Researchers Have Found Possible Mechanism That May Help Develop New HIV Therapy

The current strategy against HIV symptoms is the use of drug cocktails that mainly target three enzymes produced by the virus. However, the periodically popping up resistant strains can thwart the drug combos. 

Researchers at the University of California, Berkeley, and the National Institutes of Health have identified a fourth protein, Nef or negative factor. This protein hijacks host proteins. The researchers have captured a high-resolution snapshot of Nef bound with a main host protein, and discovered a portion of the host protein that will make a promising target for the next-generation of anti-HIV drugs. It could be possible to slow or stop HIV by blocking the part of a key host protein to which Nef binds.  

The report comes a month after President Barack Obama pledged to redirect $100 million in the NIH budget to accelerate development of a cure for AIDS, though therapies to halt the symptoms of AIDS will remain necessary for the immediate future, Bonifacino said.

"We have imaged the molecular details for the first time," said structural biologist James H. Hurley, UC Berkeley professor of molecular and cell biology. "Having these details in hand puts us in striking distance of designing drugs to block the binding site and, in doing so, block HIV infectivity." The findings are reported in online journal eLife.

"For many patients, current drug therapies have transformed HIV infection into a chronic condition that doesn't lead to AIDS, but anything we can develop to further interfere with replication and propagation of the virus would help keep it in check until we find a way to completely eliminate the virus from the body," Hurley said.

There are a small number of genes within HIV that produce just about 15 proteins but each of them hijack some aspect of immune cells' internal machinery producing more copies of the virus. 

The anti-AIDS drugs currently available block three HIV enzymes. These are proteins that transcribe and insert virus' genetic material and snip some encoded proteins. Researchers are now looking for drugs to target the other proteins and thereby support current therapies. In other words, they are searching for ways to block sites on host proteins to which the virus proteins bind in order to stop HIV. This has to be done without interfering with normal cell function, however.  

Over two decades ago, scientists discovered that HIV is far less infective in the absence of the protein Nef. With a Nef-defective virus, patients can live for decades without complications. More details about Nef have been coming in over the years. HIV enters immune system cells via a receptor called CD4, but once "HIV gets into cells through the CD4 door, it slams the door shut behind itself to prevent unproductive re-infection," Hurley said. Scientists do not know why HIV slams door on other viruses. This could possibly be strategy to make viral replication more effective. 

The virus prevents further HIV infection by ridding the cell surface of all other CD4 receptors. Nef achieves this by tagging the CD4 receptor so that the cell thinks it is trash and carries it to the cell's incinerator, the lysosome, where it is destroyed. This was observed by Bonifacino and colleagues six years ago, when they found that Nef does this by directly binding to a host protein, AP2, that latches onto a protein called clathrin. This causes the cell membrane to bulge inward and pinch off to form a small membrane bubble that carries attached CD4 receptors to the lysosome for destruction.

"The new high-resolution image reveals a cavity at the site where Nef binds to AP2, that could be a good site for drug targeting," Bonifacino said.

"This cavity on AP2 is not known to be used by any other host protein, so if we interfere with the cavity we are not going to interfere with any host cell function, only the function of Nef," he said. "This will inform better searches for inhibitors."

Hurley cautioned, however, that the research "needs more validation to prove that the cavity is a target. But we are excited because it is a potential target, and these things don't come along every day."

"This work was an extension of our work on clathrin adaptors, an opportunity to do something relevant to fighting HIV that was based on the purely basic research we are doing on the sorting of proteins to lysosomes," Hurley said.

Parents Likely to Spank Less If They Know Spanking Is Linked to Short and Long Term Behavioral Problems Among Children

Parents who think spanking will discipline their kids need to rethink. Decades of research has found that spanking can give rise to short as well as long term behavioral problems among kids. 

Child psychologist George Holden favors humane alternatives to corporal punishment. He wanted to see if parents' positive views toward spanking could be reversed if they were made aware of the research. So Holden along with three colleagues at Southern Methodist University, Dallas designed a test for parents in which they were exposed to short research summaries detailing negative impact of spanking. The researchers claim that it is the first study to demonstrate that brief exposure to spanking research can alter people's views toward spanking. 

In addition, this study in contrast to the previous studies is efficient, less costly and less time consuming."Given the brevity of our intervention, the results are notable," said the authors. "Our Web-based approach is less expensive, potentially quicker, and more easily scaled up to use at a community level." The study is published online in the international journal of Child Abuse & Neglect.  

The researchers carried out two studies, one with parents and the other with non-parents and found that attitudes were significantly altered. 

"Parents spank with good intentions — they believe it will promote good behavior, and they don't intend to harm the child. But research increasingly indicates that spanking is actually a harmful practice," said Holden, lead author on the study. "These studies demonstrate that a brief exposure to research findings can reduce positive corporal punishment attitudes in parents and non-parents."

"If we can educate people about this issue of corporal punishment, these studies show that we can in a very quick way begin changing attitudes," said Holden, a professor in the SMU Department of Psychology who has carried out extensive research on spanking.

With spanking a public health concern, this approach offers a simple way to reach a large audience to change attitudes and reduce parents' reliance on corporal punishment, said Holden, who was recently elected president of Dallas' oldest child abuse prevention agency, Family Compass. 

Automated Osteoporosis Follow Up Plan Could Efficiently Identify High-Risk Osteoporosis Patients

Penn State College of Medicine researchers have developed an automated system that can identify high risk osteoporosis patients under treatment for fractures along with generating letters that generate follow up. This according to the researchers is an effective way to prevent future fractures and promote osteoporosis intervention. 

