrate the importance of early detection of immune organ changes in patients with type 1 diabetes.
An analysis of Parkinson’s disease (PD) on Physical and Mental HealthArian Bashtar
NEUR 3403 Term Assignment at Carleton University, describing the various etiologic determinants of Parkinson's Disease (PD), mechanisms of disease pathology, as well as the impact of genetics and environmental considerations. Authored by Arian Bashtar, 2017.
A mild reduction of food intake slows disease progression in an orthologous m...Mina Rezaei
A mild 23% reduction in food intake (RFI) significantly slowed disease progression in a mouse model of polycystic kidney disease (PKD). RFI suppressed renal cyst growth, with kidney weight increasing 41% compared to 151% in controls. Proliferation of cyst-lining cells was also reduced from 15.9% in controls to 7.7% with RFI. RFI maintained kidney function and prevented progression to end-stage renal disease. RFI activated AMPK and inhibited both branches of mTOR signaling in cyst cells, more broadly than rapamycin which primarily inhibits one branch. These results suggest a mild decrease in caloric intake may slow disease progression in human ADPKD patients.
This summary analyzes a scientific article that uses proteomics analysis to study molecular and cellular mechanisms associated with anxiety in the cingulate cortex synapses of mice with high versus low anxiety-related behaviors. The key findings are:
1) Proteins overrepresented in high anxiety mice indicate stabilization and enlargement of existing excitatory dendritic spines through reinforcement of glutamatergic synaptic structures and long-term potentiation maintenance mechanisms.
2) There is evidence of increased spontaneous synaptic activity in non-glutamatergic networks coupled with relatively weakened GABAergic inhibitory control.
3) Mitochondrial proteins point to increased oxidative phosphorylation, fatty acid oxidation, and ATP production, suggesting adaptations to persistent synaptic
This document provides information about the July 2013 issue of Biomed, the newsletter of the Department of Biochemistry at Adichunchanagiri Institute of Medical Sciences. It discusses the retirement of a senior technician after 25 years of service and the expansion of department facilities. It also announces the MCI grant for increased undergraduate admissions and approval of university status for the institution. Short articles summarize research on Saposin B deficiency, Irisin, Sirtuins, Visfatin, and provide a crossword puzzle related to biochemical bases of diseases.
This document describes a study that investigated the effects of acetate supplementation and selective serotonin reuptake inhibitors (SSRIs) on stress levels and blood glucose in immobilized rats. Rats were subjected to immobilization stress for 28 days. Some rats were treated with fluoxetine (an SSRI), glyceryl triacetate (GTA/acetate supplement), or a combination. Stress levels were assessed using open field and hole board tests. Blood glucose and adrenal gland weight were also measured. Results showed acetate and SSRI treatment reduced stress levels and blood glucose compared to untreated stressed rats. The study concluded acetate and SSRIs have stress-reducing and blood glucose-lowering effects by enhancing brain histone acetylation
Novel ligands acting as SERT blockers and dopamine D2 receptor partial agonis...Monika Marcinkowska
The document describes a novel series of arylsulfonamide derivatives that were designed to selectively target the serotonin transporter (SERT) and 5-HT7 receptor with the goal of developing new treatments for mood disorders. The lead compound, ADN-3662, was found to potently block SERT and act as a partial agonist at dopamine D2 and 5-HT1A receptors with reduced activity at other targets. In vivo tests showed ADN-3662 had antidepressant and anxiolytic effects in animal models of mood deficits at doses with a wide therapeutic window and no side effects. Further development of ADN-3662 is warranted for the treatment of mood disorders and related conditions.
ENDO SOCIETY - MAHMUDA AHMED Insulinoma CaseMeghana Gudala
A 15-year-old female presented with unexplained hypoglycemia, including episodes where her blood glucose levels dropped below 20 mg/dL. Testing revealed hyperinsulinemic hypoglycemia indicating an insulinoma. Imaging found a 1.1 cm hypervascular mass on her pancreas. She underwent surgical resection of the insulinoma and partial pancreatectomy. Follow up showed she remained euglycemic without episodes of hypoglycemia four months post-surgery.
This document describes a study investigating the relationship between colitis-induced inflammation in the gut and neuroinflammation in the brain. The study found that a mild acute colitis model resulted in a small, non-significant increase in microglia activation in the brain, but a more severe acute colitis model did not. In a chronic colitis model, some animals showed increased microglia activation in the brain while others did not, indicating variable responses. The results provide preliminary evidence that gut inflammation may be linked to neuroinflammation, but the relationship requires further investigation.
