Now, a new screening process will simplify non-viral transfection, providing a method researchers and clinicians use to find an optimal set of biomaterials to deliver genes to cells.

Developed by William Murphy, the Harvey D. Spangler professor of biomedical engineering at the University of Wisconsin-Madison, the method gives researchers greater control over how cells react to the gene delivery mechanism. The broader implication is more nuanced, effective control over cell behavior. “We’ve been exploring using this concept for reprogramming of adult cells, as well as controlling differentiation of stem cell types,” Murphy says.

Murphy and his collaborators published news of their advance in a recent issue of Nature Scientific Reports.*

In a current successful approach, researchers use specialized viruses to deliver genetic material to cells. While efficient, that method also carries a greater risk of turning on unwanted genes or provoking an immune response from the body – making it less attractive for sensitive biomedical applications like controlling stem cell behavior, says Murphy.

His team has developed a process that does not rely on viruses. Rather, the researchers can grow specific calcium phosphate coatings that serve as a medium via which genetic material can be delivered to cells more efficiently. By matching a coating to a specific application for delivering genes, Murphy has seen up to a 70-fold increase in successful expression of those genes in human stem cells.

“From an application standpoint, the advance could be really impactful, and could enable gene delivery to become an integral part of medical device design and tissue engineering applications,” says Murphy.

The process could be critical to further advances in regenerative medicine. Since researchers can apply it to any size or shape of tissue engineering structure, it could help provide engineers with a simpler way to build the complex tissue structures required to deliver next-generation drug screening and patient therapies.

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The new Journal of Health Politics, Policy, and Law appeared in my mailbox. It includes a useful symposium on the policy and politics of reproductive health:

Lynn Paltrow and Jeanne Flavin, “Arrests of and Forced Interventions on Pregnant Women in the United States, 1973–2005: Implications for Women’s Legal Status and Public Health.”

Miranda Waggoner, “Motherhood Preconceived: The Emergence of the Preconception Health and Health Care Initiative.”

Amanda Dennis, Kelly Blanchard, Denisse Córdova, Britt Wahlin, Jill Clark, Karen Edlund, Jennifer McIntosh, and Lenore Tsikitas, “What Happens to the Women Who Fall through the Cracks of Health Care Reform? Lessons from Massachusetts.”

Amy Dworsky, Kym Ahrens, and Mark Courtney. “Health Insurance Coverage and Use of Family Planning Services among Current and Former Foster Youth: Implications of the Health Care Reform Law.”

Debra Stulberg. “The Patient Protection and Affordable Care Act and Reproductive Health: Harnessing Data to Improve Care.”

Oh yeah. Here’s one more: Adam Sonfield and Harold Pollack on reproductive health issues here:

After nearly a century of failed or incomplete legislative efforts, the Patient Protection and Affordable Care Act (PPACA), enacted by Congress in March 2010, establishes the principle that every American is entitled to affordable and effective health insurance coverage regardless of income or health status. Although many aspects of the act have received broad attention, its impact on reproductive health has received considerably less scrutiny, except when debated through the specific lens of particularly polarized ideological concerns. If fully implemented as planned, the PPACA has the potential to improve reproductive health in the United States in at least three ways: increasing the number of women and men with insurance coverage; increasing the value of insurance coverage for addressing reproductive health needs; and improving access to reproductive health services and information more generally. Several PPACA provisions stand out as having particular importance for reproductive health, including Medicaid family planning expansions, standards for an essential health benefits package, expanded coverage for contraception and other clinical preventive services, and teen pregnancy prevention programs. All these potential gains, however, are threatened by political, economic, and logistical challenges to the PPACA and by flaws in the legislation itself.

Our piece was almost two years in the making on the slow academic brew. I’m struck by the number of issues here that never reached the public discourse. The abortion issue dominated during the legislative debate. Then religious institutions’ coverage of contraception consumed much of the oxygen during the 2012 campaign. Much more was going on. And there were many more reproductive health provisions contained within the apparent junk DNA of the health reform bill.

