metabolism

Benefits to being furry, but not fat, in a cold environment

dr. dolittle — Thu, 24 Aug 2017 23:01:30 +0000

Benefits to being furry, but not fat, in a cold environment

Image of a genetically obese mouse (left) from Wikipedia.

To deal with cold environments, mammals have several options. They could produce heat by increasing metabolism or shivering or they could conserve heat by constricting blood vessels in their skin or snuggling with a friend or insulating materials. With this in mind, researchers wondered how varying levels of insulation (obesity, fur) in mice affected heat loss and how much energy the animals used to maintain body heat. Their thinking was that more insulation would prevent heat loss and lower energy needs. Sounds logical, right?

This reasoning was indeed logical for the amount of fur an animal had. Mice with shaved fur did have increased metabolism compared to those with normal body hair. What was surprising to the researchers was that obesity was not at all related to preventing heat loss in the mice. In fact, obese mice lost just as much heat as non-obese mice.

Source:

Fischer AW, Csikasz RI, von Essen G, Cannon B, Nedergaard J. No insulating effect of obesity. American Journal of Physiology - Endocrinology and Metabolism. Published 5 July 2016 Vol. 311 no. 1, E202-E213 DOI: 10.1152/ajpendo.00093.2016

dr. dolittle Thu, 08/24/2017 - 19:01

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Life Science

metabolism

mouse

obese

temperature

New site, new stories

jhalper — Sun, 03 Jan 2016 05:05:53 +0000

New site, new stories

Cells that “spit” out their contents and messenger RNA that is not so swift at delivering its message. Those are two brand new stories on our new and improved website. Check it out and let us know what you think.

The first story arose from a simple question: How do secretory cells – those that produce copious amounts of such substances as tears, saliva or all those bodily fluids – manage to get their contents out of the cell? Cells are walled all the way around; they don’t really have doors for letting things the size of a drop of fluid out. Instead, they use the vesicle system – small globes made of the same stuff as the cell membrane that transport the drops out to the edge. The vesicles then fuse with the membrane, releasing their cargo to the outside.

Prof. Ben-Zion Shilo and his group realized that this was all well and fine for small amounts of biochemicals, but secretory cells would need a better system. Their results, which involved a lot of intricate time-lapse observation in the saliva glands of fruit-fly larvae, are beautiful to watch as well as instructive.

Salivary gland of a larval fruit fly. Vesicles (red) carrying the glue must empty their contents quickly and efficiently

The second story arose from a surprising observation: Certain liver cells that are involved in metabolism seemed to have large amounts of messenger RNA in their nuclei. Why would RNA stick around in the cell nucleus, instead of rushing out to make proteins? Dr. Shalev Itzkovitz and his group followed up on this question by asking further questions: How many cells keep RNA in their nuclei? How long does this RNA tend to stay? Which genes produce the homebody RNA?

Although they have not yet answered every one of their questions, they have uncovered a new level of regulation in the cell – one that is not immediately intuitive.

Nuclei of liver cells, mRNA of certain genes in white

Revealing how some cells get rid of their contents or discovering that others hoard things deep within – neither finding will cure disease tomorrow. Both are changing our understanding of how the human cell functions, and both are going to contribute, in the future, to human health and welfare. We promise to keep bringing you these stories and more.

jhalper Sun, 01/03/2016 - 00:05

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basic research

biochemistry

biological regulation

biological regulation

Biophysics

genes

Polar bear survival during summer

dr. dolittle — Tue, 21 Jul 2015 00:41:04 +0000

Polar bear survival during summer

If you happen to be in the Arctic this summer polar bears (Ursus maritimus) can be spotted spending their time on the sea ice or on the shore in areas where ice has melted. While it is difficult to study the physiology of bears living on the ice, it had been hypothesized that bears living on shore experience a state similar to winter hibernation in which they attempt to decrease their energy expenditure when food resources are low. However, new research published in Science shows that bears living on the ice as well as those on shore experience some decrease in activity as well as body temperature while their energy expenditure is actually similar to that of animals that are fasting but not hibernating.

The research team enlisted help from the US Geological Survey, US Fish and Wildlife Service, two helicopters and an ice-breaking vessel to help capture and tag over two dozen polar bears as well as implant 17 bears with a probe that can measure body temperature. It took 36 days just to recapture the animals with the temperature probes!