The researchers identified 103 patients that were at least 50 years old with fractures. All the patients identified were seeking medical help at the emergency department of Penn State Milton S. Hershey Medical Center. The researchers further went on to analyze treatment codes to find fractures that seemed to be from bone fragility -- a broken bone caused by a fall from standing height or less.

The researchers received data every month from the hospital's finance department. The data was used to autopopulate a spreadsheet created specifically to screen for osteoporosis. Further screening of the data base ensured elimination of those patients whose injuries were not consistent with fragility fractures. Finally, the computer generated letters were mailed to the final list. The researchers found that less than 30 percent of postmenopausal women and less than 10 percent of men with a prior fragility fracture are treated for osteoporosis. 

"Our almost fully automated osteoporosis system identifies these patients, requires minimal resources -- many of which are already currently in U.S. hospitals, but just need to be tapped -- and delivers substantially improved osteoporosis intervention results," said Edward Fox, professor of orthopedics.

Patients were sent a letter within three months of their emergency room visit that explained that they may be at risk for osteoporosis and encouraged them to schedule an appointment with their doctor or the hospital's bone health clinic. A follow-up phone call was placed three months after the letter, asking if follow-up treatment had occurred.

For comparison, a group of 98 patients who did not receive letters were also contacted by phone six months after being treated in the emergency department for a fragility fracture. These patients were asked if they were being treated or had plans for follow-up after their fracture.

Of those who received letters, 60 percent had followed up. Only 14 percent of those who did not receive a letter had, or planned, follow-up care. Results were published in Geriatric Orthopaedic Surgery & Rehabilitation.

Past research has been conducted on osteoporosis intervention programs, but the majority of programs have lacked automation or could be difficult to implement in an average hospital. Since it is automated, this system reduces the potential for human error in identifying high-risk patients.

Nationally, osteoporosis contributes to more than 2 million fractures per year.

"Progressive bone fragility leads to greater risk for fractures," Fox said. "Hospitals treat fragility fractures, but they have no system in place to evaluate those same patients for osteoporosis to prevent the next fracture. This study's results are better than no letter or doing nothing, which is what most hospitals are doing, including the one piloting our program before it started this program."

Future studies should examine the effectiveness of using both a phone call and a letter to improve follow-up rates.

Scientists Find A Way to Identify Individuals Susceptible to Type 1 Diabetes Before the Actual Onset

Not everything is known about Type 1 diabetes even as it is pretty well known that it is a genetically driven autoimmune disease of pancreatic beta-cells. Yet its origin remains unknown. 

In a recent study, researchers from the Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) found that skin cells from patients with type 1 diabetes display abnormal activity. This abnormal activity is triggered by immune response mechanisms to environmental stimuli like a viral infection. The findings are published online in PLoS One.

The researchers found that these skin cells when exposed to cytokines or fat have elevated levels of calcium. It is known that cytokines or cells signalling molecules essential to the body's immune response in humans increase with the onset of infection. This is quite similar to increased fatty acids when people stop eating or are sick. This is a common occurrence in children when they are infected with virus.  

"This is significant as it is known that a viral illness usually precedes the development of type 1 diabetes in children but no one knows why it should be related," says Barbara Corkey, PhD, Zoltan Kohn Professor of Medicine at BUSM and vice chair for Research in the Obesity Research Center at BMC. "Our findings that diabetic cells have a different sensitivity as indicated by higher levels of calcium to an environmental event such as a virus, may help to explain why the onset of type 1 diabetes might be triggered by an environmental stimulus as well as a genetic predisposition."

The data collected by scientists showed that skin cells of those relatives of someone with type 1 diabetes who do not have type 1 diabetes themselves show an intermediate calcium response to circulating signaling molecules. These data indicate that a genetic trait in combination with unique environmental stimulus may likely initiate diabetes. 

"Determination of this trait before development of diabetes could help to identify susceptible individuals prior to disease onset," Corkey said.

New Study Finds Permanent Changes in Brain Genes May Not be So Permanent After All

In a new study published in the January 28 issue of Nature Neuroscience, a team of researchers at Johns Hopkins a new gene control mechanism and how it may contribute to Rett Syndrome, a nervous system disorder affecting mostly girls that causes problems with movement and communication.

Normally cells turnoff genes they don't need by attaching a chemical methyl group to the DNA. This process is called methylation. Scientists for a long time believed that methyl groups could only stick to a particular DNA sequence - a cytosine followed by a guanine - called CpG. In recent years, however, it has been found that they can follow other sequences. The non-CpG methylation has been found in stem cells as well as in neurons in the brain. 

Johns Hopkins research team has discovered that non-CpG methylation occurs later and more dynamically in neurons than previously appreciated, and that it acts as a system of gene regulation, which can be independent of traditional CpG methylation.

The team, led by Hongjun Song, Ph.D., professor of neurology and director of Johns Hopkins Medicine's Institute for Cell Engineering's Stem Cell Program, had found non-CpG methylation prevalent in neurons. The finding is surprising because this wasn't found in any other cells besides stem cells.

The scientists examined the genes that were being transcribed in neurons and found that non-CpG methylation stops genes from being expressed  like the form of methylation scientists had seen in stem cells. On the basis of genome mapping, the scientists also identified the location of non-CpG methylation. It was also found that it carves out its own niche, and are distributed in regions without CpG methlyation. "That was the first hint that maybe it can function independently of CpG methylation," Song said.

The new kind of methylation also seems to operate under different rules. Scientists have long thought methylation was final. Once a cytosine gets a methyl stuck to it, so the story went, that gene is shut off forever. "This became dogma," Song said. "Once cells become the right type, they don't change their identity or DNA methylation."

