#Diabetes debate: Triglycerides form in liver despite insulin resistance In type 2 diabetics insulin fails to suppress blood sugar production by the liver
while paradoxically allowing the production of hepatic triglycerides. This combination results in multiple health risks including high blood sugar and fatty liver disease.
For years to gain insight into this phenomenon researchers focused on the role of altered insulin action in the liver in the production of triglycerides.
I. Shulman the George R. Cowgill professor of medicine and cellular & molecular physiology--developed a novel method to measure the rate of triglyceride production from fatty acids in three types of animals:
The findings also explain the longstanding paradox of why insulin therapy does not exacerbate but instead reduces fatty liver disease in patients with type 2 diabetes.
These results provide new insights into the pathogenesis of nonalcoholic liver disease and provides new approaches to treat fatty liver disease
which is now the most common liver disease in the world said Shulman. Shulman and his team plan to apply similar methodology to translate their findings to insulin-resistant patients with type 2 diabetes hyperlipidemia and fatty liver disease e
#'Crispr'science: Newer genome editing tool shows promise in engineering human stem cells In a recent online report on the work in Molecular Therapy the Johns Hopkins team says the findings could streamline
and speed efforts to modify and tailor human-induced pluripotent stem cells (ipscs) for use as treatments
or in the development of model systems to study diseases and test drugs. Stem cell technology is quickly advancing
and we think that the days when we can use ipscs for human therapy aren't that far away says Zhaohui Ye Ph d. an instructor of medicine at the Johns hopkins university School of medicine.
This is one of the first studies to detail the use of CRISPR in human ipscs showcasing its potential in these cells CRISPR originated from a microbial immune system that contains DNA segments known as clustered regularly interspaced short palindromic repeats.
The engineered editing system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.
Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions far more efficiently than other gene editing techniques such as TALEN short for transcription activator-like effector nuclease.
Despite CRISPR's advantages a recent study suggested that it might also produce a large number of off-target effects in human cancer cell lines specifically modification of genes that researchers didn't mean to change.
Linzhao Cheng Ph d. a professor of medicine and oncology in the Johns hopkins university School of medicine; and their colleagues pitted CRISPR against TALEN in human ipscs adult cells reprogrammed to act like embryonic stem cells.
and studying disease. The researchers compared the ability of both genome editing systems to either cut out pieces of known genes in ipscs
or cut out a piece of these genes and replace it with another. As model genes the researchers used JAK2 a gene that when mutated causes a bone marrow disorder known as polycythemia vera;
SERPINA1 a gene that when mutated causes alpha1-antitrypsin deficiency an inherited disorder that may cause lung and liver disease;
and AAVS1 a gene that's been discovered recently to be a safe harbor in the human genome for inserting foreign genes.
Their comparison found that when simply cutting out portions of genes the CRISPR system was significantly more efficient than TALEN in all three gene systems inducing up to 100 times more cuts.
However when using these genome editing tools for replacing portions of the genes such as the disease-causing mutations in JAK2
It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.
CRISPR-mediated genome editing opens the door to many genetic applications in biologically relevant cells that can lead to better understanding of
and potential cures for human diseases says Cheng g
#Computing: Common'data structure'revamped to work with multicore chips Today hardware manufacturers are making computer chips faster by giving them more cores or processing units.
But while some data structures are adapted well to multicore computing others are not. In principle doubling the number of cores should double the efficiency of a computation.
With algorithms that use a common data structure called a priority queue that's been true for up to about eight cores
--but adding any more cores actually causes performance to plummet. At the Association for Computing Machinery's Symposium on Principles and Practice of Parallel Programming in February researchers from MIT's Computer science and Artificial intelligence Laboratory will describe a new way of implementing priority queues that lets them keep pace with the addition of new cores.
In simulations algorithms using their data structure continued to demonstrate performance improvement with the addition of new cores up to a total of 80 cores.
A priority queue is a data structure that as its name might suggest sequences data items according to priorities assigned them
when they're stored. At any given time only the item at the front of the queue--the highest-priority item--can be retrieved.
Priority queues are central to the standard algorithms for finding the shortest path across a network
and for simulating events and they've been used for a host of other applications from data compression to network scheduling.
With multicore systems however conflicts arise when multiple cores try to access the front of a priority queue at the same time.
The problem is compounded by modern chips'reliance on caches--high-speed memory banks where cores store local copies of frequently used data.