With the Arctic ice beginning to melt earlier in the summer and also taking longer to freeze in the winter, these prolonged periods of ice melt may be a challenge to the animal's survival over time according to study co-author Merav Ben-David (University of Wyoming - Laramie).

Sources:

Whiteman JP, Harlow HJ, Durner GM, Anderson-Sprecher R, Albeke SE, Regehr EV, Amstrup SC, Ben-David M. Summer declines in activity and body temperature offer polar bears limited energy savings. Science, 349(6245), 295-298, July 2015.
DOI: 10.1126/science.aaa8623

Image of a "shore" polar bear from National Geographic.

dr. dolittle Mon, 07/20/2015 - 20:41

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Amazing what a "cool" summer can do:
http://www.bbc.com/news/science-environment-33594654

Thank you for sharing this article. The polar bears in this research were studied in 2008 and 2009.

The summer will be amazing.

Passing rewarming saves energy

dr. dolittle — Thu, 05 Feb 2015 17:45:16 +0000

Passing rewarming saves energy

Image of Gould's long-eared bat from http://www.wiresnr.org/Microbats.html
Image by: Lib Ruytenberg

I came across a neat study published recently in the American Journal of Physiology - Regulatory, Integrative and Comparative Physiology which examined how bats arouse from hibernation, a period during which their body temperature and metabolism are low. To minimize the high energetic costs of warming up during arousal, bats use solar radiation or take advantage of fluctuations in the ambient temperatures (i.e. environmental).

Researchers studied hibernating long-eared bats (Nyctophilus gouldi) to learn how increasing the ambient temperature (i.e. atmospheric) affected heart rate and metabolism in comparison to arousal in a constant low ambient temperature environment. What they found was that heart rate and metabolism remained low for a longer period of time and gradually increased as the ambient temperatures were likewise increased. In contrast, the animals that actively aroused in low ambient temperatures had higher heart rates and metabolisms.These findings show that passive rewarming does conserve energy and arousal time in the bats resulting in less stress on the cardiovascular system.

I wonder if passive rewarming could help bats afflicted with white-nose syndrome conserve energy and perhaps increase survival?

White Nose Syndrome Part 1

White Nose Syndrome Part 2

Source:

, ,

dr. dolittle Thu, 02/05/2015 - 12:45

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Life, Death, and ERVs

milhayser — Mon, 01 Dec 2014 12:55:01 +0000

Life, Death, and ERVs

In a phenomenon known as Peto's paradox, large mammals do not develop cancer more often than small mammals, despite having more cells that could go haywire. On Life Lines, Dr. Dolittle writes "Some researchers suggested that perhaps smaller animals developed more oxidative stress as a result of having higher metabolisms. Others proposed that perhaps larger animals have more genes that suppress tumors." But a new hypothesis argues that large mammals have evolved to minimize the activity of ERVs, which are ancient viral elements integrated into our DNA. Active ERVs can cause cancer and possibly other diseases; mice exhibit about 3300 active ERVs, while humans exhibit about 350. On the blog known as ERV, Abbie Smith writes "some of the young ERVs in humans, the ones that can still code for a protein here and there, are reactivated in HIV+ patients." Researchers are considering targeting these ERVs in order to combat HIV; as Abbie writes, "You could train the HIV+ individuals immune system to ‘see’ the ERV components in an HIV infected CD4+ T-cell, and BAM! Kill the HIV infected cell!" But she warns that other ERV components are expressed in many normal human cells, and teaching our immune system to target them might be a very bad idea.

milhayser Mon, 12/01/2014 - 07:55

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Eyeless Mexican cavefish lost metabolic circadian rhythm

dr. dolittle — Thu, 25 Sep 2014 15:08:54 +0000

Eyeless Mexican cavefish lost metabolic circadian rhythm

Image of eyeless Mexican tetra fish from www.seriouslyfish.com by H-J Chen.

The metabolism of most animals follows a circadian rhythm that differs between the day and night. Mexican cavefish living in constant darkness, lost this circadian rhythm some time ago. In a newly published study in PLOS ONE, researchers compared the metabolic rate of both cave- and surface-dwelling Mexican tetra fish (Astyanax mexicanus). They hypothesized that since the fish living in each location naturally experience differences in food, predation as well as exposure to daily light fluctuations, they might also have different metabolic needs. When they exposed surface-dwelling fish to constant darkness, the circadian rhythm in terms of metabolism was consistent with oxygen demands normally seen in the daytime resulting in the expenditure of 38% more energy than the cave-dwelling fish. In contrast, the eyeless cave-dwelling fish do not have a metabolic circadian rhythm which the researchers say conserves 27% of their energy in comparison to surface fish. In a quote published in Discovery News, lead study author Dr. Damian Moran said, "These cave fish are living in an environment without light, without the circadian presence of food or predators, they've got nothing to get ready for, so it looks like they've just chopped away this increase in anticipation for the day." The study authors suggest that conserving energy is important for life in a cave where food may be scarce.