Иммунная система влияет на социальное поведение человекаAnatol Alizar
1) Mice deficient in adaptive immunity (SCID mice) exhibited social deficits and hyper-connectivity in frontal cortical brain regions. Repopulating SCID mice with wild-type lymphocytes restored normal social behavior and connectivity.
2) IFN-γ signaling appears to mediate the influence of adaptive immunity on social behavior and connectivity. IFN-γ-deficient mice and mice with reduced meningeal T cells both showed social deficits and hyper-connectivity. Injecting IFN-γ into the CSF of IFN-γ-deficient mice restored social preference.
3) Transcriptome analysis implicated IFN-γ-driven immune responses, particularly from meningeal T cells, in regulating social behavior and other behaviors influenced by
Иммунная система влияет на социальное поведение человека
kellyoh_sciencepub
1. mTOR Inhibition Alleviates Mitochondrial Disease in a Mouse
Model of Leigh Syndrome
Simon C. Johnson1, Melana E. Yanos1,2, Ernst-Bernhard Kayser3, Albert Quintana4, Maya
Sangesland1, Anthony Castanza1, Lauren Uhde1, Jessica Hui1, Valerie Z. Wall1, Arni
Gagnidze1, Kelly Oh1, Brian M. Wasko1, Fresnida J. Ramos1, Richard D. Palmiter4, Peter S.
Rabinovitch1, Philip G. Morgan3, Margaret M. Sedensky3, and Matt Kaeberlein1,*
1Department of Pathology, University of Washington, Seattle, WA 98195, USA
2Department of Psychology, University of Washington, Seattle, WA 98195, USA
3Anesthesiology and Pain Medicine, Seattle Children’s Hospital, Seattle, WA 98105, USA
4Howard Hughes Medical Institute and Department of Biochemistry, University of Washington,
Seattle, WA 98195, USA
Abstract
Mitochondrial dysfunction contributes to numerous health problems, including neurological and
muscular degeneration, cardiomyopathies, cancer, diabetes, and pathologies of aging. Severe
mitochondrial defects can result in childhood disorders such as Leigh syndrome, for which there
are no effective therapies. We found that rapamycin, a specific inhibitor of the mechanistic target
of rapamycin (mTOR) signaling pathway, robustly enhances survival and attenuates disease
progression in a mouse model of Leigh syndrome. Administration of rapamycin to these mice,
which are deficient in the mitochondrial respiratory chain subunit Ndufs4 [NADH dehydrogenase
(ubiquinone) Fe-S protein 4], delays onset of neurological symptoms, reduces neuroinflammation,
and prevents brain lesions. Although the precise mechanism of rescue remains to be determined,
rapamycin induces a metabolic shift toward amino acid catabolism and away from glycolysis,
alleviating the buildup of glycolytic intermediates. This therapeutic strategy may prove relevant
for a broad range of mitochondrial diseases.
Leigh syndrome is a clinically defined disease resulting from genetic defects that disrupt
mitochondrial function. It is the most common childhood mitochondrial disorder, affecting 1
in 40,000 newborns in the United States (1). Leigh syndrome is characterized by retarded
growth, myopathy, dyspnea, lactic acidosis, and progressive encephalopathy primarily in the
brainstem and basal ganglia (2, 3). Patients typically succumb to respiratory failure from the
neuropathy, with average age of death at 6 to 7 years (1).
*
Corresponding author. kaeber@uw.edu.
Supplementary Materials
www.sciencemag.org/content/342/6165/1524/suppl/DC1
Materials and Methods
Figs. S1 to S14
Tables S1 to S3
NIH Public Access
Author Manuscript
Science. Author manuscript; available in PMC 2014 June 20.
Published in final edited form as:
Science. 2013 December 20; 342(6165): 1524–1528. doi:10.1126/science.1244360.
NIH-PAAuthorManuscriptNIH-PAAuthorManuscriptNIH-PAAuthorManuscript
2. We recently observed that reduced nutrient signaling, accomplished by glucose restriction or
genetic inhibition of mTOR, is sufficient to rescue short replicative life span in several
budding yeast mutants defective for mitochondrial function (4), including four mutations
associated with human mitochondrial disease (fig. S1). These observations led us to examine
the effects of rapamycin, a specific inhibitor of mTOR, in a mammalianmodel of Leigh
syndrome, the Ndufs4 knockout (Ndufs4−/−) mouse (5). Ndufs4 encodes a protein involved
in assembly, stability, and activity of complex I of the mitochondrial electron transport chain
(ETC) (6, 7). Ndufs4−/− mice show a progressive neurodegenerative phenotype
characterized by lethargy, ataxia, weight loss, and ultimately death at a median age of 50
days (5, 8). Neuronal deterioration and gliosis closely resemble the human disease, with
primary involvement of the vestibular nuclei, cerebellum, and olfactory bulb.