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A new University of Iowa study identifies a protein within certain brain cells as a communications hub for controlling blood pressure, and suggests that abnormal activation of this protein may be a mechanism that links cardiovascular disease and obesity to elevated blood pressure.

“Cardiovascular diseases are the leading cause of death worldwide, and hypertension is a major cardiovascular risk factor,” says Kamal Rahmouni, UI associate professor of pharmacology and internal medicine, and senior study author. “Our study identifies the protein called mTORC1 in the hypothalamus as a key player in the control of blood pressure. Targeting mTORC1 pathways may, therefore, be a promising strategy for the management of cardiovascular risk factors.”

The hypothalamus is a small region of the brain that is responsible for maintaining normal function for numerous bodily processes, including blood pressure, body temperature, and glucose levels. Signaling of mTORC1 protein in the hypothalamus has previously been shown to affect food intake and body weight.

The new study, which was published in the journal Cell Metabolism, shows that the mTORC1 protein is activated by small molecules and hormones that are associated with obesity and cardiovascular disease, and this activation leads to dramatic increases in blood pressure.

Leucine is an amino acid that we get from food, which is known to activate mTORC1. The UI researchers showed that activating mTORC1 in rat brains with leucine increased activity in the nerves that connect the brain to the kidney, an important organ in blood pressure control. The increased nerve activity was accompanied by a rise in blood pressure. Conversely, blocking this mTORC1 activation significantly blunted leucine’s blood pressure-raising effect.

This finding may have direct clinical relevance as elevated levels of leucine have been correlated with an increased risk of high blood pressure in patients with cardiovascular disease.

“Our new study suggests a mechanism by which leucine in the bloodstream might increase blood pressure,” Rahmouni says.

Previous work has also suggested that mTORC1 is a signaling hub for leptin, a hormone produced by fat cells, which has been implicated in obesity-related hypertension.

Rahmouni and his colleagues showed that leptin activates mTORC1 in a specific part of the hypothalamus causing increased nerve activity and a rise in blood pressure. These effects are blocked by inhibiting activation of mTORC1.

“Our study shows that when this protein is either activated or inhibited in a very specific manner, it can cause dramatic changes in blood pressure,” Rahmouni says. “Given the importance of this protein for the control of blood pressure, any abnormality in its activity might explain the hypertension associated with certain conditions like obesity and cardiovascular disease.”

Rahmouni and his team hope that uncovering the details of the pathways linking mTORC1 activation and high blood pressure might lead to better treatments for high blood pressure in patients with cardiovascular disease and obesity.

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The spatial-organization tactics their model organism, Bacillus subtilis, takes to evolve and adapt might be imitated in other related Gram-positive bacteria, including harmful, ever-changing germs like staph, strep, and listeria, to strengthen their virulence or cause persistent infections. The researchers think that these mechanisms for accelerating evolution may be found in other living creatures as well.

Replication – the duplicating of the genetic code to create a new set of genes – and transcription – the copying of DNA code to produce a protein – are not separated by time or space in bacteria. Therefore, clashes between these machineries are inevitable. Replication traveling rapidly along a DNA strand can be stalled by a head-on encounter or same-direction brush with slower-moving transcription.

The senior authors of the study, Houra Merrikh, UW assistant professor of microbiology, and Evgeni Sokurenko, UW professor of microbiology, and their research teams are collaborating to understand the evolutionary consequences of these conflicts. The major focus of Merrikh and her research team is on understanding mechanistic and physiological aspects of conflicts in living cells – including why and how these collisions lead to mutations.

Impediments to replication, they noted, can cause instability within the genome, such as chromosome deletions or rearrangements, or incomplete separation of genetic material during cell division. When dangerous collisions take place, bacteria sometimes employ methods to repair, and then restart, the paused DNA replication, Merrikh discovered in her earlier work at the Massachusetts Institute of Technology.

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OK, so the position of the sign implies that at MIT, it’s some kind of bizarro world where hordes of drunk people stumble out of labs, rather than hordes of drunk people bumbling into labs from the main campus. Wouldn’t you expect it to be more the latter?