Sources:
Moran D, Softley R, Warrant EJ. Eyeless Mexican Cavefish Save Energy by Eliminating the Circadian Rhythm in Metabolism. PLOS ONE. September 24, 2014. DOI: 10.1371/journal.pone.0107877

Discovery News

dr. dolittle Thu, 09/25/2014 - 11:08

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Last Week on ResearchBlogging.org

milhayser — Mon, 31 Mar 2014 18:57:04 +0000

Last Week on ResearchBlogging.org

Scientists use a 'gene gun' to insert a gene from a flowering plant called rockcress into the cells of wheat seeds. The genetically modified wheat became more resistant to a fungus called take-all, which in real life can cause "a 40-60% reduction in wheat yields."

T-cells from six HIV+ patients were removed from their bodies, treated with a zinc-finger nuclease designed to snip a gene out of the cell's DNA, and put back in the patients. Removal of the gene mimics a naturally occurring mutation which confers resistance to the HIV virus. But only 25% of the treated cells showed evidence of being successfully edited.

Researchers "use time-resolved X-ray microtomography to visualize the muscles and hinges in three-dimensions" of fly wings, modelling the complex physical processes that enable flies' flight.

Even with the cost of building new energy storage infrastructure, wind energy will continue to offer a net gain of power. Plus: wind produces enough surplus electricity to offer 72 hours of backup power (vs. 24 hours for solar panels). Researchers say that the industry of onshore wind turbines can "double in size each year—and still maintain an energy surplus."

Researchers cremated the remains of young piglets to investigate why there's little evidence of high infant mortality in the archaeological record. To no avail.

Men in 'traditional' marriages (whose wives are not employed) are more likely to look negatively upon women in the workplace.

Regardless of the structural integrity of a shoulder (rotator cuff) repair, patients have improved function and reduced pain after surgery.

Stem cells are influenced by the rigidity of the substrate they grew up on: "spending 10 days on a particular bed leads to irreversible future differentiation of the stem cells into stiff-environment-loving bone or soft-loving fat cells." That could lead to considerable demand for a new scaffolding material "based on a biocompatible silk-alginate hydrogel" which can be made to varying standards of firmness.

By appearing to tap test subjects on the hand with a small hammer while playing the recorded sounds of a hammer tapping stone, researchers made people feel their hands were more stone-like (or numb).

A gene coincidentally named FAT10 ( for F Adjacent Transcript) actually "regulates lipid metabolism and longevity," and model mice who lacked the gene were leaner, had a faster metabolism, and lived up to 20% longer.

Encapsulating immature pancreatic cells grown from human stem cells and implanting them under the skin of mice showed the cells could produce insulin whenever needed and reduce diabetic symptoms.

The CDC revised it autism prevalence rate upward again; in 2010 about 1 in 68 eight-year-olds had an autism spectrum disorder.

At age six, children award beneficial resources to members of their 'in-group;' at age eight they also assign harmful or negative resources to members of an 'out-group.'

People with OCD were less likely than controls to believe they could influence a light bulb by pressing a space bar whenever they want. The light bulb blinked randomly on and off.

A virus affecting crickets not only sterilizes them, but makes them more eager to initiate courtship. Males perhaps uninhibited by the virus would start playing a courtship song for a female much sooner than their healthy peers. Intimacy may be the virus's way of spreading.

Within the ultrapure water purification system of a nuclear reactor, scientists found oligotrophic bacteria, including new species, growing in biofilms "visible to the naked eye" on ceramic filter surfaces.

milhayser Mon, 03/31/2014 - 14:57

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Sharks have more proteins in common with humans than zebrafish!

dr. dolittle — Tue, 03 Dec 2013 17:43:47 +0000

Sharks have more proteins in common with humans than zebrafish!

Image of a great white shark from Wikimedia Commons.