We first examined the effects of delivering rapamycin (8 mg/kg) every other day by
intraperitoneal injection beginning at weaning [approximately postnatal day 20 (P20)]. This
treatment reduces mTOR signaling in wild-type mice (9) and provided significant increases
in median survival of male (25%) and female (38%) knockout mice (Fig. 1A). A slight
reduction in maximum body size and a delay in age of disease onset were also observed
(Fig. 1B and fig. S2). Although these results showed that Ndufs4−/− mice benefit from
rapamycin treatment, we noted that by 24 hours after injection, rapamycin levels in blood
were reduced by more than 95% (fig. S3). We therefore performed a follow-up study
delivering rapamycin (8 mg/kg) daily by intra-peritoneal injection starting at P10, which
resulted in blood levels ranging from >1800 ng/ml immediately after injection to 45 ng/ml
trough levels (fig. S3). For comparison, an encapsulated rapamycin diet that extends life
span in wild-type mice by about 15% achieves steady-state blood levels of about 60 to 70
ng/ml, and trough levels between 3 and 30 ng/ml are recommended for patients receiving
rapamycin (10). In the daily-treated cohort, we observed a striking extension of median and
maximum life span; the longest-lived mouse survived 269 days. Median survival of males
and females was 114 and 111 days, respectively (fig. S2C).
Vehicle-injected knockout mice first displayed neurological symptoms around P35,
coinciding with a body weight peak (Fig. 1, B to D, and fig. S2D). After this point, disease
symptoms progressively worsened and weight declined. Daily rapamycin treatment
dampened developmental weight gain and prevented the progressive weight loss phenotype
(Fig. 1B and fig. S2E). This effect was robust, even among mice from the same litter (fig.
S4). Incidence and severity of clasping, a commonly reported and easily scored phenotype
that progresses with weight loss and neurological decline, was also greatly attenuated in
rapamycin-treated knockouts (Fig. 1, C to E). Performance in a rotarod assay, which
measures balance, coordination, and endurance, was assessed in a separate cohort of mice.
Vehicle-treated knockout mouse performance worsened as the disease progressed, whereas
rapamycin-treated knockout mice maintained their performance with age (Fig. 1F and fig.
S5). Dyspnea, previously observed in vehicle-treated knockout mice (5), was not observed
in the mice injected daily with rapamycin.
Rapamycin-treated knockout mice also did not develop the neurological lesions associated
with this disease (red arrows in Fig. 2, A and B; see also fig. S6). The lesions, characterized
by astrocyte activation and glial reactivity [detected by glial fibrillary acidic protein (GFAP)
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3. and Iba1 staining, respectively] were detectable in all vehicle-treated knockout mice over 50
days of age (5).We were unable to detect lesions in the cerebellum of age-matched
rapamycin-treated knockout mice. GFAP, Iba1, and laminin (a marker of
neovascularization) were markedly increased in olfactory bulbs of vehicle-treated but not in
rapamycin-treated knockout mice (Fig. 2B and fig. S6). Rapamycin did not affect GFAP,
Iba1, or laminin levels in wild-type mice (fig. S6). Western blotting for GFAP using whole-
brain lysates from ~50-day-old mice revealed a significant increase in GFAP in knockout
mice that was attenuated by rapamycin (Fig. 2C). Furthermore, no lesions were detected in
100-day-old and 268-day-old rapamycin-treated knockout mice (fig. S7). Overall, the
percentage of mice showing neurological symptoms was much reduced at every age point
after P35 in rapamycin-treated knockout mice, with about half never exhibiting overt signs
of neurological disease before death (Fig. 2, D and E).
Given the pleiotropic effects of mTOR inhibition [reviewed in (11, 12)], we sought to
identify downstream mechanisms associated with attenuation of mitochondrial disease.