Heck, maybe not. It’s been some time since I’ve been in school. But if I were at MIT, I’d be more likely to knock a few beers back at the Cambridge Brewing Company and then stagger into some engineering lab.

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If you think the purpose of the individual mandate is to avert a death spiral by addressing health-based selection into the insurance pool, I would agree with you. But, it turns out, there’s another economics argument. Read about it on the LDI site.

@afrakt

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Lead researcher, Ingrid Scheffer, professor and pediatric neurologist, of the Florey Neuroscience Institute in Melbourne, Victoria, Australia, and an international team of colleagues, write about their discovery of the focal epilepsy gene in the 31 March online issue of Nature Genetics.

Scheffer said in an interview broadcast on the ABC News AM radio show on Monday:

“This discovery is paradigm shifting.”

Epilepsy affects about 1 in 50 people. There are many different forms, but about 60% of epilepsies are known as focal epilepsy or partial epilepsy, where the seizures come from one part of the brain.

It was thought that this type of epilepsy was only caused by brain injury or tumors, but Scheffer says their discovery means:

“…if you have focal epilepsy and there is no cause known, then this gene should be tested to look for a mutation.”

She and her colleagues made their discovery after studying about 90 families where two members had epilepsy.

Their results showed that a gene called DEPDC5 causes focal epilepsy in about 12% per cent of families in which only two people have focal epilepsy.

In their study report they write:

“This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies.”

As well as opening new opportunities for diagnosing epilepsy, the researchers believe their discovery will also lead to better targeted treatments.

But Scheffer cautions there is a still a way to go. First we need to understand more about DEPDC5. All we know at present is that the protein it codes for is involved with signalling inside cells.

When we understand what goes wrong, then we can start to think about targeting it and “really improve outcomes,” she adds.

In the families they studied, the researchers noted there were some individuals with intellectual disabilities, and some with autism spectrum disorders and psychiatric features.

Scheffer says they think DEPDC5 may well play a role in these other disorders too, but they will need to study a lot more patients with the gene mutations and these disorders to establish a causal connection.

In another recent study led by Columbia University Medical Center in New York, researchers propose that epilepsy and migraine share a genetic link.

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When infected with the bacteria Wolbachia, mosquitoes are unable to spread viruses such as dengue, a disease which kills round 40,000 people each year with no vaccines or specific treatments currently available. There have been around 2,400 cases of dengue infection in Northern Australia in recent years.

However, the bacteria has been difficult to spread within the mosquito population because it reduces the mosquitoes’ ability to lay viable eggs.

Now Professor Hoffmann from the University of Melbourne and Professor Michale Turelli from the University of California have shown that by introducing an insecticide resistance gene alongside the Wolbachia bacteria into the mosquito, that the insects pass on the disease-blocking bacteria to other mosquitoes faster. The results are published in the journal Proceedings of the Royal Society B.

This could mean that the spread of disease can be stopped faster, and less infected mosquitoes would need to be released in a disease control program said Professor Ary Hoffmann from the University of Melbourne’s Bio21 Institute and Department of Genetics.

“Our results show that Wolbachia-based strategies could hold the key to a cheap and sustainable approach to disease control,” Professor Hoffmann said.

Wolbachia bacteria strains live naturally inside up to 70% of all insects and are known to protect them against viral infection. The disease-blocking strain of Wolbachia was first discovered in Australian fruit flies in 1988 by Prof Hoffmann, and trials with collaborators at Monash and James Cook Universities in 2011 showed that Wolbachia-infected mosquitoes were unable to spread the dengue virus.

The approach taken in this new work involves adding a pesticide resistance gene to a newer strain of Wolbachia called wMelPop, which is a strong blocker of dengue and other viruses . Insecticide use is very common in dengue and malaria-prone regions and so this strategy should select for the survival of only the Wolbachia-infected mosquitoes, but then these insects would be unable to pass on a virus to humans.

Prof Hoffmann added that insecticide resistance genes would not spread to the uninfected mosquito populations because a Wolbachia-infected female with a resistance gene will always pass on both the gene and the bacteria to her offspring. Then, when an uninfected female mates with an infected male, the bacterium causes cytoplasmic incompatibility, which leads to the death of embryos.