As you're reading the front of the queue the whole front of the queue will be in your cache says Justin Kopinsky an MIT graduate student in electrical engineering
and computer science and one of the new paper's co-authors. All of these guys try to put the first element in their cache
and then do a bunch of stuff with it but then somebody writes to it and it invalidates everybody else's cache.
And this is like an order-of-magnitude slowdown--maybe multiple orders of magnitude. To avoid this problem Kopinsky;
fellow graduate student Jerry Li; their advisor professor of computer science and engineering Nir Shavit; and Microsoft Research's Dan Alistarh a former student of Shavit's relaxed the requirement that each core has to access the first item in the queue.
If the items at the front of the queue can be processed in parallel --which must be the case for multicore computing to work anyway--they can simply be assigned to cores at random.
But a core has to know where to find the data item it's been assigned
which is harder than it sounds. Data structures generally trade ease of insertion and deletion for ease of addressability.
You could for instance assign every position in a queue its own memory address: To find the fifth item you would simply go to the fifth address.
But then if you wanted to insert a new item between say items four and five you'd have to copy the last item in the queue into the first empty address then copy the second-to-last item into the address you just vacated and so on until you'd vacated address five.
Priority queues are constantly being updated so this approach is woefully impractical. An alternative is to use
Each element of a linked list consists of a data item and a pointer to the memory address of the next element.
if multiple cores are trying to modify data items simultaneously. Say that a core has been assigned element five.
It goes to the head of the list and starts working its way down. But another core is already in the process of modifying element three
so the first core has to sit and wait until it's done. The MIT researchers break this type of logjam by repurposing yet another data structure called a skip list.
The skip list begins with a linked list and builds a hierarchy of linked lists on top of it.
Only say half the elements in the root list are included in the list one layer up the hierarchy.
But the MIT researchers'algorithm starts farther down the hierarchy; how far down depends on how many cores are trying to access the root list.
Each core then moves some random number of steps and jumps down to the next layer of the hierarchy.
It repeats the process until it reaches the root list. Collisions can still happen particularly
when a core is modifying a data item that appears at multiple levels of the hierarchy
a research team led by investigators at Beth Israel Deaconess Medical center (BIDMC) has uncovered previously unknown steps in the development of insulin resistance, a hallmark of type 2 diabetes.
Reported in the January 2015 issue of Nature Cell biology, their surprising new findings identify two transcription factors--the glucocorticoid receptor (GR)
therapies for type 2 diabetes.""We wanted to understand what was initially happening to cause the body to become unresponsive
"explains senior author Evan Rosen, MD, Phd, of the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical school."
but most work has focused on rapid events that happen in cells immediately after the hormone is produced.
and that involve previously unsuspected biological pathways. Perhaps most importantly, we found that these pathways work completely in the nucleus of the cell by regulating the expression of key target genes,
However, epidemiological and molecular data have suggested that events leading to insulin resistance might also take place in the nucleus,
One such piece of evidence comes from an observation surrounding fetal programming, says Rosen.""Fetal programming centers on a person's exposure in utero,
"he explains.""So, for example, whether a fetus has received too few or too many nutrients from the mother can lead to a person becoming obese or diabetic in adulthood,
and this in turn can be passed along to the next generation. There is a lot of evidence that insulin resistance can be passed on this way
and this type of intergenerational event almost certainly develops in the nucleus."Epigenomic modifications refer to changes in the structure of DNA that are distinct from mutations
we could discern which epigenomic events might be at the core of insulin resistance.""Because the types of epigenomic changes being analyzed occur at locations where transcription factors bind,
the team was able use their data to infer which transcription factors might be involved in the development of insulin resistance."
Most importantly, these data tell us that we have an awful lot still to learn about the basic mechanisms by which diabetes is triggered
which we can approach drug therapy for this disorder
#Byproducts from bacteria awaken dormant T-cells HIV viruses Dental and medical researchers from Case Western Reserve University found another reason to treat periodontal disease as soon as possible.
They discovered that byproducts of bacteria in gum disease, called metabolic small chain fatty acid (SCFA),
can work together to wake up HIV in dormant T-cells and cause the virus to replicate.
Their findings help explain why people with the HIV-infections and periodontal disease have higher levels of the virus in their saliva than HIV patients with healthy gums.