Rapamycin has well-documented immune-modulatory effects, so we first considered that the
benefit might arise from reduced neuroinflammation. To test this model, we treated mice
with FK-506 (tacrolimus), a clinically approved immunosuppressive drug that binds the
same target as rapamycin, FKBP12, but inhibits calcineurin signaling rather than mTOR
(13). FK-506 did not affect disease onset or progression (Fig. 3, A and B, and fig. S8),
indicating that neither immunosuppression nor off-target disruption of calcineurin by
binding of FKBP12 are likely to account for the effects of rapamycin. We next considered
that rapamycin might improve mitochondrial function by increasing macroautophagy,
removing the least functional components of the mitochondrial network. Although we were
able to detect evidence of induction of autophagy in the liver and brain of rapamycin-treated
mice (fig. S9), there was no corresponding rescue of mitochondrial function (Fig. 3C and
fig. S10). Complex I assembly and stability, assessed by blue native gel electrophoresis,
were also unaltered by rapamycin (Fig. 3D and fig. S11), as were levels and localization of
ETC proteins (Fig. 3E and F, and fig. S12). We found no evidence for induction of HSP60, a
component of the mitochondrial unfolded protein response, either by NDUFS4 loss or by
rapamycin (Fig. 3F and fig. S12).
As a central coordinator of nutrient sensing and growth, mTOR regulates metabolism by
integrating levels of amino acids at the lysosome, energetic sensing by adenosine
monophosphate–activated protein kinase (AMPK), and extracellular signals through insulin
and insulin-like growth factor (IGF) (11, 14). We reasoned that loss of NDUFS4 might
perturb metabolic signaling and affect mTOR activity. Consistent with this idea,
phosphorylation of ribosomal protein S6, a target of mTOR complex 1 (mTORC1)
signaling, was significantly increased in the brains of knockout mice (Fig. 4A), and
rapamycin reduced phosphorylation of S6 in both wild-type and knockout mice. IGF1
receptor (IGF1R) phosphorylation was also increased in Ndufs4−/− mice and reduced by
rapamycin (Fig. 4A). Whole-body quantitative magnetic resonance revealed a progressive
loss in body fat in the Ndufs4−/− mice that was ameliorated by daily rapamycin injections
(Fig. 4B). Furthermore, Oil Red O staining and metabolomic analysis of liver indicated that
knockout mice had a marked deficiency in liver fat droplets and free fatty acids that was
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4. partially rescued by rapamycin (Fig. 4, C and D, and fig. S13). Whole-brain metabolomics
of 30-day-old mice revealed an abnormal metabolic profile in the Ndufs4−/− mice that
included an accumulation of pyruvate, lactate, and all detected glycolytic intermediates,
consistent with clinical reports of Leigh syndrome (2, 15) (Fig. 4E and table S1). The
metabolomic signature of the Ndufs4−/− mouse brain includes a decrease in free amino
acids, free fatty acids, nucleotides, and products of nucleotide catabolism, increased
oxidative stress markers, and reduced levels of γ-aminobutyric acid (GABA) and dopamine
(fig. S14 and table S1). Rapamycin rescued many of these metabolomic defects associated
with NDUFS4 deficiency, including levels of GABA, dopamine, and free fatty acids.
Increased amino acids, metabolites of amino acid and nucleotide catabolism, and free fatty
acids accompanied the decrease in glycolytic intermediates, whereas markers of oxidative
stress were unchanged. Moreover, hexokinase—the first enzyme in glycolysis—was
increased in Ndufs4−/− mice and reduced by rapamycin in knockout and control mice,
consistent with the decrease in glycolytic intermediates (Fig. 4A).
Taken together, our results demonstrate that inhibition of mTOR improves survival and
health in the Ndufs4−/− model of Leigh syndrome. These findings raise the possibility that
mTOR inhibitors may offer therapeutic benefit to patients with Leigh syndrome and
potentially other mitochondrial disorders. Rapamycin derivatives have several adverse
effects, however, including immunosuppression, hyperlipidemia, and decreased wound
healing, which may limit their utility in this context, particularly in very young patients.
Thus, a more detailed understanding of the mechanisms by which rapamycin alleviates
disease in Ndufs4−/− mice should allow for the development of more targeted interventions
to improve health in patients suffering from mitochondrial diseases for which there are no
effective treatments.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
We thank the University of Washington School of Medicine and Department of Pathology for funding to M.K. that
allowed these studies to be performed. Supported by NIH training grant T32AG000057 (S.C.J., M.E.Y., and
F.J.R.), NIH training grant T32ES007032 (B.M.W.), and an Amgen Scholar summer research scholarship (M.S.).