Dr. Michael Stanhope from Cornell University has discovered that great white sharks actually share more proteins involved in metabolism and biochemistry in common with humans than zebrafish, a common fish model used in biomedical research. They made this discovery by sequencing the transcriptome of a heart isolated from a great white shark. I find it fascinating that sharks have more proteins in common with mammals than with bony fish, even though sharks and bony fish are not very closely related.

Source:

Cornell University Press

dr. dolittle Tue, 12/03/2013 - 12:43

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Alright all you evolutionary biologists, I expect to see you all replace your zebrafish tanks for shark tanks!

someone is gonna use this to try to discredit evolution again

anyway, just heart transcriptome? what if it was different in other organs? we need more sharks to sample

Endlessly Adaptable Animals

milhayser — Tue, 30 Apr 2013 06:57:57 +0000

Endlessly Adaptable Animals

Dr. Dolittle spent a few days at the Experimental Biology meeting of the American Physiological Society, learning incredible facts about animal adaptability. In the Sunday session, researchers showed that metabolic byproducts called ketones can protect against seizures caused by hyperbaric oxygen therapy, while seal pups, who fast for up to three months once weaned, increase their insulin resistance and become effectively diabetic. Monday taught us that insects lack lungs, instead exchanging gas through tiny valves called spiracles along their abdomen, while a Burmese python, after eating a meal up to 25% of its body weight, develops an enlarged heart to facilitate metabolism. From Tuesday Dr. Dolittle reports the pitfalls of doping elephants with LSD, and that specialized mitochondria supercharge hummingbird wings and rattlesnake tails. There are even more findings about low-oxygen, or hypoxic, adaptations, including turtle shells that prevent lactic acid buildup, and one researcher who raised geese so she could train them to fly in a wind tunnel while wearing gas masks.

milhayser Tue, 04/30/2013 - 02:57

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From Metabolism to Oncogenes and Back - Part II

apalazzo — Fri, 21 Mar 2008 07:56:27 +0000

From Metabolism to Oncogenes and Back - Part II

Last time I told you about how the view of cancer switched from the perspective of metabolism to oncogenes. Today we'll see how recent developments have placed the spotlight back on metabolic pathways.

I'll begin this tale with a quote from a review written by Andrew M Arshama and Thomas P Neufeld:

The TOR (target of rapamycin) signaling pathway has been the subject of a 30-year-long reverse engineering project, beginning in the 1970s when the macrocyclic lactone antifungal compound rapamycin was purified from soil bacteria found on the Pacific island of Rapa Nui, famous for its moai (giant carved heads).

The story begins with this funny compound that was named after the island of Rapa Nui, aka Easter Island. Rapamycin had very interesting properties, it not only acted as an antifungal agent but inhibited the immune system and slowed down cell division in mammalian organisms. In 1991 it was discovered that the target of rapamycin in yeast was a kinase that was then named TOR, for "target of rapamycin". Curiously, TOR was present in mammals, vertebrates, plants ... it was a pretty old protein, and was the central player in an ancient signaling cascade.

A couple of digressions and then we'll move on.

First, it is now known that rapamycin inhibits TOR activity by binding a complex formed between TOR (or mTOR in mammals) and a second protein called FKBP12. Second, kinases are enzymes that can add phosphates to specific locations on other proteins. Often the addition or removal of a phosphate will change the activity of a protein. As mentioned in Part I, kinases often phosphorylate other kinases. When one kinase activates a second kinase which in turn activates a third, this is known as a signaling cascade. Of course other types of proteins can act in such a cascade (G-proteins for example), but usually these "pathways" are full of kinases.

OK back to the story.

While some scientists played with rapamycin, other investigators were asking a different question: what regulates cell size? A very academic sounding question, but one that gave very intriguing answers. When cells duplicate their DNA and accumulate enough cytoplasm, only then do they divide. Cytoplasm is the cellular goo found inside the cell and outside of the nucleus. It's jam-packed with proteins, about 300 mg/ml, and contains everything that the cell needs, including ribosomes, sugars, organelles. It turns out that cells closely monitor their size and quantity of cytoplasm. This assement of size is accomplished by the activity of a bucket full of genes that are thought to form some sensing device. From a few genetic screens, it appeared that some mutant cells didn't wait to make enough cytoplasm before dividing. These cells had normal cytoplasm, just a lot less of it - in other words these mutants were smaller. The fundamental questions became:

1) How do cells sense the total amount of cytoplasmic components (proteins, ribosomes etc.)?
2) How do cells regulate the production and destruction of these cytoplasmic components?