However, non-CpG methylation was found to happen later, when the neuron is mature. The conventional wisdom said it was irreversible. The researchers learned this from an experiment in which they knocked out in adult mice the enzymes that attach methyl groups to DNA. They found the neurons still had just as much CpG methylation, but the non-CpG methylation dropped off. This suggests that non-CpG methylation is an active process, according to Song, with methyl groups continually being taken off and put back on, adding to evidence that non-CpG methylation may play more of a role in managing operations in mature cells.

The researchers also found a way that non-CpG methylation is similar to CpG methylation in one important way: it's read by MeCP2, an enzyme long identified as a player in methylation.

That's significant because a mutation in MeCP2 causes Rett Syndrome, and understanding DNA methylation is key to understanding this syndrome. The disorder occurs, Song says, when working copies of the gene for MeCP2 are silenced during development.

New Study Finds Aging Linked to Specific Diets

Which is the best diet for health and longevity? Whether you swear by Paleo diet, or Atkins or gluten free or any other, the scientists have found that nearly all diets are the best diets for health and longevity because scientists have identified a collection of genes that allow an organism to adapt to different diets. Otherwise, even minor tweaks to diet can cause premature aging and death. The new research conducted by USC scientists Sean Curran and Shanshan Pang is published this month in Cell Metabolism.  

In other words, scientists have found a genetic basis for an organism's dietary needs. Accordingly, it is suggested that different individuals may be genetically predisposed to thrive on different diets and therefore, in the current age of commercial gene sequencing, a simple blood test might reveal to people the diet that might work best for them.  

"These studies have revealed that single gene mutations can alter the ability of an organism to utilize a specific diet. In humans, small differences in a person's genetic makeup that change how well these genes function, could explain why certain diets work for some but not others," said Curran, corresponding author of the study and assistant professor with joint appointments in the USC Davis School of Gerontology, the USC Dornsife College of Letters, Arts and Sciences, and the Keck School of Medicine of USC.

The researchers Curran and Pang conducted their study on Caenorhabditis elegans. This is a one-milimeter-long worm that scientists have used as a model organism since the '70s. Decades of tests have shown that genes in C. elegans are likely to be mirrored in humans while its short lifespan allows scientists to do aging studies on it.

In this study, Curran and Pang identified a gene called alh-6, which delayed the effects of aging depending on what type of diet the worm was fed by protecting it against diet-induced mitochondrial defects. "This gene is remarkably well-conserved from single celled yeast all the way up to mammals, which suggests that what we have learned in the worm could translate to a better understanding of the factors that alter diet success in humans," Curran said.

Future work will focus on identifying what contributes to dietary success or failure, and whether these factors explain why specific diets don't work for everyone. This could be the start of personalized dieting based on an individual's genetic makeup, according to Curran.

"We hope to uncover ways to enhance the use of any dietary program and perhaps even figure out ways of overriding the system(s) that prevent the use of one diet in certain individuals," he said.

Study Finds High Level Of Food Insecurity Among Students

Oregon State University has set up a "Food Pantry " program that disburses community-donated food to assist students who have inadequate food supplies. Photo Courtesy: (Photo by Larry Pribyl, courtesy Oregon State University) 

A recent study by researchers from the Oregon State University, the Benton County Health Department, and Western Oregon University has found that a whopping 59 percent of college students at one Oregon university were at some point in the previous year were "food insecure" with several implications including academic success, physical and emotional health and other issues. The findings of the study appear in the Journal of Nutrition Education and Behavior   

These findings were based on a survey of 354 students at Western Oregon University, a mid-size public university in a small town near the state capitol in Salem, Ore. Students at Western Oregon supported and assisted in this research, and Doris Cancel-Tirado and Leticia Vazquez with Western Oregon co-authored the study.

In others words, concerns about obesity is not the entire truth. A large part of the truth is that many students do not get enough healthy food to eat as they face the challenges of costs, income, and unevenly distributed food and social support systems. The study surveyed the students at Western Oregon.

"Based on other research that's been done, we expected some amount of food concerns among college students," said Daniel López-Cevallos, associate director of research at OSU's Center for Latino/a Studies and Engagement. "But it was shocking to find food insecurity of this severity. Several recent trends may be combining to cause this."

Several factors including rising college costs, more low-income and first-generation students attending college, and changing demographic trends in combination have significant implications for the study. 

"For past generations, students living on a lean budget might have just considered it part of the college experience, a transitory thing," said Megan Patton-López, lead author of the study with Oregon's Benton County Health Department.

"But rising costs of education are now affecting more people," she said. "And for many of these students who are coming from low-income families and attending college for the first time, this may be a continuation of food insecurity they've known before. It becomes a way of life, and they don't have as many resources to help them out."

The study found that many students may not have enough money for healthy food at all times despite the fact that many of them work one or more jobs. The financial demands could be draining their meager resources. In addition, most college students are not eligible for food stamps and many among them already carry heavy debt load. 

Food insecurity means uncertain or limited availability of nutritionally adequate and safe foods in addition to the ability to acquire such food in acceptable ways. Food insecurity is associated with depression, stress, poor health and the trouble learning in the classroom. 

When food insecurity issues were addressed among elementary school students, improvements were seen in academic performance, behavior and retention of knowledge. However, these problems have received no attention among 19-24 year old demographic, a population that predominates in college, according to researchers. 

According to the findings of the study:

• While about 14.9 percent of all households in the nation report food insecurity, the number of college students voicing similar concerns in this report was almost four times higher, at 59 percent.
  