The researchers speculate that byproducts from other bacteria infections in other diseases might change gene expression using similar mechanisms.
For dental patients with HIV their findings further support how important it is to treat bacterial infections in gum disease early.
This interaction by SCFA and T-cells surprised co-investigators Fengchun Ye, assistant professor of biological sciences at the Case Western Reserve University School of dental medicine,
and Jonathan Karn, director of the Center for Aids Research and professor and chair of the Department of Molecular biology and Microbiology at Case Western Reserve's medical school.
Their findings are described in the article, "Short chain fatty acids potently induce latent HIV-1 in T-cells by activating P-TEFB and multiple histone modifications,"
In the interaction between gum disease and HIV, five SCFA byproducts from two prevalent oral bacteria--Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn)--are involved in activating resting immune T-cells carrying latent (inactive
) HIV-1 virus. The process acts much like the jumper cables attached to a live battery recharging a dead one to get it running again,
and respond to inflammation to ward off an infection in the body.""As long as someone is healthy,
Last year, Ye and Karn discovered that one SCFA--butyric acid--induced a chain of events that reactivate the virus associated with Kaposi's sarcoma, the most common malignancy in HIV patients.
Karn, the Reinberger Professor of Molecular biology.""It surprised us to find they all work as an aggregate."
"The impact on waking up T-cells and activating HIV replication was a"double whammy"find that contributes to understanding the little-known microbiome in HIV disease,
That prompted the researchers to investigate the mechanism that drives the replication of the virus in gum disease.
HIV antiviral therapy prevents active HIV cells from replicating and doesn't affect the quiet viruses in sleeping T-cells.
As long as the patient is free of gum disease, the virus sleeps and remains in check, Karn said d
#Blood test for prostate cancer investigated Mitchell believes the technique will be transformative in providing improved cancer diagnostics that can both predict treatment outcomes and monitor patient responses to therapy.
In a large retrospective study of blood samples the researchers showed that the method called a liquid biopsy could accurately distinguish prostate cancer from normal controls without prior knowledge of the genetic signature of the tumors and with over three times the sensitivity of current prostate specific-antigen
antigen (PSA) screening. The study appears in the January issue of Clinical Chemistry (volume 61 page 239) which is dedicated to Molecular Diagnostics:
Based on the reported data and work in progress I believe the'liquid biopsy'will revolutionize cancer diagnostics
not only before a patient begins therapy but also following patient responses to therapy said Mitchell the paper's corresponding author and professor of Pathology Microbiology and Immunology.
The study collected serum from more than 200 patients with prostate cancer and more than 200 controls.
The samples included PSA levels and prostate tissue biopsy grading called the Gleason score. The researchers reported that the technique distinguished prostate cancer from normal controls with 84-percent accuracy and cancer from benign hyperplasia and prostatitis with an accuracy of 91 percent.
Because the method quantifies the inherent chromosomal instability of cancer and can be followed as a function of time without having to do an invasive tissue biopsy it is called a liquid biopsy.
It's been known for many years that dying cells including tumor cells shed DNA into the bloodstream.
But only recently has technology notably next-generation sequencing made it possible to reliably distinguish
and quantify cancer-specific DNA from normal controls by the identification and chromosomal location of billions of specific DNA fragments present in blood as cell-free DNA.
The prostate cancer study identified 20 hotspots of greatest chromosomal instability as additions or deletions in less than 0. 5 percent of the total DNA present in human chromosomes.
While researchers around the world are working on their own liquid biopsies Mitchell said the group's technique takes a broader approach.
It examines the entire genome rather than known specific gene point mutations. Robust mutation panels vastly improve monitoring
since cancer cells are constantly deleting chromosomal DNA and liquid biopsies with only one or two mutations will allow cancer cell escape variants to go undetected he said.
Since the entire genome was surveyed the researchers were able to identify a non-coding region of the genome as a hotspot which may be generating previously unrecognized chromosomal control elements in prostate cancer.
The other 19 hotspots were involved rich in genes in replication and cell control processes that are highly relevant to cancer.
Since cell-free DNA has a relatively short half-life in the circulation sequencing of cell-free DNA soon after therapy may be used to detect minimal residual disease in solid tumors Mitchell said.
The researchers reported similar results in a study of breast cancer at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago.