Curiously, it was not only the size of the cells that were affected, but also the size of the animal. For example, two mutant flies that had small cells, also had small body sizes. The mutated genes were named hamartin and tuberin and encoded very conserved genes. Many other signaling molecules were picked up in those genetic screens performed in flies, including genes involved in insulin production and detection. From the insulin result you might be thinking - Aha so cells that are messed up in sensing sugar don't grow well. And indeed, for many years, researchers identified mutants that acted as if they were subjected to starvation in the presence of normal levels of nutrients. To grow properly, cells need amino acids, sugars, phosphates etc. If you starved yeast, they stop making protein and stop dividing. But it wasn't just a case of cells passively taking in nutrients and growing; instead, it seemed like cells had some sophisticated method of measuring the nutrient availability. Based on this nutrient sensor the cells decide whether

a) to grow, make proteins, divide and be happy
b) to stop protein synthesis, conserve energy and turn off cell division
c) and if things were really bad, to make protective proteins, eat its excess organelles and really prepare for the upcoming disaster.

Over the years, researchers found mutants that acted as if they were being starved even while in the midst of plenty. One such mutant identified in yeast was a protein called Rheb. This G-protein was similar in sequence to Ras, a nasty oncogene, and seemed to be required for the cell's ability to sense its metabolic condition. Mutant cells that lacked Rheb were stressed out even when there was no need. They stopped making amino acids, they shut down protein production and started to eat their own organelles (the process of eating yourself is known as autophagy).

So lets sum it up:

- rapamycin: stops cells from growing and dividing
- tuberin hamartin mutants: small cells (non-functioning cell-size sensor?)
- insulin mutants: small cells (non-functioning cell-size sensor? non-functioning metabolic sensor?)
- Rheb mutants: stressed out cells (overactive "lack of nutrient" sensor?)

Then some scientists started to add the facts together and thought that perhaps rapamycin had something to do with this nutrient/cell-size sensor? Sure enough, TOR mutants were paranoid little fellows. As with the Rheb mutants, TOR mutants acted as if Armageddon were upon them while swimming in a sea of milk and honey.

So what's the link between metabolic sensor mutants and size sensor mutants? Biochemists filled in all the connections between the players discovered by the geneticists. It turned out that all these genes were part of an evolutionarily conserved signaling pathway that acted to sense all sorts of metabolic levels. Metablic and cellular function information would be funneled into one master signal integrator, TOR, that would then turn on specific cellular programs. If the signaling pathway was overactive, cells would act as if they were swimming in ample amounts of nutrients, even when they weren't, and would divide before they had produced enough cytoplasm, leading to the small cell/small animal phenotype. If the signaling pathway was dampened, cells would act as if there wasn't enough and turned on all these stress signals. It looked like the TOR signaling pathway was the master metabolic sensory system of the cell.

About the same time as all these pieces of the puzzle fell together, other scientists discovered that quite a few of the nastiest tumor suppressors and proto-oncogenes also affected the activity of the TOR pathway. Some examples are Phospho-inositide-3 kinase (PI3K), Akt and the phosphoinosited phosphotase PTEN, one of the most important tumor suppressors. In addition, when the mammalian homologs of the hamartin and tuberin genes were mutated, the result was ... tuberous sclerosis, a disease associated with the apearance of numerous benign tumors. PI3K itself was regulated by growth factors and their receptors. Now the circle was complete.

A big picture of cell division was coming into focus. Cells need to sense many things before they can begin to divide. They need to take into account whether they have enough metabolites to make more proteins, ribosomes, and all the goodies needed to furnish the two new cells. In addition, the cells of multicellular organisms must work together. A cell can only divide if the larger organism needs more cells. There was no need for the cell to activate the cell division program if there was no need to replace tissue or for the multicellular organism to grow.

So let's draw out a diagram of what we know so far. When one set of proteins activates the next set of proteins, the connection is represented by an arrow. When one set of proteins (or factors) inhibits the next set, the connection is represented by a line ending with a blunt end.

Note that the most mysterious part of this pathway is how metabolites affect the tuberous sclerosis proteins (TSC1 and TSC2).

As you can guess, this signaling pathway is at the heart of what the cell has to do: whether to live a swinger's life full of fun and reproduction, a peaceful life of cellular-retirement, or a stress-filled life of poverty. Signals used by the cell to make this decision come from both metabolic sensors and cell-to-cell communication sensors. If a mutation arises in a gene on any of these branch points, you could wind up with an over-stimulated cell that divides way too fast (i.e. cancer).