• In the past three decades the cost of higher education has steadily outpaced inflation, the cost of living and medical expenses.
  
• Food insecurity during college years could affect cognitive, academic and psychosocial development.
  
• Factors correlated with reports of food insecurity include fair to poor health, a lower grade point average, low income and employment.

Employment, by itself, is not adequate to resolve this problem, the researchers found. Students reporting food insecurity also worked an average of 18 hours a week – some as high as 42 – but the financial demands they faced more than offset that income.

The findings probably reflect similar concerns at colleges and universities across the nation, the researchers said, although more research is needed in many areas to determine the full scope of this problem.

"One thing that's clear is that colleges and universities need to be having this conversation and learning more about the issues their students may be facing," said López-Cevallos. "There may be steps to take locally that could help, and policies that could be considered nationally. But it does appear this is a very serious issue that has not received adequate attention, and we need to explore it further."

Development of Drug To Reverse the Spread of Breast Cancer Underway

A novel compound known to reverse the spread of malignant breast cancer is being developed by the researchers at Cardiff University. Most of the cancer deaths result from the progressive spread of malignant cells to vital organs known as metastasis. It is estimated that about 12,000 patients develop this form of disease, several years after the initial diagnosis of a breast lump.   

In a recent series of studies researchers identified a previously unknown critical role for a potential cancer causing gene, Bcl3, in metastatic breast cancer. "We showed that suppressing this gene reduced the spread of cancer by more than 80%," said Dr Richard Clarkson from Cardiff University's European Cancer Stem Cell Research Institute.

"Our next goal was to then find a way to suppress Bcl3 pharmacologically. Despite great improvements in therapy of early stage breast cancer, the current therapeutic options for patients with late stage metastatic disease are limited.

"There is therefore a clear unmet clinical need to identify new drugs to reverse or at least to slow down disease progression" he added.

Dr Clarkson and his team joined up with researchers Dr Andrea Brancale and Dr Andrew Westwell from the Cardiff University School of Pharmacy and Pharmaceutical Sciences, to develop small chemical inhibitors of the Bcl3 gene.

Computer aided modeling of how the Bcl3 gene functions inside the cell allowed the group to identify a pocket on the surface of Bcl3 essential for its function. By screening a virtual compound library for chemicals that could fit inside this pocket, using state-of-the-art computer software, they identified a drug candidate that potently inhibits Bcl3.

The compound was then trialed on mice with metastatic disease. The resulting effect was that the drug completely inhibited the development of the mice's metastatic tumours.

With financial backing from Tiziana Pharmaceuticals*, work is now underway to progress the compound to clinical trials. The aim is to develop a therapeutic agent capable of blocking metastatic disease in breast cancer and a variety of tumour types.

Cleveland Researchers Discover Why Good Cholesterol Becomes Bad

Can high density lipoprotein (HDL) or good cholesterol become dysfunctional, loses its cardio-protective properties, and instead promote inflammation and atherosclerosis, or the clogging and hardening of the arteries? The answer is yes, and the way this happens is discovered by Cleveland Clinic researchers. The study is published in the journal Nature Medicine.

The beneficial and cardio-protective properties of HDL have been studied and reported extensively. However, all clinical trials of pharmaceuticals designed to raise HDL levels have so far failed to show that they significantly improve cardiovascular health. Therefore, a research team led by Stanley Hazen, M.D., Ph.D., Vice Chair of Translational Research for the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart and Vascular Institute at Cleveland Clinic  have attempted to explain this disconnect. They have also gone on to demonstrate that a protein abundant in HDL is present in an oxidized form in diseased artery walls. 

Apolipoprotein A1 (apoA1) is the primary protein present in HDL, providing the structure of the molecule that allows it to transfer cholesterol out of the artery wall and deliver it to the liver, from which cholesterol is excreted. It's apoA1 that normally gives HDL its cardio-protective qualities, but Dr. Hazen and his colleagues have discovered that in the artery wall during atherosclerosis, a large proportion of apoA1 becomes oxidized and no longer contributes to cardiovascular health, but rather, contributes to the development of coronary artery disease.

Over the course of more than five years, Dr. Hazen and his colleagues developed a method for identifying dysfunctional apoA1/HDL and discovered the process by which it is oxidized and turned dysfunctional in the artery wall. They then tested the blood of 627 Cleveland Clinic cardiology patients for the dysfunctional HDL and found that higher levels raised the patient's risk for cardiovascular disease.

"Identifying the structure of dysfunctional apoA1 and the process by which it becomes disease-promoting instead of disease-preventing is the first step in creating new tests and treatments for cardiovascular disease," said Dr. Hazen. 

"Now that we know what this dysfunctional protein looks like, we are developing a clinical test to measure its levels in the bloodstream, which will be a valuable tool for both assessing cardiovascular disease risk in patients and for guiding development of HDL-targeted therapies to prevent disease."

The research also points toward new therapeutic targets for pharmaceuticals, such as those designed to prevent the formation of dysfunctional HDL and the development or progression of atherosclerosis.

How Does Brain Create Meaningful Sequences?

In an article published in Nature Neuroscience, datelined January 26, 2014, neuroscientist Rui Costa, and his postdoctoral fellow, Fatuel Tecuapetla, both working at the Champalimaud Neuroscience Programme (CNP) in Lisbon, Portugal, and Xin Jin, an investigator at the Salk Institute, in San Diego, USA, reveal that neurons in the basal ganglia can signal the concatenation of individual elements into a behavioral sequence.