Mitchell further predicted that liquid biopsies will quantify immediate tumor responses to therapy y
#New technology focuses diffuse light inside living tissue In the Jan 5 issue of Nature Communications Wang the Gene K. Beare Professor of Biomedical engineering at Washington University in St louis reveals for the first time a new
technique that focuses diffuse light inside a dynamic scattering medium containing living tissue. In addition they have improved the speed of optical focusing deep inside tissue by two orders of magnitude.
This improvement in speed is an important step toward noninvasive optical imaging in deep tissue and photodynamic therapy.
In the new research Wang and his team have built on a technique they developed in 2010 to improve the focusing speed of time-reversed ultrasonically encoded (TRUE) optical focusing for applications in living tissue.
To focus light the engineers use a virtual internal guide star at the targeted location.
By detecting the wavefront of light emitted from the guide star they can determine an optimum phase pattern that allows scattered light moving along different paths to focus at the targeted location.
When light is shined into living biological tissue breathing and blood flow changes the optical interference or speckle pattern
To overcome this obstacle the team used a fast-responding photorefractive crystal that is sensitive to light at the 790-nanometer wavelength making it suitable to focus light deep into biological tissue.
The improved speed allowed Wang to achieve the first optical focusing of diffuse light inside a scattering medium containing living biological tissue.
#Technology to recycle all type of plastics without using water The technology developed by Marco Adame founder of Ak Inovex can process more than 90 percent of any type of plastic avoids water waste
and reduces production costs by half without reducing the quality of the pellets (small beads of recycled plastic) by avoiding stages with severe changes in temperature.
However this type of plastic has the distinction of being hygroscopic (when it comes in contact with water it retains moisture at a molecular level)
As a result the energy consumption is reduced by half and also the physical space required to perform the operation is less
Similarly the production of pellets is of better quality a situation that makes the recycling process more profitable.
which are responsible for cooling the plastic through contact with special walls and form the plastic beads the founder of the company explained.
The advantage of this technology is its ability to process any type of plastic such as styrofoam polystyrene PET and ABS;
and add an ecological washing machine for plastics that uses a special biodetergent which will reduce the cost of operation even more.
Marco Adame commented that during their participation in the Cleantech Challenge Mexico a contest to promote the development of green companies he had contact with the ALINSA group which is engaged in the manufacture of environmentally friendly cleaning products using biodegradable chemicals.
After the competition the two companies started talking and joined efforts with the aim of integrating the ecological washing machine system using degradable plastic substances in less than 28 days without affecting the environment hence replacing lye
To accomplish that Duke university researchers used software they developed to predict a constantly-evolving infectious bacterium's countermoves to one of these new drugs ahead of time before the drug is tested even on patients.
When the researchers treated live bacteria with the new drug two of the genetic changes actually arose just as their algorithm predicted.
This gives us a window into the future to see what bacteria will do to evade drugs that we design before a drug is deployed said co-author Bruce Donald a professor of computer science and biochemistry at Duke.
Developing preemptive strategies while the drugs are still in the design phase will give scientists a head start on the next line of compounds that will be effective despite the germ's resistance mutations.
or plan for the next one or rule out therapies that are unlikely to remain effective for long said Duke graduate student Pablo Gainza-Cirauqui who co-authored the paper.
Since the first antibacterial drugs were introduced in the 1940s bacteria have evolved ways to resist every new antibiotic that has been developed--a process that has been accelerated by the use of antibiotics in livestock to help them gain weight
and in humans to treat viral infections that antibiotics are powerless to cure. My kids are now 15 and 13
The percentage of infections caused by the bacterium Staphylococcus aureus that have proven resistant to treatment has risen steadily from just over 2 percent in 1975 and 29 percent in 1991 to more than 55 percent today--resulting in more than 11000 deaths in the U s. each year a higher death
Until now scientists trying to predict the genetic changes that would enable a bacterium to evade a particular drug have had to look up possible mutations from libraries of resistance mutations that have been observed previously.
With a new drug there is always the possibility that the organism will develop different mutations that had never been seen before.
and Amy Anderson at the University of Connecticut used a protein design algorithm they developed called OSPREY to identify DNA sequence changes in the bacteria that would enable the resulting protein to block the drug from binding
while still performing its normal work within the cell. The team focused on a new class of experimental drugs that work by binding
and inhibiting a bacterial enzyme called dihydrofolate reductase (DHFR) which plays an essential role in building DNA and other processes.