As you can see we've come full circle. Cancer was a problem with signals - those that sensed metabolites or those that sensed cell-to-cell communication.

Some further notes: Judging from this diagram, you might think that Rapamycin, which inhibits TOR activity, must be a fabulous chemotherapeutic agent. But it isn't. Why? Well it turns out that there is a major feedback loop in this pathway. Basically TOR inhibition activates Akt. You don't want to mess with Akt: it's a major oncogene and its activation regulates many pathways that promote cell division.

Enter Ribosomes

Recently a lot of investigators have looked downstream of TOR to see how exactly it stimulates cell growth, in terms of how big cells get and in terms of how fast cells divide. And in an interesting twist, it seems as if TOR's main purpose is to regulate how the ribosome operates. First off, TOR signaling turns on the expression of ribosome proteins and ribosomal RNA. Since the ribosome is the main factory in the cell, it is no surprise that a regulator of cell size would also regulate ribosome production. But that's not all. Active TOR actually sits on ribosomes as they get ready to translate an mRNA into protein. This active TOR adds tons of phosphates directly to ribosomal proteins and even activates other kinases, such as S6 kinase, an enzyme that adds even more phosphates to the ribosome (S6 is a small ribosomal subunit). Yes, TOR activates a big phosphorylation orgy on the ribosome; however, it remains unclear what is the outcome of all these ribosomal phosphorylation events.

In addition, TOR signaling promotes the ability of RNA unwinding proteins (aka helicases) to remove RNA folds from the start of certain transcripts. TOR accomplishes this task through eIF4E, a protein that I've written about before. eIF4E is a regulator mRNA translation. It binds to the cap present at the beginning of most transcripts and can recruit helicases (eIF4A and eIF4B). In the absence of TOR signaling, the 4E inhibitors (called 4EBPs) prevent eIF4E from recruiting the helicases to the start of the transcript. When TOR is active, it phosphorylates eIF4E inhibitors and turns them off. eIF4E recruits helicases and the ribosome can now translate the mRNA in question. Having told you all this, I will now say that TOR signaling normally doesn't affect the translation of most mRNAs, but it does have a profound effect on the translation of a small set of transcripts that contain extensive RNA folds right after the cap. And what are these transcripts? Here is the real kicker. Many are mRNAs from proto-oncogenes whose protein products are critical for promoting cell division. From very recent experiments in Nahum Sonenberg's lab, we found out that just increasing the level of eIF4E by two fold can lead to the over-expression of a whole group of proto-oncogenes like myc. In fact, many drugs that target eIF4E are in clinical trials for a variety of cancers. So in the end it looks like the cell's metabolic state could stimulate the translation of genes that promote cell division. How's that for a turn of events?

In the next entry I'll talk about some of the newest TOR signaling papers (some published, and others soon to be published), and a surprisingly new connection between metabolism and cancer.

Further notes:
-I've been furiously typing this post in between experiments - I'll be correcting any typos over time. I'll also try to stick in some references here and in the previous entry as soon as I can get to it. Also feel free to add any extra info in the comments section. I didn't want to complicate this entry so note that I did not talk about TORC1 & TORC2 or autophagy, or memory or any of the gadzillion processes affected by TOR signaling.

apalazzo Fri, 03/21/2008 - 03:56

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I have nothing to add rather than saying that this is really fantastic summary of the TOR story. Thanks for posting it, looking forward to your next entry.

Great blog, thanks! Clear, interesting/appropriate details, nice style. Added to my regular rounds.

(I was pointed here from ouroboros.wordpress.com.)

I am trying to make mTOR signalling understandeable for my non-biologist co-workers and your blog has helped me immensely - thanks! The pitfall of AKT upregulation at mTOR inhibition is substantial, but can be reduced if mentioned, that rapamycin (or analogs) cannot block the action of TORC2, which is the activator of AKT. Unfortunately at permanent addition of rapamycin, it can inhibit the formation of new TORC2, which may lead in consequence to the feedback loop you have mentioned - but at the late stage of the cancer when the drugs are administered, this might be your smallest concern...

Some time before, I really needed to buy a car for my corporation but I didn't have enough money and could not order something. Thank God my sister proposed to get the personal loans from trustworthy bank. So, I acted so and was satisfied with my student loan.