When you learn how to play the piano, first you have to learn notes, scales and chords and only then will you be able to play a piece of music. The same principle applies to speech and to reading, where instead of scales you have to learn the alphabet and the rules of grammar.

But how do separate small elements come together to become a unique and meaningful sequence?

It has been shown that a specific area of the brain, the basal ganglia, is implicated in a mechanism called chunking, which allows the brain to efficiently organize memories and actions. Until now little was known about how this mechanism is implemented in the brain.

"We trained mice to perform gradually faster sequences of lever presses, similar to a person who is learning to play a piano piece at an increasingly fast pace." explains Rui Costa. "By recording the neural activity in the basal ganglia during this task we found neurons that seem to treat a whole sequence of actions as a single behavior."

The basal ganglia encompass two major pathways, the direct and the indirect pathways. The authors found that although activity in these pathways was similar during the initiation of movement, it was rather different during the execution of a behavioral sequence.

"The basal ganglia and these pathways are absolutely crucial for the execution of actions. These circuits are affected in neural disorders, such as Parkinson or Huntington's disease, in which learning of action sequences is impaired", adds Xin Jin.

The work published in this article "is just the beginning of the story", says Rui Costa. The Neurobiology of Action laboratory at the CNP, a group of around 20 researchers headed by Rui Costa, will continue to study the functional organisation of the basal ganglia during learning and execution of action sequences. Earlier this year, Rui Costa was awarded a 2 million euro consolidation Grant by the European Research Council to study the mechanism of Chunking.

Breast Stem Cells Live Long And May Trigger Cancer Decades Later

(Breast cancer research team Professor Jane Visvader, Dr. Nai Yang Fu, Dr. Anne Rios and Professor Geoff Lindeman (left to right) have found that breast stem cells and their 'daughter' progenitor cells are long-lived in the breast.  Photo Courtesy: Walter and Eliza Hall Institute)

                                                   
A new research has found out that breast stem cells and their daughters have much longer life span than previously thought. In addition, they are active in puberty and throughout life, according to researchers from Melbourne's Walter and Eliza Hall Institute. The research is published in the journal Nature.
                                
The implication of the longevity of breast stem cells and their daughters is that the genetic defects or damage could progress to cancer decades later while shifting back the timeline of breast cancer development. The finding may also possibly identify the cells from which breast cancer originates and help develop new treatments and diagnostics for breast cancer. 

Professors Jane Visvader and Geoff Lindeman and their colleagues at the Walter and Eliza Hall Institute isolated breast stem cells in 2006. Now in another project led by Dr Anne Rios and Dr Nai Yang Fu, it was found that breast stem cells actively maintain breast tissue for most of the life of the individual and contribute to all major stages of breast development. 

"Given that these stem cells – and their 'daughter' progenitor cells – can live for such a long time and are capable of self renewing, damage to their genetic code could lead to breast cancer 10 or 20 years later," Professor Lindeman said. "This finding has important applications for our understanding of breast cancer. We hope that it will lead to the development of new treatment and diagnostic strategies in the clinic to help women with breast cancer in the future," said Professor Lindeman, who is also an oncologist at The Royal Melbourne Hospital. 

In order to understand why and how breast cells become cancerous, it is important to understand the hierarchy and development of breast cells, according to Professor Visvader. "Without knowing the precise cell types in which breast cancer originates, we will continue to struggle in our efforts to develop new diagnostics and treatments for breast cancer, or developing preventive strategies," Professor Visvader said.

Immature breast cells were already implicated in cancer development in an earlier research by scientists from the same institute. "In 2009, we showed that luminal progenitor cells, the daughters of breast stem cells, were the likely cell of origin for the aggressive BRCA1-associated basal breast cancers," Professor Visvader said. "The meticulous work of Anne and Nai Yang, using state-of-the-art three-dimensional imaging, has significantly improved our understanding of normal breast development and will have future applications for breast cancer." 

The current project may likely settle a debate on the issue, confirming once for all that breast cells were 'true' stem cells capable of renewing themselves and making all the cells of the mammary gland.

Researchers Discover Potential Drug Targets For Early Onset Glaucoma

Scientists have for the first time identified molecules that block the accumulation of a toxic eye protein leading to early onset of glaucoma using a novel high-throughput screening process. 

Glaucoma is actually a groups of eye diseases leading to vision loss and blindness as it damages the optic nerve. 

The increased eye pressure, according to researchers is actually caused by a mutant form of protein called myocilin. Mutant myocilin impacts with its toxicity to cells in the part of the eye that regulates pressure. These genetically inherited mutants of myocilin clump together in the front of the eye, preventing fluid flow out of the eye, which then raises eye pressure. This cascade of events can lead to early onset-glaucoma, which affects several million people from childhood to age 35.

The researchers designed a simple, high-throughput assay to find molecules that bind to mutant myocilin and block its aggregation. Thereafter they screened a library of compounds. Eventually, two molecules were identified which can be useful for future drug development to treat early onset glaucoma.  

"These are really the first potential drug targets for glaucoma," said Raquel Lieberman, an associate professor in the School of Chemistry and Biochemistry at the Georgia Institute of Technology in Atlanta, whose lab led the research.

The study was published on Nov. 26, 2013, in the journal ACS Chemical Biology. The National Institutes of Health and the Pew Scholar in Biomedical Sciences program provided support for the research. The work was a collaboration involving Georgia Tech, Emory University and the University of South Florida.