The drugs called propargyl-linked antifolates show promise as a treatment for MRSA infections but have yet to be tested in humans.
Will they be the same old mutations we've seen before or might the bacteria do new things instead?
From a ranked list of possible mutations the researchers zeroed in on four tiny differences known as single nucleotide polymorphisms
Though none of the mutations they identified had been reported previously experiments with live bacteria in the lab showed their predictions were right.
When the scientists treated MRSA with the new drugs and sequenced the bacteria that survived more than half of the surviving colonies carried the predicted mutation that conferred the greatest resistance--a tiny change that reduced the drugs'effectiveness by 58-fold.
The fact that we actually found the new predicted mutations in bacteria is very exciting Donald said.
The researchers are now using their algorithm to predict resistance mutations to other drugs designed to combat pathogens like E coli and Enterococcus.
We might even be able to coax a pathogen into developing mutations that enable it to evade one drug
Their computational approach could be especially useful for forecasting drug resistance mutations in other diseases such as cancer HIV
and influenza where raising resistant cells or strains in the lab is more difficult to do than with bacteria the researchers say.
The software they developed called OSPREY is open-source and freely available for any researcher to use e
Skin adipocytes help protect against infections Richard Gallo MD Phd professor and chief of dermatology at UC San diego School of medicine and colleagues have uncovered a previously unknown role for dermal fat cells known as adipocytes:
They produce antimicrobial peptides that help fend off invading bacteria and other pathogens. It was thought that once the skin barrier was broken it was entirely the responsibility of circulating (white blood cells like neutrophils
and macrophages to protect us from getting sepsis said Gallo the study's principal investigator. But it takes time to recruit these cells (to the wound site.
We now show that the fat stem cells are responsible for protecting us. That was unexpected totally.
It was known not that adipocytes could produce antimicrobials let alone that they make almost as much as a neutrophil.
The human body's defense against microbial infection is tiered complex multi and involves numerous cell types culminating in the arrival of neutrophils
and monocytes--specialized cells that literally devour targeted pathogens. But before these circulating white blood cells arrive at the scene the body requires a more immediate response to counter the ability of many microbes to rapidly increase in number.
That work is done typically by epithelial cells mast cells and leukocytes residing in the area of infection.
Staphylococcus aureus is a common bacterium and major cause of skin and soft tissue infections in humans.
The emergence of antibiotic-resistant forms of S. aureus is a significant problem worldwide in clinical medicine.
Prior published work out of the Gallo lab had observed S. aureus in the fat layer of the skin
if the subcutaneous fat played a role in preventing skin infections. Ling Zhang Phd the first author of the paper exposed mice to S. aureus and within hours detected a major increase in both the number and size of fat cells at the site of infection.
More importantly these fat cells produced high levels of an antimicrobial peptide (AMP) called cathelicidin antimicrobial peptide or CAMP.
AMPS are used molecules by the innate immune response to directly kill invasive bacteria viruses fungi and other pathogens.
AMPS are our natural first line defense against infection. They are evolutionarily ancient and used by all living organisms to protect themselves said Gallo.
However in humans it is becoming increasingly clear that the presence of AMPS can be a double-edged sword particularly for CAMP.
Too little CAMP and people experience frequent infections. The best example is atopic eczema (a type of recurring itchy skin disorder.
These patients can experience frequent Staph and viral infections. But too much CAMP is also bad.
Evidence suggests excess CAMP can drive autoimmune and other inflammatory diseases like lupus psoriasis and rosacea.
The scientists confirmed their findings by analyzing S. aureus infections in mice unable to either effectively produce adipocytes or
whose fat cells did not express sufficient antimicrobial peptides in general and CAMP in particular. In all cases they found the mice suffered more frequent and severe infections.
Further tests confirmed that human adipocytes also produce cathelicidin suggesting the immune response is similar in both rodents and humans.
Interestingly obese subjects were observed to have more CAMP in their blood than subjects of normal weight.
The potential clinical applications of the findings will require further study said Gallo. Defective AMP production by mature adipocytes can occur due to obesity
or insulin resistance resulting in greater susceptibility to infection but too much cathelicidin may provoke an unhealthy inflammatory response.
For example current drugs designed for use in diabetics might be beneficial to other people who need to boost this aspect of immunity.
Conversely these findings may help researchers understand disease associations with obesity and develop new strategies to optimize care e
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