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6. Fig. 1. Reduced mTOR signaling improves health and survival in a mouse model of Leigh
syndrome
(A) Survival of the Ndufs4−/− mice was significantly extended by rapamycin injection every
other day; life span more than doubled with daily rapamycin treatment (log-rank P = 0.0002
and P < 0.0001, respectively). (B) Body weight plots of Ndufs4−/− mice. (C) Representative
forelimb clasping behavior, a widely used sign of neurological degeneration. Clasping
involves an inward curling of the spine and a retraction of forelimbs (shown here) or all
limbs toward the midline of the body. (D and E) Clasping in vehicle-treated (D) and daily
rapamycin-treated (E) Ndufs4−/− mice as a function of age. A total of 15 mice were
observed for clasping daily for each treatment. Age of onset of clasping behavior is
significantly delayed in rapamycin-treatedmice (**P<0.001 by log-rank test). (F) Ndufs4−/−
mice show a progressive decline in rotarod performance that is rescued by rapamycin (*P <
0.05, **P < 0.005, Student’s t test; error bars are ± SEM). (See also fig. S5, which indicates
replicate numbers.)
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7. Fig. 2. Rapamycin reduces neurological disease in Ndufs4−/− mice
(A) Representative cerebellar staining for neurological lesions in 55- to 60-day-old mice. All
vehicle-treated mice showed glial activation and lesions at this age, whereas lesions were
not detected in age-matched daily rapamycin-treated mice (n = 6; scale bars, ~500 µm) (see
also figs. S6 and S7). (B) Representative olfactory bulb staining shows activation of glia by
GFAP staining and neovascularization by laminin staining in vehicle-treated knockout (KO)
mice and a robust attenuation in rapamycin-treated KO mice (n = 6 per treatment; scale bars,
~500 µm). (C) Western blotting of whole-brain lysates from a separate cohort of mice shows
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8. increased GFAP in vehicle KO mice and rescue to control levels by rapamycin (*P < 0.05,
Student’s t test; error bars are ± SEM). (D and E) The percentage of living mice showing
neurological symptoms is greatly reduced by daily rapamycin treatment (D), as is the
number of mice showing neurological symptoms at the time of death (E).
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9. Fig. 3. Rapamycin does not substantially alter mitochondrial function or complex I assembly
(A and B) FK-506 delivered at the highest tolerated dose (see fig. S8) failed to enhance
survival (A) or attenuate disease (B) in Ndufs4−/− mice. (C) Rapamycin has no observed
effect on respiratory activity or complex I deficiency of mitochondria isolated from ~50-
day-old Ndufs4−/− mice; n = 4 to 6 mice per data point. (see also fig. S10). (D) Native-in-gel
activity assays reveal that rapamycin does not influence assembly or stability of complex I
(see also fig. S11). (E and F) Complex I subunits (NDUFS3 and NDUFS9) are significantly
reduced in Ndufs4−/− mice, and rapamycin has no effect on their total levels (F) or
subcellular localization (E) in brain. Levels of other mitochondrial proteins (cytochrome c,
the complex IV subunit COXIV, and HSP60) are independent of both Ndufs4 genotype and
treatment (see also fig. S9). *P < 0.05,**P < 0.005, Student’s t test; ns, not significant. Error
bars are ±SEM.
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10. Fig. 4. Ndufs4−/− mice exhibit mTOR activation and metabolic defects that are suppressed by
rapamycin
(A) mTOR activity, as indicated by phosphorylation of S6, is increased in Ndufs4−/− mouse
brain. Total IGF1R and S6 are decreased in Ndufs4−/− mice, suggesting feedback inhibition
from chronic mTOR activation. Rapamycin potently inhibits phosphorylation of S6 and
rescues levels of IGF1R and S6. (B) Total body fat progressively decreases in Ndufs4−/−
mice but is maintained in rapamycin-treated mice. Fat mass differs by sex in control but not
Ndufs4−/− mice (n = 4 to 6 mice per data point). (C and D) Liver fat droplets are deficient in
vehicle-treated Ndufs4−/− mice and partially rescued by rapamycin (representative images, n
> 6 stained per treatment; scale bar, ~100 µm) (C), as are free fatty acids detected by
metabolomics (D) (n = 4 per treatment). (E) Accumulation of glycolytic intermediates in
Ndufs4−/− brain is suppressed by rapamycin (n = 4 per treatment) (see fig. S14 and tables S1
to S3). *P < 0.05, **P < 0.005, Student’s t test; error bars are ±SEM.
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