At the heart of the study was an assay that Lieberman's lab created to take advantage of the fundamental principles of ligand binding. In their assay, mutant myocilin is mixed with a fluorescent compound that emits more light when the protein is unwound. When a molecule from the library screen binds to myocilin, the pair becomes highly stable – tightly wound – and the fluorescent light emitted decreases. By measuring fluorescence, researchers were able to identify molecules that bound tightly to mutant myocilin.

The researchers then added these molecules to cultured human cells that were making the toxic aggregating myocilin. Treating the cells with the newly identified molecules blocked the aggregation and caused the mutated version of myocilin to be released from the cells, reducing toxicity.

"We found two molecules from that initial screen that bound to our protein and also inhibited the aggregation," Lieberman said. "When we saw that these compounds inhibited aggregation then we knew we were onto something good because aggregation underlies the pathogenesis of this form of glaucoma."

In a separate study, Lieberman's lab characterized the toxic myocilin aggregates. That study was published in December 2013 in the Journal of Molecular Biology. The study found that myocilin aggregates are similar to the protein deposits called amyloid, which are responsible for Alzheimer's disease and other neurodegenerative diseases.

"In Alzheimer's disease, the deposits are extracellular and kill neurons. In glaucoma the aggregates are not directly killing neurons in the retina to cause vision loss, but they are cytotoxic in the pressure-regulating region of the eye," Lieberman said. "It's parallel to all these other amyloids that are out there in neurodegenerative disease."

The researchers are now focusing on mapping the structure of myocilin to learn more about what myocilin does and why it is in the eye in the first place.

"The underlying problem with myocilin is that for 14 years it has been studied and still nobody really knows what its biological role is inside the eye," Lieberman said.

(Image Courtesy: Hill, et al., 2013.)

Asthma Treatment Likely With Salmonella

This is the research that can pave way for effective asthma treatment. Researchers from Germany experimenting on mice have found that Salmonella infections can reduce the incidence of asthma. The research is published in the journal Infection and Immunity. The research may likely lead to treatments. 

There has been a dramatic increase in incidence of allergies in recent years. The surge in allergies is explained with the help of a leading theory known as "hygiene hypothesis". According to this theory, the surge results from modern obsession with cleanliness resulting in improperly developed immune systems. Earlier researches had indicated that there is a reduced incidence of asthma in children infected with Salmonella. 

The study based on previous research the investigators found that Salmonella infection correlated with reduced airway inflammation, according to first author Venkateswaran Ganesh. The reduction in inflammation, according to Ganesh is linked to reduced production of an inflammatory compound called interleukin-4, which is produced by T helper-2 cells. The researchers found that the T helper-2 cells is regulated by a certain  type of "myelod" immune cell which can induce lesser production of less interleukin-4. Myeloid cells include an array of immune cells, and are ultimately derived from the bone marrow.   

"By performing cell culture assays and studies in rodents, we could determine the influence of myeloid cells on Th2 cells," he explained. The research could lead to treatments based on the use of commensal bacteria (harmless, oft-helpful inhabitants of the body) resembling Salmonella as probiotics, or the application of myeloid cells as therapeutics, Ganesh said.

Roughly 26 million Americans, 8.2 percent of the population, have asthma, including 7.1 million (9.5%) children, according to the US Centers for Disease Control and Prevention.

Long Term Spinal Cord Stimulation Shown to Stall Parkinson's and Other Neurological Disorders

Researchers from Duke Medicine have shown that symptoms of Parkinson's disease can be improved with continual spinal cord stimulation. The stimulation will also protect critical neurons from injury or deterioration. The study was conducted in rats and is published in the journal Scientific Reports. The Duke team had in an earlier study found that stimulating the spinal cord with electrical signals temporarily eased symptoms of the neurological disorder in rodents. Parkinson's disease is caused by progressive loss of neurons. Neurons produce an essential molecule in the brain known as dopamine which affect balance, muscle control and movement. 

"Finding novel treatments that address both the symptoms and progressive nature of Parkinson's disease is a major priority," said the study's senior author Miguel Nicolelis, M.D., Ph.D., professor of neurobiology at Duke University School of Medicine. "We need options that are safe, affordable, effective and can last a long time. Spinal cord stimulation has the potential to do this for people with Parkinson's disease."

The standard drug treatment for Parkinson's disease is L-dopa, which works by replacing dopamine. L-Dopa may help many people but is also known to cause side effects and it also loses its effectiveness over time. Another valuable therapy that has emerged recently is deep brain stimulation which emits electrical signals from an implant in the brain. However, not more than 5 percent of those with Parkinson's qualify for this therapy. 

"Even though deep brain stimulation can be very successful, the number of patients who can take advantage of this therapy is small, in part because of the invasiveness of the procedure," Nicolelis said.

 Nicolelis and his colleagues in 2009 had developed a device for rodents that was based on electrical stimulation to the dorsal column, a main sensory pathway in the spinal cord carrying information from the body to the brain, according to their report in the journal Science. The device attached to the surface of the spinal cord in rodents with depleted levels of dopamine mimicked the biological characteristics of someone with Parkinson's disease. The animals' slow, stiff movements were replaced with the active behaviors of healthy mice and rats when the device was turned on 

In the present study, Nicolelis and his colleagues investigated the long-term effects of the treatment in rats with the Parkinson's-like disease because research on spinal cord stimulation in animals has been limited to the stimulation's acute effects.   

The researchers applied electrical stimulation to a particular location in the dorsal column of the rats' spinal cords twice a week for 30-minute sessions, for six weeks at the end of which they observed a significant improvement in the rats' symptoms including improved motor skills and a reversal of severe weight loss. 