“So the association between resistance and the infection is maintained, the resistance does not move into the rest of the population, and the strategy can utilize insecticides that are no longer part of active mosquito control programs.”

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Fragile X chromosome syndrome (FXS) is the most frequent known cause of inherited mental retardation and disorders in the autistic range. It involves a genetic disease, with an incidence in Spain estimated at 1 in every 4,000 individuals. The syndrome arises from a deficit in the expression of the FMRP protein (fragile X mental retardation protein), which plays a fundamental role in the regulation of the neuronal function. Patients with FXS present mental retardation, attention deficit, anxiety, self-harming and autistic behaviour, hyposensitivity to pain and a high rate of epileptic crises. All these anomalous neuronal expressions are regulated by the endocannabinoid system.

The research, using genetically modified mice that lacked FMRP protein and that partially reproduced the symptomatology of fragile X chromosome syndrome in humans, have shown that blocking CB1 cannabinoid receptors with the Rimonabant pharmaceutical drug normalizes cognitive alterations, sensitivity to pain and epileptic crises. This finding suggests that the administration of pharmaceutical drugs that block the function of the cerebral endocannabinoid system may well be a new strategy for treating patients with fragile X chromosome syndrome.

Rimonabant pharmaceutical drug has been on the market for some time “for the treatment of obesity“, explained Ms Mato. “Then, however, it was used in much higher doses and these high dosages gave rise to certain psychiatric problems, and this is why it was taken off the market”. Nonetheless, it involves a drug which “has been used a lot in preclinical research into the endocannabinoid system, and its action mechanism is very well established”.

The next step, Ms Mato pointed out, should be “to better characterise the action mechanism of this treatment, and test the various dosages to see what would be the optimum one to normalize the deficit. And the following stage would be the clinical trials. In fact, we believe this would be relatively feasible, because as it has already been marketed, all that preclinical stage regarding toxicity of the drug for humans has been undertaken, and it is a relatively safe pharmaceutical drug”.

Although Ms Mato considers it to be a great advance that it has been shown in animal models that “the cognitive deficit caused by the disease has been normalised to a certain extent”, she is aware that it could be that “the clinical trials do not produce such good results, as it is common for this to happen when developing therapies for psychiatric disorders”.

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“The interactions between asbestos exposure, asbestosis and smoking, and their influence on lung cancer risk are incompletely understood,” said lead author Steven B. Markowitz, MD DrPH, professor of occupational and environmental medicine at the School of Earth & Environmental Sciences at Queens College in New York. “In our study of a large cohort of asbestos-exposed insulators and more than 50,000 non-exposed controls, we found that each individual risk factor was associated with increased risk of developing lung cancer, while the combination of two risk factors further increased the risk and the combination of all three risk factors increased the risk of developing lung cancer almost 37-fold.”

The findings were published online ahead of print publication in the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

The study included 2,377 long-term North American insulators and 54,243 male blue collar workers with no history of exposure to asbestos from the Cancer Prevention Study II. Causes of death were determined from the National Death Index.

Among non-smokers, asbestos exposure increased the rate of dying from lung cancer 5.2-fold, while the combination of smoking and asbestos exposure increased the death rate more than 28-fold. Asbestosis increased the risk of developing lung cancer among asbestos-exposed subjects in both smokers and non-smokers, with the death rate from lung cancer increasing 36.8-fold among asbestos-exposed smokers with asbestosis.

Among insulators who quit smoking, lung cancer morality dropped in the 10 years following smoking cessation from 177 deaths per 10,000 among current smokers to 90 per 10,000 among those who quit. Lung cancer rates among insulators who had stopped smoking more than 30 years earlier were similar to those among insulators who had never smoked.

There were a few limitations to the study, including the fact that smoking status and asbestosis were evaluated only once and that some members of the control group could have been exposed to relatively brief periods of asbestos.

“Our study provides strong evidence that asbestos exposure causes lung cancer through multiple mechanisms,” said Dr. Markowitz. “Importantly, we also show that quitting smoking greatly reduces the increased lung cancer risk seen in this population.”

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