The stimulation not only resulted in recovery in clinical symptoms but was also observed to lead to better survival of neurons and a higher density of dopaminergic innervation in two brain regions controlling movement – the loss of which cause Parkinson's disease in humans. The research findings, therefore, lead to the conclusion that this form of treatment protects against the loss or damage of neurons. 

A similar application of dorsal column stimulation is currently in use to manage certain chronic pain syndromes in humans. Electrodes implanted over the spinal cord are connected to a portable generator, which produces electrical signals that create a tingling sensation to relieve pain. Studies in a small number of humans worldwide have shown that dorsal column stimulation may also be effective in restoring motor function in people with Parkinson's disease.

"This is still a limited number of cases, so studies like ours are important in examining the basic science behind the treatment and the potential mechanisms of why it is effective," Nicolelis said.

The researchers are continuing to investigate how spinal cord stimulation works, and are beginning to explore using the technology in other neurological motor disorders.

  (Photo Courtesy: Duke Medicine)



                                                                               

Research Finds Climate Change in Antarctica is Influenced by Distant Forces in North and Tropical Atlantic Ocean

The climate change in Antarctica, according to a team of scientists from New York University is largely impacted by the gradual warming of the North and Tropical Atlantic Ocean. 

The study is based on over three decades of atmospheric data and the study further identifies new ways in which distant regional conditions are contributing to Antarctic climate change. The study is published in the journal Nature.                                  

"Our findings reveal a previously unknown—and surprising—force behind climate change that is occurring deep in our southern hemisphere: the Atlantic Ocean," says Xichen Li, a doctoral student in NYU's Courant Institute of Mathematical Sciences and the study's lead author. "Moreover, the study offers further confirmation that warming in one region can have far-reaching effects in another."

The Antarctica has experienced dramatic climate change over the past few decades. Its peninsula has experienced the strongest warming on the planet. Antarctic changes during its summer have been attributed to greenhouse gas increase and stratospheric ozone loss. However, forces behind the climate change during winter are less clear. Moreover, the effects of changes during the cold season are of complex nature making it difficult to identify the atmospheric culprit.

Scientists have known for long that the distant Pacific Ocean affects the Antarctic climate in part. However, the El-Nino brought about by Pacific have short term influence. Long term forces that have produced warming along the Antarctic are less understood. These long term forces have produced warming along the Antarctic Peninsula or the sea-ice redistribution in the southern hemisphere's winter over many decades.

In order to address this question, the NYU researchers focused on the Atlantic Ocean which has been overlooked as a force behind Antarctic climate change. More specifically, the scientists studied the North and Tropical Atlantic's Sea Surface Temperature (SST) variability—changes in the ocean's surface temperature—focusing on the last three decades. The metric, the Atlantic Multidecadal Oscillation(AMO) had previously not been considered in seeking explanations for Antarctic climate change.  

The scientists found strong correlations between changes in the North and Tropical Atlantic's SST and subsequent changes in Antarctic climate when they used a time-series analysis. The scientists observed that warming Atlantic waters were followed by changes in sea-level pressure in the Antarctic's Amundsen Sea. Further, the warming patterns also preceded redistribution of sea ice between the Antarctic's Ross and Amundsen-Bellingshausen-Weddell Seas. 

The research comprised of the use of observational data and computer modeling.The observational data, found a link, or correlation, between the Atlantic and Antarctic data sets. However, a correlation does not explain what may be causing a phenomenon. The second part of the study used a global atmospheric model, which allowed the researchers to create a simulated warming of the North Atlantic. The model responded, as the researchers had suspected, by "changing" the climate in Antarctica.

"While our data analysis showed a correlation, it was the use of a state-of-the-art computer model that allowed us to see that North Atlantic warming was causing Antarctic climate change and not vice versa," said David Holland, co-author of the study, a professor at NYU's Courant Institute and past director of NYU's Center for Atmospheric Ocean Science.

The study's findings show that Antarctic sea-ice change is fundamentally different from the well-reported changes in the Arctic. In contrast to the sea-ice decline over the Arctic, Antarctic sea ice has not diminished. Rather, it has redistributed itself in ways that have perplexed scientists, with declines in some areas and increases in others. "From this study, we are learning just how Antarctic sea-ice redistributes itself, and also finding that the underlying mechanisms controlling Antarctic sea ice are completely distinct from those in the Arctic," Holland said

(Photograph By: Jefferson Beck/NASA IceBridge, National Science Foundation)                                                                                 

                                                                                                                                                                   

Most Aggressive Kids Come From World's Dangerous Neighborhoods

A new Duke University led study has found that children around the world who grow up in dangerous neighborhoods exhibit more aggressive behavior. This is the first study to examine the topic across a wide range of countries, while there are a number of U.S studies that have described a link between dangerous neighborhoods and children's aggressive behavior  

Authors of the new study wanted to determine whether the pattern held true in other cultures. To find out, researchers interviewed parents and children from 1,293 families in nine countries: China, Colombia, Italy, Jordan, Kenya, the Philippines, Sweden, Thailand and the United States. The study is published online in the journal Societies.

The researchers scored the neighborhoods according  to their degree of danger based on the responses to the questions about dangers in the neighborhood addressed to the families. 

To measure children's aggressive behavior, researchers asked parents and children to complete a widely used child-behavior checklist that captures behaviors such as screaming and threatening people. The researchers sought answers from mothers, fathers and children for the surveys, in order to obtain a fuller portrait.

In neighborhoods that parents described as highly dangerous, children exhibited higher levels of aggressive behavior. This link held true across all nine countries studied, based on parents' responses, said lead author Ann T. Skinner, a researcher with Duke's Center for Child and Family Policy. "This is an incredibly diverse set of countries from around the world, representing countries from the developing and the developed world and including individualistic and collectivist societies," Skinner said. "In all the countries we studied, we see that living in a dangerous neighborhood may affect kids negatively."

The study further suggests that perilous neighborhoods may affect children indirectly, through their parents. In all nine countries, when children reported living in more dangerous neighborhoods, harsh parenting practices were more common, as was child aggression. However, adults' and children's perceptions differed on that point. More research is needed to determine whether or not dangerous neighborhoods promote harsh parenting practices, Skinner said.

Study Finds Exposure to Cold Temperatures Can Help Lose Weight in Healthy and Sustainable manner

If you want to lose weight in a healthy manner, expose yourself to mild cold. In other words, exposure to mild cold is a healthy and sustainable way to lose weight, according  to a new research published in Trends in Endocrinology & Metabolism datelined January 22nd. The flip side of this finding is that your warm and cozy home and offices could be partly responsible for expanding waistlines.  

"Since most of us are exposed to indoor conditions 90 percent of the time, it is worth exploring health aspects of ambient temperatures," said first author of the article Wouter van Marken Lichtenbelt of Maastricht University Medical Center in The Netherlands. "What would it mean if we let our bodies work again to control body temperature? We hypothesize that the thermal environment affects human health and more specifically that frequent mild cold exposure can significantly affect our energy expenditure over sustained time periods."

The researchers Marken Lichtenbelt and his colleagues began this study about 10 years ago, because the effects of mild cold had not received attention. Earlier studies on temperature focused attention on the extreme impacts of application relevant to the military, fire fighters and others. However, the studies began to show that people responded differently and often in a big way to mild cold conditions. So, the researchers stumbled on an important discovery that heat-generating, calorie-burning brown fat isn't just for babies. Adults have it too and some more than others.

According to Marken Lichtenbelt, they now have evidence to suggest that a more variable indoor temperature – one that is allowed to drift along with temperatures outside – might be beneficial, although long-term effects still await further investigation. 

A research group from Japan found a decrease in body fat after people spent 2 hours per day at 17 degrees Celsius (62.6 degrees F) for six weeks. The Netherlands team also found that people get used to the cold over time. After six hours a day in the cold for a period of 10 days, people in their study increased brown fat, felt more comfortable and shivered less at 15 degree Celsius (59 degrees F).

In young and middle-aged people at least, non-shivering heat production can account for a few percent up to 30 percent of the body's energy budget, they say. That means lower temperatures can significantly affect the amount of energy a person expends overall.

So perhaps, in addition to our exercise training, we need to train ourselves to spend more time in the cold. Managing that in practice might take some convincing, however.

"Indoor temperature in most buildings is regulated to minimize the percentage of people dissatisfied," the researchers write. "This results in relatively high indoor temperatures in wintertime. This is evident in offices, in dwellings and is most pronounced in care centers and hospitals. By lack of exposure to a varied ambient temperature, whole populations may be prone to develop diseases like obesity. In addition, people become vulnerable to sudden changes in ambient temperature."

Paid Search Ads Do Not Give Returns on Your Investment, Study Finds

If you thought paid online advertising can bring you value for your money, think again. A recent study by Universality of California, Berkeley's Haas School of Business found that advertisers do not get value for their money with paid search ads.

Economist Steven Tadelis at UC Berkeley's Haas School of Business used data from eBay to compare whether consumers are more likely to click on paid ads than on free, generic search results and found that advertisers may not be getting their money's worth.

"We found that when you turn off the paid advertising, almost all of the traffic that came through the paid search is just substituted by the other free channels," said Tadelis, associate professor in the Haas Business and Public Policy Group. Tadelis conducted the study, "Consumer Heterogeneity and Paid Search Effectiveness: A Large Scale Field Experiment," at eBay. The study was co-authored by Thomas Blake, an economist in the economics research team that Tadelis started at eBay, and former eBay economist Chris Nosko of the University of Chicago.

To measure the effectiveness of paid search, the researchers turned off eBay's paid search in 68 direct marketing areas in the U.S. In other words, if a consumer typed in the search term "white blouse" while online in these markets, he or she would only see the generic search results at the top of the list; not the paid ad that typically appears in a shaded box at the top of the search. She would not see any retail ads by eBay for "white blouse" but only from other advertisers who bid on the "white blouse" keywords.

At the end of 60 days, Tadelis and his colleagues compared sales of two groups: one group that received no paid search results and another group in which paid search remained untouched. Again, consumer sales as a result of the paid search showed no measurable increase off those who made purchases via unpaid channels (such as organic searches, or directly visiting eBay.com).

In order to ensure the robustness of their results, in a second experiment, the researchers also eliminated eBay's paid keyword searches throughout the country and then compared sales for that period to an equivalent period with paid search on.

"If advertising is indeed a strong driver of sales, we should have seen sales plummet," says Tadelis. "But the impact on sales was indistinguishable and not significantly different than zero."

Furthermore, for "brand" keywords such as "eBay" or other company name keywords, paid ads sit just above the generic search results. For example, a search for "Macy's" results in a Macy's free search below the Macys paid ad. Consequently, Tadelis says the paid search result adds no additional benefit to the advertiser. "It's not that clicking on the result caused engagement, it's that the intent to engage caused people to click on it," says Tadelis.

On any given day advertisers, including eBay, bid on millions of keywords. Tadelis hopes their work will encourage other e-commerce businesses to conduct this type of microeconomic research to better measure the impact of paid search traffic on the web.

(Image Courtsey: Adventuretravelnews.com)